Wendy K Chung1, Kimberly Martin2, Chaim Jalas3, Stephen R Braddock2, Jane Juusola4, Kristin G Monaghan4, Barbara Warner5, Samuel Franks6, Marc Yudkoff7, Lauren Lulis7, Roy H Rhodes8, Vinay Prasad9, Erin Torti2, Megan T Cho4, Marwan Shinawi10. 1. Departments of Pediatrics and Medicine, Columbia University Medical Center, New York, New York, USA. 2. Genetics Division, Department of Pediatrics, Saint Louis University School of Medicine, St. Louis, Missouri, USA. 3. Bonei Olam, Center for Rare Jewish Genetic Disorders, Brooklyn, New York, USA. 4. GeneDx, Gaithersburg, Maryland, USA. 5. Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA. 6. Departments of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA. 7. Division of Metabolism, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA. 8. Department of Pathology, Rutgers Robert Wood Johnson Medical School, Rutgers University, Piscataway, New Jersey, USA. 9. Department of Pathology, Nationwide Children's Hospital, The Ohio State University, Columbus, Ohio, USA. 10. Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA.
Abstract
BACKGROUND: The identification of the molecular basis of mitochondrial disorders continues to be challenging and expensive. The increasing usage of next-generation sequencing is facilitating the discovery of the genetic aetiology of heterogeneous phenotypes associated with these conditions. Coenzyme Q(10) (CoQ(10)) is an essential cofactor for mitochondrial respiratory chain complexes and other biochemical pathways. Mutations in genes involved in CoQ(10) biosynthesis cause primary CoQ(10) deficiency syndromes that can be treated with oral supplementation of ubiquinone. METHODS: We used whole exome sequencing to evaluate six probands from four unrelated families with clinical findings suggestive of a mitochondrial disorder. Clinical data were obtained by chart review, parental interviews, direct patient assessment and biochemical and pathological evaluation. RESULTS: We identified five recessive missense mutations in COQ4 segregating with disease in all four families. One mutation was found in a homozygous state in two unrelated Ashkenazi Jewish probands. All patients were female, and presented on the first day of life, and died in the neonatal period or early infancy. Clinical findings included hypotonia (6/6), encephalopathy with EEG abnormalities (4/4), neonatal seizures (3/6), cerebellar atrophy (4/5), cardiomyopathy (5/6) and lactic acidosis (4/6). Autopsy findings in two patients revealed neuron loss and reactive astrocytosis or cerebellar and brainstem hypoplasia and microdysgenesis. CONCLUSIONS: Mutations in COQ4 cause an autosomal recessive lethal neonatal mitochondrial encephalomyopathy associated with a founder mutation in the Ashkenazi Jewish population. The early mortality in our cohort suggests that COQ4 is an essential component of the multisubunit complex required for CoQ(10) biosynthesis. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
BACKGROUND: The identification of the molecular basis of mitochondrial disorders continues to be challenging and expensive. The increasing usage of next-generation sequencing is facilitating the discovery of the genetic aetiology of heterogeneous phenotypes associated with these conditions. Coenzyme Q(10) (CoQ(10)) is an essential cofactor for mitochondrial respiratory chain complexes and other biochemical pathways. Mutations in genes involved in CoQ(10) biosynthesis cause primary CoQ(10) deficiency syndromes that can be treated with oral supplementation of ubiquinone. METHODS: We used whole exome sequencing to evaluate six probands from four unrelated families with clinical findings suggestive of a mitochondrial disorder. Clinical data were obtained by chart review, parental interviews, direct patient assessment and biochemical and pathological evaluation. RESULTS: We identified five recessive missense mutations in COQ4 segregating with disease in all four families. One mutation was found in a homozygous state in two unrelated Ashkenazi Jewish probands. All patients were female, and presented on the first day of life, and died in the neonatal period or early infancy. Clinical findings included hypotonia (6/6), encephalopathy with EEG abnormalities (4/4), neonatal seizures (3/6), cerebellar atrophy (4/5), cardiomyopathy (5/6) and lactic acidosis (4/6). Autopsy findings in two patients revealed neuron loss and reactive astrocytosis or cerebellar and brainstem hypoplasia and microdysgenesis. CONCLUSIONS: Mutations in COQ4 cause an autosomal recessive lethal neonatal mitochondrial encephalomyopathy associated with a founder mutation in the Ashkenazi Jewish population. The early mortality in our cohort suggests that COQ4 is an essential component of the multisubunit complex required for CoQ(10) biosynthesis. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
Entities:
Keywords:
Epilepsy and seizures; Genetics; Metabolic disorders; Molecular genetics; Neurology
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