Metachromatic leukodystrophy

Metachromatic leukodystrophy (MLD) is the most common hereditary (autosomal recessive) leukodystrophy and is one of the lysosomal storage disorders. It has characteristic imaging features including peri-atrial and to a lesser extent frontal horns leukodystrophy as well as periventricular perivenular sparing results in "tigroid pattern" on fluid-sensitive MRI sequences. 

Epidemiology

Metachromatic leukodystrophy has an estimated prevalence of ~1:100,000 and typically manifests between 12 to 18 months of age. The disease can sometimes be classified according to the time of onset:

• late infantile: most common ~65% (range 50-80%)

• juvenile (onset between 3-10 years)

• adult (after age 16)

Clinical presentation

Clinical presentation depends on the age of onset. 

• late infantile form

  • gait abnormality, muscle rigidity, loss of vision, impaired swallowing, convulsions, dementia

• juvenile form

  • impaired school performance; similar features as in late infantile form but slower progression

• adult form

  • adult presentation accounts for 20% of all cases

  • neuropsychiatric disorders

  • gradual cognitive decline and dementia

  • motor symptoms are a late feature

  • often protracted course over 10 years

Because sulfatide accumulates also in the wall of the gallbladder, cholecystitis is a recognized complication ⁸. 

Pathology

Metachromatic leukodystrophy is classified as a dysmyelinating disease and carries an autosomal recessive inheritance. It arises from a deficiency of the enzyme arylsulfatase A as a result of a mutation in the arylsulfatase A (ARSA) gene located on chromosome 22q13. This results in the accumulation of 3-O-sulfogalactosylceramide (sulfatide) in various organs including the central nervous system (Schwann cells, oligodendrocytes, and some neurons) impairing myelination and function ⁸.

Metachromatic refers to the histologic staining characteristic caused by abnormal accumulations of sulfatides in white matter ⁶.

Markers

• serum/urine arylsulfatase A levels: reduced

Radiographic features

MRI

Characterized by bilateral symmetrical confluent areas of periventricular deep white matter signal change, in particular around the atria and frontal horns with sparing of subcortical U fibers leading to a "butterfly pattern". Progression can lead to cortical and subcortical atrophy ⁸. Occasionally, optic nerve enlargement can be seen ⁹.

Signal characteristics

• T1: affected areas are low signal

• T1 C+ (Gd)

  • no enhancement is characteristic

  • however, some cases may show a linear punctate enhancement pattern within lesions ²

  • multiple cranial nerve enhancement has been reported ⁷

• T2

  • affected areas are high signal and may show a "tigroid pattern" on axial plane or "leopard pattern" on sagittal plane representing sparing along the venules

  • subcortical U-fibers are usually spared ⁸

• MR spectroscopy: (of affected white matter)

  • reduced N-acetyl aspartate (NAA)

  • increased myoinositol

  • increased lactate

Treatment and prognosis

Management is generally supportive in nature. Emerging therapies include gene therapies such as atidarsagene autotemcel ¹⁰.

Differential diagnosis

Krabbe disease is one of the main differential diagnoses both clinically and by imaging ⁹. In addition to many of the other leukodystrophies, a tigroid pattern of involvement may also be seen in:

• Pelizaeus-Merzbacher disease

• autosomal recessive spastic ataxia of Charlevoix