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Metachromatic Leukodystrophy


Metachromatic leukodystrophy is an autosomal recessive lysosomal storage disease consisting of progressive demyelination of the peripheral and central nervous systems. In most patients, it is attributed to a mutation in the arylsulfatase A (ARSA) gene, which in turn hinders the production of arysulfatase A. This enzyme is necessary for the desulfation of cerebroside, a glycolipid of myelin.


There are three subtypes of metachromatic leukodystrophy. The clinical presentation is dependent on the subtype.

Impaired Balance
  • We also discuss the complementary role of VR therapy, which was successfully integrated with a conventional rehabilitation program for a young patient with MLD who had impaired balance and gait.[ncbi.nlm.nih.gov]
Respiratory Distress
  • A 5-year-old boy with metachromatic leukodystrophy, debilitated by spastic quadriparesis presented to us with massive ascites and respiratory distress.[ncbi.nlm.nih.gov]
  • During this period he also developed speech difficulty, seizure followed by unconsciousness and severe respiratory distress for ten days. His investigations were suggestive of metachromatic leukodystrophy.[ncbi.nlm.nih.gov]
  • Six years after diagnosis, the other control has a slowly progressive course with spastic dystonic quadriplegia, epilepsy, dysphagia, continual drooling and incontinence.[ncbi.nlm.nih.gov]
Gallbladder Enlargement
  • One presented with gastric outlet obstruction secondary to gallbladder enlargement, which was treated by percutaneous aspiration. He later developed gallbladder carcinoma with liver metastases.[ncbi.nlm.nih.gov]
  • Macroscopically, the gallbladder measured 4.6 cm in length and showed an opaque serous surface and focal brown petechiae. Moreover, a yellow polypoid lesion of 2 cm in diameter and a diffuse thickening of the fundus wall were observed.[ncbi.nlm.nih.gov]
Muscle Hypotonia
  • The first symptom is usually an unsteady gait due to muscle hypotonia. There are signs of a progressive polyneuropathy, ending in a generalized flaccid paresis of the arms and legs and a loss of tendon reflexes. The neuropathy may be painful.[78stepshealth.us]
  • Patients with the early juvenile form (4-6 y) tend to present with loss of motor developmental milestones; the most obvious signs are gait disturbances, ataxia, hyperreflexia followed by hyporeflexia, seizures, and decreased cognitive function.[emedicine.medscape.com]


Workup of metachromatic leukodystrophy consists of a history and physical exam, nerve conduction testing, cerebrospinal fluid (CSF) evaluation, and imaging tests. A definitive diagnosis can be established with genetic testing.

The diagnosis of metachromatic leukodystrophy is established by demonstrating reduced arylsulfatase A gene activity in cultured skin fibroblasts or leukocytes. However, a diagnosis based only on the activity of ARSA should be differentiated from ARSA pseudodeficiency, which is present in about one percent of the population [5]. Arylsulfatase A pseudodeficiency can be differentiated form metachromatic leukodystrophy by performing a radiolabeled sulfatide fibroblast loading test, assessment of sulfatide levels in the urine, and/or genetic analysis for mutations [6].

Prenatal testing can be performed by measurement of arylsulfatase A activity to identify carriers. Newborn screening is done using immune-quantification assays which screen numerous lysosomal proteins [7].

Magnetic resonance imaging (MRI) shows symmetric lesions in the white matter; lesions are predominant in the periventricular region during the early stages of the disease [8] [9]. Late stage disease is characterized by cortical atrophy [8] [9]. Results of clinical trials have shown that N-acetylaspartate levels, which are measured by magnetic resonance spectroscopy, may act as a marker of disease progression [10].

Nerve conduction studies demonstrate reduced nerve conduction velocity; in the early stages of the disease, sensory potentials are affected more severely than motor responses [11] [12]. A peripheral nerve biopsy, which is often not necessary for diagnosis, is characterized by segmental demyelination with metachromatic material in schwann cells and macrophages. Neurocognitive and neuropsychological testing may be performed when clinically indicated.

  • The most commonly reported adverse events were cytopenia (reported in all patients) and mucositis of different grades of severity (in five of nine patients [grade 3 in four of five patients]).[ncbi.nlm.nih.gov]


  • Complication rates related to ITB treatment were similar in both groups. ITB treatment course in the first 6 months after pump implantation appears to show more dose increase in most patients MLD, compared to patients with spastic CP.[ncbi.nlm.nih.gov]
  • For this ad-hoc analysis, we assessed safety and efficacy outcomes in all patients who had received treatment and been followed up for at least 18 months post-treatment on June 1, 2015.[ncbi.nlm.nih.gov]
  • Clinical evaluation: The patients will undergo clinical assessment prior to starting the treatment and at the end of the treatment period.[clinicaltrials.gov]
  • This paper provides an overview of developing treatment options among patients with MLD.[ncbi.nlm.nih.gov]
  • Until superior, novel treatment strategies are demonstrated, MLD patients should be carefully considered for HSCT.[ncbi.nlm.nih.gov]


  • Therefore, our results confirm the importance of functional characterization of mutant alleles for a precise genotype-based classification and definition of prognosis in MLD patients, which is particularly relevant for pre-symptomatic diagnosis.[ncbi.nlm.nih.gov]
  • So proper counseling was done regarding the bad prognosis of the disease with symptomatic treatment.[ncbi.nlm.nih.gov]
  • Prognosis is often poor unless treatment is carried out before the onset of clinical symptoms. Pre-symptomatic detection of affected individuals may be possible with the introduction of newborn screening programs.[ncbi.nlm.nih.gov]
  • PROGRESSION The prognosis for MLD is poor. In young children with MLD late infantile form, progressive loss of motor and cognitive functions is rapid. Death usually results within five years after the onset of clinical symptoms.[secure.ssa.gov]
  • Quantitative MR spectroscopic imaging in metachromatic leukodystrophy: value for prognosis and treatment Diane F van Rappard 1 , 2 , Antoine Klauser 3 , Marjan E Steenweg 1 , 2 , Jaap Jan Boelens 4 , Marianna Bugiani 1 , 2 , 5 , Marjo S van der Knaap[jnnp.bmj.com]


  • The leukodystrophies constitute a wide spectrum of cerebral disorders of varying etiology.[ncbi.nlm.nih.gov]


  • Based on epidemiological surveys the incidence of MLD per 100,000 live births varied from 0.6 to 2.5.[ncbi.nlm.nih.gov]
  • Further studies on the epidemiology and natural history of this disease with larger samples are needed, especially now when specific treatments should be available in the near future.[ncbi.nlm.nih.gov]
  • Epidemiology Frequency United States Incidence is estimated to be 1 case per 40,000 births. Mortality/Morbidity Morbidity and mortality rates vary with each form of the disease.[emedicine.medscape.com]
  • Jones, Daniel Ory, Bruno Bembi & Marc Patterson Orphanet Journal of Rare Diseases (2018) Epidemiology of Sanfilippo syndrome: results of a systematic literature review Tamás Zelei, Kata Csetneki, Zoltán Vokó & Csaba Siffel Orphanet Journal of Rare Diseases[dx.doi.org]
Sex distribution
Age distribution


  • Cerebral inflammation may contribute to the pathophysiology of MLD. To date, cytokine levels in the cerebral spinal fluid of MLD patients have not previously been reported.[ncbi.nlm.nih.gov]
  • For detailed information regarding the different forms of MLD, its genetics, pathophysiology, diagnosis, genetic counseling, treatment options, visit ELA page on MLD.[leukotreat.eu]
  • Pathophysiology In patients, the inability to degrade sulfated glycolipids, especially the galactosyl-3-sulfate ceramides, characterizes metachromatic leukodystrophy.[emedicine.medscape.com]
  • The occurrence of spared myelin may provide important insight into the pathophysiology of MLD.[ajnr.org]


  • This is, to our knowing, the third case reported in Literature, and thus hemorrhagic cholecystitis may be considered a life-threatening complication of MLD to be prevented with cholecystectomy as soon as signs of gallbladder pathology (papillomatosis[ncbi.nlm.nih.gov]
  • As novel therapies for this patient group are emerging leading to increased life expectancy, we recommend screening for gallbladder abnormalities by ultrasound in order to prevent early death.[ncbi.nlm.nih.gov]
  • Importantly, we finally show how a careful acid-base balance monitoring and prompt correction of imbalances might prevent severe consequences of acidosis.[ncbi.nlm.nih.gov]
  • Thus, the assessment of a variant impact is needed to prevent delayed diagnosis or misdiagnosis in patients with PSAP mutations.[ncbi.nlm.nih.gov]
  • Stem cell transplantation may prevent disease progression in selected cases. Enzyme replacement is being evaluated, and gene therapies are being developed. Copyright 2013 Elsevier B.V. All rights reserved.[ncbi.nlm.nih.gov]



  1. 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(5):572.
  2. Zafeiriou DI, Kontopoulos EE, Michelakakis HM, Anastasiou AL, Gombakis NP. Neurophysiology and MRI in late-infantile metachromatic leukodystrophy. Pediatr Neurol. 1999;21:843.
  3. Quigley HA, Green WR. Clinical and ultrastructural ocular histopathologic studies of adult-onset metachromatic leukodystrophy. Am J Ophthalmol. 1976;82:472.
  4. Kehrer C, Blumenstock G, Gieselmann V, Krageloh-Mann I. The natural course of gross motor deterioration in Metachromatic Leukodystrophy. Dev Med Child Neurol. 2011;53:850–5.
  5. Barth ML, Ward C, Harris A, Saad A, Fensom AT. Frequency of arylsulphatase A pseudodeficiency associated mutations in a healthy population. J Med Genet. 1994;31:667.
  6. von Figura K, Gieselman V, Jaeken J. Metachromatic leukodystrophy. Scriver C, Beadet A, Valle D, Sly W, et al, eds. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. McGraw-Hill Professional; 2001.
  7. Meikle PJ, Grasby DJ, Dean CJ. Newborn screening for lysosomal storage disorders. Mol Genet Metab. 2006;88:307-14.
  8. Faerber EN, Melvin J, Smergel EM. MRI appearances of metachromatic leukodystrophy. Pediatr Radiol. 1999; 29:669-72.
  9. Schiffmann R, van der Knaap M. Invited article: an MRI-based approach to the diagnosis of white matter disorders. Neurology. 2009;72:750.
  10. Dali C, Hanson LG, Barton NW, Fogh J, Nair N, Lund AM. Brain N-acetylaspartate levels correlate with motor function in metachromatic leukodystrophy. Neurology. 2010;75:1896.
  11. Takakura H, Nakano C, Kasagi S, Takashima S, Takeshita K. Multimodality evoked potentials in progression of metachromatic leukodystrophy. Brain Dev. 1985;7:424.
  12. Wulff CH, Trojaborg W. Adult metachromatic leukodystrophy: neurophysiologic findings. Neurology. 1985;35:1776.

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Last updated: 2019-06-28 09:52