Neuropathy, Hereditary Sensory And Autonomic, Type Ia

A number sign (#) is used with this entry because hereditary sensory neuropathy type IA (HSAN1A) is caused by heterozygous mutation in the SPTLC1 gene (605712) on chromosome 9q22.

Description

The hereditary sensory and autonomic neuropathies (HSAN), which are also referred to as hereditary sensory neuropathies (HSN) in the absence of significant autonomic features, are a genetically and clinically heterogeneous group of disorders associated with sensory dysfunction.

HSAN1 is a dominantly inherited sensorimotor axonal neuropathy with onset in the first or second decades of life.

Genetic Heterogeneity of Hereditary Sensory and Autonomic Neuropathy

See also HSAN1C (613640), caused by mutation in the SPTLC2 gene (605713) on 14q24; HSN1D (613708), caused by mutation in the ATL1 gene (606439) on 14q; HSN1E (614116), caused by mutation in the DNMT1 gene (126375) on 19p13; HSN1F (615632), caused by mutation in the ATL3 gene (609369) on 11q13; HSAN2A (201300), caused by mutation in the HSN2 isoform of the WNK1 gene (605232) on 12p13; HSAN2B (613115), caused by mutation in the FAM134B gene (613114) on 5p15; HSN2C (614213), caused by mutation in the KIF1A gene (601255) on 2q37; HSAN2D (see 243000), caused by mutation in the SCN9A gene (603415) on 2q24; HSAN3 (223900), caused by mutation in the IKBKAP gene (603722) on 9q31; HSAN4 (256800), caused by mutation in the NTRK1 gene (191315) on 1q23; HSAN5 (608654), caused by mutation in the NGF gene (162030) on 1p13; HSAN6 (614653), caused by mutation in the DST gene (113810) on 6p; HSAN7 (615548), caused by mutation in the SCN11A gene (604385) on 3p22; and HSAN8 (616488), caused by mutation in the PRDM12 gene (616458) on chromosome 9q34.

Adult-onset HSAN with anosmia (608720) is believed to be another distinct form of HSAN, and HSAN1B (608088) with cough and gastroesophageal reflux maps to chromosome 3p24-p22.

Clinical Features

Hicks (1922) described an English family in which 10 members suffered from perforating ulcers of the feet, shooting pains, and deafness. Age of onset ranged from 15 to 36 years. Presentation was usually with a corn on a big toe followed by a painless ulcer with bony debris. Patients later experienced shooting pains similar to the lightning pains of tabes dorsalis and developed bilateral deafness progressing to total deafness over several years. Neurologic examination showed disappearance of ankle and knee jerks and absence of an extensor plantar response. There was loss of pain, touch, heat, and cold sensation over the feet, but sensation of the arms remained normal. Cranial nerves were normal, with the exception of the auditory nerve, pupils reacted normally, and there was no nystagmus. Hicks (1922) noted that although hereditary perforating ulcers of the feet had been reported in patients in the past, there had been no previous mention of accompanying deafness or shooting pains. Denny-Brown (1951) reported the clinical and autopsy findings of a 53-year-old woman who was a member of the family reported by Hicks (1922). When she was 22 years of age, an ulcer formed on her right great toe, requiring a year to heal. She subsequently suffered from recurrent ulceration, each episode lasting 6 to 9 months and sometimes extending to bone. In her early twenties, she first noticed shooting pains in her legs, sometimes in her arms. Deafness began at the age of 40 years and progressed to almost total deafness by 53 years of age. Neurologic examination at 53 years of age showed loss of all sensation in the lower legs, with loss of pain and temperature sensation in the thighs and hands. Autopsy showed a small brain and marked loss of ganglion cells in the sacral and lumbar dorsal root ganglia. Remaining ganglion cells showed proliferation of subcapsular dendrites and hyaline bodies, possibly representing an amyloid mass around capillaries. There were less severe changes in C-8 and T-1 ganglia. The affected families reported by Ervin and Sternbach (1960) and Silverman and Gilden (1959) appeared to show autosomal dominant inheritance. Mandell and Smith (1960) observed sensory radicular neuropathy in 3 generations of a family. Clinical features included neuropathic arthropathy, recurrent ulceration of the lower extremities, and signs of radicular sensory deficiency in both the upper and the lower extremities without any motor dysfunction. Dyck et al. (1965) described a family with sensory neuropathy accompanied by peroneal muscular atrophy and pes cavus. Campbell and Hoffman (1964) and DeLeon (1969) also reported cases in which amyotrophy was a feature. Using a cholinesterase technique on skin biopsies from the pad of the great toe of affected persons, Dyck et al. (1965) found normal numbers of Meissner corpuscles in a 14-year-old boy with early signs suggestive of the disorder, but no corpuscles in a 37-year-old man and a 28-year-old woman with well-developed disease.

Dyck et al. (1983) noted that 'burning feet' may be the only manifestation of dominantly inherited sensory neuropathy. The symptoms are ameliorated by cold and aggravated by heat. Restless legs and lancinating pain are other presentations of the disorder, which often resulted in severe distal sensory loss, mutilating acropathy, and neurotrophic arthropathy.

In a detailed clinical study of a patient with HSN1, including audiometric testing, autonomic functions, electromyography, transcranial magnetic stimulation, and brain imaging, Hageman et al. (1992) determined that there were no signs of central nervous system involvement and stated that HSN1 is a disorder of the dorsal root ganglia and peripheral nerves.

Wallace (1968, 1970) studied an extensively affected Australian kindred. In a study of this kindred and 3 other Australian kindreds with HSAN1, Nicholson et al. (1996) found that a typical history included lightning pains, painless skin injuries and ulceration, and signs including distal sensory loss to sharp, hot, and cold sensation, with loss of distal reflexes and distal muscle wasting. Nerve conduction velocities showed an axonal neuropathy, particularly of the lower limbs.

Dubourg et al. (2000) reported a French family with autosomal dominant hereditary sensory neuropathy suggestive of linkage to chromosome 9q. Mean age at onset was 34 years. All patients presented with distal sensory loss and distal muscle weakness of both the upper and lower limbs. Four patients had foot ulcerations, and 3 patients had hyperhidrosis. Motor nerve conduction velocities were normal or mildly decreased, consistent with an axonal neuropathy. Sensory nerve action potentials were either reduced or could not be recorded.

Clinical Variability

Rotthier et al. (2009) reported a French Gypsy patient with an unusually severe form of HSAN1. The patient had congenital onset, insensitivity to pain with eschar and foot ulceration, pes cavus/equinovarus, vocal cord paralysis, and gastroesophageal reflux. The patient also had severe growth and mental retardation, microcephaly, hypotonia, amyotrophy, and respiratory insufficiency. Nerve conduction studies showed absent sensory and motor responses in the upper and lower limbs. Genetic analysis identified a de novo heterozygous mutation in the SPTLC1 gene (S331F; 605712.0005). The phenotype expanded the clinical spectrum of HSAN1.

Mapping

Nicholson et al. (1996) undertook a genomewide linkage screen in 4 Australian kindreds with hereditary sensory neuropathy, including 1 family that had been reported by Jackson (1949) and followed up by Wallace (1968, 1970). Nicholson et al. (1996) found that the disease locus, which they symbolized HSN1, mapped to an 8-cM region flanked by D9S318 and D9S176 on 9q22.1-q22.3. Multipoint linkage analysis suggested a most likely location at D9S287, within a 4.9-cM confidence interval.

Blair et al. (1997) refined the mapping of HSN1 to a 3- to 4-cM interval within the 9q22.1-q22.3 region, and excluded GAS1 (139185) and XPA (611153) as candidate genes. Using composite mapping data, Blair et al. (1998) estimated the HSN1 critical region, flanked by D9S1781 and FB19B7, at 3 to 4 Mb.

Pathogenesis

In studies of Chinese hamster ovary (CHO) cells and yeast, Gable et al. (2010) demonstrated that the mutant SPTLC1 C133W protein (605712.0002) provided sufficient SPT activity to support growth, although total enzyme activity was only 10 to 20% of wildtype. Yeast and CHO cells expressing the C133W mutant along with SPTLC2 (605713) and SSSPTA (613540) or SSSPTB (610412) showed a preferential condensation of palmitoyl-CoA to alanine rather than serine. These results were not found with wildtype SPTLC1. Kinetic studies showed that the mutant protein had the same affinity to serine as the wildtype protein, but a lower Vmax for serine. These results suggested that the mutation perturbs the active site of the protein, facilitating the formation of alanine condensation products. However, small increases in extracellular serine levels were able to inhibit the reaction with alanine. The palmitoyl-CoA/alanine product, 1-deoxysphinganine (1-deoxySa), was shown to increased endoplasmic reticulum stress and the unfolded protein response, which may ultimately be toxic to neurons. Gable et al. (2010) concluded that their findings were consistent with a gain of function that is responsible for the HSAN1 phenotype.

SPT catalyzes the condensation of serine and palmitoyl-CoA, the initial step in the de novo synthesis of sphingolipids. Penno et al. (2010) showed that HSAN1A-related mutations in the SPTLC1 gene induced a shift in the substrate specificity of SPT, which leads to the formation of 2 atypical deoxysphingoid bases: 1-deoxysphinganine from condensation with alanine and 1-deoxymethylsphinganine from condensation with glycine. Neither of these metabolites can be converted to complex sphingolipids or degraded, resulting in their intracellular accumulation. These atypical agents showed pronounced neurotoxic effects on neurite formation in cultured sensory neurons, and was associated with disturbed neurofilament structure. Penno et al. (2010) found increased levels of these atypical agents in lymphocytes and plasma of HSAN1A patients with different SPTLC1 mutations. The findings indicated that HSAN1 results from gain-of-function mutations that cause the formation of atypical and neurotoxic sphingolipid metabolites, rather than from lack of de novo sphingolipid synthesis.

Population Genetics

Nicholson et al. (2001) found that 3 Australian families of English extraction and 3 English families with HSAN1A had the same SPTLC1 mutation (605712.0002), the same chromosome 9 haplotype, and the same phenotype. They therefore concluded that the Australian and English families had the same founder who, on the basis of historical information, lived in southern England before 1800. The phenotype caused by this mutation is the same as that in the English families of Campbell and Hoffman (1964) and possibly in the original English family of Hicks (1922).

Molecular Genetics

In all affected members of 11 HSN1 families, Dawkins et al. (2001) identified mutations in the SPTLC1 gene (C133Y, 605712.0001; C133W, 605712.0002; V144D, 605712.0003). Bejaoui et al. (2001) independently identified 2 of the same SPTLC1 mutations in 2 unrelated families with HSN1.

In twin sisters with HSN1 from a Belgian family originally reported by Montanini (1958), Verhoeven et al. (2004) identified a mutation in the SPTLC1 gene (G387A; 605712.0004).

The findings of Hornemann et al. (2009) cast doubt on the pathogenicity of the G387A mutation. By in vitro functional expression assays in HEK293 cells, Hornemann et al. (2009) found that none of the 4 SPTLC1 mutations, C133Y, C133W, V144D, or G387A, interfered with formation of the SPT complex. The first 3 mutant proteins resulted in 40 to 50% decreased SPT activity, but the G387A protein showed no effect on SPT activity. Further studies showed that the G387A protein could rescue a SPTLC1-deficient cell line. Finally, Hornemann et al. (2009) identified an unaffected woman who was homozygous for the G387A mutation, suggesting that it is not pathogenic. Hornemann et al. (2009) postulated that the G387A variant, and perhaps the other 3 SPTLC1 variants previously associated with HSN1, may not be directly disease-causing, but rather have an indirect or bystander effect by increasing the risk for HSN1 in conjunction with another mutation.