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Published on: April 4, 2018
Adult onset metachromatic leukodystrophy without electroclinical peripheral nervous system involvement: a new
Ana M Marcão1, Roland Wiest, Kaspar Schindler
1Institute of Physiological Chemistry, University of Bonn, Bonn, Germany.
Background:
Metachromatic leukodystrophy (MLD) is a lysosomal storage disease caused by the deficiency of arylsulfatase A (ARSA). Clinically, the disease is heterogeneous with respect to the age of onset, affection of peripheral and central nervous systems, and progression.
Objectives:
To analyze mutations in the ARSA gene of a patient with adult-onset MLD with no signs of peripheral polyneuropathy and to emphasize the clinical, neuroradiologic, neuropathologic, and genetic features of the disease.
Design:
Case study of a patient clinically presenting with rapidly progressive dementia and behavioral abnormalities. We report the findings of clinical evaluation and neurophysiologic and neuropathologic studies of peripheral nerves; we also performed DNA sequence analysis, transfections, metabolic labeling, and immunoprecipitation of mutant ARSA polypeptides.
Setting:
Genetic research and clinical unit, university hospital.
Results:
Genetic analysis revealed homozygosity for a novel mutation in exon 3 of ARSA (F219V). This substitution leads to a misfolded unstable enzyme with a specific activity less than 1% of normal. There were no clinical or neurophysiologic signs of peripheral nervous system dysfunction. Typical neuropathologic signs for MLD were absent from nerve biopsy specimens.
Conclusions:
This novel mutation is associated with progressive psychocognitive impairment without clinical or electrophysiologic signs and only minor morphologic signs of peripheral nerve affection. The F219V substitution causes reduction in enzyme activity to an extent unexpected for an adult patient with MLD.
Insights
A novel arylsulfatase A (ARSA) gene mutation (F219V) causes adult-onset metachromatic leukodystrophy (MLD) with cognitive decline but minimal peripheral nerve issues. This mutation severely reduces enzyme activity, presenting atypically for MLD.
Area of Science:
- Biochemistry
- Genetics
- Neurology
Background:
- Metachromatic leukodystrophy (MLD) is a genetic lysosomal storage disorder resulting from arylsulfatase A (ARSA) deficiency.
- Clinical presentations of MLD are diverse, impacting the central and peripheral nervous systems with variable progression rates.
Observation:
- A case study of a patient with adult-onset MLD presenting with rapid dementia and behavioral changes.
- Clinical evaluation included neurophysiologic and neuropathologic studies of peripheral nerves.
- Genetic analysis involved DNA sequencing, transfections, metabolic labeling, and immunoprecipitation.
Findings:
- A novel homozygous mutation, F219V, was identified in the ARSA gene.
- This mutation resulted in a misfolded, unstable ARSA enzyme with <1% normal activity.
- The patient showed no clinical or neurophysiologic signs of peripheral nervous system dysfunction, with minimal neuropathologic findings.
Implications:
- The F219V mutation is linked to progressive psychocognitive impairment in adult-onset MLD, despite a lack of significant peripheral nerve disease.
- This mutation leads to a profound reduction in ARSA enzyme activity, which is unusual for adult MLD patients.
- Highlights the complex genotype-phenotype correlations in MLD and the need for comprehensive genetic analysis.
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