Spinal Muscular Atrophy, Distal, Autosomal Recessive, 1

A number sign (#) is used with this entry because autosomal recessive distal spinal muscular atrophy-1 (DSMA1), also referred to as spinal muscular atrophy with respiratory distress (SMARD1) and distal hereditary motor neuronopathy type VI (dHMN6 or HMN6), is caused by homozygous or compound heterozygous mutation in the IGHMBP2 gene (600502) on chromosome 11q13.

Biallelic mutations in the IGHMBP2 gene can also cause axonal Charcot-Marie-Tooth disease type 2S (CMT2S; 616155), a less severe neurologic phenotype.

For a general phenotypic description and a discussion of genetic heterogeneity of distal HMN, see HMN type I (HMN1; 182960).

Clinical Features

Mellins et al. (1974) and Bertini et al. (1989) delineated diaphragmatic spinal muscular atrophy (SMA) as a variant of infantile SMA (SMA1; 253300). The most prominent symptoms are severe respiratory distress resulting from diaphragmatic paralysis with eventration shown on chest x-ray and predominant involvement of the upper limbs and distal muscles. In contrast to classic SMA1, in diaphragmatic SMA the upper spinal cord is more severely affected than the lower section.

In a series of more than 200 patients with early-onset SMA, Rudnik-Schoneborn et al. (1996) found that approximately 1% presented with diaphragmatic SMA and did not have a deletion of the survival of motor neuron gene on chromosome 5q (see 600354).

Grohmann et al. (1999) reported on 9 patients from 3 families with diaphragmatic SMA following autosomal recessive inheritance. They referred to this disorder as SMARD (spinal muscular atrophy with respiratory distress). The 3 families were of Lebanese, German, and Italian origin, respectively. In family 1, the parents were first cousins. The first affected son died at the age of 10 weeks of suspected sudden infant death syndrome (SIDS; 272120). One daughter presented, at the age 6 weeks, with feeding difficulties and progressive respiratory distress. Chest x-ray showed eventration of the diaphragm. She developed progressive muscular atrophy with complete paralysis of the upper and lower limbs and mild contractures of the knee and ankle joints. Three other sibs died of respiratory failure at an early age. Autopsy specimens showed neurogenic atrophy of skeletal muscle without signs of reinnervation. The diameter of the anterior of the spinal roots was reduced in the upper spinal cord. The remaining motor neurons showed chromatolysis. In family 2, the first affected child had severe muscular hypotonia and died at the age of 9 weeks of cardiorespiratory failure. A third child had been mechanically ventilated since the age of 3 months. Family 3 had been reported in detail by Novelli et al. (1995),

Grohmann et al. (2003) reported the clinical features of 29 infants with SMARD1, confirmed by mutation in the IGHMBP2 gene. Intrauterine growth retardation, prematurity, weak cry, and foot deformities were the earliest symptoms. Most patients presented at the age of 1 to 6 months with severe respiratory distress due to diaphragmatic paralysis, and progressive muscular weakness with predominantly distal lower limb muscle involvement. Sensory and autonomic nerves were also affected in some patients, as demonstrated by decreased pain perception, excessive sweating, constipation, and bladder incontinence.

Pitt et al. (2003) reported 13 infants with early-onset diaphragmatic palsy in association with a progressive axonal neuropathy who showed similar characteristics. The authors stated that none of the patients shared the exact characteristics of patients with SMARD1, most notably the absence of pathologic changes in anterior horn cells of 1 patient examined. Pitt et al. (2003) developed a set of diagnostic criteria to classify the syndrome, including low birth weight (below the third percentile), onset within the first 3 months of life, early onset of respiratory compromise with ventilator dependence and inability to wean, slow motor nerve conduction velocities, and a general decrease in the size of myelinated fibers on sural nerve biopsy. All of 8 patients tested were found to have mutations in the IGHMBP2 gene, indicating that a broader spectrum of phenotypic features may be associated with mutations in that gene.

Joseph et al. (2009) reported a sister and brother with very different phenotypic manifestations of SMARD1 despite having the same compound heterozygous mutations in the IGHMBP2 gene. The older less affected sister showed onset of delayed motor development and distal muscle weakness after 1 year of age. She had respiratory weakness and recurrent chest infections with nocturnal hypoventilation, as well as feeding difficulties necessitating gastrostomy insertion. At age 13 years, she remained clinically stable but was wheelchair-bound and showed profound muscle weakness affecting both proximal and distal muscles. In contrast, her younger brother showed respiratory insufficiency at age 4 months. This was followed by progressive distal lower limb weakness and evidence of widespread denervation. He died at age 6 months from respiratory failure. Joseph et al. (2009) suggested that compensatory mechanisms may play a role in modifying the phenotype of SMARD1.

Diagnosis

Guenther et al. (2007) used the mathematical algorithm of hierarchical cluster analysis to determine appropriate clinical criteria that would predict SMARD1 due to mutations in the IGHMBP2 gene. Among 141 patients with a phenotype of respiratory distress and spinal muscular atrophy, 47 (33%) were found to have IGHMBP2 mutations. Manifestation of respiratory failure between 6 weeks and 6 months and either the presence of diaphragmatic eventration or preterm birth predicted the presence of IGHMBP2 mutations with 98% sensitivity and 92% specificity. However within the SMARD1-confirmed patient group, 2 patients manifested before age 6 weeks and 4 after age 6 months.

Mapping

In an affected family reported by Novelli et al. (1995), linkage to SMA1 on chromosome 5q was excluded.

Grohmann et al. (1999) confirmed that in their first 2 families there was no linkage to the SMA locus on 5q. They also excluded human 1q and 7p, which are orthologous regions corresponding to the murine pmn gene region. Genomewide linkage scanning of family 1 revealed linkage of diaphragmatic SMA only to markers on 11q13-q21. Consistent with parental consanguinity, all affected sibs in family 1 were homozygous for all markers within the cosegregating segment on chromosome 11. In family 2, the affected sibs shared 2 identical parental haplotypes in the SMARD cosegregating segment on 11q13-q21, a finding that supported the assignment of the SMARD locus to that region. In family 3, however, haplotype analysis was inconsistent with linkage to the markers tested, thus excluding the SMARD locus in that family.

Molecular Genetics

Grohmann et al. (2001) demonstrated that SMARD type 1 results from mutations in the gene encoding immunoglobulin mu-binding protein 2 (IGHMBP2; 600502.0001). In 6 SMARD1 families, Grohmann et al. (2001) detected 3 recessive missense mutations, 2 nonsense mutations, 1 frameshift deletion, and 1 splice donor site mutation. Mutations in mouse Ighmbp2 have been shown to be responsible for spinal muscular atrophy in the 'neuromuscular degeneration' (nmd) mouse, whose phenotype resembles the SMARD1 phenotype (see ANIMAL MODEL).

Among 29 infants with SMARD1, Grohmann et al. (2003) identified 26 novel mutations in the IGHMBP2 gene, including 14 missense, 6 nonsense, 4 frameshift, 1 in-frame deletion, and 1 frameshift insertion.

In a patient from a nonconsanguineous Italian family who had SMARD1 with juvenile onset of respiratory distress, Guenther et al. (2004) identified compound heterozygosity for a missense mutation and a large genomic rearrangement of the IGHMBP2 gene (600502.0008 and 600502.0009, respectively).

Associations Pending Confirmation

For discussion of a possible association between a phenotype similar to SMARD and homozygous variation in the REEP1 gene, see 609139.0007.

Pathogenesis

Guenther et al. (2009) purified catalytically active recombinant IGHMBP2 and found that it functioned as an ATP-dependent 5-prime-to-3-prime helicase that unwound RNA and DNA duplexes in vitro. IGHMBP2 localized predominantly to the cytoplasm of neuronal and nonneuronal cells and associated with ribosomes. DSMA1-causing amino acid substitutions in IGHMBP2 did not affect ribosome binding, but they severely impaired ATPase and helicase activity. The authors proposed that IGHMBP2 is functionally linked to translation and that mutations in its helicase domain interfere with this function in DSMA1 patients.

Animal Model

The 'nmd' mouse mutation causes progressive degeneration of spinal motor neurons and muscle atrophy. Cox et al. (1998) identified the mutated gene in the nmd mouse as the putative transcriptional activator and ATPase/DNA helicase previously described as Smbp2 or Catf1. In addition, Cox et al. (1998) found that the nmd phenotype is attenuated in a semidominant fashion by a major genetic locus on mouse chromosome 13.

The 'pmn' mouse presents with progressive motor neuropathy and a disorder that closely resembles diaphragmatic SMA (Schmalbruch et al., 1991). The pmn locus maps to murine chromosome 13 (Brunialti et al., 1995).