Metachromatic leukodystrophy

Metachromatic leukodystrophy (MLD) is an autosomal recessive disorder. It is a lysosomal lipid storage disorder caused by the deficiency of arylsulfatase A, an enzyme involved in the degradation of sulfatide. This membrane lipid can be found in various cell types, but in particularly high concentrations in the myelin of the central and peripheral nervous system. Deficiency of arylsulfatase A results in accumulation of sulfatide, leading to progressive, finally lethal, demyelination in the central and peripheral nervous system of patients. Disease severity is strongly linked to residual enzyme level.

Based on the age at onset, MLD is usually classified into these forms:

  • Late infantile form (manifests in the second year of life)
  • Juvenile variants (onset between 4 and 12 years)
  • Early juvenile (onset before 6 years)
  • Late juvenile (onset after 6 years)
  • Adult form (onset after 12 years of age)


Symptoms

Patients with MLD suffer from progressive demyelination which results in various neurological symptoms. In the typical late infantile form of disease, symptoms usually start at the age of about 2 years. Children lose previously acquired neuromotor capabilities. They initially present with gait disturbances due to ataxia and paresis. They become wheelchair bound, develop seizures, optic atrophies and die in a decerebrated state some years after the onset of symptoms. Clinically, MLD is heterogeneous with respect to the age at onset and the course of the disease. In contrast to the late infantile form, juvenile patients develop symptoms at any age between 3 and 16 years, while adults may present with symptoms when in their 20s. These late onset forms of the disease usually have a milder more protracted course. In particular, adult patients frequently present with psychiatric symptoms before the neurological symptoms develop. Most patients die before age 20.

 

Diagnosis

MLD is diagnosed through several tests, including a physical exam to check for abnormal gait, increased muscle tone and stiffness, abnormal deep tendon reflexes, abnormal eye movements and other signs of vision problems. Blood samples are tested for arylsulfatase A deficiency in the white blood cells. Urine samples are tested for an accumulation of sulfatides. A nerve conduction study (electroneurograph) which measures electrical nerve impulses may be performed to assess peripheral neuropathy (nerve damage), a common finding in patients with MLD. Patients may also have a brain MRI to determine if characteristics of MLD are present, including abnormal white matter (leukodystrophy) and atrophy (shrinking) of the brain. For patients who may have late juvenile or adult forms of MLD, psychological and cognitive tests may be performed to determine the extent and severity of MLD on the patient's brain functions.

Incidence

The disease is rare; its frequency among newborns is estimated at approximately 1 in 70,000 (the range of incidence is 1 in 40,000 to 1 in 100,000).

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