Inherited Leukoencephalopathies

Transcription

1 3 Inherited Leukoencephalopathies Deborah L. Renaud, M.D. 1 1 Departments of Neurology and Pediatrics, Mayo Clinic, Rochester, Minnesota Semin Neurol 2012;32:3 8. Leukoencephalopathies are conditions that selectively involve the white matter of the brain. A great deal has been written about acquired causes of leukoencephalopathy, which include inflammatory conditions such as multiple sclerosis, infections, nutritional disorders, neoplasia, acquired toxic causes, and disturbances of blood flow. This special issue of Seminars in Neurology focuses on hereditary leukoencephalopathies. In the past, the primary focus has been on those hereditary leukoencephalopathies with progressive destruction or loss of previously acquired myelin (leukodystrophies). In recent years, several new hereditary leukoencephalopathies have been described that are associated with impaired formation or metabolism of myelin (including conditions with dysmyelination or hypomyelination). Despite recent advances in our knowledge about the molecular causes of leukoencephalopathy ( Table 1), 50% of patients with hereditary leukoencephalopathies remain undiagnosed. The contributions in this issue first outline the formation and metabolism of normal myelin and the developmental evolution of normal myelin as seen on magnetic resonance imaging (MRI). A general approach to leukoencephalopathies is provided that forms a foundation for a clinical / etiology-based approach to hereditary leukoencephalopathies. The articles in this issue of Seminars in Neurology focus not on individual disorders, but present a more expansive evaluation of hereditary leukoencephalopathies based on common clinical features or underlying etiology. M. Mateo Paz Soldán, M.D., Ph.D., and Istvan Pirko, M.D., multiple sclerosis specialists at the Mayo Clinic, share their extensive knowledge of normal myelin formation and metabolism in a concise and very understandable introductory article that forms the basis for the understanding of the pathology associated with hereditary leukoencephalopathies. To evaluate the pattern of abnormal myelination demonstrated by MRI, it is important to understand the evolution of normal myelin development. Kirk M. Welker, M. D., and Alice Patton, M.D., pediatric neuroradiologists at the Mayo Clinic, present the normal neuroimaging appearance of myelin at different ages. Leukoencephalopathies associated with macrocephaly comprise a distinct group including Alexander's disease and Canavan's disease as well as less known leukoencephalopathies that should be considered in the differential diagnosis of these conditions. Bwee Tien Poll-The, M.D., Ph.D., an internationally recognized expert in peroxisomal disorders from Emma Children's Hospital AMC and the University of Amsterdam, presents a thorough review of peroxisomal biogenesis defects and single enzyme disorders that present with leukoencephalopathy. Metachromatic leukodystrophy and Krabbe disease are among the most recognized hereditary disorders of white matter. In recent years, white matter abnormalities have been found in other lysosomal storage disorders, which are also described. Mitochondrial disorders are increasingly recognized in patients with hereditary leukoencephalopathy. Lee-Jun C. Wong, Ph.D., Professor of Molecular and Human Genetics at Baylor College of Medicine, has recently described a detailed molecular algorithm for mitochondrial disorders and shares her approach to the classification and diagnosis of these complicated disorders with us. Pelizaeus-Merzbacher disease is by the far the most recognized leukoencephalopathy associated with hypomyelination. Grace M. Hobson, Ph.D., Head of the Neurogenetics Research Laboratory and Director of Diagnostics for Pelizaeus-Merzbacher Disease at the Nemours Alfred I. dupont Hospital for Children, has contributed significantly to our understanding of the molecular mechanisms in Pelizaeus-Merzbacher disease. Address for correspondence and reprint requests Deborah L. Renaud, M.D., Co-Director, Mayo Clinic Peroxisomal Disorders Program; Consultant and Assistant Professor, Division of Child and Adolescent Neurology, Departments of Neurology and Pediatrics, Mayo Clinic, 200 First St. SW, Rochester, MN ( renaud.deborah@mayo. edu). Issue Theme Inherited Leukoencephalopathies; Guest Editor, Deborah L. Renaud, M.D. Copyright 2012 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) DOI /s ISSN

2 4 Table 1 Hereditary Leukoencephalopathies Alexander's disease AD GFAP Glial fibrillary acidic protein Childhood ataxia with central hypomyelination/ vanishing white matter disease (CACH/VWMD) Megalencephalic leukoencephalopathy MLC1 with subcortical cysts (MLC) Megalencephalic leukoencephalopathy with subcortical cysts (MLC) Lysosomal disorders Metachromatic Leukodystrophy SA PSAP EIF2B1, EIF2B2, EIF2B3, EIF2B4, EIF2B5 HEPACAM GlialCAM Eukaryotic translation initiation factor 2B, subunits 1 5 Arylsulfatase-A Saposin B Multiple sulfatase deficiency SUMF1 Sulfatase modifying factor-1 Krabbe's disease GALC PSAP Galactosylceramidase Saposin A GM1-gangliosidosis GLB1 Beta galactosidase Tay-Sachs disease, HEXA Hexosaminidase A GM2-gangliosidosis Mucolipidosis IV MCOLN1 Mucolipin-1 Fucosidosis FUCA1 Alpha-1-fucosidase Fabry's disease X-Linked GLA Alpha-galactosidase A Salla's disease (free sialic acid storage disease) SLC17A5 Solute carrier family 17 (sodium phosphate cotransporter) Peroxisomal disorders Adrenoleukodystrophy X-linked ABCD1 (ALDP) ATP-binding cassette (ABC) transporter Peroxisomal biogenesis defects Multiple PEX genes Various peroxins (Zellweger's spectrum disorders) D-bifunctional protein deficiency HSD17B4 D-bifunctional protein Peroxisomal acyl-coa oxidase 1 deficiency ACOX1 Peroxisomal acyl-coa oxidase 1 Rhizomelic chondrodysplasia punctata type 1 PEX7 Peroxisomal type 2 targeting signal (PTS2) receptor Rhizomelic chondrodysplasia punctata type 2 GNPAT Dihydroxyacetone phosphate acyltransferase Rhizomelic chondrodysplasia punctata type 3 AGPS Alkyl-DHAP synthase Mitochondrial disorders Respiratory chain defects Any Multiple nuclear Multiple and mtdna genes MNGIE (mitochondrial neurogastrointestinal TYMP Thymidine phosphorylase encephalopathy syndrome) MNGIE with normal thymidine RRM2B P53 inducible-ribonucleotide reductase POLG-related disorders AD, POLG DNA polymerase gamma Navaho neurohepatopathy (NNH) MPV17 LBSL (leukoencephalopathy with brainstem andspinalcordinvolvement and lactate elevation) DS2 Mitochondrial aspartyl-trna synthetase

3 5 Remethylation cycle disorders MTHFR (methylenetetrahydrofolate reductase deficiency) MTHFR Methylenetetrahydrofolate reductase Cobalamin C disease MMACHC Cerebral folate deficiency FOLR1 Folate receptor alpha Organic acidemias Canavan's disease ASPA aspartoacylase Glutaric aciduria type 1 GCDH Glutaryl-CoA dehydrogenase L-2-hydroxyglutaric aciduria L2HGDH L2-hydroxyglutarate dehydrogenase 3-methylglutaconic aciduria type 1 AUH 3-methylglutaconyl-CoA hydratase Biotinidase deficiency BTD biotinidase Amino acid disorders Serine synthesis defects PSAT1 Phosphoserine aminotransferase PHGDH Phosphoglycerate dehydrogenase Phenylketonuria (PKU) PAH Phenylalanine hydroxylase Associated with calcifications Aicardi-Goutieres' syndrome AGS1 AD, TREX1 3'! 5' DNA exonuclease AGS2 RNASEH2B ribonuclease H2, subunit B AGS3 RNASEH2C ribonuclease H2, subunit C AGS4 RNASEH2A ribonuclease H2, subunit A AGS5 SAMHD1 SAM-domain and HD-domain-containing protein 1 Cystic leukoencephalopathy RNASET2 Ribonuclease T2 without megalencephaly Labrune's syndrome (cerebroretinal microangiopathy with calcifications and cysts) Unknown Unknown Nasu-Hakola's disease TREM2 DAP12 Cockayne's syndrome ERCC6 ERCC8 Associated with hypomyelination Triggering receptor expressed on myeloid cells 2 DNAX-activation protein 12 Excision repair cross-complementing group 6 and 8 Pelizaeus-Merzbacher disease X-linked PLP1 Proteolipid protein 1 Pelizaeus-Merzbacher-like disease GJC2 Connexin 46.6 Allan-Herndon-Dudley's disease X-linked MCT8 (SLC16A2) MCT8-specific thyroid hormone cell transporter Hypomyelination with congenital cataracts (HCC) FAM126A Hyccin Hypomyelination with hypogonadotrophic hypogonadism and hypodontia (4H) Tremor-ataxia with central hypomyelination (TACH) Leukodystrophy with hypodontia (LO) POLR3A POLR3B RNA polymerase III subunit 3A RNA polymerase III subunit 3B (Continued)

4 6 Hypomyelination with cerebellar atrophy and hypoplasia of the corpus callosum (HCAHC) Hypomyelination with atrophy of basal ganglia and cerebellum (HABC) Waadenburg-Hirshsprung's syndrome with peripheral neuropathy and central hypomyelination Tay's syndrome (trichothiodystrophy with hypersensitivity to sunlight) POLR3A POLR3B Unknown Unknown Unknown RNA polymerase III subunit 3A RNA polymerase III subunit 3B SOX10 Sry box10 transcription factor ERCC3 ERCC2 GTF2H5 General transcription factor IIH subunits Oculodentodigital syndrome AD () GJA1 Connexin-43 West's syndrome with severe cerebral hypomyelination, spastic quadriplegia and developmental delay AD SPTAN1 Alpha-II spectrin Hypomyelinating leukodystrophy 3 (HLD3) AIMP1 Aminoacyl-tRNA Synthetase complex-interacting multifunctional protein 1 Associated with vasculopathy CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) AD NOTCH3 Notch receptor CASIL (cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy) HTRA1 SerineproteaseHTRA1 Hereditary angiopathy with nephropathy, AD COL4A1 Collagen, type IV, alpha-1 aneurysms, and muscle cramps (HANAC) Retinal vasculopathy with AD TREX1 3'! 5' DNA exonuclease cerebral leukodystrophy Associated with abnormal lipid metabolism Cerebrotendinous xanthomatosis CYP27A1 Sterol 27-hydroxylase Sjögren-Larsson's syndrome ALDH3A2 Fatty aldehyde dehydrogenase ELOVL4 deficiency ELOVL4 Elongation of very long chain fatty acids-4 Spastic paraplegia 35 FA2H Fatty acid 2-hydroxylase Associated with muscular dystrophy Merosin-deficient congenital muscular dystrophy (MDC1A) LAMA2 Laminin alpha-2 Muscular dystrophy-dystroglycanopathy (congenital with mental retardation), type B, 6 (MDDGB6) Muscular dystrophy-dystroglycanopathy (congenital with and without mental retardation), type B, 5 (MDDGB5) LGE Acetylglucosaminyltransferase-like protein FKRP Fukutin-related protein Adult-onset leukodystrophies Adult-onset autosomal dominant AD LMNB1 Lamin B1 duplication leukodystrophy (ADLD) Adult polyglucosan body disease GBE1 Glycogen brancher enzyme Neuroaxonal leukodystrophy with spheroids AD Unknown Unknown

5 7 Chromosome abnormalities 18q-deletion syndrome Fragile X-associated tremor/ ataxia syndrome (FXTAS) Klinefelter's syndrome Microdeletion syndromes AD, autosomal dominant;, autosomal recessive. X-linked FMR1 Trinucleotide repeat expansion Fragile X mental retardation 1 James Y. Garbern, M.D., Ph.D., was an internationally recognized expert in Pelizaeus-Merzbacher disease who traveled the world to share his clinical expertise. The leukodystrophy community was saddened by Dr. Garbern's death on November 10, 2011 after a battle with cancer. Disorders of vitamin B12 and folate metabolism are underrecognized but potentially treatable causes of leukoencephalopathy. It is a privilege to have Dr. Bridget Wilcken, an internationally recognized expert in homocysteine and vitamin B12 metabolism from The Children's Hospital at Westmead, Australia, describe these important pathways and their contribution to white matter disorders. Neuroicthyoses are also underrecognized causes of leukoencephalopathies. William B. Rizzo, M.D., is at the forefront of this field and provides a unique perspective and approach to the patient with neuroicthyosis. In recent years, an increasing number of hereditary leukoencephalopathies have been described with onset in adulthood. Jan-Mendelt Tillema, M.D., a Multiple Sclerosis Fellow at the Mayo Clinic, reviews our current knowledge of adultonset leukoencephalopathies.