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

被引：50

作者：

Maas, Roeltje R. ^{[1
]}

Iwanicka-Pronicka, Katarzyna ^{[2
]}

Ucar, Sema Kalkan ^{[3
]}

Alhaddad, Bader ^{[4
]}

AlSayed, Moeenaldeen ^{[5
,6
]}

Al-Owain, Mohammed A. ^{[5
,6
]}

Al-Zaidan, Hamad I. ^{[5
,6
]}

Balasubramaniam, Shanti ^{[7
,8
]}

Baric, Ivo ^{[9
,10
]}

Bubshait, Dalal K. ^{[11
]}

Burlina, Alberto ^{[12
]}

Christodoulou, John ^{[7
,13
,14
,15
,16
]}

Chung, Wendy K. ^{[17
,18
]}

Colombo, Roberto ^{[19
,20
]}

Darin, Niklas ^{[21
]}

Freisinger, Peter ^{[22
]}

Garcia Silva, Maria Teresa ^{[23
,24
,25
]}

Grunewald, Stephanie ^{[26
]}

Haack, Tobias B. ^{[4
,27
]}

van Hasselt, Peter M. ^{[28
]}

Hikmat, Omar ^{[29
,30
]}

Hoerster, Friederike ^{[31
]}

Isohanni, Pirjo ^{[32
,33
,34
]}

Ramzan, Khushnooda ^{[5
,6
]}

Kovacs-Nagy, Reka ^{[4
]}

Krumina, Zita ^{[35
]}

Martin-Hernandez, Elena ^{[23
,24
,25
]}

Mayr, Johannes A. ^{[36
,37
]}

McClean, Patricia ^{[38
]}

De Meirleir, Linda ^{[39
]}

Naess, Karin ^{[40
]}

Ngu, Lock H. ^{[41
]}

Pajdowska, Magdalena ^{[42
]}

Rahman, Shamima ^{[43
]}

Riordan, Gillian ^{[44
]}

Riley, Lisa ^{[7
,15
,16
]}

Roeben, Benjamin ^{[45
,46
]}

Rutsch, Frank ^{[47
]}

Santer, Rene ^{[48
]}

Schiff, Manuel ^{[49
,50
]}

Seders, Martine ^{[51
]}

Sequeira, Silvia ^{[52
]}

Sperl, Wolfgang ^{[36
,37
]}

Staufner, Christian ^{[31
]}

Synofzik, Matthis ^{[45
,46
]}

Taylor, Robert W. ^{[53
]}

Trubicka, Joanna ^{[54
]}

Tsiakas, Konstantinos ^{[48
]}

Unal, Ozlem ^{[55
]}

Wassmer, Evangeline ^{[56
]}

机构：

[1] Radboud Univ Nijmegen, Dept Lab Med, Translat Metab Lab, Med Ctr, Nijmegen, Netherlands

[2] Childrens Mem Hlth Inst, Dept Audiol & Phoniatr, Warsaw, Poland

[3] Ege Univ, Div Metab Dis, Dept Pediat, Fac Med, Izmir, Turkey

[4] Tech Univ Munich, Inst Human Genet, Munich, Germany

[5] King Faisal Specialist Hosp & Res Ctr, Dept Genet, Riyadh, Saudi Arabia

[6] Alfaisal Univ, Dept Anat & Cell Biol, Coll Med, Riyadh, Saudi Arabia

[7] Childrens Hosp Westmead, Western Sydney Genet Program, Sydney, NSW, Australia

[8] Univ Sydney, Discipline Genet Med & Paediat & Child Hlth, Sydney, NSW, Australia

[9] Univ Hosp Ctr, Dept Pediat, Zagreb, Croatia

[10] Univ Zagreb, Sch Med, Zagreb, Croatia

[11] Imam Abdulrahman Bin Faisal Univ, Dept Pediat, Coll Med, Dammam, Saudi Arabia

[12] Univ Hosp Padua, Div Inherited Metab Dis, Dept Pediat, Padua, Italy

[13] Univ Melbourne, Murdoch Childrens Res Inst, Neurodev Genom Res Grp, Melbourne, Vic, Australia

[14] Univ Melbourne, Melbourne Med Sch, Dept Paediat, Melbourne, Vic, Australia

[15] Childrens Hosp Westmead, Genet Metab Disorders Res Unit, Sydney, NSW, Australia

[16] Univ Sydney, Sydney Med Sch, Discipline Child & Adolescent Hlth & Genet Med, Sydney, NSW, Australia

[17] Columbia Univ, Dept Pediat, New York, NY 10027 USA

[18] Columbia Univ, Dept Med, New York, NY USA

[19] Univ Cattolica Sacro Cuore, Inst Clin Biochem, Fac Med, Rome, Italy

[20] Niguarda Ca Granda Metropolitan Hosp, Ctr Study Rare Hereditary Dis, Milan, Italy

[21] Univ Gothenburg, Inst Clin Sci, Queen Silvias Childrens Hosp, Dept Pediat, Gothenburg, Sweden

[22] Klinikum Reutlingen, Childrens Hosp, Reutlingen, Germany

[23] 12 Octubre Univ Hosp, Inborn Errors Metab & Mitochondrial Dis Unit, Ave Cordoba Sn, Madrid 28041, Spain

[24] Rare Dis Biomed Res Ctr CIBERER, Madrid, Spain

[25] Univ Complutense Madrid, Madrid, Spain

[26] UCL, Great Ormond St Hosp Children Natl Hlth Serv Fdn, Inst Child Hlth, Metab Med Dept, London, England

[27] Inst Med Genet & Appl Genom, Tubingen, Germany

[28] Univ Med Ctr Utrecht, Wilhelmina Childrens Hosp Utrecht, Utrecht, Netherlands

[29] Haukeland Hosp, Dept Pediat, Bergen, Norway

[30] Univ Bergen, Dept Clin Med K1, Bergen, Norway

[31] Univ Hosp Heidelberg, Div Neuropediat & Pediat Metab Med, Dept Gen Pediat, Heidelberg, Germany

[32] Univ Helsinki, Childrens Hosp, Helsinki, Finland

[33] Helsinki Univ Hosp, Helsinki, Finland

[34] Univ Helsinki, Res Programs Unit, Mol Neurol, Biomedicum Helsinki, Helsinki, Finland

[35] Riga Stradins Univ, Dept Biol & Microbiol, Riga, Latvia

[36] Salzburg State Hosp, Dept Pediat, Salzburg, Austria

[37] Paracelsus Med Univ, Mullner Hauptsrasse 38, A-5020 Salzburg, Austria

[38] Leeds Teaching Hosp Natl Hlth Serv Trust, Leeds, W Yorkshire, England

[39] Brussels Univ Hosp, Pediat Neurol, Brussels, Belgium

[40] Karolinska Univ Hosp, Dept Pediat Neurol, Stockholm, Sweden

[41] Kuala Lumpur Hosp, Div Clin Genet, Dept Genet, Kuala Lumpur, Malaysia

[42] Childrens Mem Hlth Inst, Dept Clin Biochem Radioimmunol & Expt Med, Warsaw, Poland

[43] UCL, Great Ormond St Inst Child Hlth, London, England

[44] Red Cross War Mem Childrens Hosp, Dept Pediat Neurol, Cape Town, South Africa

[45] Univ Tubingen, Hertie Inst Clin Brain Res, Dept Neurodegenerat, Tubingen, Germany

[46] German Ctr Neurodegenerat Dis DZNE, Tubingen, Germany

[47] Munster Univ, Dept Gen Pediat, Childrens Hosp, Munster, Germany

[48] Univ Med Ctr Eppendorf, Dept Pediat, Hamburg, Germany

[49] Univ Paris Diderot, Reference Ctr Inherited Metab Dis, Robert Debre Hosp, AP HP,Sorbonne Paris Cite, Paris, France

[50] INSERM, U1141, Paris, France

来源：

ANNALS OF NEUROLOGY | 2017年 / 82卷 / 06期

基金：

英国医学研究理事会; 奥地利科学基金会;

关键词：

MEGDEL SYNDROME; 3-METHYLGLUTACONIC ACIDURIA; MITOCHONDRIAL DYSFUNCTION; DEFICIENCY; PHENOTYPE; ENCEPHALOPATHY; BIOSYNTHESIS; MANAGEMENT; DIAGNOSIS; DISORDER;

D O I：

10.1002/ana.25110

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

Objective3-Methylglutaconic aciduria, dystonia-deafness, hepatopathy, encephalopathy, Leigh-like syndrome (MEGDHEL) syndrome is caused by biallelic variants in SERAC1. MethodsThis multicenter study addressed the course of disease for each organ system. Metabolic, neuroradiological, and genetic findings are reported. ResultsSixty-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. InterpretationMEGDHEL 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

引用

页码：1004 / 1015

页数：12

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