The latest on leukodystrophies.
OBJECTIVE
Important advances in our understanding of genetic disorders of the white matter have been made and are discussed here.


RESULTS
It has recently been discovered that mutations in the genes encoding the five subunits of eukaryocytic initiation factor 2B (eIF2B) are the cause of vanishing white-matter disease/childhood ataxia with central hypomyelination syndrome. The extension of the clinical features of the eIF2B-related disorders to encompass both infant- and adult-onset disorders is discussed. New clinico-imaging syndromes such as hypomyelination with atrophy of the basal ganglia and cerebellum and leukoencephalopathy with brain-stem and spinal cord involvement and elevated white-matter lactate are described. Recent findings include evidence that mitochondrial fat-oxidation abnormalities may be important in the pathogenesis of adrenoleukodystrophy, and that a mutant myelin protein can cause maldistribution of other myelin proteins, causing dysmyelination, axonal damage, or both.


CONCLUSIONS
This review focuses on advances in the understanding of the role of eIF2B as a cause of a common leukodystrophy syndrome. eIF2B-related disorders have a clinical spectrum ranging from a severe, rapidly progressive congenital or early infantile encephalopathy to a slowly progressive cognitive and motor deterioration often associated with premature ovarian failure. Two newly recognized leukodystrophy syndromes are described: hypomyelination with atrophy of the basal ganglia and cerebellum, and leukoencephalopathy with brain-stem and spinal cord involvement and elevated white-matter lactate. An update is also given for adrenoleukodystrophy and myelin-protein-related disorders. This update demonstrates that an increasing number of genetic defects are being identified that may cause primary white-matter disorders.
Schiffmann
Raphael
R
Developmental and Metabolic Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
van der Knaap
Marjo S
MS
D000326:Adrenoleukodystrophy / Q000175:diagnosis / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D000328:Adult; D001284:Atrophy; D001921:Brain / Q000473:pathology / Q000503:physiopathology*; D002648:Child; D004252:DNA Mutational Analysis; D003937:Diagnosis, Differential; D004734:Energy Metabolism / Q000235:genetics / Q000502:physiology; D020717:Eukaryotic Initiation Factor-2B / Q000235:genetics*; D020279:Hereditary Central Nervous System Demyelinating Diseases / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D007223:Infant; D009185:Myelin Proteins / Q000235:genetics; D009413:Nerve Fibers, Myelinated / Q000473:pathology; D011510:Proteolipids / Q000378:metabolism; D013106:Sphingolipidoses / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D013116:Spinal Cord / Q000473:pathology / Q000503:physiopathology*; D013577:Syndrome
D020717:Eukaryotic Initiation Factor-2B; D009185:Myelin Proteins; D011510:Proteolipids