Single large-scale mitochondrial DNA deletion syndromes (SLSMDSs) comprise overlapping clinical phenotypes including Kearns-Sayre syndrome (KSS), KSS spectrum, Pearson syndrome (PS), chronic progressive external ophthalmoplegia (CPEO), and CPEO-plus. KSS is a progressive multisystem disorder with onset before age 20 years characterized by pigmentary retinopathy, CPEO, and cardiac conduction abnormality. Additional features can include cerebellar ataxia, tremor, intellectual disability or cognitive decline, dementia, sensorineural hearing loss, oropharyngeal and esophageal dysfunction, exercise intolerance, muscle weakness, and endocrinopathies. Brain imaging typically shows bilateral lesions in the globus pallidus and white matter. KSS spectrum includes individuals with KSS in addition to individuals with ptosis and/or ophthalmoparesis and at least one of the following: retinopathy, ataxia, cardiac conduction defects, hearing loss, growth deficiency, cognitive impairment, tremor, or cardiomyopathy. Compared to CPEO-plus, individuals with KSS spectrum have more severe muscle involvement (e.g., weakness, atrophy) and overall have a worse prognosis. PS is characterized by pancytopenia (typically transfusion-dependent sideroblastic anemia with variable cell line involvement), exocrine pancreatic dysfunction, poor weight gain, and lactic acidosis. PS manifestations also include renal tubular acidosis, short stature, and elevated liver enzymes. PS may be fatal in infancy due to neutropenia-related infection or refractory metabolic acidosis. CPEO is characterized by ptosis, ophthalmoplegia, oropharyngeal weakness, variable proximal limb weakness, and/or exercise intolerance. CPEO-plus includes CPEO with additional multisystemic involvement including neuropathy, diabetes mellitus, migraines, hypothyroidism, neuropsychiatric manifestations, and optic neuropathy. Rarely, an SLSMDS can manifest as Leigh syndrome, which is characterized as developmental delays, neurodevelopmental regression, lactic acidosis, and bilateral symmetric basal ganglia, brain stem, and/or midbrain lesions on MRI.

GNPTAB-related disorders comprise the phenotypes mucolipidosis II (ML II) and mucolipidosis IIIa/ß (ML IIIa/ß), and phenotypes intermediate between ML II and ML IIIa/ß. ML II is evident at birth and slowly progressive; death most often occurs in early childhood. Orthopedic abnormalities present at birth may include thoracic deformity, kyphosis, clubfeet, deformed long bones, and/or dislocation of the hip(s). Growth often ceases in the second year of life; contractures develop in all large joints. The skin is thickened, facial features are coarse, and gingiva are hypertrophic. All children have cardiac involvement, most commonly thickening and insufficiency of the mitral valve and, less frequently, the aortic valve. Progressive mucosal thickening narrows the airways, and gradual stiffening of the thoracic cage contributes to respiratory insufficiency, the most common cause of death. ML IIIa/ß becomes evident at about age three years with slow growth rate and short stature; joint stiffness and pain initially in the shoulders, hips, and fingers; gradual mild coarsening of facial features; and normal to mildly impaired cognitive development. Pain from osteoporosis becomes more severe during adolescence. Cardiorespiratory complications (restrictive lung disease, thickening and insufficiency of the mitral and aortic valves, left and/or right ventricular hypertrophy) are common causes of death, typically in early to middle adulthood. Phenotypes intermediate between ML II and ML IIIa/ß are characterized by physical growth in infancy that resembles that of ML II and neuromotor and speech development that resemble that of ML IIIa/ß.

VPS13A disease, caused by VPS13A loss-of-function pathogenic variants, is characterized by a spectrum of movement disorders (chorea, dystonia, tics, sometimes parkinsonism); predominant orofacial choreic and dystonic movements and tics (with involuntary tongue protrusion on attempted swallowing, habitual tongue and lip biting resulting in self-mutilation, involuntary vocalizations); dysarthria and dysphagia; psychiatric, cognitive, and behavioral changes ("frontal lobe type"); seizures; and progressive neuromuscular involvement. Huntingtonism (triad of progressive movement disorder and cognitive and behavioral alterations) is a typical presentation. Phenotypic variability is considerable even within the same family, including for monozygotic twins. Mean age of onset is about 30 years. VPS13A disease runs a chronic progressive course and may lead to major disability within a few years. Some affected individuals are bedridden or wheelchair dependent by the third decade. Age at death ranges from 28 to 61 years; several instances of sudden unexplained death or death during epileptic seizures have been reported.

GJB1 disorders are typically characterized by peripheral motor and sensory neuropathy with or without fixed CNS abnormalities and/or acute, self-limited episodes of transient neurologic dysfunction (especially weakness and dysarthria). Peripheral neuropathy typically manifests in affected males between ages five and 25 years. Although both men and women are affected, manifestations tend to be less severe in women, some of whom may remain asymptomatic. Less commonly, initial manifestations in some affected individuals are stroke-like episodes (acute fulminant episodes of reversible CNS dysfunction).

COMP-related pseudoachondroplasia (COMP-PSACH) is characterized by normal length at birth and normal facies. Often the presenting feature is a waddling gait, recognized at the onset of walking. Typically, the growth rate falls below the standard growth curve by approximately age two years, leading to a moderately severe form of disproportionate short-limb short stature. Joint pain during childhood, particularly in the large joints of the lower extremities, is common. Degenerative joint disease is progressive; approximately 50% of individuals with COMP-PSACH eventually require hip replacement surgery.

Spinocerebellar ataxia type 4 (SCA4) is a progressive neurologic disease characterized by cerebellar involvement (gait ataxia, balance disturbances, eye movement abnormalities), brain stem involvement (dysarthria, dysphagia), sensory neuropathy, motor neuron involvement (muscle wasting and spasticity), autonomic dysfunction (especially orthostatic hypotension), and cognition and/or behavior manifestations. Age of onset ranges from 12 to 65 years. In the approximately 10% of individuals whose onset is before age 25 years disease manifestations are more severe and often different from those with later-onset disease. As the disease progresses, particularly in those with early-onset disease, eye movement abnormalities, dysarthria, dysphagia, sensory neuropathy, upper and lower motor neuron involvement, and orthostatic hypotension can further aggravate balance and gait problems. Most individuals eventually require a walker or wheelchair. Reduced life expectancy in individuals with earlier-onset severe SCA4 is associated with weight loss, infections, and cardiac arrhythmia. Life expectancy is normal or near normal in individuals with later-onset SCA4.

Spinocerebellar ataxia type 6 (SCA6) is characterized by adult-onset, slowly progressive cerebellar ataxia, dysarthria, and nystagmus. The age of onset ranges from 19 to 73 years; mean age of onset is between 43 and 52 years. Initial symptoms are gait unsteadiness, stumbling, and imbalance (in ~90%) and dysarthria (in ~10%). Eventually all persons have gait ataxia, upper-limb incoordination, intention tremor, and dysarthria. Dysphagia and choking are common. Visual disturbances may result from diplopia, difficulty fixating on moving objects, horizontal gaze-evoked nystagmus, and vertical nystagmus. Hyperreflexia and extensor plantar responses occur in up to 40%-50%. Basal ganglia signs, including dystonia and blepharospasm, occur in up to 25%. Mentation is generally preserved.

X-linked recessive Charcot-Marie-Tooth disease-4 with or without cerebellar ataxia (CMTX4) is a mitochondrial disorder manifest as progressive neurologic dysfunction with highly variable features. The age at onset ranges from infancy to young adulthood, and patients can present with different features, including hearing loss, delayed motor development, or difficulty walking due to peripheral neuropathy and/or cerebellar ataxia. Most patients develop all features, including a progressive sensorimotor axonal neuropathy and deafness due to auditory neuropathy. Additional more variable features can include cognitive impairment, cerebellar atrophy on brain imaging, cerebellar signs, such as dysarthria, abnormal extraocular movements, tremor, and dysmetria, as well as spasticity. There is significant intrafamilial variability: the variable features are consistent with mitochondrial dysfunction. Prolonged treatment with riboflavin may result in some mild improvement in the ataxia (summary by Rinaldi et al., 2012, Heimer et al., 2018, Bogdanova-Mihaylova et al., 2019).

Hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC), a neurodevelopmental and neurodegenerative disorder, is characterized by severe progressive sensorimotor neuropathy with resulting hypotonia, areflexia, and amyotrophy, and by variable degrees of dysgenesis of the corpus callosum. Mild-to-severe intellectual disability and "psychotic episodes" during adolescence are observed. Sensory modalities are moderately to severely affected beginning in infancy. The average age of onset of walking is 3.8 years; the average age of loss of walking is 13.8 years; the average age of death is 33 years.

Mitochondrial DNA-associated Leigh syndrome spectrum (mtDNA-LSS) is part of a continuum of progressive neurodegenerative disorders caused by abnormalities of mitochondrial energy generation, which includes the overlapping phenotypes mtDNA-associated Leigh syndrome and mtDNA-associated Leigh-like syndrome. Mitochondrial DNA-LSS is characterized by onset of manifestations typically between ages three and 12 months, often following an intercurrent illness (usually viral) or metabolic challenge (vaccinations, surgery, prolonged fasting). Decompensation (often with elevated lactate levels in blood and/or cerebrospinal fluid) is typically associated with developmental delay and/or regression. Neurologic features include hypotonia, spasticity, seizures, movement disorders, cerebellar ataxia, and peripheral neuropathy. Brain stem dysfunction may manifest with respiratory symptoms, swallowing difficulties, ophthalmoparesis, and abnormalities in thermoregulation. Extraneurologic manifestations may include poor weight gain, cardiomyopathy, and conduction defects. Up to 50% of individuals die by age three years, most often from respiratory or cardiac failure.

A severe form of axonal Charcot-Marie-Tooth disease, a peripheral sensorimotor neuropathy. Onset in the second or third decade has manifestations of ulceration and infection of the feet. Symmetric and distal weakness develops mostly in the legs together with a severe symmetric distal sensory loss. Tendon reflexes are only reduced at ankles and foot deformities including pes cavus or planus and hammer toes, appear in childhood.

SCA8 is a slowly progressive ataxia with onset typically in the third to fifth decade but with a range from before age one year to after age 60 years. Common initial manifestations are scanning dysarthria with a characteristic drawn-out slowness of speech and gait instability. Over the disease course other findings can include eye movement abnormalities (nystagmus, abnormal pursuit and abnormal saccades, and, rarely, ophthalmoplegia); upper motor neuron involvement; extrapyramidal signs; brain stem signs (dysphagia and poor cough reflex); sensory neuropathy; and cognitive impairment (e.g., executive dysfunction, psychomotor slowing and other features of cerebellar cognitive-affective disorder in some). Life span is typically not shortened.

Spinocerebellar ataxia-25 (SCA25) is an autosomal dominant neurologic disorder characterized by the onset of lower limb ataxia resulting in gait difficulties in the first few decades of life, although later onset has been reported. Affected individuals often have upper limb involvement, dysarthria, scoliosis, abnormal eye movements, and sensory neuropathy with decreased reflexes. Some patients have sensorineural hearing loss. Brain imaging shows cerebellar atrophy. There is incomplete penetrance and variable expressivity, even within families (Barbier et al., 2022). For a general discussion of autosomal dominant spinocerebellar ataxia, see SCA1 (164400).

Spinal and bulbar muscular atrophy (SBMA) is a gradually progressive neuromuscular disorder in which degeneration of lower motor neurons results in muscle weakness, muscle atrophy, and fasciculations in affected males. Affected individuals often show gynecomastia, testicular atrophy, and reduced fertility as a result of mild androgen insensitivity.

A hereditary sensory neuropathy characterized by X-linked inheritance of slowly progressing neuropathy with onset in the first or second decade of life.

The autosomal dominant TRPV4 disorders (previously considered to be clinically distinct phenotypes before their molecular basis was discovered) are now grouped into neuromuscular disorders and skeletal dysplasias; however, the overlap within each group is considerable. Affected individuals typically have either neuromuscular or skeletal manifestations alone, and in only rare instances an overlap syndrome has been reported. The three autosomal dominant neuromuscular disorders (mildest to most severe) are: Charcot-Marie-Tooth disease type 2C. Scapuloperoneal spinal muscular atrophy. Congenital distal spinal muscular atrophy. The autosomal dominant neuromuscular disorders are characterized by a congenital-onset, static, or later-onset progressive peripheral neuropathy with variable combinations of laryngeal dysfunction (i.e., vocal fold paresis), respiratory dysfunction, and joint contractures. The six autosomal dominant skeletal dysplasias (mildest to most severe) are: Familial digital arthropathy-brachydactyly. Autosomal dominant brachyolmia. Spondylometaphyseal dysplasia, Kozlowski type. Spondyloepiphyseal dysplasia, Maroteaux type. Parastremmatic dysplasia. Metatropic dysplasia. The skeletal dysplasia is characterized by brachydactyly (in all 6); the five that are more severe have short stature that varies from mild to severe with progressive spinal deformity and involvement of the long bones and pelvis. In the mildest of the autosomal dominant TRPV4 disorders life span is normal; in the most severe it is shortened. Bilateral progressive sensorineural hearing loss (SNHL) can occur with both autosomal dominant neuromuscular disorders and skeletal dysplasias.

A rare genetic syndrome characterized by the association of congenital hypertrichosis in the anterior cervical region with peripheral sensory and motor neuropathy. Associated features may include retinal anomalies, spina bifida, kyphoscoliosis and hallux valgus, and developmental delay (one case). There have been no further descriptions in the literature since 1993.

Typical Friedreich ataxia (FRDA) is characterized by progressive ataxia with onset from early childhood to early adulthood with mean age at onset from 10 to 15 years (range: age two years to the eighth decade). Ataxia, manifesting initially as poor balance when walking, is typically followed by upper-limb ataxia, dysarthria, dysphagia, peripheral motor and sensory neuropathy, spasticity, autonomic disturbance, and often abnormal eye movements and optic atrophy. Hypertrophic cardiomyopathy is present in about two thirds of individuals; occasionally it is diagnosed prior to the onset of ataxia. Diabetes mellitus and impaired glucose tolerance can also occur. Among individuals with FRDA, about 75% have "typical Friedreich ataxia" and about 25% of individuals with biallelic FXN full-penetrance GAA repeat expansions have "atypical Friedreich ataxia" that includes late-onset FRDA (LOFA) (i.e., onset after age 25 years), very late-onset FRDA (VLOFA) (i.e., onset after age 40 years), and FRDA with retained reflexes (FARR).

Okinawa-type hereditary motor and sensory neuropathy (HMSNO) is an autosomal dominant neurodegenerative disorder characterized by young adult onset of proximal or distal muscle weakness and atrophy, muscle cramps, and fasciculations, with later onset of distal sensory impairment. The disorder is slowly progressive and clinically resembles amyotrophic lateral sclerosis (ALS; see 105400) (summary by Ishiura et al., 2012).

Spastic paraplegia 11 (SPG11) is characterized by progressive spasticity and weakness of the lower limbs frequently associated with the following: mild intellectual disability with learning difficulties in childhood and/or progressive cognitive decline; peripheral neuropathy; pseudobulbar involvement; and increased reflexes in the upper limbs. Less frequent findings include: cerebellar signs (ataxia, nystagmus, saccadic pursuit); retinal degeneration; pes cavus; scoliosis; and parkinsonism with characteristic brain MRI features that include thinning of the corpus callosum. Onset occurs mainly during infancy or adolescence (range: age 1-31 years) and in rare cases as late as age 60 years. Most affected individuals become wheelchair bound one or two decades after disease onset.

A complex form of hereditary spastic paraplegia, with onset in childhood or adulthood of progressive spastic paraplegia (with spastic gait, spasticity, lower limb weakness, pes cavus and urinary urgency) associated with the additional manifestation of peripheral sensorimotor neuropathy. The SPG36 phenotype has been mapped to a locus on chromosome 12q23-q24.

DNMT1-related disorder is a degenerative disorder of the central and peripheral nervous systems comprising a phenotypic spectrum that includes hereditary sensory and autonomic neuropathy type 1E (HSAN1E) and autosomal dominant cerebellar ataxia, deafness, and narcolepsy (ADCA-DN). DNMT1 disorder is often characterized by moderate-to-severe sensorineural hearing loss beginning in the teens or early 20s, sensory impairment, sudomotor dysfunction (loss of sweating), and dementia usually beginning in the mid-40s. In some affected individuals, narcolepsy/cataplexy syndrome and ataxia are predominant findings.

Hereditary sensory and autonomic neuropathy type VI (HSAN6) is a severe autosomal recessive disorder characterized by neonatal hypotonia, respiratory and feeding difficulties, lack of psychomotor development, and autonomic abnormalities including labile cardiovascular function, lack of corneal reflexes leading to corneal scarring, areflexia, and absent axonal flare response after intradermal histamine injection (summary by Edvardson et al., 2012). For a discussion of genetic heterogeneity of hereditary sensory and autonomic neuropathy, see HSAN1 (162400).

ADCADN is an autosomal dominant neurologic disorder characterized by adult onset of progressive cerebellar ataxia, narcolepsy/cataplexy, sensorineural deafness, and dementia. More variable features include optic atrophy, sensory neuropathy, psychosis, and depression (summary by Winkelmann et al., 2012).

Autosomal recessive spastic paraplegia-61 (SPG61) is a complicated, early-onset spastic paraplegia (summary by Chukhrova et al., 2019).

CAGSSS, which comprises cataracts, growth hormone deficiency, sensory neuropathy, sensorineural hearing loss, and skeletal dysplasia, is an autosomal recessive multisystemic disorder with a highly variable phenotypic spectrum. Not all of these features are always present, and almost all the features may present at different times and/or become more apparent with age. The skeletal features are consistent with spondyloepimetaphyseal dysplasia (SEMD) (summary by Vona et al., 2018). One family had a distinctive presentation with infantile-onset intractable seizures and cortical abnormalities reminiscent of Leigh syndrome (see 256000). The correlation between genotype and phenotype remains unclear, but since the IARS2 gene is involved in mitochondrial function, heterogeneous manifestations can be expected (Takezawa et al., 2018).

In patients with SSMED, short stature and microcephaly are apparent at birth, and there is progressive postnatal growth failure. Endocrine dysfunction, including hypergonadotropic hypogonadism, multinodular goiter, and diabetes mellitus, is present in affected adults. Progressive ataxia has been reported in some patients, with onset ranging from the second to fifth decade of life. In addition, a few patients have developed tumors, suggesting that there may be a predisposition to tumorigenesis. In contrast to syndromes involving defects in other components of the nonhomologous end-joining (NHEJ) complex (see, e.g., 606593), no clinically overt immunodeficiency has been observed in SSMED, although laboratory analysis has revealed lymphopenia or borderline leukopenia in some patients (Murray et al., 2015; Bee et al., 2015; de Bruin et al., 2015; Guo et al., 2015).

Neurodegeneration with brain iron accumulation-7 (NBIA7) is characterized by iron accumulation in the basal ganglia and manifests as a progressive extrapyramidal syndrome with dystonia, rigidity, and choreoathetosis. Severity and rate of progression are variable (Drecourt et al., 2018). For a general phenotypic description and a discussion of genetic heterogeneity of NBIA, see NBIA1 (234200).

Neurodegeneration with brain iron accumulation-8 (NBIA8) is characterized by iron accumulation in the basal ganglia and manifests as a progressive extrapyramidal syndrome with dystonia, rigidity, and choreoathetosis (Drecourt et al., 2018). For a general phenotypic description and a discussion of genetic heterogeneity of NBIA, see NBIA1 (234200).

Hereditary motor and sensory neuropathies (HMSN) are a heterogeneous group of peripheral nervous system disorders affecting motor and sensory function. HMSN I, also known as Charcot-Marie-Tooth (CMT) disease, or peroneal muscular atrophy, type 1, is a demyelinating neuropathy (see CMT1B; 118200) and HMSN II, also known as CMT type 2, is an axonal neuropathy (see CMT2A1; 118210). See also HMSN III (145900) and HMSN IV (266500). For an autosomal recessive disorder with similarities to HMSN V, see 607731.

Spinocerebellar ataxia with axonal neuropathy type 1 (SCAN1) is characterized by late-childhood-onset slowly progressive cerebellar ataxia and distal sensorimotor axonal neuropathy. Gaze nystagmus and dysarthria usually develop after the onset of ataxic gait. As the disease advances, pain and touch sensation in the hands and feet become impaired; vibration sense is lost in hands and lower thighs. Individuals with advanced disease develop a steppage gait and pes cavus and eventually become wheelchair dependent. Cognitive dysfunction – present in some – manifests as mild intellectual disability and poor executive function. To date only seven affected individuals have been described from three apparently unrelated consanguineous families (one from Saudi Arabia and two from Oman); therefore, it is likely that the full phenotypic spectrum of this disorder is not yet known.

Neuronal ceroid lipofuscinosis-15 (CLN15) is characterized by severe global developmental delay apparent in infancy or early childhood. Affected individuals have hypotonia with impaired motor development, respiratory insufficiency, and feeding difficulties requiring intervention. Intellectual and speech development is also delayed, and most have visual defects, including cortical visual blindness, nystagmus, and esotropia. The disorder is progressive, as manifest by developmental regression consistent with neurodegeneration. Although overt seizures are not observed, some patients may have episodic hypertonia or apnea, and EEG may show nonspecific abnormalities. Brain imaging shows unique diffusion restriction signal abnormalities affecting the brainstem, cerebellum, and corticospinal tracts. Early death may occur (summary by Polovitskaya et al., 2020).

Aicardi-Goutieres syndrome-9 (AGS9) is a type I interferonopathy characterized by severe developmental delay and progressive neurologic deterioration. Patients present in infancy with irritability and spasticity. Brain imaging shows diffusely abnormal white matter, cerebral atrophy, and intracranial calcification. Premature death has been associated with renal and/or hepatic failure (Uggenti et al., 2020). For a general phenotypic description and discussion of genetic heterogeneity of Aicardi-Goutieres syndrome, see AGS1 (225750).

Childhood-onset variegate porphyria (VPCO), also called 'homozygous' variegate porphyria, is a rare disorder of heme biosynthesis characterized by severe PPOX deficiency, onset of photosensitization by porphyrins in early childhood, skeletal abnormalities of the hand, and, less consistently, short stature, impaired intellectual development, and seizures. The term 'homozygous' refers to the presence of mutations on both alleles of the PPOX gene, resulting in earlier onset and more severe manifestations than those seen in variegate porphyria (VP), a low-penetrance disorder inherited as an autosomal dominant trait (summary by Roberts et al., 1998). Heterozygous family members of VPCO patients are usually clinically silent, but symptomatic heterozygotes have been reported (Mustajoki et al., 1987; Palmer et al., 2001; Kauppinen et al., 2001). Nomenclature 'Homozygous' variegate porphyria was so designated before the molecular defect in PPOX was elucidated, on the basis of severe reduction in PPOX activity (between 5 and 20% of control values) compared to that seen in variegate porphyria (approximately 50% reduction), in which autosomal dominant transmission had been observed. It is probable that most cases of 'homozygous' variegate porphyria actually result from compound heterozygosity for PPOX mutations (Frank et al., 1998; Palmer et al., 2001).

Neurodevelopmental disorder with hyperkinetic movements, seizures, and structural brain abnormalities (NEDMSB) is a severe autosomal recessive disorder characterized by failure to thrive in infancy, global developmental delay, hypotonia, motor abnormalities with inability to walk, involuntary movements, impaired intellectual development, absent speech, seizures, and structural brain abnormalities (Alkhater et al., 2018; Dafsari et al., 2022).