Metachromatic leukodystrophy (MLD) is a rare lysosomal disorder occurring in about 1 in 40.000. An enzyme called arylsulfatase A (ASA) which usually degrades sulfatides in brain and peripheral nerves is not working in this disorder. Sulfatides accumulate and are toxic for myelinating cells. According to the age of onset, there are several forms: the (late) infantile form starting before the age of three years, the juvenile form starting from the age of 3 years, and the adult form with first symptoms after the age of 16 years. Generally speaking, disease progression depends on the age of onset: early forms progress at a much faster rate than late forms.
First symptoms of patients with the late infantile form of the disease start mostly between 12 and 24 months of age and include rapidly progressive spasticity (stiffness), ataxia (balance and fine motor problems), loss of walking and sitting and problems with speech and swallowing (pseudobulbar symptoms). If peripheral neuropathy is prominent, hypotonia and ataxia are present from the start, later changing into spastic paresis. Painful tonic spasms are common. Loss of speech and dementia ensue as well as loss of vision. Epilepsy is frequent in the late stage. The early juvenile form resembles the late-infantile form, but with a slower decline. In the late-juvenile and the adult forms, psychiatric symptoms are much more prominent with attention problems, slow dementia and psychosis. These symptoms often have an insidious beginning, making it difficult to pinpoint the start of the disease. Motor symptoms as spasticity and ataxia are usually mild and progress at a slow pace. Peripheral neuropathy is found in almost all patients, but may be very mild.
Another organ to be affected is the gallbladder. Sulfatides are stored in its wall and may be secreted in the bile, which may lead to colics, development of polyps and hemobilia.
There is a correlation between residual enzyme activity and clinical phenotype. In general, a higher residual enzyme activity is associated with a later onset and slower disease course. There is also variation in disease severity that can be observed within families that cannot be explained by enzyme activity of gene mutations in a straightforward fashion.
Diagnosis is suspected on the basis of clinical presentation and typical abnormalities at brain MRI and confirmed by undetectable or low activity of ASA in a blood sample. Pseudo-deficiency of ASA is relatively frequent (present in 0.2 to 0.5 % of Caucasians) with a residual enzyme activity of 10%; this is not associated with disease and due to a frequent allele with one or two polymorphisms causing the decreased ASA activity. Sulfatide excretion in urine which is elevated in patients with MLD is normal in people with ASA pseudo-deficiency. The enzymatic diagnosis is as a rule followed by mutational analysis of the ARSA gene.
Figure A and B are from a 2-year-old child with MLD, C and D are from a healthy child the same age. All images are axial T2-weighted images. Normally, the white matter has a dark signal as in (C) o (D), cerebrospinal fluid signal is white and the signal of the grey matter (e.g. the cortex) is grey. In (A), the white matter signal is abnormal especially round the posterior part of the ventricles. In (B), you can see again abnormally high ("white") white matter signal. The signal of the white matter which is just next to the cortex is normal. In the affected white matter in (B), there are small black dots. This is preserved myelin round small blood vessels.
Hematopoietic stem cell transplantation (HSCT), often also called bone marrow transplantation, has been tried in all forms of the disease. If the infantile form has already become symptomatic, treatment is no longer possible as the disease process cannot be stopped once begun. In patients with the juvenile or adult form of the disease, HSCT can stabilize the disease even after first symptoms have started; it is, however, not successful if performed too late in the disease process. It is a very intensive form of treatment with the risk of severe complications and death.
In children with the late-infantile form who have been diagnosed before they have developed symptoms (e.g. if an older sibling has been diagnosed with the disease), there is a trial in Milano/Italy going on testing the efficacy and safety of gene therapy. More information can be found at their site (http://www.mldfoundation.org/research-SanRaffaele.html).
Enzyme replacement therapy where the missing enzyme is administered in an infusion to patients has been tried in small children with the early form. Unfortunately, this therapy was not successful and has therefore been abandoned. The enzyme cannot cross the blood-brain barrier and therefore cannot become active in the brain.
In patients who cannot be treated with HSCT, it is important to achieve comfort, and this is the main goal of therapy. Irritability and painful spasms can be partly improved by medication, also epilepsy can be treated with drugs. Children with the early form will develop feeding problems and have then to be fed via a nasogastric tube or a PEG.
MLD is genetic. It is inherited in an autosomal recessive manner and caused by mutations in the gene coding for arylsulfatase A (ARSA). This means that parents are healthy, but carry each one defective copy of the responsible gene. Click here for more infromation. If a child inherits two defective copies of this gene, it will be affected. Prenatal diagnosis is possible.
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