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

Roeltje R Maas; Katarzyna Iwanicka-Pronicka; Sema Kalkan-Ucar; Bader Alhaddad; Moeenaldeen AlSayed; Mohammed Al-Owain; Hamad I Al-Zaidan; Shanti Balasubramaniam; Ivo Barić; Dalal K Bubshait; Alberto Burlina; John Christodoulou; Wendy K. Chung; Roberto Colombo; Niklas Darin; Peter Freisinger; Maria Teresa Garcia Silva; Stephanie Grunewald; Tobias B. Haack; Peter M van Hasselt; Omar Hikmat; Friederike Hörster; Pirjo Isohanni; Khushnooda Ramzan; Reka Kovacs-Nagy; Zita Krumina; Elena Martin-Hernandez; Johannes A Mayr; Patricia McClean; Linda De Meirleir; Karin Naess; Lock H Ngu; Magdalena Pajdowska; Shamima Rahman; Gillian Riordan; Lisa Riley; Benjamin Roeben; Frank Rutsch; Rene Santer; Manuel Schiff; Martine Seders; Silvia Sequeira; Wolfgang Sperl; Christian Staufner; Matthis Synofzik; Robert W Taylor; Joanna Trubicka; Konstantinos Tsiakas; Ozlem Unal; Evangeline Wassmer; Yehani Wedatilake; Toni Wolff; Holger Prokisch; Eva Morava; Ewa Pronicka; Ron A. Wevers; Arjan P M de Brouwer; Saskia B. Wortmann

doi:10.1002/ana.25110

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

Roeltje R Maas, Katarzyna Iwanicka-Pronicka, Sema Kalkan-Ucar, Bader Alhaddad, Moeenaldeen AlSayed, Mohammed Al-Owain, Hamad I Al-Zaidan, Shanti Balasubramaniam, Ivo Barić, Dalal K Bubshait, Alberto Burlina, John Christodoulou, Wendy K. Chung, Roberto Colombo, Niklas Darin, Peter Freisinger, Maria Teresa Garcia Silva, Stephanie Grunewald, Tobias B. Haack, Peter M van HasseltOmar Hikmat, Friederike Hörster, Pirjo Isohanni, Khushnooda Ramzan, Reka Kovacs-Nagy, Zita Krumina, Elena Martin-Hernandez, Johannes A Mayr, Patricia McClean, Linda De Meirleir, Karin Naess, Lock H Ngu, Magdalena Pajdowska, Shamima Rahman, Gillian Riordan, Lisa Riley, Benjamin Roeben, Frank Rutsch, Rene Santer, Manuel Schiff, Martine Seders, Silvia Sequeira, Wolfgang Sperl, Christian Staufner, Matthis Synofzik, Robert W Taylor, Joanna Trubicka, Konstantinos Tsiakas, Ozlem Unal, Evangeline Wassmer, Yehani Wedatilake, Toni Wolff, Holger Prokisch, Eva Morava, Ewa Pronicka, Ron A. Wevers, Arjan P M de Brouwer, Saskia B. Wortmann

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

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.

Original language	English
Pages (from-to)	1004-1015
Number of pages	12
Journal	Annals of Neurology
Volume	82
Issue number	6
DOIs	https://doi.org/10.1002/ana.25110
Publication status	Published - Dec 2017

Keywords

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
Journal Article
Male
Multicenter Study
Mutation
Optic Atrophy
Young Adult

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Maas, R. R., Iwanicka-Pronicka, K., Kalkan-Ucar, S., Alhaddad, B., AlSayed, M., Al-Owain, M., Al-Zaidan, H. I., Balasubramaniam, S., Barić, I., Bubshait, D. K., Burlina, A., Christodoulou, J., Chung, W. K., Colombo, R., Darin, N., Freisinger, P., Garcia Silva, M. T., Grunewald, S., Haack, T. B., ... Wortmann, S. B. (2017). Progressive deafness-dystonia due to SERAC1 mutations: A study of 67 cases. Annals of Neurology, 82(6), 1004-1015. https://doi.org/10.1002/ana.25110

@article{8fd0e4fe47784cceaffb3fcb99b2c2ec,

title = "Progressive deafness-dystonia due to SERAC1 mutations: A study of 67 cases",

abstract = "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.",

keywords = "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, Journal Article, Male, Multicenter Study, Mutation, Optic Atrophy, Young Adult",

author = "Maas, {Roeltje R} and Katarzyna Iwanicka-Pronicka and Sema Kalkan-Ucar and Bader Alhaddad and Moeenaldeen AlSayed and Mohammed Al-Owain and Al-Zaidan, {Hamad I} and Shanti Balasubramaniam and Ivo Bari{\'c} and Bubshait, {Dalal K} and Alberto Burlina and John Christodoulou and Chung, {Wendy K.} and Roberto Colombo and Niklas Darin and Peter Freisinger and {Garcia Silva}, {Maria Teresa} and Stephanie Grunewald and Haack, {Tobias B.} and {van Hasselt}, {Peter M} and Omar Hikmat and Friederike H{\"o}rster and Pirjo Isohanni and Khushnooda Ramzan and Reka Kovacs-Nagy and Zita Krumina and Elena Martin-Hernandez and Mayr, {Johannes A} and Patricia McClean and Meirleir, {Linda De} and Karin Naess and Ngu, {Lock H} and Magdalena Pajdowska and Shamima Rahman and Gillian Riordan and Lisa Riley and Benjamin Roeben and Frank Rutsch and Rene Santer and Manuel Schiff and Martine Seders and Silvia Sequeira and Wolfgang Sperl and Christian Staufner and Matthis Synofzik and Taylor, {Robert W} and Joanna Trubicka and Konstantinos Tsiakas and Ozlem Unal and Evangeline Wassmer and Yehani Wedatilake and Toni Wolff and Holger Prokisch and Eva Morava and Ewa Pronicka and Wevers, {Ron A.} and {de Brouwer}, {Arjan P M} and Wortmann, {Saskia B.}",

note = "Publisher Copyright: {\textcopyright} 2017 American Neurological Association",

year = "2017",

month = dec,

doi = "10.1002/ana.25110",

language = "English",

volume = "82",

pages = "1004--1015",

journal = "Annals of Neurology",

issn = "0364-5134",

publisher = "John Wiley & Sons Inc.",

number = "6",

}

Maas, RR, Iwanicka-Pronicka, K, Kalkan-Ucar, S, Alhaddad, B, AlSayed, M, Al-Owain, M, Al-Zaidan, HI, Balasubramaniam, S, Barić, 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, Hörster, F, Isohanni, P, Ramzan, K, Kovacs-Nagy, R, Krumina, Z, Martin-Hernandez, E, Mayr, JA, McClean, P, Meirleir, LD, 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, APM & Wortmann, SB 2017, 'Progressive deafness-dystonia due to SERAC1 mutations: A study of 67 cases', Annals of Neurology, vol. 82, no. 6, pp. 1004-1015. https://doi.org/10.1002/ana.25110

TY - JOUR

T1 - Progressive deafness-dystonia due to SERAC1 mutations

T2 - 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

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 - Meirleir, Linda De

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 M

AU - Wortmann, Saskia B.

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 - Journal Article

KW - Male

KW - Multicenter Study

KW - Mutation

KW - Optic Atrophy

KW - Young Adult

U2 - 10.1002/ana.25110

DO - 10.1002/ana.25110

M3 - Article

C2 - 29205472

SN - 0364-5134

VL - 82

SP - 1004

EP - 1015

JO - Annals of Neurology

JF - Annals of Neurology

IS - 6

ER -

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

Abstract

Keywords

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