Alternative titles; symbols
SNOMEDCT: 79385002; ICD10CM: E72.03; ORPHA: 534; DO: 1056;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xq26.1 | Lowe syndrome | 309000 | X-linked recessive | 3 | OCRL | 300535 |
A number sign (#) is used with this entry because Lowe oculocerebrorenal syndrome (OCRL) is caused by mutation in the OCRL gene (300535) on chromosome Xq26.
Also see Dent disease-2 (300555), an allelic disorder with a less severe phenotype.
Lowe oculocerebrorenal syndrome (OCRL) is a rare X-linked multisystemic disorder characterized by the triad of congenital cataracts, severely impaired intellectual development, and renal tubular dysfunction with slowly progressive renal failure. Other features include postnatal growth retardation independent of kidney function, areflexia, nontender joint swelling, subcutaneous nodules, and arthropathy, which can be observed in about 50% of adult patients (review by Bokenkamp and Ludwig, 2016).
The features of Lowe syndrome are hydrophthalmia, cataract, mental retardation, vitamin D-resistant rickets, amino aciduria, and reduced ammonia production by the kidney. Hyporeflexia and hypotonia are usual features, and 'ragged red fiber' muscle pathology has been described (Bailey et al., 1992).
Charnas et al. (1991) investigated 23 patients with Lowe syndrome who ranged in age from 4 months to 31 years. Linear growth decreased after 1 year of age; bone age was found to lie between chronologic age and height age. Renal dysfunction, characterized by proteinuria, generalized amino aciduria, carnitine wasting, and phosphaturia, occurred in the first year of life. Urinary wasting of individual amino acids was milder than in cystinosis (see 219800), and branched-chain amino acids were relatively spared. Reciprocal serum creatinine levels fell linearly with age, predicting renal failure in the fourth decade. In the blood, concentrations of the muscle enzymes creatine kinase, aspartate aminotransferase, and lactate dehydrogenase, as well as those of total serum protein, serum alpha-2-globulin, and high-density lipoprotein cholesterol, were elevated. Most patients required alkalinization therapy and many benefited from supplemental potassium, phosphate, calcium, and carnitine. The serum enzyme elevations suggested muscle involvement.
Kenworthy et al. (1993) reviewed IQ and behavior in 47 affected males. Mean IQ was in the moderate to mental retardation range (40-54), with 25% of tested individuals in the normal range (IQ = 70 or more). More than 80% had maladaptive behaviors, particularly stubbornness, temper tantrums, and stereotypic behaviors.
Matsuda et al. (1969) described a Japanese boy with typical clinical features of Lowe syndrome, but the metabolic acidosis was shown to be due to failure of bicarbonate reabsorption rather than of urinary acidification. The proband's father showed amino aciduria after ornithine loading. Matsuda et al. (1970) proposed that this is a special type of Lowe syndrome that may have autosomal recessive inheritance. They suggested that the cases described by Oetliker and Rossi (1969) were of this type.
Although there is a wide range of intellectual function in affected individuals, it is often compromised by a high prevalence of maladaptive behaviors, including tantrums, stubbornness, and stereotypy (complex repetitive behaviors). Kenworthy and Charnas (1995) conducted a study to determine whether these behaviors simply reflect the multiple disabilities found in developmentally impaired individuals with or without OCRL or represent a specific genetically determined behavioral phenotype of OCRL. Forty-three cases of OCRL were paired with 43 controls matched for age, sex, visual impairment, and adaptive functioning. Individuals with OCRL displayed significantly more severe maladaptive behaviors than controls. Discriminate function analysis identified 5 behaviors as significantly distinguishing between controls and OCRL individuals: temper tantrums, irritability, stereotypy/mannerisms, obsessions/unusual preoccupations, and negativism. These behavioral features may be a specific effect of the OCRL gene on the central nervous system.
Gropman et al. (2000) described a mildly affected boy with a diagnosis of Lowe syndrome, confirmed by enzymatic activity of skin fibroblasts, in whom there was a history of congenital cataracts and mild developmental delay and who had hematuria with proteinuria but minimal signs of renal tubular dysfunction. Renal biopsy was compatible with the diagnosis of noncomplement fixating chronic glomerulonephritis. Thus, OCRL should be considered in boys with cataracts and glomerular disease, even in the absence of renal tubular defects and frank mental retardation.
Dumic et al. (2020) reported a 4.5-year-old boy with Lowe syndrome. The patient had generalized hypotonia, absent deep tendon reflexes and congenital cataracts at 9 days of life. Laboratory testing showed elevated creatine kinase (CK) and lactate dehydrogenase (LDH). At 3 months of age, he had surgery for cataracts and glaucoma. He developed infantile spasms and was treated with vigabatrin. At the age of 13 months, he had severely delayed psychomotor development, hypotonia, absent deep tendon reflexes, and increased joint laxity. Laboratory testing showed low serum phosphate and elevated CK, LDH, and AST. Urinalysis showed generalized aminoaciduria, proteinuria, and high normal urinary excretion of phosphate and calcium. Examination of skin, muscle tissue, and sural nerve by electron microscopy demonstrated swollen mitochondria and disrupted mitochondrial cristae.
Carrier Females
By slit-lamp examination, Richards et al. (1965) found lens opacities in heterozygotes. Mild 'snowflake' lenticular opacities in carrier females were described by Martin and Carson (1967) and by Gardner and Brown (1976).
Amino aciduria in the mother of a patient, after loading with ornithine, was reported as a heterozygote manifestation by Chutorian and Rowland (1966); a high incidence of maternal cataract had been noted.
Affected Females
Svorc et al. (1967) described an affected female child and referred to 2 others in the literature. Such cases may have a different genetic mechanism than X-linkage or may represent infelicitous lyonization in heterozygous females.
Harris et al. (1970), Hodgson et al. (1986), and Mueller et al. (1991) each reported female patients with Lowe syndrome.
Cau et al. (2006) reported a young woman with classic Lowe syndrome caused by a de novo OCRL mutation in the active paternal X chromosome. Studies showed extremely skewed X inactivation (100:0) of the maternal chromosome. Family studies found 5 of 7 unaffected females with extremely skewed X-inactivation of the maternal chromosome transmitted the disorder as an X-linked dominant trait (300179).
Because of the allelic heterogeneity exhibited by the OCRL gene, prenatal diagnosis by molecular analysis is limited to families in which the mutation is already known or in which linkage is informative. Suchy et al. (1998) sought a more generally applicable diagnostic test based on biochemical testing. They reported for the first time prenatal diagnosis for Lowe syndrome by measuring phosphatidylinositol 4,5-bisphosphate 5-phosphatase activity in cultured amniocytes.
Carrier Females
To determine the sensitivity and specificity of ocular examination for the carrier state of Lowe syndrome in females known to be either carriers or noncarriers by direct DNA analysis, Lin et al. (1999) studied 31 females at risk for carrying Lowe syndrome in 3 families. Slit-lamp biomicroscopy after pupillary dilation was performed by a single observer who was uninformed as to the carrier status of the women examined. Adult carrier women had small, irregularly-shaped, off-white, nonrefractile, radially arrayed, peripheral cortical lens opacities. No false-positives were found among the 31 females examined. Only one false-negative was found in a 5-year-old girl. Lin et al. (1999) concluded that slit-lamp examination is a highly accurate and sensitive test for carrier detection in Lowe syndrome, particularly in women of reproductive age.
Lowe syndrome cells have an elevated concentration of phosphatidylinositol 4,5-bisphosphate, the substrate for the OCRL protein (300535) (Zhang et al., 1998). Suchy and Nussbaum (2002) demonstrated a reproducible cellular abnormality of the actin cytoskeleton in fibroblasts from patients with Lowe syndrome. They also demonstrated an abnormal distribution of gelsolin (GSN; 137350) and alpha-actinin (see 102575), actin-binding proteins regulated by both phosphatidylinositol 4,5-bisphosphate and calcium that would be expected to be altered in Lowe cells. Actin polymerization plays a key role in the formation, maintenance, and proper function of tight junctions and adherens junctions, which have been demonstrated to be critical in renal proximal tubule function, and in the differentiation of the lens.
Streiff et al. (1958) suggested X-linkage of Lowe syndrome because all cases were male and affected brothers had been described. In 1 case, 2 brothers and a cousin (the mothers were sisters) were affected.
Hittner et al. (1982) concluded that the Lowe syndrome is not closely linked to either G6PD (305900) or Xg (314700). They studied a family with 2 affected males. On the basis of lenticular opacities, all 3 females in the pedigree were found to be carriers; each had 1 son--2 affected and 1 unaffected. At least 1 recombination between G6PD and Lowe syndrome and at least 2 between Xg and Lowe syndrome were observed.
Hodgson et al. (1986) found a seemingly balanced X/autosome translocation, t(X;3)(q25;q27), in a girl with Lowe syndrome. (The patient had inherited a translocation, t(14;17)(q24;q23), from the normal father.) By reasoning parallel to that applied to Duchenne muscular dystrophy and several other X-linked disorders, Hodgson et al. (1986) suggested that the Lowe syndrome locus is in band Xq25.
By molecular linkage analysis of 4 extensively affected families, Silver et al. (1987) found close linkage of OCRL to RFLPs that map to Xq24-q26, thus confirming the conclusion from the X/autosome translocation. For DXS10, the maximum lod was 6.450 at theta = 0.00; for DXS42, the maximum lod was 5.087 at theta = 0.00. Reilly et al. (1988) showed linkage of OCRL to other markers in the Xq25 region. Furthermore, they used the Xq25 breakpoint in the patient reported by Hodgson et al. (1986) to determine the position of OCRL relative to linked markers. Each derivative chromosome was isolated away from its normal counterpart in somatic cell hybrids. Marker DXS10, which showed 3% recombination with OCRL, stayed with the X chromosome and is therefore proximal to q25, whereas DXS42, which showed no recombination with OCRL, mapped to the derivative chromosome 3. Thus, these are flanking markers which should be useful in carrier determination. Indeed, when compared with carrier detection by ophthalmologic examination, slit-lamp examination proved to be a sensitive and specific method of carrier determination in many cases. By genetic and physical mapping, Reilly et al. (1990) further ordered markers in the Xq24-q26 region.
Wadelius et al. (1989) found that DXS42 was the most closely linked marker, giving a lod score of 3.12 at theta = 0.0. They also found that lens examination with slit-lamp illumination and a count of the total number of lenticular opacities is a reliable method of ascertaining the carrier state.
Nelson et al. (1991) identified 3 overlapping YAC clones that crossed a chromosomal translocation implicated in Lowe syndrome. Mueller et al. (1991) localized the X-chromosome breakpoint at q26.1 in a female patient with Lowe syndrome and a balanced X;20 translocation. They found that DXS10 and DXS53 were distal to the breakpoint, whereas DXS37 and DXS42 were located proximal to it. The translocation chromosome originated de novo from the unaffected father.
Bokenkamp and Ludwig (2016) stated that the prevalence of Lowe syndrome has been estimated to be 1 in 500,000 in the general population.
For a discussion of the molecular genetics of Lowe oculocerebrorenal syndrome, see the entry for the OCRL gene (300535).
McCance et al. (1960) described a condition that is probably distinct from Lowe syndrome but may also be X-linked since their subjects were 2 brothers with unrelated, unaffected parents. Features were poor appetite, failure to grow, corneal opacities, partial blindness, nystagmus, mental retardation, intention tremor, hyperchloremic acidosis, very acid urine, defect in urinary production of ammonium ion, death from progressive renal failure, underdeveloped glomeruli, structural abnormalities in the brain, and absence of testes.
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