2 The condition

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.

2.2 The prevalence of MLD is estimated as 1 in 147,000 live births in England and Wales, equating to about 4 to 5 children born with MLD per year.

2.3 Timely diagnosis of MLD may be challenging, particularly in families without a previous history of the condition. Generally, the LI type is identified because children are unable to meet a major motor development milestone, whereas children with EJ MLD may initially have some cognitive or coordination changes. Adults with MLD mainly present with dementia-like symptoms. Tests include brain MRI, and blood and urine tests to detect sulphatides. When MLD is confirmed, genetic testing is done to identify the specific mutation. Diagnosis of the later-onset forms may take longer than for the LI type because of their non-specific signs and symptoms.

2.4 MLD is managed in the NHS by neurodisability and metabolic consultants at regional centres, who advise local hospital and community-based teams. There are 3 paediatric lysosomal storage disorders specialist centres in England providing multidisciplinary treatment led by a paediatric metabolic consultant at:

  • Birmingham Children's Hospital

  • Great Ormond Street Hospital, London

  • St Mary's Hospital, Manchester.

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  • National Institute for Health and Care Excellence (NICE)