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Neuropathies associated with hereditary disorders

Neuropathies associated with hereditary disorders
Author:
Peter B Kang, MD, FAAP, FAAN
Section Editors:
Douglas R Nordli, Jr, MD
Helen V Firth, DM, FRCP, FMedSci
Deputy Editor:
Richard P Goddeau, Jr, DO, FAHA
Literature review current through: Jul 2022. | This topic last updated: Aug 31, 2022.

INTRODUCTION — The hereditary peripheral neuropathies have been classified based upon clinical characteristics, mode of inheritance, electrophysiologic features, metabolic defects, and, more recently, specific genetic loci. The primary hereditary neuropathies predominantly affect peripheral nerves and produce symptoms of peripheral nerve dysfunction. Other hereditary neuropathies affect both the central and peripheral nervous systems and, in some cases, other organs; in such patients, symptoms related to the peripheral neuropathy may be overshadowed by additional manifestations of the disease (table 1A-D).

The last group of disorders is reviewed here. The primary motor-sensory and sensory–autonomic neuropathies are discussed separately. (See "Charcot-Marie-Tooth disease: Genetics, clinical features, and diagnosis" and "Hereditary sensory and autonomic neuropathies".)

FRIEDREICH ATAXIA — Friedreich ataxia is an autosomal recessive degenerative disorder. Most cases are caused by loss of function mutations in the frataxin (FXN) gene. The majority of patients have an expanded trinucleotide (GAA) short tandem repeat sequence in intron 1 of both alleles of the FXN gene. The repeat expansion results in reduced transcription of the gene (ie, silencing) and decreased expression of the gene product frataxin. The GAA triplet repeat expansion is found mainly in individuals of European, North African, Middle Eastern, and Indian origin. (See "Friedreich ataxia", section on 'Genetics'.)

The onset of symptoms is usually in the adolescent years. The major clinical manifestations are neurologic dysfunction and cardiomyopathy. Almost all patients present with limb and gait ataxia. Deep tendon reflexes eventually are lost in most patients. Additional manifestations can include optic atrophy, dysphagia, dysarthria, motor weakness, distal loss of position and vibration sense, reduced visual acuity, hearing loss, bladder dysfunction, kyphoscoliosis, and diabetes mellitus. Atypical phenotypes include those with late-onset disease, preserved reflexes, lower limb spasticity, and/or absence of cardiomyopathy. (See "Friedreich ataxia", section on 'Clinical features'.)

The diagnosis is based upon clinical findings and should be confirmed by genetic testing. Neuroimaging of the brain and spinal cord with magnetic resonance imaging (MRI) is recommended for all patients presenting with ataxia to exclude other causes (eg, tumor or other structural lesions, inflammation, infarction, hemorrhage) and to evaluate for cerebellar atrophy. (See "Friedreich ataxia", section on 'Evaluation and diagnosis'.)

There is no specific disease-modifying therapy for Friedreich ataxia, though several candidate therapies have advanced as far as phase II human clinical trials [1]. The management of patients with this disorder requires a multidisciplinary team of special services. An occupational and physical therapy program should be initiated early. Periodic evaluation of cardiac function is required. Similarly, patients should be monitored for the development of dysphagia, scoliosis, vision loss, hearing loss, bladder dysfunction, sleep apnea, and diabetes mellitus. Genetic and psychological counseling are also important. (See "Friedreich ataxia", section on 'Management'.)

SPINOCEREBELLAR ATAXIAS — The spinocerebellar ataxias (SCA) are a heterogeneous group of dominantly inherited disorders with different neuropathological profiles reflecting the degree of cerebellar and brainstem dysfunction or degeneration. A peripheral neuropathy is described in some but not all (table 1A). Peripheral neuropathy has been best characterized in SCA4, in which a prominent axonal neuropathy is present [2]. A mild peripheral neuropathy with decreased deep tendon reflexes and reduced vibration sense has been described in SCA1 [3], SCA2 [4], SCA3 [5], and SCA6 [6].

A detailed review of the spinocerebellar ataxias is found separately. (See "The spinocerebellar ataxias".)

INFANTILE NEUROAXONAL DYSTROPHY — Infantile neuroaxonal dystrophy (INAD; MIM 256600), also called PLA2G6-associated neurodegeneration or Seitelberger disease, is an autosomal recessive disorder. It is considered one of several subtypes of neurodegeneration with brain iron accumulation (NBIA). (See "Bradykinetic movement disorders in children", section on 'Neurodegeneration with brain iron accumulation'.)

The classification of infantile neuroaxonal dystrophy has been evolving since the discovery that nearly 80 percent of children with infantile neuroaxonal dystrophy have pathogenic variants in the PLA2G6 gene with a locus on chromosome 22q13.1 [7-9]. Pathogenic variants in the PLA2G6 gene have also been detected in patients previously diagnosed with other subtypes of NBIA, and it now appears that the PLA2G6 variants are associated with a characteristic clinical and radiologic phenotype called PLA2G6-associated neurodegeneration (PLAN) [8].

Clinical features — Children with infantile neuroaxonal dystrophy typically present by two to three years of age [10]. In a series of 14 children with PLAN, the median age of symptom presentation was 14 months (range 12 to 22 months) [8]. Of these, five died at median age of nine years (range 6.5 to 14 years).

Symptoms related to infantile neuroaxonal dystrophy reflect involvement of the peripheral nerves, central nervous system, and autonomic nervous system (table 1B) [10,11]. The peripheral neuropathy is characterized by loss of distal sensation, which may lead to limb mutilation and muscle atrophy. Hypotonia and loss of motor milestones are associated with early onset of the disease. Deep tendon reflexes typically are hypoactive.

Central nervous system manifestations include cognitive deterioration, spasticity, optic atrophy, and hypothalamic dysfunction with diabetes insipidus and hypothyroidism [12]. Autonomic symptoms may include urinary retention, decreased tearing, and dysfunction of temperature regulation. Early studies reported rare seizures in children with late-onset neuroaxonal dystrophy [13], but seizures have not been reported in children with PLA2G6 variants [8].

Nerve conduction velocities often show severe drops in motor and sensory amplitudes with milder slowing of conduction velocities, while needle electromyography frequently shows signs of denervation [11]; fast rhythms may be present on electroencephalography, and visual evoked potentials are usually abnormal [8,11].

MRI may be suggestive of the diagnosis. Cerebellar atrophy and gliosis is universally present, with increased signal on fluid-attenuated inversion recovery (FLAIR) and T2-weighted MRI sequences [8,11,14]. Other common MRI findings include hypointensity of the globus pallidus, dentate nuclei, substantia nigra on high-susceptibility gradient echo (T2*) sequences, and hypointensity of the globus pallidus on fast spin echo sequences [8,15].

Pathology — The pathologic findings, which are seen best by electron microscopy, are similar in the peripheral, central, and autonomic nervous systems. Spheroids containing mitochondria, glycogen-like granules, and dense bodies occur in both central and peripheral nerve fibers [16,17]. Spheroid formation leads to axonal swelling.

Other findings in the central nervous system include cerebellar atrophy with neuronal atrophy and astrogliosis and involvement of the corticospinal tracts. Immunohistochemistry reveals the presence of ubiquitin but not beta-tuberculin or beta-amyloid [18]. These findings suggest that loss of microtubule function is part of the mechanism of spheroid formation.

Diagnosis — The presence of infantile neuroaxonal dystrophy is suggested by the progressive neurologic symptoms beginning in infancy, but further testing is required to establish the diagnosis.

The diagnosis of infantile neuroaxonal dystrophy generally is confirmed by the demonstration of spheroids on peripheral nerve or conjunctival biopsy [10,16,19]. A diagnostic conjunctival biopsy is not dependent upon the presence of optic atrophy. Where available, PLA2G6 genetic analysis may confirm the diagnosis in patients with PLA2G6-associated neurodegeneration [8].

The differential diagnosis of infantile neuroaxonal dystrophy includes other subtypes of NBIA, as these exhibit broad phenotypic overlap. (See "Bradykinetic movement disorders in children", section on 'Neurodegeneration with brain iron accumulation'.)

TANGIER DISEASE — Tangier disease is an autosomal codominant condition in which homozygotes have no serum high-density lipoprotein (HDL) and heterozygotes have serum HDL concentrations of approximately one-half of those in normal individuals [20]. HDL-mediated cholesterol efflux from macrophages and intracellular lipid trafficking are impaired in this disorder, leading to the presence of foam cells in macrophages and other cells of the reticuloendothelial system throughout the body (table 1B) [21].

Genetics — The defect in Tangier disease involves pathogenic variants in the ATP-binding cassette transporter A1 (ABCA1) gene on chromosome 9q31, which encodes the cholesterol efflux regulatory protein [20,22-25]. ABCA1 appears to play a central role in intracellular cholesterol transport and is associated with increased HDL catabolism [25,26]. One suggestion is that reduced cholesterol efflux onto nascent HDL particles leads to lipid depleted particles that are then rapidly catabolized [27]. (See "HDL cholesterol: Clinical aspects of abnormal values", section on 'Introduction'.)

Clinical manifestations — Individuals with biallelic pathogenic variants develop cholesterol ester deposition in tonsils, liver, spleen, gastrointestinal tract, lymph nodes, bone marrow, and Schwann cells. The main clinical manifestations are orange-colored tonsils, hepatosplenomegaly, corneal opacity, lymphadenopathy, and premature coronary disease [28]; a neuropathy occurs in at least 50 percent of patients and is the most debilitating feature of the disease [21]. In a review in which the findings in 51 patients with homozygous Tangier disease were compared with over 3000 controls, the patients were more likely to have both peripheral neuropathy (54 versus <1 percent) and cardiovascular disease, defined as angina, myocardial infarction, or stroke (20 versus 5 percent overall and 44 versus 7 percent in those between the ages of 35 and 65) [21].

Two major types of neurologic syndromes are seen [29]:

A peripheral neuropathy occurs in childhood with fluctuating numbness, tingling, distal sensory loss, and distal weakness with muscle atrophy [30].

Progressive loss of sensory and motor function in the upper body in a pattern similar to that which occurs in syringomyelia (a cystic degeneration of the spinal cord) [31,32].

Electrodiagnostic studies show evidence for both demyelination and axonal loss [33]. The major pathologic findings on nerve biopsy are loss of smaller myelinated and unmyelinated nerve fibers and lipid vacuole accumulation in Schwann cells. The cause of nerve death is unknown, but nerve loss appears to precede the development of the lipid-laden Schwann cells [34].

Treatment — Initiation of a low-fat diet may reduce the number of abnormal particles and can be associated with symptomatic improvement in the peripheral neuropathy. The administration of drugs that can increase serum HDL in other patients (gemfibrozil, niacin, or a statin) has little effect in those with Tangier disease [21]. Possible future therapies involve pharmacologic manipulation of the reverse cholesterol transport pathway such as increasing cellular ABC1 expression to augment cellular efflux of cholesterol to HDL, preventing the catabolism of HDL without interfering with its cholesterol transport function, or increasing the rate of hepatic HDL cholesterol uptake [35].

ABETALIPOPROTEINEMIA — Abetalipoproteinemia (Bassen-Kornzweig syndrome) is a rare autosomal recessive disorder caused by pathogenic variants in the microsomal triglyceride transfer protein (MTTP) [36]. The neurologic manifestations result from the inability to absorb and transport vitamin E and include progressive ataxia, sensory-motor neuropathy, and vision impairment with retinitis pigmentosa. Other clinical manifestations include acanthocytosis along with fat malabsorption and steatorrhea.

The diagnosis is made in the setting of the typical clinical findings accompanied by laboratory findings of acanthocytosis, very low triglyceride and total cholesterol levels, absent beta-lipoproteins, and genetic confirmation by the presence of an MTTP variant. Neurologic manifestations can be prevented and partially reversed with the administration of vitamin E (150 mg/kg per day) along with other fat-soluble vitamins. However, correction of vitamin E levels may be limited by fat malabsorption issues, which have proven refractory to different formulations of vitamin E supplements [37]. (See "Neuroacanthocytosis", section on 'Abetalipoproteinemia'.)

Abetalipoproteinemia is discussed in greater detail separately. (See "Neuroacanthocytosis", section on 'Abetalipoproteinemia'.)

REFSUM DISEASE — Refsum disease (MIM #266500), previously known as hereditary motor and sensory neuropathy IV, is a disorder of peroxisomal function. Peroxisomes are subcellular organelles that catalyze numerous functions in cellular metabolism. A group of genetic diseases in which impairment in one or more peroxisomal functions exists is expanding. The peroxisomal disorders usually are classified into three groups according to the presence or absence of intact peroxisomes and whether one or more than one peroxisomal enzyme or function is affected. (See "Peroxisomal disorders".)

Refsum disease has been classified into classic and infantile forms; both are associated with excessive phytanic acid accumulation. Classic Refsum disease (heredopathia atactica polyneuritiformis) is an autosomal recessive disorder associated with the accumulation of phytanic acid in plasma and tissues. Phytanic acid is a branched-chain fatty acid present in the typical human diet. Normally, it is metabolized by activation to its CoA ester, phytanoyl-CoA, and then alpha-oxidation to pristanic acid (table 1B). (See "Peroxisomal disorders", section on 'Refsum disease'.)

The first gene to be associated with Refsum disease was PHYH, also known as PAHX [38,39]. Pathogenic variants in this gene lead to the inability to degrade phytanic acid because of deficient activity of phytanoyl-CoA hydroxylase, a peroxisomal enzyme that catalyzes the first step of phytanic acid alpha-oxidation.

The second gene associated with Refsum disease is PEX7, which encodes the peroxin 7 receptor that is required for peroxisomal import of proteins [40]. The peroxin 7 receptor plays a role in the incorporation of the peroxisomal enzyme phytanoyl-CoA hydroxylase (PhyH) into peroxisomes. Defects in the PEX7 gene are also found in another hereditary disorder, rhizomelic chondrodysplasia punctata type 1. (See "Peroxisomal disorders", section on 'Rhizomelic chondrodysplasia punctata type 1'.)

A different defect is present in infantile Refsum disease, which is one of a group of lethal peroxisome biogenesis disorders (the others being Zellweger syndrome and neonatal adrenoleukodystrophy). This disorder is characterized by pathogenic variants in PEX1 and PEX6, which encode for members of the AAA protein family (ATPases associated with multiple cellular activities) [41]. (See "Peroxisomal disorders", section on 'Zellweger spectrum disorders'.)

Clinical features — The age of onset varies, but most patients are symptomatic by 20 years of age. (See "Peroxisomal disorders", section on 'Refsum disease'.)

Classic Refsum disease is characterized by the presence of four clinical features:

Retinitis pigmentosa

Polyneuropathy

Cerebellar ataxia

Cytoalbuminologic dissociation, with a cerebrospinal fluid protein concentration of 100 to 600 mg/dL without a pleocytosis

Affected patients also may have sensorineural deafness, ichthyosis, anosmia, and cardiac conduction defects. Nerve conduction studies typically show a slowed conduction velocity. Peripheral nerve biopsy reveals hypertrophic changes with onion bulb formation and paracrystalline inclusions on electron microscopy.

The diagnosis in patients with characteristic clinical features and elevated serum phytanic acid concentrations is confirmed by genetic testing.

Strict reduction in dietary phytanic acid intake may be associated with a significant improvement in the clinical manifestations in patients with classic Refsum disease [42]. Another method to reduce serum phytanic acid in these patients is plasmapheresis, which can be performed serially if necessary [43,44].

Refsum disease is discussed in greater detail separately. (See "Peroxisomal disorders", section on 'Refsum disease'.)

CHEDIAK-HIGASHI SYNDROME — Chediak-Higashi syndrome (CHS) is an autosomal recessive disorder caused by biallelic pathogenic variants in the LYST gene [45]. CHS is characterized by recurrent infections, partial albinism, hepatosplenomegaly, an increased risk of lymphoreticular malignancy, and multiple neurologic manifestations.

Patients who survive early childhood despite serious infections develop severe neurologic manifestations in adolescence and early adulthood. Both the peripheral and central nervous systems are involved [46-48]. Neurologic features may include nystagmus, photosensitivity, seizures, intellectual disability, generalized weakness, spinocerebellar degeneration, and parkinsonism. Electrodiagnostic studies have shown signs of sensory neuropathy and sensorimotor neuropathy in various patients [49]. Biopsy of peripheral nerves reveals perivascular intracytoplasmic inclusions, loss of myelinated sensory fibers, and the presence of peroxidase-positive granules in Schwann cells, similar to those seen in leukocytes, which are thought to be giant lysosomes [46,50,51]. Muscle biopsy reveals neurogenic atrophy with peroxidase positive granules similar to those seen in leukocytes.

Patients who do not die from infection eventually enter the accelerated phase of the disease characterized by massive lymphohistiocytic infiltration of virtually all organ systems. Treatment with hematopoietic cell transplantation prevents infections and the accelerated phase, but patients still develop neurologic deficits [52]. (See "Chediak-Higashi syndrome", section on 'Treatment' and "Chediak-Higashi syndrome", section on 'Prognosis'.)

LYSOSOMAL STORAGE DISEASES — Lysosomes are acidic cellular organelles that function as terminal degradative compartments. Lysosomal storage diseases are a group of approximately 36 heterogeneous disorders characterized by the accumulation of undigested macromolecules within the lysosomes. They result from a deficiency of a specific lysosomal enzyme or protein, although how the accumulated substrates relate to the observed pathology is not known. Many are associated with a neurodegenerative phenotype, and a peripheral neuropathy occurs in Fabry disease, Krabbe disease, metachromatic leukodystrophy, and Niemann-Pick disease (table 1C).

Fabry disease — Fabry disease (also called angiokeratoma corporis diffusum, ceramide trihexosidosis, and Anderson-Fabry disease) is an X-linked recessive glycolipid storage disease caused by hemizygous pathogenic variants in GLA, the gene that encodes alpha-galactosidase A [53]. It is classically associated with a painful neuropathy and primarily affects males. The clinical manifestations, diagnosis, and treatment of Fabry disease are discussed separately. (See "Fabry disease: Clinical features and diagnosis" and "Fabry disease: Neurologic manifestations" and "Fabry disease: Treatment and prognosis".)

Krabbe disease — Krabbe disease (globoid cell leukodystrophy) is an autosomal recessive disorder caused by pathogenic variants in GALC that lead to the deficiency of the encoded enzyme galactocerebrosidase [54]. The neuropathy that accompanies Krabbe disease is demyelinating and nerve conduction studies typically show a uniform pattern of slowing, though nonuniform patterns have also been reported. The genetics, clinical manifestations, diagnosis, and treatment of Krabbe disease are discussed separately. (See "Krabbe disease".)

Metachromatic leukodystrophy — Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal storage disease that occurs in 1 of 40,000 births and is caused by pathogenic variants in ARSA, the gene that encodes arylsulfatase A [55]. The neuropathy that accompanies metachromatic leukodystrophy is demyelinating, with either uniform or nonuniform slowing of conduction velocities on nerve conduction studies [56]. Hematopoietic stem cell transplantation has been a therapeutic strategy used for some years in affected patients. The genetics, clinical manifestations, diagnosis, and treatment of metachromatic leukodystrophy are discussed in detail separately. (See "Metachromatic leukodystrophy".)

Niemann-Pick disease — Niemann-Pick disease (NPD; sphingomyelin-cholesterol lipidosis) is a group of autosomal recessive disorders associated with splenomegaly, variable neurologic deficits, and the storage of sphingomyelin. Niemann-Pick disease is discussed in greater detail separately. (See "Overview of Niemann-Pick disease".)

MITOCHONDRIAL DISORDERS — Defects in structure or function of mitochondria, mainly involving the oxidative phosphorylation, mitochondrial biogenesis, and other metabolic pathways, are associated with a wide spectrum of clinical phenotypes. Peripheral neuropathy is a prominent feature in several (table 1D).

Leigh syndrome — Leigh syndrome (subacute necrotizing encephalomyelopathy) is an inherited neurodegenerative disorder of infancy or childhood. It is characterized by developmental delay or psychomotor regression, signs of brainstem dysfunction, ataxia, dystonia, external ophthalmoplegia, seizures, lactic acidosis, vomiting, and weakness [57-59]. Peripheral neuropathy with reduced nerve conduction velocity and demyelination also are frequent findings [60,61], though axonal neuropathies have also been described depending on the genotype [62]. The prognosis is poor, with survival typically being a matter of months to a few years after disease onset [58,59].

The pathologic hallmarks of Leigh syndrome are bilateral, symmetric necrotizing lesions with spongy changes and microcysts in the basal ganglia, thalamus, brainstem, and spinal cord [58].

The phenotype of Leigh syndrome is related to dysfunction of mitochondrial metabolism, as reviewed elsewhere. (See "Mitochondrial myopathies: Clinical features and diagnosis", section on 'Leigh syndrome'.)

Leber hereditary optic neuropathy — Leber hereditary optic neuropathy (LHON) is a maternally inherited bilateral subacute optic neuropathy caused by pathologic variants in the mitochondrial genome. It is the first human disease to be associated with a mitochondrial DNA (mtDNA) point mutation [63].

Three mtDNA pathologic variants, at nucleotide positions 3460G>A in the gene ND1 [64], 11778G>A in the gene ND4 [63], and 14484T>C in the gene ND6 [65], are specific for LHON. These variants account for more than 90 percent of worldwide cases and are designated as primary [66]. They are missense mutations in the subunit genes for the subunits of the electron transport chain complexes I, III, and IV. The three primary LHON pathologic variants appear to cause profound impairment of complex I-dependent ATP synthesis, suggesting that they result in a common disease-causing mechanism [67]. However, the pathogenesis remains uncertain [68]. At least 15 other secondary genetic variants have been identified, but their pathogenicity is unclear; they may serve as exacerbating genetic factors.

LHON typically produces severe and permanent visual loss and predominantly affects males [69]. The initial symptoms include visual dysfunction with blurring of vision and loss of central vision, most often beginning in the late teens. However, variability in the age of onset, spectrum of clinical expression, and outcome exists. In one series of 72 patients with the G11778A variant, 82 percent were males [70]. The age at onset of visual loss ranged from 8 to 60 years, the time interval between affected eyes averaged 1.8 months, and progression to visual acuity of 20/200 or worse occurred in 98 percent of eyes over an average time of 3.7 months. Telangiectatic microangiopathy, disk pseudoedema, and vascular tortuosity, which are classic features of LHON, were seen in 58 percent of patients.

However, not all patients have such rapid progression, as illustrated in a report of 53 patients, 15 of whom had favorable outcomes [71]. In the latter group, seven had subclinical disease, two had slowly progressive LHON with a favorable visual outcome, and six had classic acute onset followed by spontaneous visual recovery. The visual outcome was better in families with the G3460A variant than in those with the G11778A variant.

Numerous factors have been considered as potential explanations for the male predominance, variable penetrance, and variable phenotype [72]. These factors include an additional X locus, impaired mitochondrial respiratory chain activity, mtDNA heteroplasmy, environmental factors, and autoimmunity.

Among environmental factors, smoking and alcohol intake may influence the expression of disease. Support for this hypothesis comes from an epidemiologic study of 125 LHON pedigrees with 196 affected and 206 unaffected carriers [73]. Both light and heavy cumulative smoking were independent risk factors for visual loss. In males who smoked, the lifetime clinical penetrance of visual loss was 93 percent. In addition, there was a trend toward increased visual failure with heavy alcohol intake.

Features other than visual loss, including tremor and a multiple sclerosis-like illness, occasionally are present [74,75]. Additional findings that can occur in children include an extrapyramidal syndrome, seizures, ataxia, spasticity, intellectual disability, and peripheral neuropathy. The peripheral neuropathy is not uniformly present and is not well-described in the literature, but when it occurs, it is typically in the setting of the G11778A variant [76]. Muscle biopsy shows aggregates of enlarged mitochondria in the subsarcolemmal region by electron microscopy [63,77]. In the central nervous system, demyelination of the optic tracts and cell loss and gliosis of the geniculate bodies occur, but the visual cortex is normal. Axonal depletion centrally in the optic nerve is present, as is loss of ganglion cells in the retina.

The diagnosis typically is made by demonstration of pathogenic variants on genetic testing. In addition, the defects in respiratory enzymes in the mitochondria can be demonstrated on muscle biopsy.

Regarding treatment options for LHON, limited evidence suggests the possibility of benefit with the antioxidant idebenone [78,79]. This treatment has been approved by the European Medicine Agency, but much uncertainty remains regarding the indications and optimal regimen [80].

As gene therapy has been particularly successful in diseases of the eye, this approach for LHON has been studied in detail. The focus has been the G11778A variant, as it is common and is associated with severe outcomes. One study focused on unilateral intravitreous injections of scAAAV2-P1ND4v2, an adeno-associated virus serotype 2 containing a self-complementary version of the complementary DNA (cDNA) of ND4, in five subjects with G11778A-associated LHON [81]. The treatment was found to be safe in this small cohort. A follow-up study evaluated unilateral intravitreous injections of scAAV2-P1ND4v2 for each of 14 subjects with LHON caused by G11778A variants; the treatment appeared to be safe and well tolerated [82]. Another study examined safety and tolerability of intravitreous injections of rAAV2/2-ND4, a recombinant, replication-defective, adeno-associated virus serotype 2 that carries the cDNA sequence of the gene ND4 into the more affected eye in each of 15 subjects [83]. The treatment was safe and well tolerated two years from the time of injection. Though efficacy was not the primary outcome, improved best-corrected visual acuity (BCVA) was noted. Improved vision for up to 3 years was reported in one trial [84]. In addition, unilateral intravitreal injection may lead to improvement in both eyes [85].

DNA REPAIR DISORDERS — The DNA repair disorders are characterized by susceptibility to chromosomal breakages, increased frequency of breaks, and interchanges occurring either spontaneously or following exposure to various DNA-damaging agents. The underlying defect in these syndromes is the inability to repair a particular type of DNA damage [86]. The inheritance of these disorders is autosomal recessive and they show an increased tendency to develop malignancies. Two of these disorders, xeroderma pigmentosum and the Cockayne syndrome, manifest a peripheral neuropathy (table 1D).

Cockayne syndrome — Cockayne syndrome (CS) is a rare multisystem disorder with characteristic physical features and progressive dementia. The characteristic facial features include prominent ears, sunken eyes, and a beaked nose. The syndrome is characterized by intellectual disability, failure to thrive, short stature, microcephaly, progressive neurologic dysfunction caused by demyelination, retinal degeneration with a pigmented retinopathy and optic atrophy, kyphoscoliosis, gait defects, and sun sensitivity but no increased frequency of cancer [87]. In 13 cases confirmed with biochemical assays (unscheduled DNA synthesis and recovery of RNA synthesis in skin fibroblasts after exposure to UV irradiation), there was wide variation in the clinical manifestations ranging from prenatal features to normal psychomotor development [88].

These observations suggest that CS should be considered in children with unexplained failure to thrive, short stature, microcephaly, and one of the characteristic features (eg, sunken eyes, limb ataxia, abnormal auditory evoked responses, or increased ventricular size and white matter changes on neuroimaging). CS presenting in adulthood may be considered in patients with gait and cognitive impairments, chorea, and neuropathy [89]. Neuroimaging may show global atrophy.

Various polyneuropathies have been described in CS [90], but the most common form is a sensorimotor demyelinating polyneuropathy [91].

Affected patients have white matter demyelination in the central nervous system, with atrophy of the cerebrum and cerebellum. Perivascular calcifications are seen in the basal ganglia and cerebellum. MRI scans show increased signal in the white matter with T2 images.

Two complementation groups (CSA and CSB) have been identified, and 80 percent of patients have been assigned to the CSB complementation group, corresponding to the ERCC6 gene, also known as CSB [92-94]. The ERCC8 (CSA) gene encodes a WD repeat protein, which interacts with the CSB protein encoded by the ERCC6 gene to enhance the transcription factor II subunit of RNA polymerase II [95,96]. The CSB protein is a helicase involved in the preferential repair of active genes [94].

Cells in patients with CS are hypersensitive to the lethal effects of UV light, but nucleotide excision repair of the bulk of genomic DNA is unaffected, as is also seen in xeroderma pigmentosum (see 'Xeroderma pigmentosum' below). CS cells are defective in a subpathway of nucleotide excision repair, known as transcription-coupled repair, whereby damage in the transcribed strand of active genes is rapidly and preferentially repaired [97,98]. Thus, in CS cells, damage in active genes is repaired at the same relatively slow rate as in the bulk DNA. It appears to be sufficient to prevent a predisposition to cancer.

No disease-modifying therapy for CS is currently known. Supportive care and management of complications are critical to optimizing quality of life and life expectancy [99]. Certain neurological complications such as tremors have in some patients been responsive to carbidopa-levodopa [90]. Patients affected by CS have fragile livers; several cases of fatal reactions to metronidazole have been described, which may be related to hepatotoxicity [100].

Xeroderma pigmentosum — Xeroderma pigmentosum (XP) is a multigenic, multiallelic autosomal recessive disease that occurs in the United States at a frequency of approximately 1:250,000. Homozygotes have severe sun sensitivity that leads to degeneration of regions of the skin and eyes, leading to various forms of cutaneous malignancy. Pathologic variants in eight genes have been identified. Seven of these genes (ie, XPA to XPG) are involved in nucleotide excision repair of carcinogen adducts after UV irradiation, while the other (ie, XPV) is involved in error-free replication of DNA damaged by UV irradiation. (See "Inherited susceptibility to melanoma", section on 'MITF (E318K) variant'.)

Approximately 25 percent of patients with XP have neurologic manifestations of varying severity caused by primary neuronal degeneration [101]. Neurologic features may be mild or severe and can include progressive cognitive impairment, ataxia, choreoathetosis, sensorineural hearing loss, spasticity, seizures, and peripheral neuropathy with diminished or absent deep tendon reflexes [89,101-103]. Based on postmortem examination, the peripheral neuropathy appears to be characterized by degeneration of sensory neurons in the dorsal root ganglions and to a lesser extent motor neurons in the anterior horn cells, with little signs of demyelination [102]. Acquired microcephaly also may be seen.

The dermatologic manifestations of XP are discussed elsewhere. (See "Cutaneous squamous cell carcinoma: Epidemiology and risk factors", section on 'Xeroderma pigmentosum'.)

HEREDITARY TYROSINEMIA — Four autosomal recessive disorders result from deficiencies in specific enzymes in the tyrosine catabolic pathway: hereditary tyrosinemia (HT) types 1, 2, and 3, and alkaptonuria.

Tyrosinemia type 1 (HT1) is the most severe disorder of tyrosine metabolism. It is characterized by severe progressive liver disease and renal tubular dysfunction. HT1 is caused by pathogenic variants in the fumarylacetoacetate hydrolase gene (FAH), which encodes the last enzyme in the tyrosine catabolic pathway.

Tyrosinemia type 2 (Richner-Hanhart syndrome) is characterized by keratitis, palmoplantar hyperkeratosis, intellectual disability, and elevated blood tyrosine levels [104]. The disease is caused by deficiency in hepatic tyrosine aminotransferase (TAT).

Tyrosinemia type 3 is caused by deficiency of 4-hydroxyphenylpyruvate dioxygenase. It is an extremely rare disorder associated with hypertyrosinemia and elevated urinary excretion of 4-hydroxyphenyl derivatives. Affected patients have neurologic dysfunction, including ataxia, seizures, and mild psychomotor retardation, but no other systemic involvement.

Severe neurologic manifestations can occur in children with HT1. These are due to the accumulation of succinylacetone, which is a potent inhibitor of ALA dehydratase (porphobilinogen synthase) [105,106]. Thus, patients may have symptoms of ALA dehydratase porphyria. (See "ALA dehydratase porphyria".)

In one study of 48 children with tyrosinemia identified with neonatal screening, neurologic crises resembling the crises of the neuropathic porphyrias occurred in 20 (42 percent) [107]. These acute episodes of peripheral neuropathy were characterized by severe pain with extensor hypertonia (in 75 percent), vomiting or paralytic ileus (69 percent), muscle weakness (29 percent), and self-mutilation (8 percent). Eight children required mechanical ventilation because of paralysis. Between crises, most survivors regained normal function. Electrophysiologic studies in seven patients and neuromuscular biopsies in three patients showed axonal degeneration and secondary demyelination. (See "Disorders of tyrosine metabolism".)

Medical therapy with nitisinone therapy is the preferred treatment for most individuals with hereditary tyrosinemia type 1 [108,109]. Liver transplantation is typically used for patients who do not respond to nitisinone and those with hepatic malignancy.

Hereditary tyrosinemia is discussed in greater detail separately. (See "Disorders of tyrosine metabolism".)

SUMMARY

Friedreich ataxia – Friedreich ataxia is an autosomal recessive degenerative disorder associated with variants in the frataxin (FXN) gene. The major clinical manifestations include limb and gait ataxia, cardiomyopathy, and sensory neuropathy. (See 'Friedreich ataxia' above.)

Spinocerebellar ataxias – The spinocerebellar ataxias are a heterogeneous group of inherited disorders with different neuropathological profiles reflecting the degree of cerebellar and brainstem dysfunction or degeneration. A peripheral neuropathy is described in some subtypes (table 1A). (See 'Spinocerebellar ataxias' above.)

Infantile neuroaxonal dystrophy – Infantile neuroaxonal dystrophy is an autosomal recessive disorder that is classified as a form of neurodegeneration with brain iron accumulation (NBIA). Symptoms reflect involvement of the peripheral nerves, central nervous system, and autonomic nervous system (table 1B). The usual onset ranges from ages 1 to 3 years. Manifestations include motor and cognitive regression, hypotonia, cerebellar ataxia, dystonia, optic atrophy, and distal sensory loss. (See 'Infantile neuroaxonal dystrophy' above.)

Tangier disease – Tangier disease is an autosomal codominant condition in which homozygotes have no serum high-density lipoprotein (HDL) and heterozygotes have serum HDL concentrations of approximately one-half of those in unaffected individuals. Homozygotes develop cholesterol ester deposition in tonsils, liver, spleen, gastrointestinal tract, lymph nodes, bone marrow, and Schwann cells. The main clinical manifestations are orange tonsils, hepatosplenomegaly, and premature coronary disease; a debilitating neuropathy occurs in many patients. (See 'Tangier disease' above.)

Abetalipoproteinemia – Abetalipoproteinemia (Bassen-Kornzweig syndrome) is a rare autosomal recessive disorder that is characterized by defective assembly and secretion of apolipoprotein B (apo B) and apo B–containing lipoproteins. A spectrum of clinical manifestations can be seen (table 1B). All patients have neurologic manifestations such as retinitis pigmentosa, peripheral neuropathy, and ataxia. (See 'Abetalipoproteinemia' above.)

Refsum disease – Refsum disease is a disorder of peroxisomal function characterized by retinitis pigmentosa, peripheral polyneuropathy, cerebellar ataxia, and elevated cerebrospinal fluid protein concentration (table 1B). (See 'Refsum disease' above.)

Chediak-Higashi – Chediak-Higashi syndrome is an autosomal recessive disorder characterized by recurrent infections, partial albinism, hepatosplenomegaly, an increased risk of lymphoreticular malignancy, and multiple neurologic manifestations (table 1B). (See 'Chediak-Higashi syndrome' above.)

Lysosomal storage diseases – Lysosomal storage diseases are a group of approximately 36 heterogeneous enzyme deficiency disorders characterized by the accumulation of undigested macromolecules within lysosomes. Peripheral neuropathy often occurs in Fabry disease, Krabbe disease, metachromatic leukodystrophy, and Niemann-Pick disease (table 1C). (See 'Lysosomal storage diseases' above.)

Mitochondrial disorders – Defects in structure or function of mitochondria, mainly involving the oxidative phosphorylation, mitochondrial biogenesis, and other metabolic pathways, are associated with a wide spectrum of clinical phenotypes that may include peripheral neuropathy (table 1D). (See 'Mitochondrial disorders' above.)

DNA repair disorders – The DNA repair disorders are autosomal recessive disorders characterized by the inability to repair a particular type of DNA damage. Two of these disorders, xeroderma pigmentosum and the Cockayne syndrome, manifest a peripheral neuropathy (table 1D). (See 'DNA repair disorders' above.)

Hereditary tyrosinemia – Four autosomal recessive disorders result from deficiencies in specific enzymes in the tyrosine catabolic pathway; these are hereditary tyrosinemia (HT) types 1, 2, and 3, and alkaptonuria. Severe neurologic manifestations can occur in children with HT1, including acute episodes of peripheral neuropathy characterized by severe pain. (See 'Hereditary tyrosinemia' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Robert P Cruse, DO, who contributed to earlier versions of this topic review.

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