- Raphael Schiffmann, MD, MHSc
Raphael Schiffmann, MD, MHSc
- Medical Director of the Institute of Metabolic Disease
- Adjunct Professor of Biomedical Studies
- Baylor University Medical Center
- Section Editors
- Marc C Patterson, MD, FRACP
Marc C Patterson, MD, FRACP
- Section Editor — Pediatric Neurology
- Professor of Neurology, Pediatrics, and Medical Genetics
- Chair, Division of Child and Adolescent Neurology
- Mayo Clinic College of Medicine
- Helen V Firth, DM, FRCP, DCH
Helen V Firth, DM, FRCP, DCH
- Section Editor — Genetics
- Consultant Clinical Geneticist
- Addenbrooke's Hospital, Cambridge, UK
Metachromatic leukodystrophy (sulfatide lipidosis) (MLD) is a rare autosomal recessive lysosomal storage disease that causes progressive demyelination of the central and peripheral nervous system.
This topic will review the clinical manifestations, diagnosis, and treatment of metachromatic leukodystrophy. Other lysosomal storage disorders and leukodystrophies are discussed separately. (See "Adrenoleukodystrophy" and "Alexander disease" and "Aspartoacylase deficiency (Canavan disease)" and "Cerebrotendinous xanthomatosis" and "Neurologic manifestations of Fabry disease" and "Krabbe disease" and "Mucopolysaccharidoses: Clinical features and diagnosis" and "Overview of Niemann-Pick disease" and "Pelizaeus-Merzbacher disease" and "Sjögren-Larsson syndrome" and "Vanishing white matter disease".)
Metachromatic leukodystrophy (MLD) is caused by deficient activity of arylsulfatase A as a result of, in almost all cases, mutations in the arylsulfatase A gene (ARSA gene). In a few patients, MLD is caused by a deficiency of sphingolipid activator protein SAP-B (saposin B), which normally stimulates the degradation of sulfatides by ARSA . This variant form of MLD is caused by mutations in the prosaposin gene (PSAP gene).
ARSA is responsible for the desulfation of cerebroside sulfate, a major glycolipid of myelin. As a result, decreased ARSA activity leads to the accumulation of cerebroside sulfate in the central nervous system, peripheral nerves, kidneys, and other visceral organs. The accumulation of cerebroside sulfate destroys oligodendroglial and Schwann cells, causing central and peripheral demyelination. Electron microscopy shows thickened lines in the myelin whorls and lamellar inclusions of sulfatides in the Schwann cells .
Genetics — At least 60 mutations in the ARSA gene have been described in MLD. Two alleles, A and I, together account for approximately 50 percent of cases [3,4]. These alleles contribute to the different clinical expressions of the disease .To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- Wrobe D, Henseler M, Huettler S, et al. A non-glycosylated and functionally deficient mutant (N215H) of the sphingolipid activator protein B (SAP-B) in a novel case of metachromatic leukodystrophy (MLD). J Inherit Metab Dis 2000; 23:63.
- Thomas PK, King RH, Kocen RS, Brett EM. Comparative ultrastructural observations on peripheral nerve abnormalities in the late infantile, juvenile and late onset forms of metachromatic leukodystrophy. Acta Neuropathol 1977; 39:237.
- Polten A, Fluharty AL, Fluharty CB, et al. Molecular basis of different forms of metachromatic leukodystrophy. N Engl J Med 1991; 324:18.
- Berger J, Löschl B, Bernheimer H, et al. Occurrence, distribution, and phenotype of arylsulfatase A mutations in patients with metachromatic leukodystrophy. Am J Med Genet 1997; 69:335.
- Rauschka H, Colsch B, Baumann N, et al. Late-onset metachromatic leukodystrophy: genotype strongly influences phenotype. Neurology 2006; 67:859.
- Harvey JS, Carey WF, Morris CP. Importance of the glycosylation and polyadenylation variants in metachromatic leukodystrophy pseudodeficiency phenotype. Hum Mol Genet 1998; 7:1215.
- Barth ML, Ward C, Harris A, et al. Frequency of arylsulphatase A pseudodeficiency associated mutations in a healthy population. J Med Genet 1994; 31:667.
- Gustavson KH, Hagberg B. The incidence and genetics of metachromatic leucodystrophy in northern Sweden. Acta Paediatr Scand 1971; 60:585.
- Von Figura K, Gieselmann V, Jacken J. Metachromatic leukodystrophy. In: The Metabolic and Molecular Bases of Inherited Disease, 8th ed, Scriver CR, Beaudet AL, Sly WS, Valle D. (Eds), McGraw-Hill, New York 2001. p.3695.
- Zlotogora J, Bach G, Barak Y, Elian E. Metachromatic leukodystrophy in the habbanite Jews: high frequency in a genetic isolate and screening for heterozygotes. Am J Hum Genet 1980; 32:663.
- Heinisch U, Zlotogora J, Kafert S, Gieselmann V. Multiple mutations are responsible for the high frequency of metachromatic leukodystrophy in a small geographic area. Am J Hum Genet 1995; 56:51.
- Holve S, Hu D, McCandless SE. Metachromatic leukodystrophy in the Navajo: fallout of the American-Indian wars of the nineteenth century. Am J Med Genet 2001; 101:203.
- Bonkowsky JL, Nelson C, Kingston JL, et al. The burden of inherited leukodystrophies in children. Neurology 2010; 75:718.
- Malone MJ, Stoffyn P. Peripheral nerve glycolipids in metachromatic leukodystrophy. Neurology 1967; 17:1033.
- Fressinaud C, Vallat JM, Masson M, et al. Adult-onset metachromatic leukodystrophy presenting as isolated peripheral neuropathy. Neurology 1992; 42:1396.
- Cameron CL, Kang PB, Burns TM, et al. Multifocal slowing of nerve conduction in metachromatic leukodystrophy. Muscle Nerve 2004; 29:531.
- Ries M, Deeg KH. Polyposis of the gallbladder associated with metachromatic leukodystrophy. Eur J Pediatr 1993; 152:450.
- Simanovsky N, Ackerman Z, Kiderman A, Fields S. Unusual gallbladder findings in two brothers with metachromatic leukodystrophy. Pediatr Radiol 1998; 28:706.
- Cappell MS, Marks M, Kirschenbaum H. Massive hemobilia and acalculous cholecystitis due to benign gallbladder polyp. Dig Dis Sci 1993; 38:1156.
- Garavelli L, Rosato S, Mele A, et al. Massive hemobilia and papillomatosis of the gallbladder in metachromatic leukodystrophy: a life-threatening condition. Neuropediatrics 2009; 40:284.
- van Rappard DF, Bugiani M, Boelens JJ, et al. Gallbladder and the risk of polyps and carcinoma in metachromatic leukodystrophy. Neurology 2016; 87:103.
- Mahmood A, Berry J, Wenger DA, et al. Metachromatic leukodystrophy: a case of triplets with the late infantile variant and a systematic review of the literature. J Child Neurol 2010; 25:572.
- Zafeiriou DI, Kontopoulos EE, Michelakakis HM, et al. Neurophysiology and MRI in late-infantile metachromatic leukodystrophy. Pediatr Neurol 1999; 21:843.
- MacFaul R, Cavanagh N, Lake BD, et al. Metachromatic leucodystrophy: review of 38 cases. Arch Dis Child 1982; 57:168.
- Quigley HA, Green WR. Clinical and ultrastructural ocular histopathologic studies of adult-onset metachromatic leukodystrophy. Am J Ophthalmol 1976; 82:472.
- Takakura H, Nakano C, Kasagi S, et al. Multimodality evoked potentials in progression of metachromatic leukodystrophy. Brain Dev 1985; 7:424.
- Wulff CH, Trojaborg W. Adult metachromatic leukodystrophy: neurophysiologic findings. Neurology 1985; 35:1776.
- Dayan AD. Peripheral neuropathy of metachromatic leucodystrophy: observations on segmental demyelination and remyelination and the intracellular distribution of sulphatide. J Neurol Neurosurg Psychiatry 1967; 30:311.
- Luijten JA, Straks W, Blikkendaal-Lieftinck LF, et al. Metachromatic leukodystrophy: a comparative study of the ultrastructural findings in the peripheral nervous system of three cases, one of the late infantile, one of the juvenile and one of the adult form of the disease. Neuropadiatrie 1978; 9:338.
- Schiffmann R, van der Knaap MS. Invited article: an MRI-based approach to the diagnosis of white matter disorders. Neurology 2009; 72:750.
- i Dali C, Hanson LG, Barton NW, et al. Brain N-acetylaspartate levels correlate with motor function in metachromatic leukodystrophy. Neurology 2010; 75:1896.
- Solders M, Martin DA, Andersson C, et al. Hematopoietic SCT: a useful treatment for late metachromatic leukodystrophy. Bone Marrow Transplant 2014; 49:1046.
- de Hosson LD, van de Warrenburg BP, Preijers FW, et al. Adult metachromatic leukodystrophy treated by allo-SCT and a review of the literature. Bone Marrow Transplant 2011; 46:1071.
- Boucher AA, Miller W, Shanley R, et al. Long-term outcomes after allogeneic hematopoietic stem cell transplantation for metachromatic leukodystrophy: the largest single-institution cohort report. Orphanet J Rare Dis 2015; 10:94.
- Groeschel S, Kühl JS, Bley AE, et al. Long-term Outcome of Allogeneic Hematopoietic Stem Cell Transplantation in Patients With Juvenile Metachromatic Leukodystrophy Compared With Nontransplanted Control Patients. JAMA Neurol 2016; 73:1133.
- Batzios SP, Zafeiriou DI. Developing treatment options for metachromatic leukodystrophy. Mol Genet Metab 2012; 105:56.
- Biffi A, Montini E, Lorioli L, et al. Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy. Science 2013; 341:1233158.
- Sessa M, Lorioli L, Fumagalli F, et al. Lentiviral haemopoietic stem-cell gene therapy in early-onset metachromatic leukodystrophy: an ad-hoc analysis of a non-randomised, open-label, phase 1/2 trial. Lancet 2016; 388:476.