Spinal Muscular Atrophy, Distal, Autosomal Recessive, 2

A number sign (#) is used with this entry because of evidence that autosomal recessive distal spinal muscular atrophy-2 (DSMA2) is caused by homozygous mutation in the SIGMAR1 gene (601978) on chromosome 9p13. One such family has been reported.

Description

Distal spinal muscular atrophy-2 is an autosomal recessive neuromuscular disorder characterized by onset of distal muscle weakness and wasting affecting the lower and upper limbs in the first decade; there is no sensory involvement (summary by Li et al., 2015).

For a general phenotypic description and a discussion of genetic heterogeneity of DSMA, see HMN1 (182960).

Clinical Features

Christodoulou et al. (2000) identified a novel form of autosomal recessive distal hereditary motor neuropathy in 27 patients belonging to a cluster of 7 consanguineous families from neighboring villages of the Jerash region of Jordan. Onset of the disease occurred between ages 6 and 10 years and was characterized by weakness and atrophy of the lower limbs associated with pyramidal features. Within 2 years, symptoms progressed to the upper limbs. Neurophysiologic studies typically showed normal conduction velocities, reduced compound motor action potential amplitudes, normal sensory nerve action potentials, and chronic neurogenic changes on needle electromyography (EMG). No significant abnormalities were seen on sural nerve biopsy.

Li et al. (2015) reported a consanguineous Chinese family in which 3 individuals had onset of distal muscular atrophy and weakness first affecting the lower limbs between 9 and 12 years of age. All had pes varus and foot drop. Upper limb involvement occurred later; at least 1 patient had claw hands. Ankle reflexes were absent, knee reflexes were hyperactive, and 2 patients had extensor plantar responses. There was no sensory impairment. The disorder was progressive until about age 20 years, and remained stable thereafter. All patients functioned independently in mid-adulthood. EMG performed in 1 patient showed distal denervation, and nerve conduction studies showed reduced motor nerve conduction velocity as well as reduced compound muscle action potential (CMAP). Sural nerve biopsy, performed in 1 patient, was normal.

Inheritance

The transmission pattern of DSMA2 in the family reported by Li et al. (2015) was consistent with autosomal recessive inheritance.

Mapping

By linkage analysis, Christodoulou et al. (2000) mapped the Jerash type of HMN, referred to here as DSMA2, to a region of approximately 0.54 cM on 9p21.1-p12. A maximum lod score of 19.80 at theta = 0.001 was obtained between the disorder and locus D9S1878.

Molecular Genetics

In 3 members of a consanguineous Chinese family with DSMA2, Li et al. (2015) identified a homozygous splice site mutation in the SIGMAR1 gene (601978.0003). The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. In vitro functional expression assays in HEK293 cells showed that the mutation resulted in reduced levels of the protein due to increased proteasomal degradation through the endoplasmic reticulum-associated degradation (ERAD) pathway. The mutant cell lines showed increased ER stress and apoptosis compared to wildtype. Li et al. (2015) noted that the SIGMAR1 gene is within the candidate region identified by Christodoulou et al. (2000) and suggested that those families should undergo testing for SIGMAR1 mutations.

Animal Model

Mavlyutov et al. (2010) found that Sigmar1-null mice had impaired motor coordination and function on the rotorod test compared to wildtype mice. Knockout mice also showed motor differences compared to wildtype mice in a swimming test: knockout mice used their tails, but not their front paws, whereas wildtype mice used their front paws and not their tails.

Bernard-Marissal et al. (2015) found that Sigmar1-null mice had motor deficits and muscle weakness associated with denervation at the neuromuscular junction and loss of motor neurons in the spinal cord; fast motor neurons and muscle fibers were particularly affected. Motor neurons derived from Sigmar1-null mice showed a decrease in the ER-mitochondria connection compared to wildtype, suggesting a disruption of mitochondria-associated membranes (MAMs). Mutant cells showed defective calcium signaling as well as disrupted intracellular calcium homeostasis and increased ER stress, resulting in motor neuron and axonal degeneration. Additional findings included abnormal mitochondrial morphology in motor neurons and disruption of mitochondrial axonal transport. Intracellular calcium scavenging and ER stress inhibition were able to restore mitochondrial function and prevent motor neuron degeneration.