Metachromatic leukodystrophy


Metachromatic leukodystrophy

Description, Causes and Risk Factors:

A metabolic disorder, with onset usually in the second year of life and death often before 5 years, with loss of myelin and accumulation of metachromatic lipids (galactosyl sulfatidates) in the white matter of the central and peripheral nervous systems leading to motor symptoms, paralysis, convulsions, and progressive cerebral deterioration;. Autosomal recessive inheritance caused by mutation in either the arylsulfatase A gene (ARSA) on 22q or the prosaposin gene (PSAP) on 10q. There is a dominant form occurring in adults.

Metachromatic leukodystrophy is a lysosomal storage disease caused by the deficiency of the enzyme arylsulfatase A (ASA). This enzyme catalyzes the first step in the degradation pathway of the sphingolipid 3'-0-sulphogalactosylceramide, also known as sulphatide. The expression of this membrane lipid is restricted to certain cell types. Sulphatide is particularly abundant in the myelin (a white fatty substance that forms a medullary sheath around the axis cylinder of some nerve fibers) of the nervous system, where it constitutes about 4% of all myelin lipids. Myelin is synthesized by oligodendrocytes (a cell of the oligodendroglia) in the central nervous system (CNS) or by Schwann cells in the peripheral nervous system. Myelin wraps around axons in a spiral fashion and is essential for electrical insulation and fast saltatory impulse conduction along the myelinated axon. Sulphatide is also found in other tissues, including the distal tubules of the kidney and bile duct epithelia. If ASA is deficient, sulphatide cannot be degraded and it accumulates. Functionally, this accumulation affects the nervous system in particular. Storage in gall bladder epithelia and renal tubules results in little or no functional impairment. The pathological hallmark of the disease is progressive demyelination, which results in a variety of neurological symptoms. Patients develop ataxia, an initially flaccid and later spastic paresis, optic atrophy and dementia. After years of suffering, they finally die in a decerebrated state. Based on the age at disease onset, three clinical forms are distinguished: a late-infantile form, with the first symptoms developing around 2 years of age, a juvenile form, with patients presenting between 3 and 16 years of age, and an adult onset form with manifestations appearing after 16 years of age. While this distinction is certainly clinically helpful, it is artificial, as disease severity is in fact a continuum.

The metachromatic leukodystrophy are almost all inherited in either an X-linked or autosomal recessive way.

    Autosomal recessive - the child can only inherit the disorder if both parents are carriers of the gene. Boys and girls are equally affected. The carrier parents won't have any symptoms, but each of their children will have a one in four chance of developing leukodystrophy and a one in two chance of being a carrier themselves.

  • X-linked - the gene is carried on the X chromosome, which is involved in determining the baby's sex. Men have an X and a Y chromosome and women have two X chromosomes. Because men only have a single copy of the genetic programs on the X chromosome, if there is a genetic change, there are no other genes to compensate. Boys and girls are therefore affected differently.

  • Leukodystrophy is different to multiple sclerosis - the white matter can be affected as a result of (secondary to) a number of conditions, including ischaemia, infection, other metabolic conditions and multiple sclerosis (MS).

To date, there is no specific treatment for metachromatic leukodystrophy, although patients with juvenile- and adult-onset disease may benefit from allogeneic bone marrow transplantation in the early stages of disease. Based on results from animal studies, clinical studies of enzyme replacement therapy are already in progress and studies are planned in the near future to investigate the direct injection of ASA-expressing viral vectors into the brain or haematopoietic stem-cell-based gene therapy.

Symptoms:

The symptoms can vary, depending on how quickly damage to the white matter occurs, whichparts of the brain (or spinal cord) are affected and sometimes, how much the peripheral nerves areaffected. The white matter has a large role in motor function (movement), so damage usually leadsto problems in this area.The onset of symptoms varies. They can include subtle or gradual changes to:

    Muscle tone.

  • Body movements.

  • Walking style.

  • Speech.

  • Ability to chew and swallow food.

  • Eye sight.

  • Hearing.

  • Mental ability.

  • Behavior.

Diagnosis:

The diagnosis of a metachromatic leukodystrophy often not easy. Frequently, it will involve the input ofa number of specialists, including neurologists, geneticists and metabolic physicians. Diagnostic methods may include:

    Physical examination.

  • Blood tests.

  • Urine tests.

  • MRI scans.

  • Nerve conduction tests.

  • Neurocognitive tests.

  • Nerve biopsy.

  • Genetic tests.

Treatment:

Currently, metachromatic leukodystrophy cannot be cured. Stem cell therapy and bone marrow transplantation have each been tried in some cases. However, the benefits depend on the timing, age of onset and severity of symptoms. Therapies such as gene therapy and enzyme replacement therapy are under investigation. Treatment is mainly supportive and may include:

    Physical therapy.

  • Occupational therapy.

  • Psychological counseling.

  • Family counseling (including genetic counseling).

  • Medications (for example, medications for seizures).

NOTE: The above information is for processing purpose. The information provided herein should not be used during any medical emergency or for the diagnosis or treatment of any medical condition.

DISCLAIMER: This information should not substitute for seeking responsible, professional medical care.

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