Arylsulfatase A Deficiency

Excerpt

Clinical characteristics: 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.

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 similar to 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 is similar to earlier-onset forms.

Diagnosis/testing: The diagnosis of MLD is established in a proband with progressive neurologic dysfunction, MRI evidence of leukodystrophy, or ARSA enzyme deficiency and identification of biallelic ARSA pathogenic (or likely pathogenic) variants on molecular genetic testing, or identification of elevated urinary excretion of sulfatides, or less commonly, identification of metachromatic lipid deposits in nervous system tissue.

Management: Treatment of manifestations: Physical therapy and an enriched environment to maximize intellect, neuromuscular function, and mobility; family support to enable parents and/or caregivers to anticipate decisions on walking aids, wheelchairs, feeding tubes, and other changing care needs; treatment of seizures using anti-seizure medication in standard protocols; treatment of contractures with muscle relaxants. Standard treatments for gastroesophageal reflux, constipation, drooling, dental care, pulmonary function, and impaired vison.

Prevention of primary manifestations: 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.

Prevention of secondary complications: Therapies designed to prevent decline in mobility, cognitive ability, communication, or food intake; safety measures for movement limitations and seizure precautions.

Surveillance: Regular monitoring by a neurologist or metabolic geneticist including evaluation for changes in motor function, development of seizures, contractions, feeding difficulties, and disease progression following anesthesia or fever; periodic brain MRI examination.

Genetic counseling: MLD is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing of at-risk family members and prenatal testing for a pregnancy at increased risk are possible if both ARSA pathogenic variants have been identified in an affected family member.