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<title>Leber Congenital Amaurosis / Early-Onset Severe Retinal Dystrophy Overview - GeneReviews® - NCBI Bookshelf</title>
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<meta name="robots" content="INDEX,FOLLOW,NOARCHIVE" /><meta name="citation_inbook_title" content="GeneReviews® [Internet]" /><meta name="citation_title" content="Leber Congenital Amaurosis / Early-Onset Severe Retinal Dystrophy Overview" /><meta name="citation_publisher" content="University of Washington, Seattle" /><meta name="citation_date" content="2023/03/23" /><meta name="citation_author" content="Neruban Kumaran" /><meta name="citation_author" content="Mark E Pennesi" /><meta name="citation_author" content="Paul Yang" /><meta name="citation_author" content="Karmen M Trzupek" /><meta name="citation_author" content="Catherine Schlechter" /><meta name="citation_author" content="Anthony T Moore" /><meta name="citation_author" content="Richard G Weleber" /><meta name="citation_author" content="Michel Michaelides" /><meta name="citation_pmid" content="30285347" /><meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK531510/" /><meta 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<div class="pre-content"><div><div class="bk_prnt"><p class="small">NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.</p><p>Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. </p></div></div></div>
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<div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><h1 id="_NBK531510_"><span class="title" itemprop="name">Leber Congenital Amaurosis / Early-Onset Severe Retinal Dystrophy Overview</span></h1><div itemprop="alternativeHeadline" class="subtitle whole_rhythm">Synonyms: EOSRD, LCA</div><div class="contrib half_rhythm"><span itemprop="author">Neruban Kumaran</span>, BSc, MBBS, FRCOphth<div class="affiliation small">UCL Institute of Ophthalmology<br />University College London<br />Moorfields Eye Hospital<br />London, United Kingdom<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ku.ca.lcu@naramuk.n" class="oemail">ku.ca.lcu@naramuk.n</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Mark E Pennesi</span>, MD, PhD<div class="affiliation small">Casey Eye Institute<br />Oregon Health Sciences University<br />Portland, Oregon<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.usho@misennep" class="oemail">ude.usho@misennep</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Paul Yang</span>, MD, PhD<div class="affiliation small">Casey Eye Institute<br />Oregon Health Sciences University<br />Portland, Oregon<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.usho@pgnay" class="oemail">ude.usho@pgnay</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Karmen M Trzupek</span>, MS, CGC<div class="affiliation small">InformedDNA<br />St Petersburg, Florida<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="moc.anddemrofni@kepuzrtk" class="oemail">moc.anddemrofni@kepuzrtk</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Catherine Schlechter</span>, MS, MBI, CGC<div class="affiliation small">Ophthalmic Genetics Clinic<br />Casey Eye Institute<br />Oregon Health Sciences University<br />Portland, Oregon<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.usho@eittaeb" class="oemail">ude.usho@eittaeb</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Anthony T Moore</span>, MA, BM BCh, FRCS, FRCOphth, FMedSci<div class="affiliation small">University of California San Francisco<br />San Francisco, California</div><div class="affiliation small">UCL Institute of Ophthalmology<br />University College London<br />London, United Kingdom<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.fscu@eroom.ynot" class="oemail">ude.fscu@eroom.ynot</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Richard G Weleber</span>, MD, DABMG, FACMG<div class="affiliation small">Ophthalmic Genetics Clinic<br />Casey Eye Institute<br />Oregon Health Sciences University<br />Portland, Oregon<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.usho@rrebelew" class="oemail">ude.usho@rrebelew</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Michel Michaelides</span>, BSc, MBBS, MD(Res), FRCOphth, FACS<div class="affiliation small">UCL Institute of Ophthalmology<br />University College London<br />Moorfields Eye Hospital<br />London, United Kingdom<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ku.ca.lcu@sedileahcim.lehcim" class="oemail">ku.ca.lcu@sedileahcim.lehcim</a></div></div></div><p class="small">Initial Posting: <span itemprop="datePublished">October 4, 2018</span>; Last Revision: <span itemprop="dateModified">March 23, 2023</span>.</p><p><em>Estimated reading time: 19 minutes</em></p></div><div class="body-content whole_rhythm" itemprop="text"><div id="lca-ov.Summary" itemprop="description"><h2 id="_lca-ov_Summary_">Summary</h2><p>The purpose of this overview is to:</p><dl class="temp-labeled-list"><dt>1.</dt><dd><p class="no_top_margin">Describe the <a href="#lca-ov.Clinical_Characteristics_of_Leber">clinical characteristics</a> of Leber congenital amaurosis (LCA) / early-onset severe retinal dystrophy (EOSRD);</p></dd><dt>2.</dt><dd><p class="no_top_margin">Review the <a href="#lca-ov.Causes_of_Leber_Congenital_Amauro">genetic causes</a> of LCA/EOSRD;</p></dd><dt>3.</dt><dd><p class="no_top_margin">Provide an <a href="#lca-ov.Evaluation_Strategies_to_Identify">evaluation strategy</a> to identify the genetic cause of LCA/EOSRD in a proband (when possible);</p></dd><dt>4.</dt><dd><p class="no_top_margin">Inform (when possible) <a href="#lca-ov.Medical_Management_of_Leber_Conge">medical management</a> of LCA/EOSRD based on genetic cause;</p></dd><dt>5.</dt><dd><p class="no_top_margin">Inform <a href="#lca-ov.Genetic_Counseling_for_Leber_Cong">genetic counseling</a> for LCA/EOSRD.</p></dd></dl>
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</div><div id="lca-ov.Clinical_Characteristics_of_Leber"><h2 id="_lca-ov_Clinical_Characteristics_of_Leber_">1. Clinical Characteristics of Leber Congenital Amaurosis / Early-Onset Severe Retinal Dystrophy</h2><p>Leber congenital amaurosis (LCA) / early-onset severe retinal dystrophy (EOSRD) comprises a spectrum of inherited retinal disorders that ranges from LCA at the severe end to EOSRD at the milder end.</p><p><b>LCA</b> is characterized by severe visual impairment from birth or the first few months of life, roving eye movements or nystagmus, poor pupillary light responses, oculodigital sign (poking, rubbing, and/or pressing of the eyes), and undetectable or severely abnormal full-field electroretinogram (ERG).</p><p><b>EOSRD</b> is characterized by the onset of visual impairment typically after infancy but before age five years, with variably preserved visual acuity and minimally preserved full-field ERG [<a class="bk_pop" href="#lca-ov.REF.kumaran.2017.1147">Kumaran et al 2017</a>].</p><p>The fundus in LCA/EOSRD can appear normal at presentation or show a variety of retinal abnormalities including pigmentary retinopathy, white deposits at the level of the retinal pigment epithelium, vascular attenuation, or pseudopapilledema and macular atrophy. Those with a normal fundus appearance at birth usually develop pigmentary retinopathy, optic disc pallor, and vascular attenuation with time. Other late changes include optic disc drusen, keratoconus, and lens opacities. Some genetic subtypes have a characteristic retinal phenotype.</p><p>The rate of visual loss varies, and some genes have been associated with faster progression (see <a href="/books/NBK531510/table/lca-ov.T.leber_congenital_amaurosis_lca/?report=objectonly" target="object" rid-ob="figoblcaovTlebercongenitalamaurosislca">Table 2</a>). Infants with severe visual impairment may also have delays or difficulties with speech, social skills, and behavior, highlighting the importance of early involvement by a developmental pediatric specialist.</p><p>Persons with LCA/EOSRD usually present with isolated ocular signs and symptoms and have manifestations that remain confined to the eye. Some infants who present with visual impairment may later develop other systemic issues, particularly kidney disease. Nephronophthisis with subsequent end-stage kidney disease can be seen with certain genetic subtypes of LCA/EOSRD (e.g., <i>IQCB1-</i>, <i>IFT140-</i>, and <i>CEP290-</i>associated LCA) as part of syndromes including Senior-Loken syndrome and Joubert syndrome (see <a href="/books/NBK531510/table/lca-ov.T.leber_congenital_amaurosis_lca/?report=objectonly" target="object" rid-ob="figoblcaovTlebercongenitalamaurosislca">Table 2</a>). Early molecular diagnosis can help identify individuals who require systemic investigations.</p><div id="lca-ov.Differential_Diagnosis"><h3>Differential Diagnosis</h3><div id="lca-ov.T.retinal_disorders_to_be_conside" class="table"><h3><span class="label">Table 1. </span></h3><div class="caption"><p>Retinal Disorders to be Considered in the Differential Diagnosis of LCA/EOSRD</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK531510/table/lca-ov.T.retinal_disorders_to_be_conside/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__lca-ov.T.retinal_disorders_to_be_conside_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_lca-ov.T.retinal_disorders_to_be_conside_1_1_1_1" colspan="2" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">Disorder</th><th id="hd_h_lca-ov.T.retinal_disorders_to_be_conside_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene(s)</th><th id="hd_h_lca-ov.T.retinal_disorders_to_be_conside_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">MOI</th><th id="hd_h_lca-ov.T.retinal_disorders_to_be_conside_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Distinguishing Clinical Features / Assessments</th></tr></thead><tbody><tr><td headers="hd_h_lca-ov.T.retinal_disorders_to_be_conside_1_1_1_1" rowspan="3" scope="rowgroup" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Nonsyndromic</b>
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||
</td><td headers="hd_h_lca-ov.T.retinal_disorders_to_be_conside_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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||
<a href="/books/n/gene/achm/">Achromatopsia</a>
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||
</td><td headers="hd_h_lca-ov.T.retinal_disorders_to_be_conside_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>CNGB3</i>
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<br />
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<i>CNGA3</i>
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<br />
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<i>GNAT2</i>
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<br />
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<i>PDE6C</i>
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<br />
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<i>ATF6</i>
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<br />
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<i>PDE6H</i>
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</td><td headers="hd_h_lca-ov.T.retinal_disorders_to_be_conside_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_lca-ov.T.retinal_disorders_to_be_conside_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">In achromatopsia:
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||
<ul><li class="half_rhythm"><div>Absent / markedly reduced cone responses w/normal rod ERG responses</div></li><li class="half_rhythm"><div>Stationary natural history</div></li></ul>
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In LCA/EOSRD:
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<ul><li class="half_rhythm"><div>Non-recordable / markedly reduced full-field ERGs</div></li><li class="half_rhythm"><div>Progressive disease</div></li></ul>
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||
</td></tr><tr><td headers="hd_h_lca-ov.T.retinal_disorders_to_be_conside_1_1_1_1" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Congenital stationary night blindness (See <a href="/books/n/gene/csnb/">X-Linked Congenital Stationary Night Blindness</a>.)</td><td headers="hd_h_lca-ov.T.retinal_disorders_to_be_conside_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">>10 genes <sup>1</sup></td><td headers="hd_h_lca-ov.T.retinal_disorders_to_be_conside_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">XL<br />AR<br />AD</td><td headers="hd_h_lca-ov.T.retinal_disorders_to_be_conside_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Can be differentiated by ERG phenotype & natural history</td></tr><tr><td headers="hd_h_lca-ov.T.retinal_disorders_to_be_conside_1_1_1_1" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Ocular (OMIM <a href="https://omim.org/entry/300500" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">300500</a>) & oculocutaneous (OMIM <a href="https://omim.org/phenotypicSeries/PS203100" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PS203100</a>) albinism (See <a href="/books/n/gene/oca4/">OCA Type 4</a> and <a href="/books/n/gene/oca-oa-ov/">OCA and OA Overview</a>.)</td><td headers="hd_h_lca-ov.T.retinal_disorders_to_be_conside_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">>10 genes <sup>2</sup></td><td headers="hd_h_lca-ov.T.retinal_disorders_to_be_conside_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">XL<br />AR</td><td headers="hd_h_lca-ov.T.retinal_disorders_to_be_conside_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Clinical exam (hypopigmentation of skin, hair, eyebrows/eyelashes, iris, retina)</div></li><li class="half_rhythm"><div>Retinal imaging (OCT & FAF); OCT can highlight foveal hypoplasia</div></li><li class="half_rhythm"><div>Normal ERG & chiasmal misrouting on VEP</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_lca-ov.T.retinal_disorders_to_be_conside_1_1_1_1" rowspan="5" scope="rowgroup" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Syndromic</b>
|
||
</td><td headers="hd_h_lca-ov.T.retinal_disorders_to_be_conside_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Neuronal ceroid lipofuscinoses (NCL) (OMIM <a href="https://omim.org/phenotypicSeries/PS256730" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PS256730</a>)</td><td headers="hd_h_lca-ov.T.retinal_disorders_to_be_conside_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">13 genes <sup>3</sup></td><td headers="hd_h_lca-ov.T.retinal_disorders_to_be_conside_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR<br />AD <sup>4</sup></td><td headers="hd_h_lca-ov.T.retinal_disorders_to_be_conside_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Infantile NCL presents w/congenital or early-onset (age <6 mos) blindness.</div></li><li class="half_rhythm"><div>Late-infantile & juvenile-onset NCL present at ages 2-4 & ≥6 yrs, respectively.</div></li><li class="half_rhythm"><div>ERG can show a negative waveform.</div></li><li class="half_rhythm"><div>NCL is assoc w/neurocognitive decline & epilepsy.</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_lca-ov.T.retinal_disorders_to_be_conside_1_1_1_1" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="/books/n/gene/joubert/">Joubert syndrome</a>
|
||
</td><td headers="hd_h_lca-ov.T.retinal_disorders_to_be_conside_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">>30 genes <sup>5</sup></td><td headers="hd_h_lca-ov.T.retinal_disorders_to_be_conside_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR<br />XL <sup>6</sup></td><td headers="hd_h_lca-ov.T.retinal_disorders_to_be_conside_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Presents w/severe visual impairment, ocular motor abnormalities</div></li><li class="half_rhythm"><div>Characteristic MRI appearance incl "molar tooth sign"</div></li><li class="half_rhythm"><div>Nephronophthisis in later childhood</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_lca-ov.T.retinal_disorders_to_be_conside_1_1_1_1" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="/books/n/gene/pbd/">Zellweger spectrum disorder</a>
|
||
</td><td headers="hd_h_lca-ov.T.retinal_disorders_to_be_conside_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">13 genes <sup>7</sup></td><td headers="hd_h_lca-ov.T.retinal_disorders_to_be_conside_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_lca-ov.T.retinal_disorders_to_be_conside_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assoc features:
|
||
<ul><li class="half_rhythm"><div>Sensorineural deafness</div></li><li class="half_rhythm"><div>Dysmorphic features</div></li><li class="half_rhythm"><div>Developmental delay</div></li><li class="half_rhythm"><div>Hepatomegaly</div></li><li class="half_rhythm"><div>Early death</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_lca-ov.T.retinal_disorders_to_be_conside_1_1_1_1" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="/books/n/gene/alstrom/">Alström syndrome</a>
|
||
</td><td headers="hd_h_lca-ov.T.retinal_disorders_to_be_conside_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>ALMS1</i>
|
||
</td><td headers="hd_h_lca-ov.T.retinal_disorders_to_be_conside_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_lca-ov.T.retinal_disorders_to_be_conside_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Presenting features:
|
||
<ul><li class="half_rhythm"><div>Infantile-onset nystagmus</div></li><li class="half_rhythm"><div>Photophobia</div></li><li class="half_rhythm"><div>Cone-rod dystrophy</div></li></ul>
|
||
Other systemic features:
|
||
<ul><li class="half_rhythm"><div>Childhood obesity</div></li><li class="half_rhythm"><div>Hyperinsulinemia</div></li><li class="half_rhythm"><div>Type 2 diabetes mellitus</div></li><li class="half_rhythm"><div>Hepatic dysfunction</div></li><li class="half_rhythm"><div>Heart failure</div></li><li class="half_rhythm"><div>Sensorineural hearing loss</div></li><li class="half_rhythm"><div>Kidney failure</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_lca-ov.T.retinal_disorders_to_be_conside_1_1_1_1" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Cobalamin C deficiency (See <a href="/books/n/gene/cbl/">Disorders of Intracellular Cobalamin Metabolism</a>.)</td><td headers="hd_h_lca-ov.T.retinal_disorders_to_be_conside_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>MMACHC</i>
|
||
</td><td headers="hd_h_lca-ov.T.retinal_disorders_to_be_conside_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_lca-ov.T.retinal_disorders_to_be_conside_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Variable phenotype. Severely affected persons have progressive, infantile-onset, metabolic, neurologic, & ophthalmic manifestations:
|
||
<ul><li class="half_rhythm"><div>Infantile nystagmus</div></li><li class="half_rhythm"><div>Bull's-eye maculopathy</div></li><li class="half_rhythm"><div>↓ responses on ERG</div></li></ul>
|
||
</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">Adapted from <a class="bk_pop" href="#lca-ov.REF.kumaran.2017.1147">Kumaran et al [2017]</a> (Table 2)</p></div></dd><dt></dt><dd><div><p class="no_margin">AD = autosomal dominant; AR = autosomal recessive; EOSRD = early-onset severe retinal dystrophy; ERG = electroretinography; FAF = fundus autofluorescence; LCA = Leber congenital amaurosis; MOI = mode of inheritance; OA = ocular albinism; OCA = oculocutaneous albinism; OCT = optical coherence tomography; VEP = visual evoked potentials; XL = X-linked</p></div></dd><dt>1. </dt><dd><div id="lca-ov.TF.1.1"><p class="no_margin">See OMIM Phenotypic Series: <a href="https://omim.org/phenotypicSeries/PS310500" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Night Blindness, Congenital Stationary</a> for a list of genes associated with this phenotype.</p></div></dd><dt>2. </dt><dd><div id="lca-ov.TF.1.2"><p class="no_margin">X-linked ocular albinism is caused by pathogenic variants in <i>GPR143</i>. See OMIM Phenotypic Series: <a href="https://omim.org/phenotypicSeries/PS203100" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Oculocutaneous Albinism</a> for a list of genes associated with oculocutaneous albinism.</p></div></dd><dt>3. </dt><dd><div id="lca-ov.TF.1.3"><p class="no_margin">Pathogenic variants in <i>PPT1</i>, <i>TPP1</i>, <i>CLN3</i>, <i>CLN5</i>, <i>CLN6</i>, <i>MFSD8</i>, <i>CLN8</i>, <i>CTSD</i>, <i>DNAJC5</i>, <i>CTSF</i>, <i>ATP13A2</i>, <i>GRN</i>, and <i>KCTD7</i> are known to cause NCL.</p></div></dd><dt>4. </dt><dd><div id="lca-ov.TF.1.4"><p class="no_margin">The NCLs are inherited in an autosomal recessive manner; adult-onset NCL can also be inherited in an autosomal dominant manner.</p></div></dd><dt>5. </dt><dd><div id="lca-ov.TF.1.5"><p class="no_margin">Pathogenic variants in <i>ARL13B</i>, <i>B9D1</i>, <i>B9D2</i>, <i>C2CD3</i>, <i>C5orf42</i>, <i>CC2D2A</i>, <i>CEP41</i>, <i>CEP104</i>, <i>CEP120</i>, <i>CEP290</i>, <i>CSPP1</i>, <i>IFT172</i>, <i>INPP5E</i>, <i>KATNIP</i> (<i>KIAA0556</i>), <i>KIAA0586</i>, <i>KIF7</i>, <i>MKS1</i>, <i>NPHP1</i>, <i>OFD1</i>, <i>PDE6D</i>, <i>POC1B</i>, <i>RPGRIP1L</i>, <i>TCTN1</i>, <i>TCTN2</i>, <i>TCTN3</i>, <i>TMEM67</i>, <i>TMEM107</i>, <i>TMEM138</i>, <i>TMEM216</i>, <i>TMEM231</i>, <i>TMEM237</i>, <i>TTC21B</i>, and <i>ZNF423</i> are known to cause Joubert syndrome.</p></div></dd><dt>6. </dt><dd><div id="lca-ov.TF.1.6"><p class="no_margin">Joubert syndrome is predominantly inherited in an autosomal recessive manner. Joubert syndrome caused by pathogenic variants in <i>OFD1</i> is inherited in an X-linked manner. Digenic inheritance has been reported.</p></div></dd><dt>7. </dt><dd><div id="lca-ov.TF.1.7"><p class="no_margin">Pathogenic variants in <i>PEX1</i>, <i>PEX6</i>, <i>PEX12</i>, <i>PEX26</i>, <i>PEX10</i>, <i>PEX2</i>, <i>PEX5</i>, <i>PEX13</i>, <i>PEX16</i>, <i>PEX3</i>, <i>PEX19</i>, <i>PEX14</i>, and <i>PEX11β are</i> known to cause Zellweger spectrum disorder.</p></div></dd></dl></div></div></div></div></div><div id="lca-ov.Causes_of_Leber_Congenital_Amauro"><h2 id="_lca-ov_Causes_of_Leber_Congenital_Amauro_">2. Causes of Leber Congenital Amaurosis / Early-Onset Severe Retinal Dystrophy</h2><p>To date, mutation of 24 genes accounts for 70%-80% of individuals with Leber congenital amaurosis (LCA) / early-onset severe retinal dystrophy (EOSRD) (<a href="/books/NBK531510/table/lca-ov.T.leber_congenital_amaurosis_lca/?report=objectonly" target="object" rid-ob="figoblcaovTlebercongenitalamaurosislca">Table 2</a>).</p><div id="lca-ov.T.leber_congenital_amaurosis_lca" class="table"><h3><span class="label">Table 2. </span></h3><div class="caption"><p>Leber Congenital Amaurosis (LCA) / Early-Onset Severe Retinal Dystrophy (EOSRD): Genes and Distinguishing Clinical Features</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK531510/table/lca-ov.T.leber_congenital_amaurosis_lca/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__lca-ov.T.leber_congenital_amaurosis_lca_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_1" rowspan="2" scope="rowgroup" colspan="1" headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_1" style="text-align:left;vertical-align:middle;">Gene <sup>1</sup></th><th id="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_2" rowspan="2" scope="col" colspan="1" headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_2" style="text-align:left;vertical-align:middle;">% of All LCA/<br />EOSRD</th><th id="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_3" colspan="2" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">Distinguishing Clinical Features</th><th id="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_4" rowspan="2" scope="col" colspan="1" headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_4" style="text-align:left;vertical-align:middle;">Other</th><th id="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_5" colspan="2" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">References</th></tr><tr><th headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_3" id="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_1" colspan="1" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">Visual function</th><th headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_3" id="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Fundus appearance</th><th headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_5" id="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_3" colspan="1" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">OMIM</th><th headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_5" id="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Selected citations</th></tr></thead><tbody><tr><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>ALMS1</i>
|
||
</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">?</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_3 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_3 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_5 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="https://omim.org/entry/606844" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">606844</a>
|
||
</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_5 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>AIPL1</i>
|
||
</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><5%</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_3 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">LCA: early profound visual loss</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_3 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Can be relatively normal in infancy</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">On OCT:
|
||
<ul><li class="half_rhythm"><div>Relative preservation of outer retinal structure before age 4 yrs</div></li><li class="half_rhythm"><div>Progressive loss from birth to total macular atrophy</div></li></ul>
|
||
</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_5 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="https://omim.org/entry/604393" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">604393</a>
|
||
</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_5 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a class="bk_pop" href="#lca-ov.REF.aboshiha.2015.862">Aboshiha et al [2015]</a>
|
||
</td></tr><tr><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>CABP4</i>
|
||
</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">?</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_3 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_3 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_5 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="https://omim.org/entry/608965" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">608965</a>
|
||
</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_5 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a class="bk_pop" href="#lca-ov.REF.aldahmesh.2010.207">Aldahmesh et al [2010]</a>
|
||
</td></tr><tr><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>CEP290</i>
|
||
</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">15%-20%</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_3 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">LCA:
|
||
<ul><li class="half_rhythm"><div>Significant variability; severe VA loss in most</div></li><li class="half_rhythm"><div>No clear progression in 1st decade</div></li></ul>
|
||
</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_3 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Can be relatively normal in infancy</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>On OCT: residual outer retinal structure often present until 4th decade</div></li><li class="half_rhythm"><div>Assoc w/nephronophthisis, Joubert syndrome</div></li></ul>
|
||
</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_5 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="https://omim.org/entry/611755" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">611755</a>
|
||
</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_5 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>CLUAP1</i>
|
||
</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">?</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_3 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_3 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_5 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="https://omim.org/entry/616787" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">616787</a>
|
||
</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_5 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a class="bk_pop" href="#lca-ov.REF.soens.2016.1044">Soens et al [2016]</a>
|
||
</td></tr><tr><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>CRB1</i>
|
||
</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">10%</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_3 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Phenotypes: LCA/ EOSRD, RP, & others <sup>2</sup></div></li><li class="half_rhythm"><div>Severity & rate of progression vary significantly.</div></li></ul>
|
||
</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_3 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Variably present:
|
||
<ul><li class="half_rhythm"><div>Nummular pigmentation</div></li><li class="half_rhythm"><div>Maculopathy</div></li><li class="half_rhythm"><div>Relative preservation of para-arteriolar RPE</div></li></ul>
|
||
</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">On OCT: retinal thickening & loss of lamination reported</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_5 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="https://omim.org/entry/613835" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">613835</a>
|
||
</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_5 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>CRX</i>
|
||
</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">1%</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_3 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_3 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_5 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="https://omim.org/entry/613829" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">613829</a>
|
||
</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_5 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a class="bk_pop" href="#lca-ov.REF.jacobson.1998.2417">Jacobson et al [1998]</a>
|
||
</td></tr><tr><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>DTHD1</i>
|
||
</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">?</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_3 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_3 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_5 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="https://omim.org/entry/616979" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">616979</a>
|
||
</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_5 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a class="bk_pop" href="#lca-ov.REF.abusafieh.2013.236">Abu-Safieh et al [2013]</a>
|
||
</td></tr><tr><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>GDF6</i>
|
||
</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">?</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_3 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_3 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_5 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="https://omim.org/entry/615360" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">615360</a>
|
||
</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_5 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>GUCY2D</i>
|
||
</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">10%-20%</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_3 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">LCA:
|
||
<ul><li class="half_rhythm"><div>Early profound visual loss</div></li><li class="half_rhythm"><div>Lack of color perception</div></li><li class="half_rhythm"><div>Significant photophobia</div></li><li class="half_rhythm"><div>Substantial residual rod-driven visual function</div></li></ul>
|
||
</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_3 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Relatively normal</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_5 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="https://omim.org/entry/204000" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">204000</a>
|
||
</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_5 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a class="bk_pop" href="#lca-ov.REF.jacobson.2013.168">Jacobson et al [2013]</a>
|
||
</td></tr><tr><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>IFT140</i>
|
||
</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">?</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_3 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_3 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assoc w/nephronophthisis, Joubert syndrome</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_5 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="https://omim.org/entry/614620" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">614620</a>
|
||
</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_5 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a class="bk_pop" href="#lca-ov.REF.xu.2015.1069">Xu et al [2015]</a>
|
||
</td></tr><tr><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>IMPDH1</i>
|
||
</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">5%</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_3 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_3 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_5 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="https://omim.org/entry/613837" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">613837</a>
|
||
</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_5 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>IQCB1</i>
|
||
</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">?</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_3 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_3 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assoc w/nephronophthisis, Joubert syndrome</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_5 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="https://omim.org/entry/609237" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">609237</a>
|
||
</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_5 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a class="bk_pop" href="#lca-ov.REF.estradacuzcano.2011.834">Estrada-Cuzcano et al [2011]</a>
|
||
</td></tr><tr><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>KCNJ13</i>
|
||
</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">?</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_3 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_3 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_5 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="https://omim.org/entry/614186" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">614186</a>
|
||
</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_5 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>LCA5</i>
|
||
</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">1%-2%</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_3 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_3 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_5 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="https://omim.org/entry/604537" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">604537</a>
|
||
</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_5 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>LRAT</i>
|
||
</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><1%</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_3 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">EOSRD: similar to <a href="/books/n/gene/rpe65-lca/"><i>RPE65</i>-LCA</a></td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_3 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_5 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="https://omim.org/entry/613341" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">613341</a>
|
||
</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_5 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>NMNAT1</i>
|
||
</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">?</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_3 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">LCA/EOSRD:
|
||
<ul><li class="half_rhythm"><div>Majority have early-onset profound vision loss & extensive maculopathy.</div></li><li class="half_rhythm"><div>Minority have milder phenotype.</div></li></ul>
|
||
</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_3 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Marked maculopathy</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_5 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="https://omim.org/entry/608553" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">608553</a>
|
||
</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_5 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a class="bk_pop" href="#lca-ov.REF.kumaran.2021.139">Kumaran et al [2021]</a>
|
||
</td></tr><tr><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>OTX2</i>
|
||
</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">?</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_3 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_3 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_5 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="https://omim.org/entry/600037" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">600037</a>
|
||
</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_5 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a class="bk_pop" href="#lca-ov.REF.henderson.2009.2442">Henderson et al [2009]</a>
|
||
</td></tr><tr><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>RD3</i>
|
||
</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><1%</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_3 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_3 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_5 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="https://omim.org/entry/610612" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">610612</a>
|
||
</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_5 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>RDH12</i>
|
||
</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">10%</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_3 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">LCA phenotype</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_3 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Early, widespread RPE & retinal atrophy</div></li><li class="half_rhythm"><div>Minimal intraretinal pigmentation in early childhood</div></li><li class="half_rhythm"><div>Dense intraretinal bone-spicule pigmentation developing over time</div></li><li class="half_rhythm"><div>Early progressive macular atrophy</div></li></ul>
|
||
</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>On OCT: macular excavation</div></li><li class="half_rhythm"><div>On FAF: loss of autofluorescence</div></li></ul>
|
||
</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_5 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="https://omim.org/entry/612712" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">612712</a>
|
||
</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_5 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a class="bk_pop" href="#lca-ov.REF.mackay.2011.2706">Mackay et al [2011]</a>
|
||
</td></tr><tr><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>RPE65</i>
|
||
</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">5%-10%</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_3 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">EOSRD:
|
||
<ul><li class="half_rhythm"><div>Profound night blindness from birth</div></li><li class="half_rhythm"><div>Minimal nystagmus</div></li><li class="half_rhythm"><div>Poor color discrimination</div></li><li class="half_rhythm"><div>Residual cone-mediated vision in 1st 3 decades w/progressive visual field loss</div></li></ul>
|
||
</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_3 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">May show blonde fundus w/peripheral, white, punctate lesions</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">FDA-approved gene therapy available (See <a href="/books/n/gene/rpe65-lca/"><i>RPE65</i>-Related LCA/EOSRD</a>.)</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_5 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="https://omim.org/entry/204100" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">204100</a>
|
||
</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_5 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a class="bk_pop" href="#lca-ov.REF.kumaran.2018a.85">Kumaran et al [2018a]</a>, <a class="bk_pop" href="#lca-ov.REF.kumaran.2018b.3330">Kumaran et al [2018b]</a></td></tr><tr><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>RPGRIP1</i>
|
||
</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">5%</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_3 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Initial rapid decline in vision followed by lack of progression</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_3 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_5 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="https://omim.org/entry/613826" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">613826</a>
|
||
</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_5 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>PRPH2</i>
|
||
</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">?</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_3 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_3 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_5 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="https://omim.org/entry/608133" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">608133</a>
|
||
</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_5 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>SPATA7</i>
|
||
</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">3%</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_3 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_3 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_5 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="https://omim.org/entry/604232" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">604232</a>
|
||
</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_5 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>TULP1</i>
|
||
</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><1%</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_3 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_3 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Maculopathy</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_5 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="https://omim.org/entry/613843" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">613843</a>
|
||
</td><td headers="hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_1_5 hd_h_lca-ov.T.leber_congenital_amaurosis_lca_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">Adapted from <a class="bk_pop" href="#lca-ov.REF.kumaran.2017.1147">Kumaran et al [2017]</a></p></div></dd><dt></dt><dd><div><p class="no_margin">? = unknown; FAF = fundus autofluorescence; OCT = optical coherence tomography; RP = retinitis pigmentosa; RPE = retinal pigment epithelium; VA = visual acuity</p></div></dd><dt>1. </dt><dd><div id="lca-ov.TF.2.1"><p class="no_margin">Genes are listed alphabetically.</p></div></dd><dt>2. </dt><dd><div id="lca-ov.TF.2.2"><p class="no_margin">Retinitis pigmentosa may or may not be accompanied by Coats-like vasculopathy, later-onset macular dystrophy, and isolated autosomal recessive foveal retinoschisis.</p></div></dd></dl></div></div></div></div><div id="lca-ov.Evaluation_Strategies_to_Identify"><h2 id="_lca-ov_Evaluation_Strategies_to_Identify_">3. Evaluation Strategies to Identify the Genetic Cause of Leber Congenital Amaurosis / Early-Onset Severe Retinal Dystrophy in a Proband</h2><p>Establishing a specific genetic cause of Leber congenital amaurosis (LCA) / early-onset severe retinal dystrophy (EOSRD):</p><ul><li class="half_rhythm"><div>Can aid in discussions of prognosis (which are beyond the scope of this <i>GeneReview</i>) and genetic counseling and management (see <a href="#lca-ov.Genetic_Counseling_for_Leber_Cong">Section 5</a>);</div></li><li class="half_rhythm"><div>Usually involves a medical history, physical examination, laboratory testing, family history, and genomic/genetic testing.</div></li></ul><p><b>Medical history.</b> See <a href="/books/NBK531510/table/lca-ov.T.leber_congenital_amaurosis_lca/?report=objectonly" target="object" rid-ob="figoblcaovTlebercongenitalamaurosislca">Table 2</a>.</p><p><b>Physical examination and other studies.</b> See <a href="/books/NBK531510/table/lca-ov.T.leber_congenital_amaurosis_lca/?report=objectonly" target="object" rid-ob="figoblcaovTlebercongenitalamaurosislca">Table 2</a>.</p><p><b>Family history.</b> A three-generation family history should be taken, with attention to relatives with manifestations of LCA/EOSRD and consanguinity. Document relevant findings in relatives through direct examination or review of medical records, including results of molecular genetic testing.</p><p><b>Molecular genetic testing.</b> Because LCA/EOSRD is both genetically heterogeneous and indistinguishable from many other inherited retinal dystrophies, recommended molecular genetic testing approaches include either gene-targeted testing (multigene panel) or comprehensive genomic testing (exome/genome sequencing). Gene-targeted testing, typically done using multigene panel tests, requires prior characterization of the causative gene as a "retinal dystrophy gene." Genomic testing enables the clinician to explore genes not previously known to be associated with retinal dystrophy.</p><p>Note: (1) Single-gene testing (sequence analysis of a given gene, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended. (2) Single-gene sequence analysis and/or targeted deletion/duplication analysis MAY be considered if previous testing has identified a heterozygous pathogenic variant in a recessive LCA-associated gene. Of note, large deletions, insertions, and duplications very rarely account for the presumed second variant.</p><ul><li class="half_rhythm"><div class="half_rhythm"><b>A multigene panel</b> that includes some or all of the genes listed in <a href="/books/NBK531510/table/lca-ov.T.leber_congenital_amaurosis_lca/?report=objectonly" target="object" rid-ob="figoblcaovTlebercongenitalamaurosislca">Table 2</a> is most likely to identify the genetic cause of LCA/EOSRD while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this <i>GeneReview</i>. Of note, given the rarity of some of the genes associated with LCA/EOSRD some panels may not include all known LCA/EOSRD genes listed in <a href="/books/NBK531510/table/lca-ov.T.leber_congenital_amaurosis_lca/?report=objectonly" target="object" rid-ob="figoblcaovTlebercongenitalamaurosislca">Table 2</a>. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.</div><div class="half_rhythm">For an introduction to multigene panels click <a href="/books/n/gene/app5/#app5.Multigene_Panels">here</a>. More detailed information for clinicians ordering genetic tests can be found <a href="/books/n/gene/app5/#app5.Multigene_Panels_FAQs">here</a>.</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Comprehensive</b>
|
||
<b>genomic testing</b> (which does not require the clinician to determine which gene[s] are likely involved) may be considered. <b>Exome sequencing</b> is most commonly used; <b>genome sequencing</b> is increasingly possible. If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.</div><div class="half_rhythm">Note: Unlike exome sequencing, genome sequencing can identify noncoding variants. Although most confirmed pathogenic variants identified by genome sequencing are within exons [<a class="bk_pop" href="#lca-ov.REF.taylor.2015.717">Taylor et al 2015</a>], likely pathogenic variants have been detected in noncoding regions of <i>CRB1</i>, <i>GUCY2D</i>, and <i>IFT140</i> in individuals with inherited retinal dystrophies [<a class="bk_pop" href="#lca-ov.REF.daich_varela.2023.595">Daich Varela et al 2023</a>].</div><div class="half_rhythm">For an introduction to comprehensive genomic testing click <a href="/books/n/gene/app5/#app5.Comprehensive_Genomic_Testing">here</a>. More detailed information for clinicians ordering genomic testing can be found <a href="/books/n/gene/app5/#app5.Comprehensive_Genomic_Testing_1">here</a>.</div></li></ul></div><div id="lca-ov.Medical_Management_of_Leber_Conge"><h2 id="_lca-ov_Medical_Management_of_Leber_Conge_">4. Medical Management of Leber Congenital Amaurosis / Early-Onset Severe Retinal Dystrophy Based on Genetic Cause</h2><p>Management of most forms of Leber congenital amaurosis (LCA) / early-onset severe retinal dystrophy (EOSRD) is symptomatic. The only form of LCA/EOSRD for which specific therapy (gene replacement therapy) is available is <i>RPE65</i>-LCA. See <a href="/books/n/gene/rpe65-lca/"><i>RPE65</i>-Related Leber Congenital Amaurosis / Early-Onset Severe Retinal Dystrophy</a>.</p><div id="lca-ov.Visual_Impairment"><h3>Visual Impairment</h3><p><b>Symptomatic management.</b> Affected children benefit from correction of refractive error, use of low vision aids when possible, and optimal access to educational and work-related opportunities.</p><p>Children and their parents should be referred to programs for visually impaired children within their state or locality.</p><p><b>Gene therapy for LCA/EOSRD.</b> In the case of LCA, gene supplementation therapy compensates for loss-of-function variants by providing a healthy copy of the gene to cells where it is required [<a class="bk_pop" href="#lca-ov.REF.kumaran.2018c.11">Kumaran et al 2018c</a>]. Viral vectors, or more specifically recombinant adeno-associated virus (AAV) vectors, have been used in LCA clinical trials.</p><p>Subretinal gene therapy administration for LCA has been investigated most extensively in <b><i>RPE65</i>-associated LCA</b> [<a class="bk_pop" href="#lca-ov.REF.kumaran.2018b.3330">Kumaran et al 2018b</a>]. A total of five Phase I/II trials [<a class="bk_pop" href="#lca-ov.REF.bainbridge.2008.2231">Bainbridge et al 2008</a>, <a class="bk_pop" href="#lca-ov.REF.hauswirth.2008.979">Hauswirth et al 2008</a>, <a class="bk_pop" href="#lca-ov.REF.maguire.2008.2240">Maguire et al 2008</a>, <a class="bk_pop" href="#lca-ov.REF.weleber.2016.1606">Weleber et al 2016</a>, <a class="bk_pop" href="#lca-ov.REF.le_meur.2018.256">Le Meur et al 2018</a>] and one Phase III trial [<a class="bk_pop" href="#lca-ov.REF.russell.2017.849">Russell et al 2017</a>] have shown that subretinal injection of a recombinant AAV vector containing the <i>RPE65</i> cDNA can improve retinal function:</p><ul><li class="half_rhythm"><div>The Phase I/II clinical trials identified varied improvements in aspects of sight [<a class="bk_pop" href="#lca-ov.REF.testa.2013.1283">Testa et al 2013</a>, <a class="bk_pop" href="#lca-ov.REF.bainbridge.2015.1887">Bainbridge et al 2015</a>, <a class="bk_pop" href="#lca-ov.REF.jacobson.2015.1920">Jacobson et al 2015</a>, <a class="bk_pop" href="#lca-ov.REF.le_meur.2018.256">Le Meur et al 2018</a>, <a class="bk_pop" href="#lca-ov.REF.pennesi.2018.1428">Pennesi et al 2018</a>].</div></li><li class="half_rhythm"><div>The Phase III trial of subretinal administration of an AAV2/2 vector has reported benefit at one year, reaching its primary end point for efficacy with improved performance on a novel test of multiluminance mobility [<a class="bk_pop" href="#lca-ov.REF.russell.2017.849">Russell et al 2017</a>]. This product, voretingene neparvovec (Luxturna™, Spark Therapeutics Inc) has been approved by the FDA for the treatment of <i>RPE65</i>-associated retinopathy.</div></li></ul><p>Following successful gene supplementation therapy in experimental models of <i>AIPL1-</i>, <i>RDH12-</i>, <i>GUCY2D-</i>, and <i>RPGRIP-</i>associated LCA, clinical trials in these subsets of LCA are likely in the future. A different technique of gene therapy utilizing antisense oligonucleotide-mediated exon skipping to abrogate the disease-causing variant has resulted in a clinical trial investigating the safety and tolerability of intravitreal injections of this type of gene therapy (ClinicalTrials.gov identifier: NCT03140969) for <i>CEP290-</i>associated LCA.</p></div><div id="lca-ov.Developmental_Delay__Intellectual"><h3>Developmental Delay / Intellectual Disability Management Issues</h3><p>Children with LCA/EOSRD who have developmental delay should be referred to a developmental pediatrician and enrolled in a continuing program of care and support.</p><p>Advice on developmental delay / intellectual disability management issues will vary from country to country, or even region to region within a country, depending on support services available. Overarching principles should include the following:</p><ul><li class="half_rhythm"><div>Involving child development and educational specialists at the earliest available opportunity, often with specialist teachers / schools for the visually impaired</div></li><li class="half_rhythm"><div>Early referral to low vision services to access low visual aids, especially with improving technologies, such as the refreshable braille display</div></li><li class="half_rhythm"><div>As affected individuals grow older, identifying further assistance (including financial or employment assistance), which in some countries is available through certification/registration processes</div></li></ul><p>Some countries have registration services to record population data on the causes and effects of visual impairment.</p><p>Note: The following information represents typical management recommendations for individuals with developmental delay / intellectual disability management issues in the United States.</p></div><div id="lca-ov.Motor_Dysfunction"><h3>Motor Dysfunction</h3><p>
|
||
<b>Gross motor dysfunction</b>
|
||
</p><ul><li class="half_rhythm"><div>Physical therapy is recommended to maximize mobility.</div></li><li class="half_rhythm"><div>Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).</div></li></ul><p><b>Fine motor dysfunction.</b> Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing.</p><p><b>Oral motor dysfunction.</b> Assuming that the individual is safe to eat by mouth, feeding therapy (typically from an occupational or speech therapist) is recommended for affected individuals who have difficulty feeding due to poor oral motor control.</p><p><b>Communication issues.</b> Consider evaluation for alternative means of communication (e.g., <a href="https://www.asha.org/NJC/AAC/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">augmentative and alternative communication</a> [AAC]) for individuals who have expressive language difficulties.</p></div><div id="lca-ov.SocialBehavioral_Concerns"><h3>Social/Behavioral Concerns</h3><p>Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one on one with a board-certified behavior analyst.</p><p>Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications (e.g., to treat attention-deficit/hyperactivity disorder) when necessary.</p></div></div><div id="lca-ov.Genetic_Counseling_for_Leber_Cong"><h2 id="_lca-ov_Genetic_Counseling_for_Leber_Cong_">5. Genetic Counseling for Leber Congenital Amaurosis / Early-Onset Severe Retinal Dystrophy</h2><p>
|
||
<i>Genetic counseling is the process of providing individuals and families with
|
||
information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them
|
||
make informed medical and personal decisions. The following section deals with genetic
|
||
risk assessment and the use of family history and genetic testing to clarify genetic
|
||
status for family members; it is not meant to address all personal, cultural, or
|
||
ethical issues that may arise or to substitute for consultation with a genetics
|
||
professional</i>. —ED.</p><div id="lca-ov.Mode_of_Inheritance"><h3>Mode of Inheritance</h3><p>Leber congenital amaurosis (LCA) / early-onset severe retinal dystrophy (EOSRD) is typically inherited in an autosomal recessive manner.</p><p>Rarely, LCA/EOSRD is inherited in an autosomal dominant manner as a result of a heterozygous pathogenic variant in <i>CRX</i>, <i>OTX2</i>, or <i>IMPDH1.</i></p><p>Note: In the estimated 30% of individuals with LCA/EOSRD in whom no molecular diagnosis is found, the mode of inheritance is most likely autosomal recessive with a small likelihood of autosomal dominant inheritance resulting from a <i>de novo</i> pathogenic variant.</p></div><div id="lca-ov.Autosomal_Recessive_Inheritance"><h3>Autosomal Recessive Inheritance – Risk to Family Members</h3><p>
|
||
<b>Parents of a proband</b>
|
||
</p><ul><li class="half_rhythm"><div>The parents of an affected child are obligate heterozygotes (i.e., carriers of one LCA/EOSRD-causing allelic variant).</div></li><li class="half_rhythm"><div>Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.</div></li></ul><p>
|
||
<b>Sibs of a proband</b>
|
||
</p><ul><li class="half_rhythm"><div>At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.</div></li><li class="half_rhythm"><div>Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.</div></li></ul><p><b>Offspring of a proband.</b> The offspring of an individual with autosomal recessive LCA/EOSRD are obligate heterozygotes (carriers) for an LCA/EOSRD-causing allelic variant.</p><p><b>Other family members.</b> Each sib of the proband's parents is at a 50% risk of being a carrier of an LCA/EOSRD-causing allelic variant.</p><p><b>Carrier detection.</b> Carrier testing for at-risk relatives requires prior identification of the LCA/EOSRD-causing allelic variants in the family.</p></div><div id="lca-ov.Autosomal_Dominant_Inheritance__R"><h3>Autosomal Dominant Inheritance – Risk to Family Members</h3><p>
|
||
<b>Parents of a proband</b>
|
||
</p><ul><li class="half_rhythm"><div>Some children diagnosed with autosomal dominant LCA/EOSRD have an affected parent.</div></li><li class="half_rhythm"><div>Most children diagnosed with autosomal dominant LCA/EOSRD have the disorder as the result of a <i>de novo CRX</i>, <i>OTX2</i>, or <i>IMPDH1</i> pathogenic variant [<a class="bk_pop" href="#lca-ov.REF.jacobson.1998.2417">Jacobson et al 1998</a>, <a class="bk_pop" href="#lca-ov.REF.sohocki.1998.1307">Sohocki et al 1998</a>, <a class="bk_pop" href="#lca-ov.REF.swaroop.1999.299">Swaroop et al 1999</a>, <a class="bk_pop" href="#lca-ov.REF.rivolta.2001.488">Rivolta et al 2001</a>, <a class="bk_pop" href="#lca-ov.REF.perrault.2003.e90">Perrault et al 2003</a>].</div></li><li class="half_rhythm"><div>Molecular genetic testing is recommended for the parents of a proband with an apparent <i>de novo</i> pathogenic variant.</div></li></ul><p><b>Sibs of a proband.</b> The risk to sibs of the proband depends on the clinical/genetic status of the proband's parents:</p><ul><li class="half_rhythm"><div>If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%.</div></li><li class="half_rhythm"><div>If the proband has a known LCA/EOSRD-causing allelic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [<a class="bk_pop" href="#lca-ov.REF.rahbari.2016.126">Rahbari et al 2016</a>].</div></li><li class="half_rhythm"><div>If the parents have not been tested for the LCA/EOSRD-causing allelic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low.</div></li></ul><p><b>Offspring of a proband.</b> Each child of an individual with LCA/EOSRD has a 50% chance of inheriting the LCA/EOSRD-causing allelic variant.</p><p><b>Other family members.</b> The risk to other family members depends on the status of the proband's parents: if a parent is affected, the parent's family members are at risk.</p></div><div id="lca-ov.Prenatal_Testing_and_Preimplantat"><h3>Prenatal Testing and Preimplantation Genetic Testing</h3><p>Once the LCA/EOSRD-causing allelic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.</p></div></div><div id="lca-ov.Resources"><h2 id="_lca-ov_Resources_">Resources</h2><p>
|
||
<i>GeneReviews staff has selected the following disease-specific and/or umbrella
|
||
support organizations and/or registries for the benefit of individuals with this disorder
|
||
and their families. GeneReviews is not responsible for the information provided by other
|
||
organizations. For information on selection criteria, click <a href="/books/n/gene/app4/">here</a>.</i></p>
|
||
<ul><li class="half_rhythm"><div>
|
||
<b>American Council of the Blind (ACB)</b>
|
||
</div><div>2200 Wilson Boulevard</div><div>Suite 650</div><div>Arlington VA 22201</div><div><b>Phone:</b> 800-424-8666 (toll-free); 202-467-5081</div><div><b>Fax:</b> 202-467-5085</div><div><b>Email:</b> info@acb.org</div><div>
|
||
<a href="http://www.acb.org" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.acb.org</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>Foundation Fighting Blindness</b>
|
||
</div><div><b>Phone:</b> 800-683-5555</div><div>
|
||
<a href="https://www.fightingblindness.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">fightingblindness.org</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>National Federation of the Blind</b>
|
||
</div><div><b>Phone:</b> 410-659-9314</div><div><b>Email:</b> nfb@nfb.org</div><div>
|
||
<a href="http://www.nfb.org" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.nfb.org</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>Retina International</b>
|
||
</div><div>Ireland</div><div>
|
||
<a href="https://retina-international.org" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">retina-international.org</a>
|
||
</div></li></ul>
|
||
</div><div id="lca-ov.Chapter_Notes"><h2 id="_lca-ov_Chapter_Notes_">Chapter Notes</h2><div id="lca-ov.Author_Notes"><h3>Author Notes</h3><p>UCL Gene and Cell Therapy Group <a href="https://www.ucl.ac.uk/ioo/research/research-labs-and-groups/gene-and-cell-therapy-group" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">website</a></p><p>Casey Eye Institute Ophthalmic Genetics Service <a href="https://www.ohsu.edu/xd/health/services/casey-eye/clinical-services/specialty-services/genetics/index.cfm" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">website</a></p></div><div id="lca-ov.Acknowledgments"><h3>Acknowledgments</h3><p>MM and NK are supported by grants from the National Institute for Health Research, the Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, the Medical Research Council, Fight for Sight, Moorfields Eye Hospital Special Trustees, Moorfields Eye Charity, the Wellcome Trust, the Macula Society, Retinitis Pigmentosa Fighting Blindness, and the Foundation Fighting Blindness.</p><p>MEP is supported by grants from the Foundation Fighting Blindness. Casey Eye Institute is supported by an unrestricted grant from Research to Prevent Blindness and NIH P30 EY010572 grant.</p></div><div id="lca-ov.Revision_History"><h3>Revision History</h3><ul><li class="half_rhythm"><div>23 March 2023 (aa/gm) Revision: <a class="bk_pop" href="#lca-ov.REF.daich_varela.2023.595">Daich Varela et al [2023]</a> and information about likely pathogenic variants in noncoding regions detected by genome sequencing added to <a href="#lca-ov.Evaluation_Strategies_to_Identify">Evaluation Strategies to Identify the Genetic Cause of LCA/EOSRD in a Proband</a></div></li><li class="half_rhythm"><div>4 October 2018 (bp) Overview posted live</div></li><li class="half_rhythm"><div>13 December 2017 (mm,nk) Original submission</div></li></ul></div></div><div id="lca-ov.References"><h2 id="_lca-ov_References_">References</h2><div id="lca-ov.Literature_Cited"><h3>Literature Cited</h3><ul class="simple-list"><li class="half_rhythm"><div class="bk_ref" id="lca-ov.REF.aboshiha.2015.862">Aboshiha
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||
J, Dubis
|
||
AM, van der Spuy
|
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J, Nishiguchi
|
||
KM, Cheeseman
|
||
EW, Ayuso
|
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C, Ehrenberg
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M, Simonelli
|
||
F, Bainbridge
|
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JW, Michaelides
|
||
M. Preserved outer retina in Aipl1 Leber's congenital amaurosis: implications for gene therapy.
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Ophthalmology
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2015;122:862-4.
|
||
[<a href="https://pubmed.ncbi.nlm.nih.gov/25596619" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25596619</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="lca-ov.REF.abusafieh.2013.236">Abu-Safieh
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L, Alrashed
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M, Anazi
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S, Alkuraya
|
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H, Khan
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AO, Al-Owain
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M, Al-Zahrani
|
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J, Al-Abdi
|
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L, Hashem
|
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M, Al-Tarimi
|
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S, Sebai
|
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MA, Shamia
|
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A, Ray-Zack
|
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MD, Nassan
|
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M, Al-Hassnan
|
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ZN, Rahbeeni
|
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Z, Waheeb
|
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S, Alkharashi
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A, Abboud
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E, Al-Hazzaa
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SA, Alkuraya
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FS. Autozygome-guided exome sequencing in retinal dystrophy patients reveals pathogenetic mutations and novel candidate disease genes.
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Genome Res.
|
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2013;23:236-47.
|
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[<a href="/pmc/articles/PMC3561865/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3561865</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/23105016" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23105016</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="lca-ov.REF.aldahmesh.2010.207">Aldahmesh
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MA, Al-Owain
|
||
M, Alqahtani
|
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F, Hazzaa
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S, Alkuraya
|
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FS. A null mutation in CABP4 causes Leber's congenital amaurosis-like phenotype.
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||
Mol Vis.
|
||
2010;16:207-12.
|
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[<a href="/pmc/articles/PMC2820108/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2820108</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20157620" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20157620</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="lca-ov.REF.bainbridge.2015.1887">Bainbridge
|
||
JW, Mehat
|
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MS, Sundaram
|
||
V, Robbie
|
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SJ, Barker
|
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SE, Ripamonti
|
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C, Georgiadis
|
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A, Mowat
|
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FM, Beattie
|
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SG, Gardner
|
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PJ, Feathers
|
||
KL, Luong
|
||
VA, Yzer
|
||
S, Balaggan
|
||
K, Viswanathan
|
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A, de Ravel
|
||
TJ, Casteels
|
||
I, Holder
|
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GE, Tyler
|
||
N, Fitzke
|
||
FW, Weleber
|
||
RG, Nardini
|
||
M, Moore
|
||
AT, Thompson
|
||
DA, Petersen-Jones
|
||
SM, Michaelides
|
||
M, van den Born
|
||
LI, Stockman
|
||
A, Smith
|
||
AJ, Rubin
|
||
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|
||
RR. Long-term effect of gene therapy on Leber's congenital amaurosis.
|
||
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|
||
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[<a href="/pmc/articles/PMC4565766/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4565766</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/26216056" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26216056</span></a>]</div></li></ul></div></div><div id="bk_toc_contnr"></div></div></div>
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