ARSA gene
Also known as: Arylsulfatase A deficiency, ARSA deficiency
OMIM#250100 https://omim.org/entry/250100
1. The Disease:
A rare lysosomal disease characterized by accumulation of sulfatides in the central and peripheral nervous system due to deficiency of the enzyme arylsulfatase A, leading to demyelination. Three clinical subtypes can be distinguished based on the age of onset: late infantile, juvenile, and adult. Lead symptoms are deterioration in motor or cognitive function or behavioral problems, depending on the subtype. Mode of inheritance is autosomal recessive.
2. The symptoms:
Arylsulfatase A deficiency (also known as metachromatic leukodystrophy or MLD) is characterized by three clinical subtypes: late-infantile MLD, juvenile MLD, and adult MLD. Age of onset within a family is usually similar. The disease course may be from several years in the late-infantile-onset form to decades in the juvenile- and adult-onset forms. Lack of early signs or symptoms does not exclude the diagnosis.
Late-infantile MLD. Onset is before age 30 months. Typical presenting findings include weakness, hypotonia, clumsiness, frequent falls, toe walking, and dysarthria. As the disease progresses, language, cognitive, and gross and fine motor skills regress. Later signs include spasticity, pain, seizures, and compromised vision and hearing. In the final stages, children have tonic spasms, decerebrate posturing, and general unawareness of their surroundings.
Juvenile MLD. Onset is between age 30 months and 16 years. Initial manifestations include decline in school performance and emergence of behavioral problems, followed by gait disturbances. Progression is like but slower than in the late-infantile form.
Adult MLD. Onset occurs after age 16 years, sometimes not until the fourth or fifth decade. Initial signs can include problems in school or job performance, personality changes, emotional lability, or psychosis; in others, neurologic symptoms (weakness and loss of coordination progressing to spasticity and incontinence) or seizures initially predominate. Peripheral neuropathy is common. Disease course is variable – with periods of stability interspersed with periods of decline – and may extend over two to three decades. The final stage seems like earlier-onset forms.
3. Actions to take in case of early diagnosis:
Biochemical correlation, if possible, is essential for confirming diagnosis with ARSA enzyme deficiency and identification of elevated urinary excretion of sulfatides. Brain MRI can show leukodystrophy.
MLD is a lifelong disease requiring lifetime management and regular follow-up with a Paediatric Neurology Center Management is provided by multidisciplinary team.
Hematopoietic stem cell transplantation (HSCT) is the only therapy for primary central nervous system manifestations. Outcomes depend on the clinical stage and the presence of neurologic symptoms. The best results are observed when HSCT is performed in pre- and very early symptomatic individuals with the juvenile or adult form of the disease.
HSCT is not recommended for individuals with symptomatic, late-infantile MLD.
Gene therapy for MLD is under investigation for the MLD.
ERT is an alternative treatment for MLD for pre-symptomatic patients.
Genetic counselling is highly recommended for family planning and evaluation of at-risk family members such as siblings.