Metachromatic Leukodystrophy

Metachromatic leukodystrophy (MLD) is an inherited lysosomal storage disorder that affects myelin in the brain and spinal cord Spinal cord The spinal cord is the major conduction pathway connecting the brain to the body; it is part of the CNS. In cross section, the spinal cord is divided into an H-shaped area of gray matter (consisting of synapsing neuronal cell bodies) and a surrounding area of white matter (consisting of ascending and descending tracts of myelinated axons). Spinal Cord. Genetic mutations result in the creation of a dysfunctional arylsulfatase A (ARSA) enzyme, which is unable to break down cerebroside sulfate. The accumulation of this metabolite results in permanent damage to oligodendroglial and Schwann cells (myelin) in both the central and peripheral nervous systems. Patients can present with seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures, weakness, and behavioral and personality changes. Blood enzyme and urine testing for ARSA-A and sulfatides, respectively, are the best diagnostic tests Diagnostic tests Diagnostic tests are important aspects in making a diagnosis. Some of the most important epidemiological values of diagnostic tests include sensitivity and specificity, false positives and false negatives, positive and negative predictive values, likelihood ratios, and pre-test and post-test probabilities. Epidemiological Values of Diagnostic Tests. Treatment is challenging and usually focuses on relieving symptoms, although new gene therapies are available for specific subgroups of MLD patients. Serious complications include dementia and seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Overview

Definition

Metachromatic leukodystrophy (MLD) is an autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritancewhite matter disease caused by a deficiency in arylsulfatase A resulting in accumulation of cerebroside sulfate. This accumulation leads to the destruction of myelin and causes neurologic deficits.

Classification

Based on age at symptom onset:

  • Late infantile form
  • Juvenile form
  • Adult form

Epidemiology

  • Rare, autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritanceinherited condition
  • Incidence: 1 in 40,000 live births in the United States
  • No racial or sexual predilection
  • Most common form of inherited leukodystrophy

Etiology

  • Caused by deficiency in gene for arylsulfatase A (ARSA): 
    • Gene located on chromosome 22 (22q13.31qter).
    • Function of ARSA: hydrolyzes sulfated glycosphingolipids
  • Pseudodeficiency: partial loss of enzyme activity; no clinical consequences
  • MLD can also be caused by deficiency in sphingolipid activator protein B (SAP-B) deficiency. SAP-B acts with ARSA to hydrolyze sulfated glycosphingolipids.

Pathophysiology

  • Deficiency in ARSA activity → excessive white matter storage of sulfated glycosphingolipids
  • Accumulate in oligodendrocytes, macrophages, and other subtypes of neurons
  • Results in demyelination and neurodegeneration

Clinical Presentation

Late infantile form

  • Most common (50% of cases)
  • Age at presentation: < 30 months
  • Symptoms:
    • Initial developmental milestones Developmental milestones Developmental milestones are the skills or abilities that most children are able to perform when they reach a certain age. Understanding the appropriate milestones and at what age they are reached helps clinicians identify symptoms of delayed development. Developmental milestones are divided into 5 important domains: gross motor, fine motor, language, social, and cognitive. Developmental Milestones and Normal Growth are met and then progressively lost.
    • Regression of motor skills
    • Seizures
    • Hypotonia
    • Extensor plantar posturing
    • Optic atrophy
  • Patients die at < 5 years of life if untreated.

Juvenile form

  • Age at presentation: 3 to < 16 years
  • Symptoms:
    • Initial developmental milestones Developmental milestones Developmental milestones are the skills or abilities that most children are able to perform when they reach a certain age. Understanding the appropriate milestones and at what age they are reached helps clinicians identify symptoms of delayed development. Developmental milestones are divided into 5 important domains: gross motor, fine motor, language, social, and cognitive. Developmental Milestones and Normal Growth are met and then progressively lost.
    • Intellectual regression
    • Behavioral and personality changes
    • Peripheral neuropathy
    • Patients presenting at later ages often have seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures
  • Death usually occurs < 2 decades after symptom onset.

Adult form

  • Similar to juvenile form but more protracted course 
  • Age at presentation: > 20 years
  • Slow progression
  • Symptoms:
    • Dementia
    • Seizures
    • Diminished reflexes
    • Optic atrophy

Diagnosis

Consider diagnostic testing in patients expressing typical clinical features.

  • Diagnosis is confirmed with biochemical, urine, and genetic analysis:
    • Decreased or absent ARSA activity in leukocytes or cultured skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin fibroblasts
    • Increased urinary sulfatide secretion (Patients with pseudodeficiency have normal secretion.)
    • Genetic analysis for common mutations
  • Brain MRI is diagnostic adjunct and may show: 
    • Hyperintensity in periventricular white matter
    • Hyperintensity in subcortical supratentorial white matter
  • Electroneurographic recordings show decreased nerve conduction velocities.
  • Other results consistent with MLD but not required for diagnosis:
    • Increased CSF protein
    • Metachromatic deposits in sural nerve
    • Metachromatic granules in urinary sediment
Tigroid pattern in mld

Brain MRI of a patient with metachromatic leukodystrophy:
Brain MRI showing hyperintensity in periventricular white matter (A) and in subcortical supratentorial white matter (B) can help confirm laboratory diagnosis of metachromatic leukodystrophy.

Image: “Tigroid pattern” by Department of Diagnostic Imaging, Hospital for Sick Children, University of Toronto, 555, University Avenue, Toronto, Ontario M5G 1X8, Canada. License: CC BY 2.0

Management

No curative therapy for MLD is widely available. Umbilical cord blood transplantation for children with presymptomatic late-infantile MLD or minimally symptomatic juvenile MLD can slow disease progression.

Supportive therapy is preferred for patients with symptoms and for all patients with juvenile and late-onset forms MLD:

  • Seizure prophylaxis with antiepileptics (e.g., levetiracetam) 
  • Treatment for spasticity (e.g., with baclofen)
  • Mood/behavioral issues should be addressed with behavioral therapy and medication (e.g., antidepressants).

Clinical trials of recombinant human arylsulfatase A (rhARSA) enzyme demonstrated its safety in children with late-infantile MLD.

Differential Diagnosis

  • Krabbe disease Krabbe disease Krabbe disease, also known as globoid cell leukodystrophy or galactosylceramide lipidosis, is a rare autosomal recessive lysosomal storage disorder caused by a deficiency of the enzyme galactocerebrosidase. Accumulation of galactocerebroside results in destruction of myelin-producing cells throughout the peripheral and central nervous systems, leading to demyelination and clinical symptoms. Krabbe Disease: autosomal recessive lysosomal storage disease Lysosomal storage disease Lysosomal storage diseases are a group of metabolic disorders caused by genetic mutations in the enzymes responsible for normal lysosomal function. The dysfunction of enzymatic processes causes an accumulation of undigested metabolites, resulting in cellular death. The main groups include sphingolipidoses, oligosaccharidoses, and mucolipidoses. Overview of Lysosomal Storage Diseases caused by deficiency in beta-galactosidase (GALC). Krabbe disease Krabbe disease Krabbe disease, also known as globoid cell leukodystrophy or galactosylceramide lipidosis, is a rare autosomal recessive lysosomal storage disorder caused by a deficiency of the enzyme galactocerebrosidase. Accumulation of galactocerebroside results in destruction of myelin-producing cells throughout the peripheral and central nervous systems, leading to demyelination and clinical symptoms. Krabbe Disease can present during all stages of life. All patients present with peripheral motor-sensory neuropathy. Common symptoms also include irritability, hypertonia, hyperesthesia, hypotonia, and abnormal deep tendon reflexes. Diagnosis is confirmed through GALC enzyme activity.
  • X-linked adrenoleukodystrophy: X-linked disorder of peroxisomes caused by mutations in ATP-binding cassette, subfamily D, member 1 gene (ABCD1) that results in accumulation of very-long-chain fatty acids Fatty acids Fatty acids are integral building blocks of lipids, and can be classified as unsaturated or saturated based on the presence/absence of carbon-carbon double bonds within their nonpolar chains. Fatty Acids and Lipids in most tissues of the body. Patients present with adrenal insufficiency Adrenal Insufficiency Adrenal insufficiency (AI) is the inadequate production of adrenocortical hormones: glucocorticoids, mineralocorticoids, and adrenal androgens. Primary AI, also called Addison’s disease, is caused by autoimmune disease, infections, and malignancy, among others. Adrenal insufficiency can also occur because of decreased production of adrenocorticotropic hormone (ACTH) from disease in the pituitary gland (secondary) or hypothalamic disorders and prolonged glucocorticoid therapy (tertiary). Adrenal Insufficiency and Addison’s Disease, decreased cognition, behavioral issues, vision and hearing impairment, and dysarthria. Brain MRI and genetic testing is diagnostic.
  • Canavan disease: progressive neurodegenerative autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritanceleukodystrophy seen primarily in Ashkenazi Jewish populations. Canavan disease is caused by aspartoacylase deficiency. Symptoms include spasticity, ataxia, seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures, hypotonia, and optic atrophy. Diagnosis is confirmed by discovering elevated levels of N-acetyl aspartate (NAA) in urine and abnormal diffuse white matter disease on MRI.

References

  1. Biffi, A., Lucchini, G., Rovelli, A., et al. (2008). Metachromatic leukodystrophy: an overview of current and prospective treatments. Bone Marrow Transplant 42:2–6.
  2. Hohenschutz, C., Eich, P., Friedl, W., Waheed, A., Conzelmann, E., Propping, P. (1989). Pseudodeficiency of arylsulfatase A. Hum Genet 82:45–48.
  3. U.S. National Library of Medicine. Metachromatic leukodystrophy. MedlinePlus. Retrieved April 27, 2021, from https://medlineplus.gov/genetics/condition/metachromatic-leukodystrophy/
  4. Friede, R. L. (1975). Metachromatic leukodystrophy (sulfatase A deficiency) and multiple sulfatase deficiency. In: Developmental Neuropathology. Vienna: Springer.

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