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Neuropediatrics. 2018 Dec;49(6):373-378. doi: 10.1055/s-0038-1667345. Epub 2018 Aug 16.

HTRA2 Defect: A Recognizable Inborn Error of Metabolism with 3-Methylglutaconic Aciduria as Discriminating Feature Characterized by Neonatal Movement Disorder and Epilepsy-Report of 11 Patients.

Author information

1
Institute of Human Genetics, Technische Universität München, Munich, Germany.
2
Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, Budapest, Hungary.
3
Service of Clinical Genetics, Amiens University Hospital, Amiens, France.
4
Department of Biotechnology, College of Science, Baghdad University, Baghdad, Iraq.
5
Centogene AG, Rostock, Germany.
6
Department of Pediatrics, College of Medicine, Children Welfare Teaching Hospital, Baghdad University, Baghdad, Iraq.
7
Department of Pediatrics, Salzburger Landeskliniken, Paracelsus Medical University, Salzburg, Austria.
8
Institute of Human Genetics, Helmholtz Zentrum München, Munich, Germany.

Abstract

Neonatal-onset movement disorders, especially in combination with seizures, are rare and often related to mitochondrial disorders. 3-methylglutaconic aciduria (3-MGA-uria) is a marker for mitochondrial dysfunction. In particular, consistently elevated urinary excretion of 3-methylglutaconic acid is the hallmark of a small but growing group of inborn errors of metabolism (IEM) due to defective phospholipid remodeling or mitochondrial membrane-associated disorders (mutations in TAZ, SERAC1, OPA3, CLPB, DNAJC19, TMEM70, TIMM50). Exome/genome sequencing is a powerful tool for the diagnosis of the clinically and genetically heterogeneous mitochondrial disorders. Here, we report 11 individuals, of whom 2 are previously unpublished, with biallelic variants in high temperature requirement protein A2 (HTRA2) encoding a mitochondria-localized serine protease. All individuals presented a recognizable phenotype with neonatal- or infantile-onset neurodegeneration and death within the first month of life. Hallmark features were central hypopnea/apnea leading to respiratory insufficiency, seizures, neutropenia, 3-MGA-uria, tonus dysregulation, and dysphagia. Tremor, jitteriness, dystonia, and/or clonus were also common. HTRA2 defect should be grouped under the IEM with 3-MGA-uria as discriminating feature. Clinical characteristics overlap with other disorders of this group suggesting a common underlying pathomechanism. Urinary organic acid analysis is a noninvasive and inexpensive test that can guide further genetic testing in children with suggestive clinical findings.

PMID:
30114719
DOI:
10.1055/s-0038-1667345

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