DEAR MAYO CLINIC:

What can you tell me about metachromatic leukodystrophy? My granddaughter was just diagnosed but she has two older siblings who are perfectly healthy. How is that possible?

ANSWER:

Metachromatic leukodystrophy (MLD) is an inherited disorder that affects the protective covering around nerve cells (myelin sheath), as well as the nerve fibers that the sheath insulates and protects. A rare, serious and progressive disease, MLD currently has no cure. But treatment may help delay the disease's progress, and research is exploring new treatment possibilities for MLD.

MLD is caused by defective genes. But not everyone who inherits a defective gene associated with MLD develops the disease. To understand why, it's helpful to know some background on how genetic disorders work. Genes come in pairs. For each pair, we inherit one from our father and one from our mother. MLD is inherited in a recessive fashion. That means for a person to develop the disease, both inherited genes associated with MLD must be defective. If a child inherits only one defective gene, he or she is a carrier of the disease, but is unlikely to develop MLD. Assuming neither of your granddaughter's parents have MLD, they must both be MLD carriers.

Because carriers only have one defective gene, and because the set of genes one child inherits isn't exactly the same as a sibling's, children of the same parents can be affected differently by a recessive genetic disorder such as MLD. Your grandchildren who don't have MLD either inherited only one defective gene (making them MLD carriers), or perhaps they received two normal genes and aren't affected at all. When both parents carry gene mutations that cause recessive genetic disorders and have children, chances are one in four that each child they conceive will be affected.

Due to the genetic defect they've inherited, people who have MLD are missing the enzyme arylsulfatase. Arylsulfatase is one in a group of enzymes that help recycle molecules which make up the myelin sheath. Without that enzyme, fatty materials (lipids), sugars and proteins build up within the recycling centers of cells (lysosomes). This accumulation causes the myelin sheath and its underlying nerve fibers to break down.

Areas most affected by MLD include the nervous system, liver and kidneys. The signs and symptoms of MLD get worse over time. Common MLD symptoms include abnormal muscle rigidity and movement (spasticity), inability to walk, seizures, and blindness. Children with MLD often experience developmental delays and progressive mental impairment. Psychiatric symptoms may be the first sign of the illness in adults.

MLD can strike from infancy through adulthood. The three forms of the disease are based on when symptoms begin. Late infantile MLD, the most common form, usually begins around ages 1 or 2. Juvenile MLD typically appears between ages 4 and 12. Adult MLD can begin during the teen years, but in some people may not appear until the 40s or 50s.

Diagnosing MLD usually involves MRI scans of the brain, which typically show changes in the myelin sheath and nerve fibers (white matter) of the brain's hemispheres. A blood test that reveals low or absent activity of arylsulfatase confirms an MLD diagnosis.

Because it's a progressive disorder and no cure is available yet, treatment of MLD often focuses on managing the symptoms. Stem cell transplantation may slow the disease, if begun during MLD's early stages, but no treatment is curative. MLD is inexorably progressive, and leads to premature death in all cases. Additional treatments are under investigation. One significant area of research is examining the feasibility of enzyme replacement therapy that could do the work of the missing arylsulfatase enzyme.

-- Marc Patterson, M.D., Chair, Division of Child and Adolescent Neurology, Department of Neurology, Mayo Clinic, Rochester, Minn.

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