2.1
Metachromatic leukodystrophy (MLD) is an autosomal recessive genetic disorder, caused by a deficiency in the enzyme arylsulphatase A (ARSA). This deficiency causes sulphatides to accumulate, producing microglial damage, progressive demyelination and neurodegeneration, leading to neurological problems. MLD is a progressive and chronically disabling condition, which substantially reduces quality of life and life expectancy. MLD can broadly be divided into a presymptomatic stage with normal motor and cognitive development, followed by a developmental plateau and early onset of first symptoms. There are 3 main types based on genotype and age of symptom onset:
-
The late infantile (LI) type is characterised by 2 null alleles (0/0 genotype). It is the most common (40% to 60% of children affected) and most aggressive form and usually starts before 30 months. Symptoms include peripheral neuropathy, muscle weakness, sight and hearing loss, difficulty walking, loss of speech, cognitive decline, and seizures. The condition progresses rapidly so that children lose awareness of their surroundings over a few years. Death normally occurs within 5 to 8 years.
-
The juvenile type is characterised by either 1 null allele and 1 residual allele (0/R genotype) or, less frequently, 2 residual alleles (R/R genotype). About 20% to 35% of children affected have this type. Symptoms include impaired fine motor skills and concentration, behavioural problems, difficulties with movement, slurred speech, incontinence and seizures. Initial disease progression is slower than with the LI type but symptoms can progress rapidly. Death normally occurs within 10 to 20 years. It can be subdivided into:
-
early juvenile (EJ) disease, starting between 30 months and 6 years
-
late juvenile disease, starting between 7 and 16 years.
-
-
The adult type (15% to 25% of people affected) is the rarest form and usually starts after 16 years. Symptoms include a decline in school or work performance, cognitive decline, personality changes and memory lapses. The decline can be slow and almost imperceptible. Death normally occurs within 25 years.