Epilepsy, Progressive Myoclonic, 6

A number sign (#) is used with this entry because of evidence that progressive myoclonic epilepsy-6 (EPM6) is caused by homozygous or compound heterozygous mutation in the GOSR2 gene (604027) gene on chromosome 17q21.

Description

Progressive myoclonic epilepsy-6 is an autosomal recessive neurologic disorder characterized by onset of ataxia in the first years of life, followed by action myoclonus and seizures later in childhood, and loss of independent ambulation in the second decade. Cognition is not usually affected, although mild memory difficulties may occur in the third decade (summary by Corbett et al., 2011).

For a discussion of genetic heterogeneity of progressive myoclonic epilepsy, see EPM1A (254800).

Clinical Features

Corbett et al. (2011) reported 6 patients, including 2 sibs, with early childhood onset of progressive myoclonic epilepsy. One child was born of consanguineous Australian parents, and the others were of German or Dutch descent. The phenotype was homogeneous: patients developed progressive ataxia between ages 1 and 3 years, followed by action myoclonus between ages 6 to 10 years. Most became wheelchair-bound with areflexia in their mid-teens, although 1 patient became wheelchair-bound at age 24. A few patients had tremor and fine motor problems. All had seizures of some sort, either drop attacks, absence seizures, or tonic-clonic seizures. EEG showed active generalized spike and wave and polyspike patterns, as well as photosensitivity. All patients developed scoliosis, 2 had syndactyly, and most had increased serum creatine kinase. Cognition was normal in all, although 2 patients showed subtle memory difficulties in the third decade.

Van Egmond et al. (2014) reported 5 additional Dutch patients with EPM6 confirmed by genetic analysis. The patients ranged in age from 7 to 26 years. All patients had symptom onset between 2 and 3 years of age, mainly gait disorder and clumsiness consistent with ataxia, although 1 patient had febrile seizures. All patients developed progressive ataxia and myoclonus, and myoclonus was exacerbated by stress or stimuli. The myoclonus was disabling, resulting in dysarthria and disruption of fine motor function. One patient became wheelchair-bound at age 8 years. Four patients developed seizures in the first decade, mainly tonic-clonic seizures. Three patients had scoliosis. Electrophysiologic studies showed cortical reflex myoclonus; additional studies showed that the areflexia was due to both a sensory neuropathy and chronic anterior horn cell involvement, suggesting peripheral nerve involvement and central neuronal cell loss in the spinal cord. Laboratory studies showed increased serum creatine kinase in only 1 patient. Brain imaging was normal, and cognition remained stable.

Praschberger et al. (2015) reported a 61-year-old woman with EPM6. She presented with mild gait ataxia at age 2 years, and had transient episodes of motor deterioration triggered by infection and fever. She developed generalized action myoclonus and epilepsy around age 14. The disorder was progressive, and she became wheelchair-bound in her thirties. Cognitive dysfunction was not a prominent feature. Brain imaging showed generalized cerebral and cerebellar atrophy. Additional features included scoliosis and areflexia. She lived in a residential facility and was dependent for activities of daily living. Praschberger et al. (2015) noted that the phenotype in this patient was somewhat milder than that in previously reported patients.

Inheritance

Progressive myoclonic epilepsy-6 shows an autosomal recessive pattern of inheritance (Corbett et al., 2011).

Molecular Genetics

In 5 unrelated patients with progressive myoclonic epilepsy-6, Corbett et al. (2011) identified a homozygous loss-of-function mutation in the GOSR2 gene (G144W; 604027.0001). Haplotype analysis indicated a founder effect, most likely of European origin, approximately 3,600 years earlier.

Van Egmond et al. (2014) reported 5 additional Dutch patients with EPM6, all of whom were homozygous for the G144W mutation.

In a 61-year-old woman with EPM6, Praschberger et al. (2015) identified compound heterozygous mutations in the GOSR2 gene: G144W and a novel in-frame deletion (604027.0002). The patient's brother, who had cervical dystonia, was heterozygous for the G144W mutation. Functional studies of the mutations were not performed. The patient was 1 of 43 patients with a similar disorder who were screened for defects in the GOSR2 gene.