Spinal Muscular Atrophy, Distal, Autosomal Recessive, 3

Description

Distal spinal muscular atrophy (DSMA), also known as distal hereditary motor neuronopathy (dHMN or HMN), is characterized by distal muscle weakness and wasting without significant sensory involvement. For a general phenotypic description and a discussion of genetic heterogeneity of distal SMA, see HMN1 (182960).

Harding (1993) classified autosomal recessive distal hereditary motor neuronopathy as dHMN IV (HMN4) and dHMN III (HMN3). Both have juvenile onset and differ only by less severe involvement in HMN3. However, Viollet et al. (2004) reported an extended Lebanese kindred in which both HMN III and HMN IV occurred, suggesting that the same gene was involved in both phenotypes (see Irobi et al., 2006).

Clinical Features

Pearn and Hudgson (1979) reported 12 patients from 8 kindreds with autosomal recessive distal spinal muscular atrophy. They estimated that DSMA accounted for about 10% of all patients with SMA in a population in northeast England. Clinically, the condition was relatively benign, although progressive. Eight patients had onset in infancy or early childhood (range 4 months to 3 years), and 4 had onset in adulthood (17 to 30 years).

In a large inbred Lebanese family with 3 major branches, Viollet et al. (2002) described multiple members affected by autosomal recessive chronic distal SMA. One of the patients had previously been reported by Pearn and Hudgson (1979). Five affected children studied had at least 1 common ancestor. Five patients were described in detail. One was considered normal at birth and during her first 2 months of life. Subluxation of the right hip was then detected. At the age of 9 months, her legs appeared to move poorly, and generalized hypotonia was recognized. At the age of 2 years, neurologic examination showed generalized motor weakness predominating in the distal part of the limbs. Motor nerve conduction velocity was normal in the distal nerves, as were distal sensory action potentials and sensory nerve conduction velocity. At the age of 6 years, lower limb weakness was stable, but she had bilateral hip subluxation and genu recurvatum. Respiratory function was normal, but a chest x-ray showed an unusually high right hemidiaphragm. A second patient, a boy, had similar onset but retained walking ability until the age of 12 years; he became wheelchair-bound after a knee fracture. At the age of 30 years, he showed severe decrease in vital capacity on measurement of respiratory function, and chest x-ray showed elevation of both hemidiaphragms, strongly suggesting bilateral diaphragmatic paralysis. At the time of the report, he used a computer keyboard to write because of hand paralysis. The third patient described by Viollet et al. (2002), a younger brother of the second patient, was able to walk at the age of 1 year, but at 2 years of age foot paralysis similar to that found in his brother occurred. At the age of 28 years, he was unable to stand up from a sitting position, but could still walk with aid. A fourth patient was seen at the age of 43 years. He had had normal motor development during infancy and childhood and practiced several sports, including water, sky, and scuba diving, until the age of 26 years. From the age of 23 years, however, he experienced progressive worsening of weakness in the lower limbs and showed spindly legs, slight foot drop contracture, and inability to walk on the heels. Respiratory function was normal and fluoroscopy showed normal position of both hemidiaphragms. The fifth patient underwent her first neurologic examination at the age of 19 years for lower back pain. At that time, physical examination showed definite atrophy of her feet and, to a lesser extent, of her hands. SMA was suspected and was confirmed when she was 26 years old, both by muscle biopsy showing denervation atrophy and by electromyography. At the age of 38 years, she was able to write and was not limited in her ability to walk or climb stairs, but she had a waddling gait. Respiratory function was normal and no diaphragmatic paralysis was detected.

Mapping

In the Lebanese family they reported, Viollet et al. (2002) tested for linkage to chromosome 11q because of clinical similarities to SMA with respiratory distress-1 (SMARD1; 604320), which is caused by mutations in the IGHMBP2 gene (600502) on chromosome 11q13. They found that the disorder in the Lebanese family mapped to a 10-cM interval between D11S1889 and D11S1321 (maximum lod score of 4.59 at locus D11S4136), which encompasses the IGHMBP2 gene; however, genotype analysis failed to detect any mutations in the IGHMBP2 gene in these patients, suggesting that SMARD1 and the chronic distal SMA in the Lebanese family may be caused by a different gene located in the same chromosomal region. The high degree of intrafamilial variability in age at onset raised the possibility of nonallelic modifying genes involved in this disorder.

Using homozygosity mapping to analyze 12 European families with distal SMA, Viollet et al. (2004) narrowed the disease locus to a 2.6-cM interval between D11S1314 and D11S916 on chromosome 11q13.3 (maximum lod score of 6.6), which definitively excluded the IGHMBP2 gene. The locus is referred to here as DSMA3.