What is Metachromatic Leukodystrophy (MLD)?
Metachromatic Leukodystrophy (MLD) is a lysosomal storage disease characterised by the deficiency of the enzyme arylsulfatase A, commonly referred to as ARSA, and is inherited in an autosomal recessive manner. The gene responsible for ARSA synthesis, the Arylsulfatase A gene, is located on chromosome 22q13.33. The mutation is commonly a missense mutation (Cesani 2016).
Enzyme deficiency leads to the accumulation of sulfatide in the peripheral and central nervous systems, resulting in widespread demyelination (loss of the myelin sheath). Demyelination and neurodegeneration cause progressive motor and cognitive decline, eventually leading to functional loss and death.
What are the Clinical Subtypes of Metachromatic Leukodystrophy (MLD)?
According to the age of onset, the disease is primarily categorised into three groups: Late Infantile (<30 months), Juvenile (Early Juvenile: 30 months to 6 years; Late Juvenile: 7 to 16 years), and Adult form (≥17 years) (Gomez-Ospina 2020; Orchard DOF 2019A).
A study has shown the disease’s prognosis, with median survival following symptom onset as 2.7 years for the late infantile group, nine years for the juvenile group, and 25 years for the adult group. The 5-year survival rates from the onset of symptoms are 25.1% for the late infantile group, 70.3% for the juvenile group, and 87.1% for the adult group (Gomez-Ospina 2020; Mahmood 2010).
How is Metachromatic Leukodystrophy Diagnosed?
- Blood ARSA activity
- Urinary sulfatide analysis
- Panel, exon/genome analysis
What are the Treatment Options for Metachromatic Leukodystrophy (MLD)?
- Hematopoietic Stem Cell Transplantation (HSCT)
- Enzyme Replacement Therapy (ERT)
- Gene Therapy (GT)
Source:
- Cesani M, et al. Mutation Update of ARSA and PSAP Genes Causing Metachromatic Leukodystrophy. Hum Mutat. 2016;37(1):16-27. doi:10.1002/humu.22919
- Gomez-Ospina N. Arylsulfatase A Deficiency. 2020 Apr 30
- Mahmood A, et al. Metachromatic leukodystrophy: a case of triplets with the late infantile variant and a systematic literature review. J Child Neurol. 2010;25(5):572-580. doi:10.1177/0883073809341669
- Pekgül F, et al. Comprehensive clinical, biochemical, radiological and genetic analysis of 28 Turkish cases with suspected metachromatic leukodystrophy and their relatives. Mol Genet Metab Rep. 2020;25:100688. Published 2020 Dec 11. doi:10.1016/j.ymgmr.2020.100688
- Shaimardanova AA, et al. Metachromatic Leukodystrophy: Diagnosis, Modeling, and Treatment Approaches. Front Med (Lausanne). 2020;7:576221. Published 2020 Oct 20. doi:10.3389/fmed.2020.576221
