Lysosomal Storage Disorders Support Society

Metachromatic Leukodystrophy (MLD)

Metachromatic leukodystrophy (MLD) is a rare genetic disorder characterized by the accumulation of sulfatides, fatty substances that damage the myelin sheath, which insulates nerve fibers in the central and peripheral nervous systems. This damage impairs the functioning of the nervous system and is caused by mutations in the ARSA gene, leading to a deficiency of the enzyme arylsulfatase A. MLD presents in three forms based on the age of onset: late-infantile, juvenile, and adult, with symptoms ranging from developmental delays and motor dysfunction to behavioral and cognitive decline. Diagnosis involves genetic testing and enzyme activity assays, and while there is no cure, treatments like stem cell transplantation and supportive therapies aim to manage symptoms and slow disease progression.

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Prevalence of MLD

The prevalence of metachromatic leukodystrophy (MLD) varies globally but is generally estimated to be between 1 in 40,000 to 1 in 160,000 live births. This makes MLD a rare disorder. The frequency can differ based on population genetics and regional factors, with certain populations experiencing higher or lower prevalence rates due to genetic variations and consanguinity.

What Causes MLD?

Metachromatic leukodystrophy (MLD) is caused by mutations in the ARSA gene, which provides instructions for producing the enzyme arylsulfatase A. This enzyme is essential for breaking down sulfatides, a type of fatty substance, in the lysosomes of cells. When there are mutations in the ARSA gene, arylsulfatase A is either deficient or malfunctioning, leading to the accumulation of sulfatides in the nervous system. This accumulation progressively damages the myelin sheath, the protective covering around nerve fibers, impairing the function of the central and peripheral nervous systems and leading to the symptoms of MLD. In rare cases, MLD can also be caused by mutations in the PSAP gene, which affects the function of a related protein, saposin B, involved in the degradation of sulfatides.

What are the symptoms of MLD?

The symptoms of metachromatic leukodystrophy (MLD) vary depending on the type and age of onset:


Late-Infantile MLD

Symptoms typically appear between 12 and 24 months of age and include:

  • Developmental delays and regression of motor skills
  • Muscle weakness and wasting
  • Hypotonia (decreased muscle tone)
  • Ataxia (loss of coordination)
  • Seizures
  • Vision and hearing loss
  • Behavioral changes such as irritability and hyperactivity


Juvenile MLD

Symptoms usually appear between 4 and 12 years of age and include:

  • Decline in school performance and cognitive abilities
  • Behavioral changes, such as emotional instability and aggression
  • Motor difficulties, including clumsiness and ataxia
  • Speech and language regression
  • Seizures
  • Peripheral neuropathy (nerve damage affecting the extremities)


Adult MLD

Symptoms can appear in late adolescence or adulthood and include:

  • Behavioral and psychiatric issues, such as depression, anxiety, and personality changes
  • Cognitive decline, including memory loss and difficulties with executive functions
  • Motor symptoms like muscle weakness, tremors, and ataxia
  • Peripheral neuropathy
  • Speech difficulties
  • Incontinence


General Symptoms Across Types

Regardless of the type, common symptoms of MLD include:

  • Progressive loss of motor and cognitive functions
  • Spasticity (increased muscle tone and stiffness)
  • Difficulty swallowing and feeding problems
  • Involuntary muscle movements (dystonia)
  • Decline in vision and hearing


The progression of symptoms and their severity can vary, but MLD generally leads to significant disability and can be fatal, particularly in the more severe, early-onset forms.

How is MLD diagnosed?

Diagnosing MLD involves several steps to confirm the presence of the disease and its underlying genetic cause:


Clinical Evaluation

  1. Medical History and Physical Examination: Initial assessment of symptoms, family history, and physical and neurological examination.


Laboratory Tests

  1. Enzyme Activity Test: Measuring the activity of the enzyme arylsulfatase A in blood or skin cells. Reduced activity indicates MLD.
  2. Urine Test: Detecting elevated levels of sulfatides in the urine, which are indicative of MLD.


Genetic Testing

  1. DNA Analysis: Identifying mutations in the ARSA gene through genetic testing. This confirms the diagnosis and helps differentiate MLD from other leukodystrophies.
  2. Carrier Testing: Genetic testing of family members to identify carriers of the ARSA mutation.


Imaging Studies

  1. Magnetic Resonance Imaging (MRI): MRI scans of the brain to detect characteristic changes in the white matter, such as demyelination (loss of the myelin sheath).


Electrophysiological Studies

  1. Nerve Conduction Studies: Assessing the function of peripheral nerves. These tests can show slowed conduction velocities due to demyelination.


Differential Diagnosis

  1. Exclusion of Other Conditions: Ensuring that similar symptoms are not caused by other neurological or metabolic disorders.


Combining these diagnostic methods provides a comprehensive approach to confirming MLD and understanding its impact on the nervous system. Early diagnosis, especially through genetic testing, is crucial for timely intervention and management.

Treatment for MLD

Currently, there is no cure for metachromatic leukodystrophy (MLD), but various treatments aim to manage symptoms and slow disease progression. The treatment approaches include:

  • Enzyme Replacement Therapy (ERT): This experimental treatment aims to replace the deficient enzyme arylsulfatase A. It involves intravenous infusion of the enzyme to potentially reduce the buildup of sulfatides and slow disease progression. More information can be found here.

  • Gene Therapy: Research is ongoing into gene therapy approaches that could correct the underlying genetic defect responsible for MLD. To know more, please visit MLD Foundation.

Prognosis of MLD

The prognosis for MLD varies based on the type and age of onset. Late-infantile MLD often leads to severe disability and early death, while juvenile and adult forms progress more slowly but still significantly impact quality of life and life expectancy. Early diagnosis and intervention can improve outcomes.