Case study
Two siblings with early infantile myoclonic encephalopathy due to mutation in the gene encoding mitochondrial glutamate/H+ symporter SLC25A22

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Abstract

Aim

To characterize a new subset of early myoclonic encephalopathy usually associated with metabolic etiologies with a new genetic entity.

Methods

We describe two siblings with early myoclonic encephalopathy born to consanguineous parents of Arab Muslim origin from Israel. We used homozygosity mapping and candidate gene sequencing to reveal the genetic basis of the myoclonic syndrome.

Results

We found a rare missense mutation in the gene encoding one of the two mitochondrial glutamate/H symporters, SLC25A22. The phenotype of early myoclonic encephalopathy was first linked to the same mutation in 2005 in patients of the same ethnicity as our family.

Conclusions

Owing to the devastating nature of this encephalopathy, we focus attention on its clinical history, epileptic semiology, distinct electroencephalography features, and genetic basis. We provide the evidence that an integrated diagnostic strategy combining homozygosity mapping with candidate gene sequencing is efficient in consanguineous families with highly heterogeneous autosomal recessive diseases.

Introduction

Early myoclonic encephalopathy (EME) is an epileptic syndrome that starts in the early neonatal period or first months of life. It is characterized clinically by erratic myoclonus, refractory partial seizures, and abnormal neurological status. The electroencephalogram (EEG) typically shows a “burst suppression” pattern consisting of bursts of spikes, sharp waves, and slow waves that alternate with periods of suppression of electrical activity.1 Similar findings are noted in Ohtahara syndrome, another of the early/infantile epileptic encephalopathies. However, Ohtahara syndrome is associated with spasms, which occur singly or in clusters, in both awake and asleep states. EME and Ohtahara syndrome are considered to be a phenotypic continuum in which clinical differences are probably related to specific gene mutations.2, 3 Nevertheless the etiology of EME can also be inborn errors of metabolism, such as nonketotic hyperglycinemia, d-glyceric acidemia, propionic acidemia, molybdenum cofactor deficiency, methylmalonic acidemia, and mitochondrial glutamate transporter defect,4 whereas Ohtahara syndrome is mainly due to brain structural abnormalities.5

The aim of the present report was to describe 2 siblings with a phenotype of EME caused by a mutation in the gene encoding mitochondrial glutamate/H+ symporter SLC25A22. The clinical manifestations and EEG findings are delineated, and the literature is reviewed.

Section snippets

Case 1

A 6-year-old girl presented to our clinic for evaluation of severe epilepsy and severe developmental delay. Her parents are first cousins of Arab Muslim origin. The father is from central Israel and the mother, from Jerusalem. The patient has two healthy brothers aged 7 and 4 years and an affected brother. She was born at term after a normal pregnancy and labor weighing 2100 gr. Past medical history revealed convulsions, starting in the first months of life and poor weight gain. The patient was

Discussion

The early/infantile epileptic encephalopathies have been linked, in some cases, to inborn errors of metabolism involving the mitochondria due either to a deficiency in complex I and IV or a mutation in the SLC25A22 gene.6 We describe two siblings with a phenotype of EME and a missense mutation in the SLC25A22 gene. The same mutation was first reported in earlier studies of another Arab-Israeli family with similar clinical features to our family. A different homozygous missense mutation,

Acknowledgment

There are no sources of financial and material support.

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Drs. R. Cohen and L. Basel-Vanagaite contributed equally to this study as first authors.

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