X-linked myoclonic epilepsy with spasticity and intellectual disability

Proband IV-47.

The proband was a 5-year-old boy who developed seizures at age 10 months, characterized by extension of his upper limbs above his head and jerking backwards. Both infantile spasms and tonic seizures were recorded on video-EEG studies. Interictal EEG showed multifocal epileptiform activity localized predominantly to the left temporal region, but also seen on the right. The infantile spasms were associated with high amplitude generalized polyphasic sharp waves and spikes with left hemisphere predominance; typical hypsarrhythmia was not seen. During a generalized tonic seizure, bilateral upper limb extension was accompanied by 2 Hz rhythmic discharges slowing to 1 Hz polyphasic spike and slow wave activity. The tonic seizure lasted 45 seconds and in the second half of the seizure, the head and eyes deviated to the left. By age 5, seizures occurred twice per day, typically in sleep and began with a scream. They involved generalized stiffening with some jerking toward the end of the seizure; it was unclear if they were all tonic seizures or if some were tonic-clonic seizures (TCS). There was often a series of myoclonic jerks at the end of the major seizure. He had daily atonic head nods with upper limb myoclonic jerks lasting 1 second with postictal irritability. He did not have febrile convulsions nor convulsive status epilepticus. He took 140 mg of carbamazepine three times daily, and had previously tried sodium valproate and clonazepam.

The pregnancy and perinatal history were unremarkable. He was able to fix and follow by 6 weeks. He smiled late but was affectionate. He acquired two single words at age 41/2, but was not able to follow a single command. At age 5, he had severe global developmental delay; he could sit but not pull to stand nor walk. He was ambidextrous and had a primitive grasp. Developmental regression had not occurred.

On examination, he had a moderately severe asymmetric spastic quadriparesis with hypertonia and hyperreflexia, more pronounced on the right. Plantar responses were down-going. He had a convergent strabismus. Head circumference was 51 cm (50th percentile) and weight was 18 kg (25th percentile). There were no dysmorphic features nor neurocutaneous stigmata and general examination was normal.

His EEG at age 5 showed continuous slow 2 Hz generalized spike wave activity awake and asleep (figure 2). MRI brain scan at 23 months showed questionable cerebral atrophy with normal myelination. There was cavum septum vergae but no dysplasia. Muscle biopsy at age 23/4 showed a mild increase in lipid but no evidence of a mitochondrial cytopathy. Other normal investigations included karyotype, CSF and blood lactate, very long chain fatty acids, phytanic acid, fragile X DNA studies, the common mutations for MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes), MERRF (myoclonic epilepsy associated with ragged-red fibers), NARP (neuropathy, ataxia, and retinitis pigmentosa), Leigh syndrome, respiratory chain enzymes in skeletal muscle, urine amino acids, and CT brain scan with contrast.

• Download figure
• Open in new tab
• Download powerpoint

Figure 2. EEG of the proband IV-47. The awake EEG shows continuous slow generalized spike wave activity with a bifrontal predominance.

Individual IV-46.

The most mildly affected boy was a 10-year-old whose absence seizures began at 18 months. These consisted of 2- to 3-second staring episodes that improved with the introduction of sodium valproate. TCS without aura began at age 9, and he had a total of three 30- to 60-second convulsions, two triggered by looking at lights. Myoclonic seizures occurred in the mornings and also toward the end of an absence seizure. He had not had febrile seizures nor drop attacks.

The pregnancy and perinatal history were unremarkable. Concerns about his developmental progress arose at 6 months. By age 2, he could crawl but not walk. A cystoperitoneal shunt was inserted at 24 months for decompression of a posterior fossa cyst with subsequent improvement in balance; he walked at 32 months. He underwent strabismus repair at age 6. By age 10, he spoke two- or three-word phrases, could follow a series of three commands, ran awkwardly, and scribbled lines. His eye contact was variable, and he was not continent. He had never regressed.

Examination revealed mild generalized spasticity with mild generalized hypertonia and sustained clonus at the left ankle and down-going plantar responses bilaterally. He had a stooped posture with a spastic gait and was not able to follow instructions. He had a convergent strabismus. There were no neurocutaneous or dysmorphic features. Head circumference was 56 cm (98th centile). His weight was 41 kg (90th percentile).

Routine EEG at age 10 showed mild to moderate diffuse background slowing without epileptiform features. CT brain scan showed a large posterior fossa cyst; the brain and ventricular system appeared normal.

Individual III-38.

This 32-year-old man was the only affected individual with a history of regression. He was the result of a normal pregnancy and forceps delivery at term. By day 1 of age, a cleft palate was noted and he seemed floppier and less alert than normal. Early development was delayed, with sitting at 1 year and walking at age 9. He spoke two single words from age 5, but was unable to follow a simple command. He was ambidextrous, and could finger feed and use a spoon.

He developed TCS at 5 months, with five TCS per day without fever. He also had diurnal myoclonic seizures. At age 19, he had convulsive status epilepticus for at least 60 minutes followed by 48 hours of coma and marked developmental regression. He was no longer able to walk or hold a cup.

On examination, he had generalized myoclonic seizures and was wheelchair bound. He had severe generalized spastic quadriparesis with bilateral up-going plantar responses. Head circumference was 55 cm (30th percentile). He had a kyphosis but no other dysmorphic or neurocutaneous stigmata.

DNA analysis for the most common mutations for the fragile X syndrome (FRAXA) and the FRAXE syndrome (OMIM*309548) were negative. Routine study EEG showed diffuse background slowing with 2 Hz slow generalized spike wave activity.

Individual IV-42.

Individual IV-42 was born by forceps delivery at term in good condition weighing 3 kg. His mother’s pregnancy was complicated by vomiting and dehydration, requiring hospitalization at 3 months. At birth, he was very floppy. Eye examination at 11 months was normal. Developmental progress was extremely slow but regression did not occur. By age 41/2, he could fix and follow and appeared to hear. He could not roll over or sit, nor did he speak, smile, or laugh. He could grasp but not reach.

Brief seizures began at 3 months; at 5 months, afebrile convulsive status epilepticus occurred and phenytoin was commenced. Thereafter, brief TCS occurred a few times per week. He also experienced absence and myoclonic seizures. Video-EEG monitoring at 9 months captured a partial seizure which began with brief tonic features then clonic activity of the left lower limb and waving of the left hand. Truncal extension occurred with head deviation to the right and tremor of the right hand. Bicycling movements of the legs were noted. Toward the latter part of the 3-minute seizure, he was still with head and eye deviation to the right. The EEG correlate of this seizure began with a 5-second generalized electrodecremental response, followed by high amplitude left temporal slow sharp activity evolving to 6 Hz sharp and spike discharges, which gradually evolved to delta activity. Frequent episodes of convulsive status epilepticus occurred and he spent much of his life in hospital. He died at age 41/2 in status epilepticus.

Examination at age 17 months revealed truncal hypotonia and increased peripheral muscle tone with scissoring. Chromosomal analysis and CT brain scan were normal.

Matriarch II-8.

The maternal grandmother of the proband was 61 years old and had a 12-year history of progressive difficulty walking and unsteadiness. She eventually became wheelchair bound because she could only walk a few meters. She had a progressive spastic quadriparesis. Her gait was wide-based and ataxic, suggestive of a superimposed truncal cerebellar component. Plantar responses were down-going. She had a tremor involving her limbs and jaw without appendicular cerebellar signs. She had a past history of a toxic goiter (treated with radioiodine), hypertension, ischemic heart disease, and agoraphobia.

Investigations showed normal mitochondrial DNA analysis for the common mutations in NARP, MELAS, and MERRF; normal myotonic dystrophy DNA and spinocerebellar ataxia type 6 DNA studies, normal thyroid function test, antinuclear antibodies, and vitamin E. Muscle biopsy revealed mild fiber atrophy but no evidence of a mitochondrial cytopathy. MRI of the cervical cord was normal. MRI of the brain showed small foci of T2 hyperintensity in the white matter, consistent with small vessel ischemic changes. Her EEG was normal.

Epileptology.

Of the six affected boys in the main branch of the family, the mean age of seizure onset was 7 months (range 2 to 18 months) with earlier onset correlating with more severe developmental impairment. Four boys presented with TCS, one (IV-46) presented with absence seizures, and one (IV-47) had infantile spasms and tonic seizures at onset. Infantile spasms were seen in one other affected boy (III-37) at 6 months while undergoing video-EEG monitoring. All boys developed myoclonic seizures and TCS over time, two had tonic seizures, convulsive status occurred in two boys, and absence and atonic seizures were seen in one boy each. Absence seizures could be difficult to discern in the affected boys. Overall, affected boys had hundreds of seizures and were refractory to multiple antiepileptic medications. Two boys died in early childhood, III-37 at 19 months and IV-42 at age 41/2, the latter during a seizure. (Data are presented in table 1.)

EEG studies were performed in all four living affected boys. All recordings showed mild to moderate diffuse background slowing with generalized spike wave activity in three. The one boy (IV-46) without epileptiform activity was the least severely affected boy. One of the two boys with infantile spasms had typical hypsarrhythmia (III-37), the other did not (see proband IV-47 case history).

Clinical features.

All affected boys had severe global developmental delay. This varied in degree. They were able to sit between ages 1 and 4; only two ever walked independently, IV-46 at 32 months, and III-38 at age 9. Only four acquired single words between 18 months and 5 years, with three gaining 10 single words at most; IV-46 put two or three words together. On history, the two deceased boys were profoundly impaired: IV-42 could grasp but not reach or fix, and III-37 could not fix nor support his head. Only one (III-38) had a history of regression, this followed status epilepticus at age 19. (Data are presented in table 1.)

All affected boys had generalized spasticity, which varied in severity from mild in IV-46, who was able to walk, to severe in the remaining three living boys who were wheelchair bound. There were no neurocutaneous stigmata.