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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.

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


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 Here, we report 11 individuals, of whom 2 are previously unpublished, with biallelic variants in high temperature requirement protein A2 (HTRA2) encoding a mitochondria-localized serine protease.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.


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