Reversible Valproate-Induced Subacute Encephalopathy Associated With a MT-ATP8 Variant in the Mitochondrial Genome

Abstract

Introduction: There are several reported cases of patients developing motor and cognitive neurological impairment under treatment with valproic acid (VPA). We describe a woman who developed a subacute encephalopathy after VPA intake, harboring a mitochondrial DNA variant, previously described as causing VPA sensitivity in one pediatric patient.Material and Methods: A 65-year old woman developed a progressive, severe neurological deterioration after a 3 month treatment with valproate sodium, 800 mg daily. Magnetic resonance spectroscopy (MRS), muscle histochemical analysis and assay of mitochondrial enzymatic activities, and mitochondrial DNA sequencing were performed.Results: Neurological examination showed drowsiness, vertical gaze palsy, inability to either stand or walk, diffuse weakness, increased tendon reflexes. Blood lactate was increased, EEG showed diffuse theta and delta activity, MRI subcortical atrophy and leukoencephalopathy, MRS marked reduction of the NAA spectrum, with a small signal compatible with presence of lactate. Muscle biopsy evidenced presence of ragged red fibers (20%) and reduced COX reactivity. Assay of the muscle enzymatic activities showed multiple deficiencies of the electron transport chain and reduced ATP production. The mt.8393C>T variant in the MT-ATP8 gene was found in homoplasmy. The patient considerably improved after valproate withdrawal.Conclusion: The variant we found has been reported both as a polymorphism and, in a single patient, as related to the valproate-induced encephalopathy. The present case is the first bearing this mutation in homoplasmy. In case of neurological symptoms after starting VPA therapy, once hyperammonemia and liver failure have been ruled out, mtDNA abnormalities should be considered.

Bi‐allelic variants in MDH2: Expanding the clinical phenotype

“…A targeted multigene resequencing panel (Nimblegen, Roche, USA) made up of 1172 genes encoding the "MitoExome" was used and bioinformatically analyzed as described elsewhere. 7 Variants in MDH2 (NM_005918.4) were confirmed by capillary Sanger sequencing with ad hoc designed oligonucleotide primers, and segregation studies were performed in the healthy parents. Total RNA was isolated from cultured skin fibroblasts, reversely transcribed to cDNA and amplified by PCR (primers available upon reasonable request) according to standard procedures.…”

The Diagnostic Approach to Mitochondrial Disorders in Children in the Era of Next-Generation Sequencing: A 4-Year Cohort Study

“…Using methods described elsewhere [ 23 ], we analyzed in 27 children the “MitoExome”, a customized multigene panel targeting the coding regions of 1172 genes associated with mitochondrial pathways [ 24 ]. Briefly, the panel was designed with the NimbleGen Design software (Roche NimbleGen Inc., Pleasanton, CA, USA), and target enrichment and amplification were performed following the SeqCap EZ HyperCap Library protocol (Roche, Madison, WI, USA), adapted for a MiSeq desktop scanner (Illumina, San Diego, CA, USA).…”

Bi-allelic variants in MTMR5/SBF1 cause Charcot-Marie-Tooth type 4B3 featuring mitochondrial dysfunction

“…Having excluded pathogenic alterations in over 1000 mitochondrial genes by massive gene testing (MitoExome analysis as in [ 22 ]), we identified bi-allelic variants in MTMR5/ SBF (NM_001365819.1) by whole-exome sequencing (WES) of the family trio; this was done by precise filtering and prioritization of over 740 variants in more than 600 rare genes with a customized in-house bioinformatic pipeline using the criteria as reported in [ 23 ]. Sanger sequencing confirmed that the patient harbored the p.R763H (c.2291G > A) variant, inherited from her father, and the p.G1064E (c.3194G > A) variant, inherited from her mother (Fig.…”