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Progressive deafness-dystonia due to SERAC1 mutations: A study of 67 cases.

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2017

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Maas, Roeltje R
Iwanicka-Pronicka, Katarzyna
Kalkan Ucar, Sema
Alhaddad, Bader
AlSayed, Moeenaldeen
Al-Owain, Mohammed A
Al-Zaidan, Hamad I
Balasubramaniam, Shanti
Barić, Ivo
Bubshait, Dalal K

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3-Methylglutaconic aciduria, dystonia-deafness, hepatopathy, encephalopathy, Leigh-like syndrome (MEGDHEL) syndrome is caused by biallelic variants in SERAC1. This multicenter study addressed the course of disease for each organ system. Metabolic, neuroradiological, and genetic findings are reported. Sixty-seven 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 the exception of 2 families with a milder phenotype, all affected individuals showed a strikingly homogeneous phenotype and time course. Severe, reversible neonatal liver dysfunction and hypoglycemia were seen in >40% of all cases. Starting at a median age of 6 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 learned to walk (68%). Seventy-nine percent suffered hearing loss, 58% never learned to speak, and nearly all had significant intellectual disability (88%). Magnetic resonance imaging features were accordingly homogenous, with bilateral basal ganglia involvement (98%); the characteristic "putaminal eye" was seen in 53%. The urinary marker 3-methylglutaconic aciduria was present in virtually all patients (98%). Supportive treatment focused on spasticity and drooling, and was effective in the individuals treated; hearing aids or cochlear implants did not improve communication skills. MEGDHEL syndrome is a progressive deafness-dystonia syndrome with frequent and reversible neonatal liver involvement and a strikingly homogenous course of disease. Ann Neurol 2017;82:1004-1015.

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Adolescent
Adult
Amino Acid Sequence
Carboxylic Ester Hydrolases
Child
Child, Preschool
Cohort Studies
Deaf-Blind Disorders
Disease Progression
Dystonia
Female
Humans
Infant
Infant, Newborn
Intellectual Disability
Male
Mutation
Optic Atrophy
Young Adult

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