title: Mutations in COQ4, an essential component of coenzyme Q biosynthesis, cause lethal neonatal mitochondrial encephalomyopathy.
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.
authors.affiliation: Departments of Pediatrics and Medicine, Columbia University Medical Center, New York, New York, USA.
authors.forename: Wendy K
authors.initials: WK
authors.lastname: Chung
authors.affiliation: Genetics Division, Department of Pediatrics, Saint Louis University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Martin
authors.affiliation: Bonei Olam, Center for Rare Jewish Genetic Disorders, Brooklyn, New York, USA.
authors.forename: Chaim
authors.initials: C
authors.lastname: Jalas
authors.affiliation: Genetics Division, Department of Pediatrics, Saint Louis University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Braddock
authors.affiliation: GeneDx, Gaithersburg, Maryland, USA.
authors.forename: Jane
authors.initials: J
authors.lastname: Juusola
authors.affiliation: GeneDx, Gaithersburg, Maryland, USA.
authors.forename: Kristin G
authors.initials: KG
authors.lastname: Monaghan
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Warner
authors.affiliation: Departments of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Samuel
authors.initials: S
authors.lastname: Franks
authors.affiliation: Division of Metabolism, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Yudkoff
authors.affiliation: Division of Metabolism, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors.forename: Lauren
authors.initials: L
authors.lastname: Lulis
authors.affiliation: Department of Pathology, Rutgers Robert Wood Johnson Medical School, Rutgers University, Piscataway, New Jersey, USA.
authors.forename: Roy H
authors.initials: RH
authors.lastname: Rhodes
authors.affiliation: Department of Pathology, Nationwide Children's Hospital, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Vinay
authors.initials: V
authors.lastname: Prasad
authors.affiliation: Genetics Division, Department of Pediatrics, Saint Louis University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Erin
authors.initials: E
authors.lastname: Torti
authors.affiliation: GeneDx, Gaithersburg, Maryland, USA.
authors.forename: Megan T
authors.initials: MT
authors.lastname: Cho
authors.affiliation: Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Marwan
authors.initials: M
authors.lastname: Shinawi
mesh_terms: D005260:Female; D006801:Humans; D007231:Infant, Newborn; D007585:Jews; D017237:Mitochondrial Encephalomyopathies / Q000235:genetics* / Q000401:mortality / Q000503:physiopathology; D024101:Mitochondrial Proteins / Q000235:genetics*; D020125:Mutation, Missense; D011247:Pregnancy; D017422:Sequence Analysis, DNA; D014451:Ubiquinone / Q000096:biosynthesis
chemical_list: C529610:COQ4 protein, human; D024101:Mitochondrial Proteins; D014451:Ubiquinone
keywords: Epilepsy and seizures; Genetics; Metabolic disorders; Molecular genetics; Neurology