Evidence for clinical, genetic and biochemical variability in spinal muscular atrophy with progressive myoclonic epilepsy

Abstract

Spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) is a recently delineated, autosomal recessive condition caused by rare mutations in the N-acylsphingosine amidohydrolase 1 (acid ceramidase) ASAH1 gene. It is characterized by motor neuron disease followed by progressive myoclonic seizures and eventual death due to respiratory insufficiency. Here we report an adolescent female who presented with atonic and absence seizures and myoclonic jerks and was later diagnosed as having myoclonic-absence seizures. An extensive genetic and metabolic work-up was unable to arrive at a molecular diagnosis. Whole exome sequencing (WES) identified two rare, deleterious mutations in the ASAH1 gene: c.850G>T;p.Gly284X and c.456A>C;p.Lys152Asn. These mutations were confirmed by Sanger sequencing in the patient and her parents. Functional studies in cultured fibroblasts showed that acid ceramidase was reduced in both overall amount and enzymatic activity. Ceramide level was doubled in the patient's fibroblasts as compared to control cells. The results of the WES and the functional studies prompted an electromyography (EMG) study that showed evidence of motor neuron disease despite only mild proximal muscle weakness. These findings expand the phenotypic spectrum of SMA-PME caused by novel mutations in ASAH1 and highlight the clinical utility of WES for rare, intractable forms of epilepsy.

ASAH1 variant causing a mild SMA phenotype with no myoclonic epilepsy: a clinical, biochemical and molecular study

“…[5][6][7]15 Phenotype is considered clinically homogenous: patients develop progressive walking difficulties and frequent falls around age 5 and PME with slow and sharp bilateral waves of 3 to 4 cycles/s on EEG around age 7 (refs. 6,16) .…”

“…3,5 Inefficient breakdown of ceramides and impaired production of its breakdown products are thought to have a role in the nerve cell damage by causing defects of motor neuron axonal branching and an increase in apoptosis in the spinal cord. 2,5,6 However, the exact pathogenic mechanism is still unknown.…”

“…5,6 SMA-PME is an autosomal recessive condition characterized by muscle weakness and wasting and a combination of drug-resistant seizures and uncontrollable muscle jerks starting in childhood. [5][6][7] Variants causing SMA-PME result in reduced acid ceramidase activity (one-third of normal) and ceramide accumulation damaging cells less extensively than FL. 5,6 However, the disorder is progressive and patients die in the teenage years.…”

“…[5][6][7] Variants causing SMA-PME result in reduced acid ceramidase activity (one-third of normal) and ceramide accumulation damaging cells less extensively than FL. 5,6 However, the disorder is progressive and patients die in the teenage years.…”

Monogenic neurological disorders of sphingolipid metabolism

“…The clinical spectrum of this disorder is quite broad, including subcutaneous nodules, joint stiffness and swelling (mimicking juvenile arthritis) and various neurological manifestations, in particular seizures and progressive deterioration. A variant, CNSrestricted form of the disease has recently been recognized, which manifests as a spinal muscular atrophy with progressive myoclonic epilepsy [34,35]. Because of the loss (or marked decrease) of acid ceramidase activity, the undegraded Cer accumulates within cells, tissues and body fluids (except, possibly, in case of progressive myoclonic seizures where Cer accumulation might occur only in neurons).…”