Spinal Muscular Atrophy With Progressive Myoclonic Epilepsy

A number sign (#) is used with this entry because spinal muscular atrophy with progressive myoclonic epilepsy (SMAPME) is caused by homozygous or compound heterozygous mutation in the ASAH1 gene (613468) on chromosome 8p22.

Description

Spinal muscular atrophy with progressive myoclonic epilepsy is an autosomal recessive neuromuscular disorder characterized by childhood onset of proximal muscle weakness and generalized muscular atrophy due to degeneration of spinal motor neurons, followed by the onset of myoclonic seizures. The disorder is progressive, and usually results in loss of ambulation and early death from respiratory insufficiency (summary by Zhou et al., 2012).

Clinical Features

Haliloglu et al. (2002) reported a consanguineous Turkish family in which 3 sibs had childhood-onset spinal muscular atrophy and progressive myoclonic epilepsy. The children presented between ages 2 and 5 years with difficulty walking, frequent falls, and tremor. Physical examination showed proximal muscle weakness, hypotonia, muscular atrophy, and Gowers sign. EMG showed chronic denervation. Two sisters developed myoclonic and generalized seizures at age 7 years, with 2-3 or 3-4 Hz sharp and slow waves on EEG. An affected brother had onset of muscle weakness and seizures at age 2 years. He also developed tremor, scoliosis, and pes cavus. The disorder was progressive, and all patients died in their teens. Another unrelated boy had normal early development, but always had an unsteady gait and was never able to run. He had proximal muscle weakness, lordosis, hypotonia, hyperreflexia, extensor plantar responses, and fasciculations, EMG showed diffuse chronic denervation, and muscle biopsy showed a neurogenic process. At age 4.5 years, he developed daily myoclonic seizures that were refractory to treatment. He also had fine tremor and recurrent lung infections.

Zhou et al. (2012) reported 5 patients from 3 unrelated families with SMAPME. The first family included 3 affected sibs born of consanguineous Turkish parents. After early normal development and walking by age 14 months, the affected children developed progressive walking difficulties and frequent falls around age 5 years. Physical examination showed proximal weakness and muscular atrophy with normal serum creatine kinase. One child had tremor of the hands. EMG and muscle biopsies showed a chronic denervation process. Around age 7, the children developed progressive myoclonic epilepsy with slow and sharp bilateral waves of 3 to 4 cycles/sec on EEG. The disease was progressive and caused recurrent lung infections, resulting in death in all 3 children in the teenage years. In a second family, 2 Italian sisters, born of unrelated parents, developed progressive muscular weakness of the lower and then upper limbs at ages 4 to 5 years. Early development was normal. Both had generalized epileptic seizures, numerous brief episodes of loss of consciousness, and myoclonic jerks starting around age 12. Both lost the ability to walk at age 17 years. Other features included mild facial weakness, difficulty swallowing, fasciculations of the tongue, areflexia, severe scoliosis, and respiratory insufficiency. EMG and muscle biopsies showed a denervation process; brain MRI was normal. The third family had 1 affected girl who showed a similar disease course, with onset of progressive muscle weakness at age 5, followed by myoclonic seizures at age 10. Neurologic examination at age 11 years showed diffuse muscle atrophy, mild facial weakness, difficulty swallowing, and fasciculations of the tongue. She died of pneumonia at age 15.

Dyment et al. (2014) reported a girl, born of unrelated parents of northern European descent, with SMAPME. She presented at age 10 years with absence and atonic seizures and myoclonic jerks. EEG showed generalized polyspike and wave discharges. Her neurologic development prior to seizure onset and neurologic examination were otherwise normal. The seizures were controlled with medication for 9 months, after which she developed frequent (over 100 per day) refractory myoclonic-absence seizures. She also developed constant tremor of the head, trunk, and extremities, as well as bilateral sensorineural hearing loss. Initial brain MRI was normal, but one at age 13 years showed mild volume loss. EMG at age 16 years showed a diffuse neurogenic disorder affecting motor neurons, with evidence of both active and chronic denervation. Dyment et al. (2014) commented on the absence of both muscle weakness and recurrent respiratory infections in this patient.

Inheritance

The transmission pattern of SMAPME in the families reported by Zhou et al. (2012) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 5 children from 2 families with spinal muscular atrophy with progressive myoclonic epilepsy, Zhou et al. (2012) identified a homozygous mutation in the ASAH1 gene (T42M; 613468.0006). The mutation was identified by genomewide linkage analysis followed by exome sequencing. Another patient from a third family was found to be compound heterozygous for the T42M mutation and a deletion of the ASAH1 gene (613468.0007). The T42M mutant protein was expressed in various patient tissues and showed decreased enzymatic activity (32% of controls) in in vitro functional studies, although the mutant enzyme still showed activity toward ceramide. Despite the severe phenotype, the disease course was less severe than that observed in the allelic disorder Farber disease (228000), and symptoms in SMAPME appeared to be restricted to the central nervous system. Zhou et al. (2012) postulated that the different phenotype in these patients was related to residual levels of ASAH1 activity.

In a girl with onset of SMAPME manifest as seizures at age 10 years, Dyment et al. (2014) identified compound heterozygous mutations in the ASAH1 gene (613468.0010 and 613468.0011). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the family. Patient fibroblasts showed about 5.5% residual acid ceramidase activity and barely detectable levels of the beta subunit.

History

Jankovic and Rivera (1979) first reported the association of distal muscular atrophy and myoclonic seizures in a large 4-generation family. Affected individuals showed adult-onset, generalized, stimulus-sensitive myoclonus and slowly progressive distal muscle weakness and wasting. Some patients showed survival into the sixties; some developed dementia. The seizures were well-controlled with clonazepam. Postmortem examination of 1 patient showed neuronal degeneration of the anterior horn cells, Clarke nucleus, and lower cranial nerve nuclei. The transmission pattern in the family reported by Jankovic and Rivera (1979) was consistent with autosomal dominant inheritance.