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

Lookup NU author(s): Professor Robert Taylor, Dr Arjan De Brouwer

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© 2017 American Neurological Association Objective: 3-Methylglutaconic aciduria, dystonia–deafness, hepatopathy, encephalopathy, Leigh-like syndrome (MEGDHEL) syndrome is caused by biallelic variants in SERAC1. Methods: This multicenter study addressed the course of disease for each organ system. Metabolic, neuroradiological, and genetic findings are reported. Results: 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. Interpretation: 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.


Publication metadata

Author(s): Maas RR, Iwanicka-Pronicka K, Kalkan Ucar S, Alhaddad B, AlSayed M, Al-Owain MA, Al-Zaidan HI, Balasubramaniam S, Baric I, Bubshait DK, Burlina A, Christodoulou J, Chung WK, Colombo R, Darin N, Freisinger P, Garcia Silva MT, Grunewald S, Haack TB, van Hasselt PM, Hikmat O, Horster F, Isohanni P, Ramzan K, Kovacs-Nagy R, Krumina Z, Martin-Hernandez E, Mayr JA, McClean P, De Meirleir L, Naess K, Ngu LH, Pajdowska M, Rahman S, Riordan G, Riley L, Roeben B, Rutsch F, Santer R, Schiff M, Seders M, Sequeira S, Sperl W, Staufner C, Synofzik M, Taylor RW, Trubicka J, Tsiakas K, Unal O, Wassmer E, Wedatilake Y, Wolff T, Prokisch H, Morava E, Pronicka E, Wevers RA, de Brouwer AP, Wortmann SB

Publication type: Article

Publication status: Published

Journal: Annals of Neurology

Year: 2017

Volume: 82

Issue: 6

Pages: 1004-1015

Print publication date: 01/12/2017

Online publication date: 02/12/2017

Acceptance date: 26/11/2017

ISSN (print): 0364-5134

ISSN (electronic): 1531-8249

Publisher: John Wiley and Sons Inc.

URL: https://doi.org/10.1002/ana.25110

DOI: 10.1002/ana.25110


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