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Progressive deafness-dystonia due to SERAC1 mutations - a study of 67 cases

Journal Contribution - Journal Article

OBJECTIVE: 3-MEthylGlutaconic aciduria, Dystonia-Deafness, Hepatopathy, Encephalopathy, Leigh-like syndrome (MEGDHEL) syndrome is caused by biallelic variants in SERAC1.

METHODS: Multi centre study concerning the course of disease for each organ system, together with metabolic, neuroradiological and genetic findings.

RESULTS: 67 individuals (39 previously unreported) from 59 families were included (age range 5 days - 33.4 years, median age 9 years). A total of 41 different SERAC1 variants were identified, including 20 that have not been reported before. With exception of two families with a milder phenotype, all affected individuals show a strikingly homogeneous phenotype and time course. Severe, reversible neonatal liver dysfunction and hypoglycemia was seen in more than 40% of all cases. Starting at a median age of six months muscular hypotonia (91%) was seen, followed by progressive spasticity (82%, median onset 15 months) and dystonia (82%, 18 months). The majority of affected individuals never learnt to walk (68%). 79% suffered hearing loss, 58% never learnt to speak, nearly all had significant intellectual disability (88%). MRI features were accordingly homogenous with bilateral basal ganglia involvement (98%), the characteristic "putaminal eye" was seen in 53%. The urinary marker 3-methylglutaconic aciduria is virtually present in all patients (98%). Supportive treatment focused on spasticity and drooling, was effective in individuals treated, hearing aids or cochlear implants did not improve communication skills.

INTERPRETATION: MEGDHEL syndrome is as a progressive deafness-dystonia syndrome with frequent and reversible neonatal liver involvement and a strikingly homogenous course of disease. This article is protected by copyright. All rights reserved.

Journal: Annals of Neurology
ISSN: 0364-5134
Issue: 6
Volume: 82
Pages: 1004-1015
Number of pages: 12
Publication year:2017
Keywords:Journal Article, Amino Acid Sequence, Mutation/genetics, Humans, Optic Atrophy/diagnostic imaging, Child, Preschool, Deaf-Blind Disorders/diagnostic imaging, Dystonia/diagnostic imaging, Infant, Male, Disease Progression, Intellectual Disability/diagnostic imaging, Young Adult, Carboxylic Ester Hydrolases/genetics, Adolescent, Adult, Female, Child, Infant, Newborn, Cohort Studies