title: Diagnosis by whole exome sequencing of atypical infantile onset Alexander disease masquerading as a mitochondrial disorder.
abstract: BACKGROUND
  There are many similarities, both clinical and radiological, between mitochondrial leukoencephalopathies and Alexander disease, an astrogliopathy. Clinically, both can manifest with a myriad of symptoms and signs, arising from the neonatal period to adulthood. Radiologically, both can demonstrate white matter changes, signal abnormalities of basal ganglia or thalami, brainstem abnormalities and contrast enhancement of white matter structures. Magnetic resonance spectroscopy may reveal elevation of lactate in the abnormal white matter in Alexander disease making the distinction even more challenging.
  
  
  METHODS
  We present a child who was considered to have an infantile onset mitochondrial disorder due to a combination of neurological symptoms and signs (developmental regression, failure to thrive, episodic deterioration, abnormal eye movements, pyramidal and cerebellar signs), urinary excretion of 3-methyl-glutaconic acid and imaging findings (extensive white matter changes and cerebellar atrophy) with a normal head circumference. Whole exome sequence analysis was performed.
  
  
  RESULTS
  The child was found to harbor the R416W mutation, one of the most prevalent mutations in the glial fibrillary acidic protein (GFAP) gene that causes Alexander disease.
  
  
  CONCLUSIONS
  Alexander disease should be considered in the differential diagnosis of infantile leukoencephalopathy, even when no macrocephaly is present. Next generation sequencing is a useful aid in unraveling the molecular etiology of leukoencephalopathies.
authors.affiliation: Metabolic-Neurogenetic Clinic, Wolfson Medical Center, Holon, affiliated to Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel; Child Development Center, Central District, Maccabi Health Services, Tel Aviv, Israel; Pediatric Neurology Unit, Wolfson Medical Center, Holon, affiliated to Sackler School of Medicine, Tel-Aviv University, Israel.
authors.forename: Daniella
authors.initials: D
authors.lastname: Nishri
authors.affiliation: Pediatric Neurology Unit, Hadassah Medical Center, Jerusalem, affiliated to Hebrew University, Jerusalem, Israel.
authors.forename: Simon
authors.initials: S
authors.lastname: Edvardson
authors.affiliation: Metabolic-Neurogenetic Clinic, Wolfson Medical Center, Holon, affiliated to Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel; Institute of Medical Genetics, Wolfson Medical Center, Holon, affiliated to Sackler School of Medicine, Tel-Aviv University, Israel.
authors.forename: Dorit
authors.initials: D
authors.lastname: Lev
authors.affiliation: Metabolic-Neurogenetic Clinic, Wolfson Medical Center, Holon, affiliated to Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel; Institute of Medical Genetics, Wolfson Medical Center, Holon, affiliated to Sackler School of Medicine, Tel-Aviv University, Israel; Molecular Genetics Laboratory, Wolfson Medical Center, Holon, affiliated to Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: Esther
authors.initials: E
authors.lastname: Leshinsky-Silver
authors.affiliation: Pediatric Radiology Unit, Tel Aviv Medical Center, Tel Aviv, affiliated to Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: Liat
authors.initials: L
authors.lastname: Ben-Sira
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Division of Pediatric Neurology, University Medical Center Göttingen, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Henneke
authors.affiliation: Metabolic-Neurogenetic Clinic, Wolfson Medical Center, Holon, affiliated to Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel; Pediatric Neurology Unit, Wolfson Medical Center, Holon, affiliated to Sackler School of Medicine, Tel-Aviv University, Israel.
authors.forename: Tally
authors.initials: T
authors.lastname: Lerman-Sagie
authors.affiliation: Metabolic-Neurogenetic Clinic, Wolfson Medical Center, Holon, affiliated to Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel; Pediatric Neurology Unit, Wolfson Medical Center, Holon, affiliated to Sackler School of Medicine, Tel-Aviv University, Israel. Electronic address: luba.blumkin@gmail.com.
authors.forename: Lubov
authors.initials: L
authors.lastname: Blumkin
mesh_terms: D038261:Alexander Disease / Q000175:diagnosis* / Q000235:genetics*; D001120:Arginine / Q000235:genetics; D002675:Child, Preschool; D059472:Exome / Q000235:genetics*; D005260:Female; D005625:Frontal Lobe / Q000473:pathology; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008279:Magnetic Resonance Imaging; D028361:Mitochondrial Diseases / Q000503:physiopathology*; D009154:Mutation / Q000235:genetics*; D014364:Tryptophan / Q000235:genetics; D066127:White Matter / Q000473:pathology
chemical_list: D005904:Glial Fibrillary Acidic Protein; D014364:Tryptophan; D001120:Arginine
keywords: Alexander disease; Lactic acid; Leukoencephalopathy; Mitochondrial disorders