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.

• Authors: Roeltje R Maas, Katarzyna Iwanicka-Pronicka, Sema Kalkan Ucar, Bader Alhaddad, Moeenaldeen AlSayed, Mohammed A 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 de Brouwer, Saskia B Wortmann
• Journal: Annals of neurology (Ann Neurol) Vol. 82 Issue 6 Pg. 1004-1015 (Dec 2017) ISSN: 1531-8249 [Electronic] United States
• PMID: 29205472 (Publication Type: Journal Article, Multicenter Study)
• Copyright: © 2017 American Neurological Association.

Chemical References

• Carboxylic Ester Hydrolases
• SERAC1 protein, human

Topics

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