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

TY - JOUR

T1 - Progressive deafness-dystonia due to SERAC1 mutations: A study of 67 cases

AU - Maas, Roeltje R

AU - Iwanicka-Pronicka, Katarzyna

AU - Kalkan Ucar, Sema

AU - Alhaddad, Bader

AU - AlSayed, Moeenaldeen

AU - Al-Owain, Mohammed A

AU - Al-Zaidan, Hamad I

AU - Balasubramaniam, Shanti

AU - Barić, Ivo

AU - Bubshait, Dalal K

AU - Burlina, Alberto

AU - Christodoulou, John

AU - Chung, Wendy K

AU - Colombo, Roberto

AU - Darin, Niklas

AU - Freisinger, Peter

AU - Garcia Silva, Maria Teresa

AU - Grunewald, Stephanie

AU - Haack, Tobias B

AU - van Hasselt, Peter M

AU - Hikmat, Omar

AU - Hörster, Friederike

AU - Isohanni, Pirjo

AU - Ramzan, Khushnooda

AU - Kovacs-Nagy, Reka

AU - Krumina, Zita

AU - Martin-Hernandez, Elena

AU - Mayr, Johannes A

AU - McClean, Patricia

AU - De Meirleir, Linda

AU - Naess, Karin

AU - Ngu, Lock H

AU - Pajdowska, Magdalena

AU - Rahman, Shamima

AU - Riordan, Gillian

AU - Riley, Lisa

AU - Roeben, Benjamin

AU - Rutsch, Frank

AU - Santer, Rene

AU - Schiff, Manuel

AU - Seders, Martine

AU - Sequeira, Silvia

AU - Sperl, Wolfgang

AU - Staufner, Christian

AU - Synofzik, Matthis

AU - Taylor, Robert W

AU - Trubicka, Joanna

AU - Tsiakas, Konstantinos

AU - Unal, Ozlem

AU - Wassmer, Evangeline

AU - Wedatilake, Yehani

AU - Wolff, Toni

AU - Prokisch, Holger

AU - Morava, Eva

AU - Pronicka, Ewa

AU - Wevers, Ron A

AU - de Brouwer, Arjan P

AU - Wortmann, Saskia B

N1 - © 2017 American Neurological Association.

PY - 2017/12

Y1 - 2017/12

N2 - 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.

AB - 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.

KW - Adolescent

KW - Adult

KW - Amino Acid Sequence

KW - Carboxylic Ester Hydrolases

KW - Child

KW - Child, Preschool

KW - Cohort Studies

KW - Deaf-Blind Disorders

KW - Disease Progression

KW - Dystonia

KW - Female

KW - Humans

KW - Infant

KW - Infant, Newborn

KW - Intellectual Disability

KW - Male

KW - Mutation

KW - Optic Atrophy

KW - Young Adult

KW - Journal Article

KW - Multicenter Study

U2 - 10.1002/ana.25110

DO - 10.1002/ana.25110

M3 - SCORING: Journal article

C2 - 29205472

VL - 82

SP - 1004

EP - 1015

JO - ANN NEUROL

JF - ANN NEUROL

SN - 0364-5134

IS - 6

ER -