Progressive Myoclonic Epilepsy Due to Lafora Body Disease with a Novel Mutation.

Sir,

A 16-year-old premorbidly asymptomatic boy presented with a history of seizures for 1.5 years, abnormal jerky movements of the extremities, worsening of cognitive skills along with unsteadiness, and slurring of speech for 9 months. There was no limitation in the movements of eyeballs, facial asymmetry, and difficulty in vision (including night vision) or hearing. He was the first child born of a nonconsanguineous marriage with no perinatal concerns. There was no history of measles-like illness or any similar illness in the family. He was completely immunized for age. On examination, he was conscious, oriented to time, place, and person, but his memory, judgment, insight, abstract thinking, and calculation were impaired. There was predominant, generalized myoclonus involving all four limbs. Fundus examination, as well as other systemic examinations, was unremarkable. Progressive myoclonic epilepsy was diagnosed and further investigations were ensued to find the etiology. Electroencephalogram (EEG) performed at the time of first seizure showed mild slowing of background activity with occasional occipital epileptiform discharges [Figure 1A]. One year later, EEG demonstrated frequent bursts of synchronous and asynchronous, generalized spikes and polyspikes on a slowed background [Figure 1B], whereas current EEG revealed marked slowing of background with very frequent bursts of 1–2.5 Hz, 150–300 μV polyspike and polyspike–wave epileptiform discharges [Figure 1C]. Magnetic resonance imaging (MRI) of the brain was suggestive of diffuse cerebral atrophy [Figure 1D]. On clinical exome sequencing, the patient was homozygous for stop-gain mutation c.C480A (p.C160X) of NHLRC1 gene; it was confirmed by Sanger sequencing. It is a novel mutation of Lafora body disease (LBD). Progressive myoclonic epilepsy (PME) refers to a group of neurodegenerative disorders of genetic etiology, characterized by myoclonus with epileptic seizures and progressive neurologic decline typically with ataxia and dementia.[1] A number of etiological entities, namely Unverricht–Lundborg disease (ULD), LBD, neuronal ceroid lipofuscinoses (NCL), mitochondrial disorders, and sialidoses, may present with this clinical syndrome.[2] The largest case series of PME from India[3] reveals LBD to be the second most common etiological diagnosis. LBD, also called PME type 2 (EPM2), may also be considered pathophysiologically as a polyglucosan storage disease. Although the disorder is primarily neurological, nonneural tissues are also involved especially the liver, muscle, and skin.[4] Mutations in the epilepsy, progressive myoclonic type 2A (EPM2A) and NHL repeat containing E3 ubiquitin protein ligase 1 (NHLRC1) gene, also known as EPM2B are responsible for approximately 80% of the cases of this autosomal-recessive condition.[5] Singh et al.[5] compiled a total of 51 mutations in NHLRC1 gene in their meta-analysis. The stop-gain mutation in our patient was predicted to be pathogenic and damaging by three prediction tools, namely, MutationTaster (www.mutationtaster.org), PolyPhen (http://genetics.bwh.harvard.edu/pph2/), and SIFT (sift.jcvi.org), and this sequence variation is not reported in 1000 genomes (http://www.1000genomes.org/), exome variant server (http://evs.gs.washington.edu/EVS/), and ExAC databases (http://exac.broadinstitute.org/). The parents were found to be heterozygous carriers of the same mutation. Genetic diagnosis being more specific makes histopathological detection of Lafora bodies almost redundant.

Figure 1

Progression of electroencephalography (EEG) changes of the patient. (A) At the time of disease onset, there is normal to slightly slowed background activity (blue circles). (B) One year later, EEG demonstrates asymmetric generalized spikes and polyspikes on a slowed background. (C) Current EEG shows marked slowing of background with frequent bursts of 1–2.5 Hz, 150–300 μV polyspike and polyspike–wave epileptiform discharges. (D) Magnetic resonance imaging of the brain shows diffuse cerebral atrophy

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