Lysosomal

Leukodystrophies are part of a larger group of lysosomal disorders. These are genetic illnesses characterized by a malfunction of lysosome enzymes.

Lysosomes are a specialised structure (organelle) within the cell containing many enzymes whose function includes the chemical breakdown and recycling of nutrients.

When the lysosome is not functioning correctly, certain nutrient molecules accumulate and this may be the root cause of the disease.

Two leukodystrophies belong to this group of diseases:

Metachromatic leukodystrophy accounts for about 20% of Leukodystrophies registered by ELA.

Metachromatic leukodystrophy (MLD) is a neurodegenerative disease caused by deficiency of a lysosomal enzyme called arylsulfatase A. Onset can occur during childhood, adolescence or in adulthood and is characterized by rapid demyelination of the central and peripheral nervous system associated with sulfatide accumulation in the brain and kidneys.

Metachromatic leukodystrophy is a hereditary disease transmitted as an autosomal-recessive. Which means that for a couple where both individuals are carriers for the defective gene, the risk factor for having a child with the disease (boy or girl) is 25% for each pregnancy. It is estimated that this disease affects 1/45 000 children at birth.

 

The different forms of MLD

The three forms of this disease can be distinguished according to the age of onset of neurological symptoms: late-infantile (60% of cases), juvenile (20-30% of cases) and adult (10-20% of cases).

1. Late-infantile form

In the late infantile form, onset of symptoms can occur between 1½ and 2½ in the form of motor function problems and parents will often seek medical advice about walking difficulties. The disease can progress very rapidly (loss of ability to walk, to sit up, and of cognitive function) over a matter of weeks or months, leading to a bed-ridden state and blindness in a few months and generally to death five years from the onset of symptoms.

2. Juvenile form

The juvenile form arises between the ages of 4 and 12. Usually the first symptoms are behavioral difficulties and a decline in intellectual performance followed later by motor function difficulties, epileptic fits, ataxia and speaking problems. This form progresses less quickly than the infantile form, but is always fatal, most patient dying before they are twenty years old.

3. Adult form

Onset of the adult form can begin from the age of 12 but is often not diagnosed before adulthood. Psychiatric disorders and progressive mental deterioration (personality changes, decline in performance at work, progressing to dementia) or motor function difficulties are all characteristic of this disease. The disease is fatal, and death usually occurs within three years of the onset of symptoms.

 

Metachromatic leukodystrophy

Metachromatic leukodystrophy accounts for about 20% of Leukodystrophies registered by ELA.

Metachromatic leukodystrophy (MLD) is a neurodegenerative disease caused by deficiency of a lysosomal enzyme called arylsulfatase A. Onset can occur during childhood, adolescence or in adulthood and is characterized by rapid demyelination of the central and peripheral nervous system associated with sulfatide accumulation in the brain and kidneys.

Metachromatic leukodystrophy is a hereditary disease transmitted as an autosomal-recessive. Which means that for a couple where both individuals are carriers for the defective gene, the risk factor for having a child with the disease (boy or girl) is 25% for each pregnancy. It is estimated that this disease affects 1/45 000 children at birth.

 

Genetics, Pathophysiology, Diagnosis and Screening for MLD

Genetics and Pathophysiology

Metachromatic leukodystrophy is caused by a mutation of the ARSA gene, mapped to chromosome 22 (22q) which codes for arylsulfatase A, a lysosomal enzyme responsible for the breakdown of sulfatides, a major lipid component of myelin sheaths. To date, more than 115 mutations have been identified in the ARSA gene.

Loss of normal ARSA activity leads to the accumulation of sulfatides in the central and peripheral nervous system resulting in demyelination. The exact mechanism underlying demyelination remains to be clarified. The infantile form is characterized by a severe deficiency of arylsulfatase A activity, or even it's complete absence. In the juvenile form, enzymatic deficiency and excessive sulfatide are still present though less extreme, whereas in the adult form there remains some residual enzyme activity.

In some rare cases, mutations have been observed in the SAP-B gene, mapped to chromosome 10 (10q21-22). SAP-B activates the enzyme for the degradation of sulfatides. Mutations of SAP-B result in sulfatase activator deficiency induced metachromatic leukodystrophy, where the clinical picture is that of classic infantile or juvenile metachromatic leukodystrophy. In this instance, there is no arylsulfatase A deficiency, yet there is excessive presence of sulfatide.

Diagnosis and Screening

Diagnosis is based on evidence of ARSA enzyme deficiency in ARSA, established by way of a simple blood test. This diagnosis is then confirmed through nerve biopsy and by the presence of excessive sulfatides in the urine. An MRI and an electromyogram may also be proposed. In families that are at risk, prenatal diagnosis is an option at the 10th week of pregnancy.

Treatment options for MLD

Allogeneic bone marrow transplant

This is the only treatment available for those affected by the juvenile or adult form of MLD which, if performed right at the onset of symptoms (and before the appearance of signs of neurological degradation), can stabilize or reverse demyelinating cerebral lesions. Bone marrow transplant is only possible if a compatible donor or compatible umbilical cord blood is found. This procedure carries a high mortality rate: 15 to 20%.

Transplant has no affect on any damage to the peripheral nervous system or upon infantile forms of the disease, once the symptoms have already developed.

Symptom-based care

Here treatment aims to improve the quality of life of the children and adults affected: pain, rigidity, epilepsy and spasticity management, treatment of orthopedic complications and the use of a gastric feeding tube to ensure adequate supply of nourishment.

Psychological care

Psychological care should not be only for the patient, but should also be available for siblings, parents, and partners and often for several members of the same family.

Krabbe's disease, also called globoid cell leukodystrophy, is an autosomal recessive condition resulting from galactosylceramidase (or galactocerebrosidase) deficiency, a lysosomal enzyme that catabolizes a major lipid component of myelin.

Incidence in France is an estimated 1:150,000 births.

The disease leads to demyelination of the central and peripheral nervous system.

Onset generally occurs during the first year and the condition is rapidly progressive, but juvenile, adolescent or adult onset forms have also been reported, with a more variable rate of progression.

The classic infantile form accounts for 85 to 90% of cases. Initial symptoms include increasing irritability, hypertonia, hyperesthesia, and signs of peripheral neuropathy. Later on, hypertonic episodes with opisthotonos occur frequently, and convulsions may appear. As the disease progresses, blindness and deafness occur, followed by a vegetative state, and finally by hypotonia.

In the forms with later onset the first signs are often gait disturbancies (spastic paraparesis or ataxia), hemiplegia, visual loss, with or without peripheral neuropathy. Mental deterioration is variable (usually absent in adult forms).

The gene coding for galactosylceramidase is located on 14q31 and has been identified. Two mutations are more frequently observed (65% of alleles in France).

Diagnosis is established from enzyme assay (galactosylceramidase deficiency).

There are several natural animal models (mouse, dog, monkey).

Pathognomonic globoid cells are derived from macrophages and induced by non-hydrolysed galactosylceramides. The early destruction of oligodendrocytes is considered to be due to the accumulation of a cytotoxic metabolite (galactosylsphingosine or 'psychosine').

 

Source: Orphanet