Summary
The child presented soon after birth with nystagmus and hyperkinetic movement disorder. Focal seizures appeared from 2 months of age and recurred at high frequency, despite several antiseizure medications, and focal epileptic status frequently required IV phenytoin. Control of seizures was achieved at the age of 8 months by the association of high doses of sodium blockers.
Original Article
Severe Epilepsy and Movement Disorder May Be Early Symptoms of TMEM106B-Related Hypomyelinating Leukodystrophy
Neurology: Genetics
Roberta Solazzi, Marco Moscatelli, Davide Rossi Sebastiano, Laura Canafoglia, Laura Pezzoli, Maria Iascone, Tiziana Granata
Abstract
Objective To report the clinical presentation of the first Italian child affected by hypomyelinating leukodystrophy (HLD) associated with the recurrent variant p.Asp252Asn in the TMEM106B gene.
Methods The methods included clinical case description, neurophysiologic assessment, brain MRI, and whole-exome sequencing (WES).
Results The child presented soon after birth with nystagmus and hyperkinetic movement disorder. Focal seizures appeared from 2 months of age and recurred at high frequency, despite several antiseizure medications, and focal epileptic status frequently required IV phenytoin. Control of seizures was achieved at the age of 8 months by the association of high doses of sodium blockers. Clinical picture worsened over time and was characterized by axial hypotonia, failure to thrive requiring gastrostomy, pyramidal sings, and severe secondary microcephaly. MRI performed at ages 2, 6, and 20 months showed diffuse supratentorial and subtentorial hypomyelination; multimodal evoked potentials showed increased latency. WES performed at 6 months of age identified the p.Asp252Asn de novo variant in the TMEM106B gene.
Discussion Hyperkinetic movement disorders and seizures may be early symptoms of TMEM106B-HLD. Our observation, supported by video EEG recordings, emphasizes that seizures may be difficult to recognize from movement disorders and that epilepsy may be a severe and prominent symptom of the disease. TMEM106B-HLD should be considered in the genetic screening of infants with early-onset seizures and movement disorders.
TMEM106B gene codifies for a transmembrane protein affecting lysosomal function (Video, links.lww.com/NXG/A538). Variants of this gene have been initially described as a disease risk modifier in frontotempolar lobar degeneration.1 More recently, the recurrent TMEM106B variant c.754G>A (p.Asp252Asn) has been reported in association with a rare and mild form of hypomyelinating leukodystrophy (HLD)2,-,5 in 7 patients. We described the first Italian case of TMEM106B-related HLD, whose clinical picture includes congenital nystagmus, hyperkinetic movement disorder, and severe early-onset epilepsy with intractable focal seizures. We provided a detailed characterization of the patient's phenotype, supported by video documentation, neuroimaging, and neurophysiologic data. This case description highlights that severe epilepsy and movement disorders may figure among the presenting symptoms of the disease and may dominate the course of disease at least in early infancy.
Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
