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Metachromatic Leukodystrophy, Genetic Testing

Metachromatic leukodystrophy (MLD) is a rare, inherited metabolic disorder that affects the nervous system. It is characterized by the buildup of a substance called sulfatide, leading to progressive degeneration of the white matter in the brain and spinal cord. MLD is classified into different forms based on the age of onset: late-infantile, juvenile, and adult. The worldwide prevalence of metachromatic leukodystrophy is approximately 1 case per 40.000-160.000.

Metachromatic leukodystrophy genetic testing is included in Diagnostiki Athinon Monogenic Diseases Genetic Testing along with approximately 100 other inherited diseases, including cystic fibrosis (71 mutations) and hereditary breast cancer (genes BRCA1 415 mutations & BRCA2 419 mutations).

Critical features of Metachromatic Leukodystrophy include:

  • Neurological Deterioration: MLD leads to a progressive loss of neurological function. Symptoms and the rate of deterioration vary depending on the age of onset.
  • Motor and Cognitive Decline: Individuals with MLD typically experience a decline in motor skills, including muscle weakness, stiffness, and difficulty coordinating movements. Cognitive decline, loss of intellectual abilities, and behavioral changes may also occur.
  • Peripheral Nervous System Involvement: Besides central nervous system involvement, MLD can affect the peripheral nerves, leading to sensory and motor abnormalities.
  • Language and Speech Impairments: Language and speech difficulties may develop, affecting communication abilities.
  • Seizures: Seizures can occur in individuals with MLD.
  • Vision and Hearing Impairments: Vision and hearing impairments may occur as the disease progresses.
  • Regression of Developmental Milestones: In the late-infantile form, affected children may show a regression of developmental milestones.
  • Genetic Basis: MLD is caused by mutations in the ARSA gene, which provides instructions for making the enzyme arylsulfatase A. Deficiency of this enzyme leads to the accumulation of sulfatide.
  • Autosomal Recessive Inheritance: MLD follows an autosomal recessive inheritance pattern, meaning that affected individuals inherit two mutated copies of the ARSA gene (one from each parent).

There are three primary forms of MLD:

  • Late-Infantile Form: This is the most common and severe form, with symptoms typically appearing between 1 and 2 years of age.
  • Juvenile Form: Symptoms typically begin between 3 and 10 years old, and progression may be slower than in the late-infantile form.
  • Adult Form: This form has a later onset, typically during adolescence or adulthood, and progresses more slowly than the other forms.

There is currently no cure for MLD, and treatment is generally supportive. Symptomatic management may involve physical therapy, occupational therapy, and medications to address specific symptoms. Genetic counseling is essential for affected individuals and their families to understand the inheritance pattern and assess the risk of having affected children.

More Information

Metachromatic leukodystrophy is a disorder caused by variants in the ARSA gene, which encodes the lysosomal enzyme arylsulfatase A. A deficiency results in the accumulation of sulfatides (sulfated glycosphingolipids, especially sulfogalactocerebrosides or sulfogalactosylceramides). Rarely, it can occur due to an enzymatic deficiency of sphingolipid activating enzyme B (SAP-B).

More than 200 pathogenic variants associated with metachromatic leukodystrophy have been described. This test analyzes the three most frequent variants causing partial or total disruption of enzyme activity: they are c.465+1G>A, c.1283C>T (p.Pro428Leu), and c.542T>G (p.Ile181Ser). The first is frequently found in late infantile stage patients, while the other two are associated with a juvenile or adult phenotype. Both account for 25% to 50% of ARSA alleles.

Variants such as c.739G>A (p.Gly247Arg) and c.899T>C (p.Leu300Ser) are less common in the population and have been associated with late infantile onset. The c.899T>C variant results in a complete loss of enzyme activity.

The c.769G>C (p.Asp257His) mutation has been identified in multiple individuals affected by late infantile and juvenile types of metachromatic leukodystrophy, with significantly reduced enzyme activity levels.

Metachromatic leukodystrophy genetic testing analyzes the 19 most frequent pathogenic mutations of the ARSA gene.

The technique used for genetic testing analyzes only the gene's specific mutations, which are the most important and frequent in the literature. However, it should be noted that there are likely other gene or chromosomal mutations in the gene to be tested that cannot be identified with this method. Different analysis techniques can be used for these cases, such as next-generation sequencing (NGS).

Additional information
Results Time4 - 5 Weeks
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