Lysosomal storage diseases (LSDs) are a group of hereditary disorders that disrupt lysosomal function, specifically, enzymes involved in cell metabolism, signaling, substrate processing, innate immunity, apoptosis, and other complex cell recycling processes. This process is extremely complex. The accumulation of undigested or partially processed molecules become toxic for the host cell. The onset tends to predominate in early infancy or childhood, with some disease onset in adulthood. LSDs tend to have a progressive neurodegenerative course and can cause multi-organ failure and, ultimately, death.[1]
Leukodystrophies are inherited disorders that predominantly affect the central nervous system (CNS) white matter tracts, and it's cellular components. These may include glial cells, myelin sheath, and axons. Genetic leukodystrophies tend to combine features of leukodystrophies with development issues caused by inborn errors of metabolism, disorders of DNA transcription, translation, production of critical CNS proteins including myelin, and neuronal cytoskeletal dysfunction.
Metachromatic leukodystrophy is a demyelinating, autosomal recessive genetic leukodystrophy and LSD, caused by an inborn error of metabolism in the arylsulfatase A lysosomal enzyme. This leads to the accumulation of sulfatides, which result in the dysfunction and destruction of the CNS/PNS myelin sheaths. It also accumulates in other organs, including the kidneys, testes, and gallbladder. It can be classified based on the age of onset and clinical features of the disease. All forms of the disease involve a progressive deterioration of neurodevelopment and neurocognitive function.[2]
Metachromatic leukodystrophy is caused by deficient activity of arylsulfatase A. In almost all cases, mutations are in the arylsulfatase A gene (ARSA gene), on chromosome 22q13.3-qter. Two alleles, A and I have contributed to approximately 50 percent of cases and are responsible for different clinical expression of the disease.[3] In some cases, it is due to the deficiency of sphingolipid activator protein SAP-B (saposin B), which is responsible for the degradation of sulfatides by ARSA. This form is caused by mutations in the prosaposin gene (PSAP gene).[4][5]
The prevalence of metachromatic leukodystrophy ranges from 1/40,000 to 1/100,000 in the northern European and North American populations.[6] Incidence is estimated to be 1/40,000 births in the United States of America. There is no sexual and racial predilection. The disease is categorized based on the age of onset.
Metachromatic leukodystrophy is a lysosomal storage disease characterized by the inability to degrade sulfated glycolipids, mainly the galactosyl-3-sulfate ceramides. It is caused by deficient activity of lysosomal enzyme arylsulfatase A, most commonly due to mutations in the arylsulfatase A (ARSA gene). During the process, the sulfated glycolipids are degraded into galactocerebroside by the enzyme Arylsulfatase A.
Metachromatic granules may be seen in the tissue specimen. In the nervous system, the loss of myelinated oligodendrocytes is seen.
Leukodystrophies are generally suspected in pediatric patients with difficulties in meeting appropriate development milestones when previously was able to do so. Peripheral neuropathy can present prior to dysarthria and other CNS manifestations.[7][8] A decline in gross and fine motor skills at any age should be evaluated for metachromatic leukodystrophy. Clinical manifestations of the diseases can be categorized by the age at which the disease onset.[9]
Laboratory Studies:
Arylsulfatase A enzyme activity in leukocytes or cultured skin fibroblasts may be decreased.[12] Values generally range from undetectable to less than 10 percent of the normal values. However, Metachromatic Leukodystrophy must be distinguished from arylsulfatase A pseudo deficiency (present in approximately one percent of the general population). Patients with arylsulfatase A pseudo deficiency has arylsulfatase A levels ranging from 5% to 20% of normal values without clinical or radiographic disease. The followings tests can be used to differentiate them:
Imaging Studies
Brain MRI shows T2-weighted FLAIR symmetric and confluent hyperintensities diffusely on the frontal and parietal periventricular white matter, which are characteristic of the diseases but nonspecific. T1-weighted images tend to be hypointense, given it is a demyelinating disorder. A normal MRI does not exclude metachromatic leukodystrophy.[13]
Ultrasound or CT abdomen may reveal hyperplastic gallbladder polyps, which can predispose for gallbladder carcinoma.[14]
Additional Tests
The following tests can be conducted with could further help in diagnosing the case.
Procedures
Newborn Screening
No curative treatment options are currently available for this disease—the focus in the enhancement of the quality of life by focusing on symptom management. Symptomatic supportive care is needed to address to neurocognitive and neuropsychiatric disturbances, seizures, dystonias, spasticity, feeding problems, and constipation.
Symptomatic Treatment
Genetic Counseling
MLD is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing of at-risk family members and prenatal testing for a pregnancy at increased risk are possible if both ARSA pathogenic variants have been identified in an affected family member.
Experimental and emerging therapies:
Hence, preliminary evidence suggests that gene therapy and hematopoietic stem cell transplantation combined with gene therapy are promising treatment options.[21] However, the cellular pathogenesis of metachromatic leukodystrophy is complex. Several other LSDs have used disease-specific gene and enzyme replacement therapies with some success. Small-molecule therapies are emergent therapy for some LSDs. Although gene therapy and genome microRNA editing are at advanced preclinical stages, there is a need for phase III/IV clinical trials.
Metachromatic leukodystrophy must be differentiated from other LSDs with similar presentation and with arylsulfatase A pseudodeficiency. Arylsulfatase A pseudodeficiency can be differentiated using gene mutation analysis or evaluation of radiolabeled sulfatide fibroblast uptake and accumulation. Other differentials that must be kept in mind while diagnosing metachromatic leukodystrophy are:
Metachromatic leukodystrophy is a progressive disease. This means that the symptoms tend to get worse over time. People who have this disease lose all muscle and mental functions eventually. Lifespan often depends on the age at which a person is first diagnosed.
Therapies focus on the quality of life, and functional activities of daily living can help in areas of mobility, cognition, communication, and oral intake. Safety measures are to avoid falls at home. The most common complications of the disease include:
Regular consultations with followings specialists are generally needed:
Patients often find it difficult to carry out activities of daily living as the condition worsens. Patients and family members should be properly counseled about the progressive nature of the disease and the prognosis. Some of the related complications and co-morbidities are gastroesophageal reflux, constipation, dental caries, impaired vision, among others. Pharmacological management, physical therapies, and family support can help prevent further decline of the patient and improve quality of life.
Metachromatic leukodystrophy is an autosomal recessive condition. Parents require counseling about the inheritance pattern of the condition if the family has a positive family history of the condition.
Metachromatic leukodystrophy is an autosomal recessive lysosomal disorder that results in a buildup of sulfatides that leads to the destruction of the myelin sheath, leading to progressive demyelination of the central and peripheral nervous system. Once the diagnosis is made, an interprofessional approach is vital.
Medical centers with specialty teams can offer information about the disorder, coordinate care among specialists, help evaluate options, and provide treatment. Primary care physicians, neurology physicians, pathologists, radiologists, physiotherapists, among others, can form a collaborative team for the best possible outcome. A physical therapist, occupational therapist, orthopedist, ophthalmologist, neuropsychologist, and other specialists may be involved are often needed for long term follow up and evaluation. Working with a nutrition specialist (dietitian) can help provide proper nutrition. Eventually, it may become difficult to swallow food or liquid. This may require assistive feeding devices as the condition progresses.
The role of the nurse in education is indispensable. The patient and the family need to know about the course of the disease, lifestyle modifications, and the need to follow up. The physical and occupational therapist should be consulted to assist with ambulation, use of an ambulatory device, and how to perform daily living activities. Couples with a family history of the disease should be offered genetic counseling during pregnancy.
[1] | Platt FM,d'Azzo A,Davidson BL,Neufeld EF,Tifft CJ, Lysosomal storage diseases. Nature reviews. Disease primers. 2018 Oct 1 [PubMed PMID: 30275469] |
[2] | Vanderver A,Prust M,Tonduti D,Mochel F,Hussey HM,Helman G,Garbern J,Eichler F,Labauge P,Aubourg P,Rodriguez D,Patterson MC,Van Hove JL,Schmidt J,Wolf NI,Boespflug-Tanguy O,Schiffmann R,van der Knaap MS, Case definition and classification of leukodystrophies and leukoencephalopathies. Molecular genetics and metabolism. 2015 Apr [PubMed PMID: 25649058] |
[3] | Cesani M,Lorioli L,Grossi S,Amico G,Fumagalli F,Spiga I,Filocamo M,Biffi A, Mutation Update of ARSA and PSAP Genes Causing Metachromatic Leukodystrophy. Human mutation. 2016 Jan; [PubMed PMID: 26462614] |
[4] | Madaan P,Jauhari P,Chakrabarty B,Kumar A,Gulati S, Saposin B-Deficient Metachromatic Leukodystrophy Mimicking Acute Flaccid Paralysis. Neuropediatrics. 2019 Oct; [PubMed PMID: 31319425] |
[5] | Kolnikova M,Jungova P,Skopkova M,Foltan T,Gasperikova D,Mattosova S,Chandoga J, Late Infantile Metachromatic Leukodystrophy Due to Novel Pathogenic Variants in the PSAP Gene. Journal of molecular neuroscience : MN. 2019 Apr; [PubMed PMID: 30632081] |
[6] | Ługowska A,Ponińska J,Krajewski P,Broda G,Płoski R, Population carrier rates of pathogenic ARSA gene mutations: is metachromatic leukodystrophy underdiagnosed? PloS one. 2011 [PubMed PMID: 21695197] |
[7] | Martinez AC,Ferrer MT,Fueyo E,Galdos L, Peripheral neuropathy detected on electrophysiological study as first manifestation of metachromatic leucodystrophy in infancy. Journal of neurology, neurosurgery, and psychiatry. 1975 Feb [PubMed PMID: 1151398] |
[8] | Duckett S,Cracco J,Graziani L,Scott TG,Solomon D,Kradin R, Inclusions in the sural nerve in metachromatic leukodystrophy. Acta neurologica latinoamericana. 1975 [PubMed PMID: 1244002] |
[9] | Kehrer C,Blumenstock G,Gieselmann V,Krägeloh-Mann I, The natural course of gross motor deterioration in metachromatic leukodystrophy. Developmental medicine and child neurology. 2011 Sep; [PubMed PMID: 21707604] |
[10] | Chauhan NS,Sharma M,Bhardwaj A, Classical case of late-infantile form of metachromatic leukodystrophy. Journal of neurosciences in rural practice. 2016 Jul-Sep; [PubMed PMID: 27365977] |
[11] | Harrington M,Whalley D,Twiss J,Rushton R,Martin S,Huynh L,Yang H, Insights into the natural history of metachromatic leukodystrophy from interviews with caregivers. Orphanet journal of rare diseases. 2019 Apr 29; [PubMed PMID: 31036045] |
[12] | Hong X,Kumar AB,Daiker J,Yi F,Sadilek M,De Mattia F,Fumagalli F,Calbi V,Damiano R,Della Bona M,la Marca G,Vanderver AL,Waldman AT,Adang L,Sherbini O,Woidill S,Suhr T,Kurtzberg J,Beltran-Quintero ML,Escolar M,Aiuti A,Finglas A,Olsen A,Gelb MH, Leukocyte and Dried Blood Spot Arylsulfatase A Assay by Tandem Mass Spectrometry. Analytical chemistry. 2020 May 5; [PubMed PMID: 31922725] |
[13] | [PubMed PMID: 19237705] |
[14] | van Rappard DF,Bugiani M,Boelens JJ,van der Steeg AF,Daams F,de Meij TG,van Doorn MM,van Hasselt PM,Gouma DJ,Verbeke JI,Hollak CE,van Hecke W,Salomons GS,van der Knaap MS,Wolf NI, Gallbladder and the risk of polyps and carcinoma in metachromatic leukodystrophy. Neurology. 2016 Jul 5 [PubMed PMID: 27261095] |
[15] | Spacil Z,Babu Kumar A,Liao HC,Auray-Blais C,Stark S,Suhr TR,Scott CR,Turecek F,Gelb MH, Sulfatide Analysis by Mass Spectrometry for Screening of Metachromatic Leukodystrophy in Dried Blood and Urine Samples. Clinical chemistry. 2016 Jan [PubMed PMID: 26585924] |
[16] | van Rappard DF,Boelens JJ,Wolf NI, Metachromatic leukodystrophy: Disease spectrum and approaches for treatment. Best practice [PubMed PMID: 25987178] |
[17] | Groeschel S,Kühl JS,Bley AE,Kehrer C,Weschke B,Döring M,Böhringer J,Schrum J,Santer R,Kohlschütter A,Krägeloh-Mann I,Müller I, Long-term Outcome of Allogeneic Hematopoietic Stem Cell Transplantation in Patients With Juvenile Metachromatic Leukodystrophy Compared With Nontransplanted Control Patients. JAMA neurology. 2016 Sep 1 [PubMed PMID: 27400410] |
[18] | [PubMed PMID: 23348427] |
[19] | van Rappard DF,Boelens JJ,van Egmond ME,Kuball J,van Hasselt PM,Oostrom KJ,Pouwels PJ,van der Knaap MS,Hollak CE,Wolf NI, Efficacy of hematopoietic cell transplantation in metachromatic leukodystrophy: the Dutch experience. Blood. 2016 Jun 16; [PubMed PMID: 27118454] |
[20] | Biffi A,Montini E,Lorioli L,Cesani M,Fumagalli F,Plati T,Baldoli C,Martino S,Calabria A,Canale S,Benedicenti F,Vallanti G,Biasco L,Leo S,Kabbara N,Zanetti G,Rizzo WB,Mehta NA,Cicalese MP,Casiraghi M,Boelens JJ,Del Carro U,Dow DJ,Schmidt M,Assanelli A,Neduva V,Di Serio C,Stupka E,Gardner J,von Kalle C,Bordignon C,Ciceri F,Rovelli A,Roncarolo MG,Aiuti A,Sessa M,Naldini L, Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy. Science (New York, N.Y.). 2013 Aug 23 [PubMed PMID: 23845948] |
[21] | Rosenberg JB,Kaminsky SM,Aubourg P,Crystal RG,Sondhi D, Gene therapy for metachromatic leukodystrophy. Journal of neuroscience research. 2016 Nov; [PubMed PMID: 27638601] |
[22] | Pastores GM, Krabbe disease: an overview. International journal of clinical pharmacology and therapeutics. 2009 [PubMed PMID: 20040316] |
[23] | Gelinas J,Liao P,Lehman A,Stockler S,Sirrs S, Child Neurology: Krabbe disease: a potentially treatable white matter disorder. Neurology. 2012 Nov 6 [PubMed PMID: 23128445] |
[24] | Kanakis G,Kaltsas G, Adrenal Insufficiency Due to X-Linked Adrenoleukodystrophy . 2000 [PubMed PMID: 25905179] |
[25] | Raymond GV,Moser AB,Fatemi A, X-Linked Adrenoleukodystrophy . 1993 [PubMed PMID: 20301491] |
[26] | Bokhari MR,Samanta D,Bokhari SRA, Canavan Disease . 2020 Jan [PubMed PMID: 28613566] |
[27] | Hoshino H,Kubota M, Canavan disease: clinical features and recent advances in research. Pediatrics international : official journal of the Japan Pediatric Society. 2014 Aug [PubMed PMID: 24977939] |
[28] | [PubMed PMID: 26627182] |
[29] | Braverman NE,Raymond GV,Rizzo WB,Moser AB,Wilkinson ME,Stone EM,Steinberg SJ,Wangler MF,Rush ET,Hacia JG,Bose M, Peroxisome biogenesis disorders in the Zellweger spectrum: An overview of current diagnosis, clinical manifestations, and treatment guidelines. Molecular genetics and metabolism. 2016 Mar [PubMed PMID: 26750748] |
[30] | Klein CJ, Adult Polyglucosan Body Disease . 1993 [PubMed PMID: 20301758] |
[31] | Köhler W,Curiel J,Vanderver A, Adulthood leukodystrophies. Nature reviews. Neurology. 2018 Feb [PubMed PMID: 29302065] |
[32] | [PubMed PMID: 31064022] |
[33] | Willems PJ,Gatti R,Darby JK,Romeo G,Durand P,Dumon JE,O'Brien JS, Fucosidosis revisited: a review of 77 patients. American journal of medical genetics. 1991 Jan [PubMed PMID: 2012122] |
[34] | Ordóñez AE,Luscher ZI,Gogtay N, Neuroimaging findings from childhood onset schizophrenia patients and their non-psychotic siblings. Schizophrenia research. 2016 Jun [PubMed PMID: 25819937] |