Neuropathy, Hereditary Sensory And Autonomic, Type Iia

A number sign (#) is used with this entry because hereditary sensory and autonomic neuropathy type IIA (HSAN2A) can be caused by mutation in the HSN2 isoform of the WNK1 gene (WNK1/HSN2; see 605232) on chromosome 12p13.

HSAN2B (613115) is caused by mutation in the FAM134B gene (613114). For a discussion of genetic heterogeneity of HSAN, see HSAN1 (162400).

Clinical Features

Giaccai (1952) reported 'neurogenic acroosteolysis' in 4 children born of an Arab man who married 2 first cousins. By the first wife, 1 of the children was affected, and by the second wife, 3 of 5 children were affected. Since the spinal cord was normal at autopsy, Giaccai (1952) concluded that the abnormality resided in peripheral sensory nerves. Heller and Robb (1955) described a French Canadian family in which 5 members had the full form of hereditary sensory neuropathy and 3 had an incomplete form, suggesting autosomal dominant inheritance. No amyloid was found on dorsal root ganglion biopsy. Heller and Robb (1955) suggested that the disease was the same as Morvan disease. The patient reported by Ogden et al. (1959) as having progressive sensory radicular neuropathy of Denny-Brown (HSAN1) may have had neurogenic acroosteolysis because symptoms began as early as 1 year and the parents were first cousins.

Biemond (1955) described 11-year-old fraternal twins (male and female) with loss of pain sensation, diminished touch and temperature sense, and absent tendon reflexes. Postmortem examination showed deficient development in the posterior root ganglia, gasserian ganglion, posterior roots, posterior horns of the spinal gray matter, and posterior columns. The spinothalamic tracts could not be demonstrated. In a child with sensory and autonomic dysfunction, Freytag and Lindenberg (1967) found decreased posterior ascending tracts, severe reduction in the number of neurons in peripheral sensory and autonomic ganglia, and hypoplasia of the pyramidal tracts.

Johnson and Spalding (1964) described a slowly progressive sensory neuropathy in 2 unrelated boys, aged 10 and 15 years, each of whom had consanguineous parents. The disorder began in early childhood and involved all modalities of sensation with no disturbance of motor or autonomic function. Involvement was predominantly distal with late involvement of the trunk, and resulted in loss of digits and Charcot joints at the ankles. Johnson and Spalding (1964) differentiated the disorder from congenital indifference to pain (147430, 243000) by the involvement of all sensory modalities, preservation of proximal sensation, including pain, loss of tendon reflexes, gradual progression, and peripheral nerve degeneration, and from autosomal dominant HSN1 by the recessive mode of inheritance, early age of onset, and ultimate involvement of the trunk.

Haddow et al. (1970) described a brother and sister, offspring of nonconsanguineous parents, with a nonprogressive sensory defect leading to extensive damage of the fingers. The patients had low spinal fluid protein and had suffered from unexplained chronic diarrhea in early life. The mother was Irish and the father was French Canadian. Haddow et al. (1970) suggested that the disorder in the French Canadian family described by Hould and Verret (1967) was the same, although onset in that family was not until the middle of the first decade. Ohta et al. (1973) reported further on the family described by Hould and Verret (1967). They suggested that the families of Schoene et al. (1970), Ogryzlo (1946), and Parks and Staples (1945) had the same condition. Ohta et al. (1973) suggested the designation 'hereditary sensory neuropathy type II,' giving the name of type I to the dominant disorder.

Murray (1973) reported 2 daughters of first cousins with a recessive form of congenital sensory neuropathy. Impairment of pain, temperature, and touch sensations in varying degrees affected the limbs and trunk. The disorder was thought to be nonprogressive and perhaps caused by a failure of sensory nerve formation rather than by sensory nerve degeneration. Murray (1973) noted that those affected with the disorder often developed painless finger and toe ulcerations which consequently led to damage to the underlying bone. Some patients also developed neuropathic joint degeneration. Murray (1973) compiled 33 cases of congenital sensory neuropathy from the literature, 20 of whom were from 6 families.

Jedrzejowska and Milczarek (1976) reported light and electron microscopic findings in the sural nerve from a patient with HSAN2. There was a marked reduction in the number of myelinated fibers due to Wallerian-like axonal degeneration, as well as segmental demyelination, most likely secondary to axonal changes. The authors suggested a progressive nature of the pathologic process.

Sirinavin et al. (1982) reported a 12-year-old Cambodian girl with digital clubbing and joint and leg pain with swelling. Acroosteolysis of the distal phalanges was accompanied by profuse hyperhidrosis of the hands and feet and thickening of soft tissues around the knees and ankles, giving a cylindrical appearance to the legs; these associated features suggested pachydermoperiostosis (167100) to the authors. However, the periosteum showed no radiologic changes and the 'clubbing,' was more suggestive of foreshortening due to collapse of the distal phalanges, similar to that seen in chronic uremia. There was generalized osteoporosis and the bones of the calvaria were thin with a single small wormian bone in the lambdoidal suture; these features suggested Cheney syndrome (102500), but the fact that the parents were first cousins favored recessive inheritance for the disorder in this patient.

Sugiura and Sengoku (1986) reported 2 kindreds with 4 affected persons. In the first family, the parents were consanguineous and had 2 affected children; in the second family, second cousins were affected. The authors suggested that the disorder referred to as the recessive form of hereditary sensory radicular neuropathy is the same as the Giaccai type of acroosteolysis. Bockers et al. (1989) observed 3 sibs in a Turkish family who developed progressive foot drop between ages 7 and 12 years and ulcers on the lateral edge of the feet. Hyperkeratotic plaques, erosions, and ulcers of the fingers developed in 1 patient at the age of 11 years. The fingers showed ainhum-like constriction bands and spontaneous amputations. Osteomyelitis and osteolysis led to amputations. A high urinary excretion of sphingomyelin and lecithin suggested that the pathogenetic mechanism might be a disorder of phospholipid metabolism. Two of the patients showed the rare blood group O (Bombay); see 211100.

Lafreniere et al. (2004) reported 5 families with HSAN2, including the large family from Newfoundland originally reported by Ogryzlo (1946). Beginning in early childhood, affected individuals experienced numbness in the hands and feet, aggravated by cold, together with reduced sensation to pain. They experienced loss of touch, pain, and temperature, with touch most severely affected. The loss was predominantly distal, extending from the elbows to the fingertips and from just above the knees down to the toes, a pattern of distribution often described as 'glove and stocking.' The lower limbs were typically more severely affected than the upper limbs, and the trunk was involved in some patients. Ulceration and infections caused spontaneous amputation of digits and surgical amputation of lower limbs. There was no overt autonomic dysfunction; sweating and tearing were within normal range, and postural hypotension was not present. As in the other hereditary sensory neuropathies, there was absence of axon flare after intradermal histamine, indicating defective nociceptive fibers. Biopsy showed a severe loss of myelinated axons, some loss of nonmyelinated fibers in the sural nerve, and the absence of cutaneous sensory receptors and nerve fibers.

Mapping

By linkage analysis of 8 affected members from the consanguineous multigenerational Newfoundland pedigree reported by Ogryzlo (1946), and an additional family with 2 affected members, Lafreniere et al. (2004) mapped the HSAN2 disease locus to 12p13.33 (maximum lod score of 8.4).

Molecular Genetics

Among 5 families with HSAN2, including those from Newfoundland reported by Ogryzlo (1946) and patients from rural Quebec and Nova Scotia, Lafreniere et al. (2004) identified 3 different truncating mutations in the HSN2 isoform of the WNK1 gene (605232.0003-605232.0005)

In 4 affected members of a large consanguineous Lebanese family with HSAN2, Riviere et al. (2004) identified a homozygous 1-bp deletion in the HSN2 isoform of the WNK1 gene (605232.0006).

In 16 patients from 13 HSAN2 families originating from southern Quebec, Roddier et al. (2005) identified 2 HSN2 founder mutations: 56% of patients were homozygous for a nonsense mutation (Q315X; 605232.0005), 6% were homozygous for a 1-bp insertion (918insA; 605232.0004), and 38% were compound heterozygous for the 2 mutations.

In a Korean man with HSAN2, Cho et al. (2006) identified compound heterozygosity for 2 mutations in the HSN2 isoform of the WNK1 gene (605232.0008 and 605232.0009).

Coen et al. (2006) reported 3 unrelated patients with HSAN2 from Italy, Austria, and Belgium, respectively. All had compound heterozygous or homozygous truncating mutations in the HSAN2 gene resulting in complete loss of protein function. All patients had early onset of a severe sensory neuropathy with mutilating acropathy but without autonomic dysfunction. Muscle strength was preserved.

In a girl with HSAN2, Shekarabi et al. (2008) identified compound heterozygosity for 2 mutations in the WNK1 gene: 1 in the WNK1/HSN2 isoform (605232.0010) and 1 in the WNK1 isoform (605232.0011). She did not have hypertension. The authors noted that all recessive mutations associated with the HSAN2 phenotype resulted in truncations of the WNK1/HSN2 nervous system-specific protein. Disease-causing mutations in WNK1 resulting in pseudohypoaldosteronism type 2 (PHA2C; 614492) were large, heterozygous intronic deletions that increase the gene expression. This impact on the expression level in PHA2C patients may explain the absence of hypertension in individuals affected with HSAN2, as the expression of the WNK1 isoform in which the HSN2 exon is not incorporated should not be affected. The findings in their patient suggested that 1 mutation in the HSN2 exon is sufficient to cause the HSAN2 phenotype when combined with a mutation in WNK1 on the other allele. Moreover, homozygous mutations disrupting WNK1 isoforms without HSN2 may be lethal, which would explain why all loss-of-function mutations reported to date have been located in the HSN2 exon.

Population Genetics

Clustering of cases of HSAN II in eastern Canada was reported by Murray (1973) and had first been noted in Newfoundland in the early 1900s. The original family members came from Dorset, United Kingdom, approximately 100 years earlier, as part of a mass migration of Protestant settlers from southwestern England and Roman Catholic settlers from southern Ireland (Lafreniere et al., 2004).

Roddier et al. (2005) reported that 12 of 16 patients with HSAN2 originated from the Lanaudiere region of Quebec, along the Saint Lawrence River, that was first settled by the French during the second half of the 17th century. Several of the families were consanguineous, and several of the families were distantly related. The affected family reported by Heller and Robb (1955) also originated from the Lanaudiere region. The regional carrier frequency for the identified Q315X and 918insA mutations was estimated at 1 in 116 and 1 in 260, respectively.