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Machado-Joseph disease in three Scandinavian families
T Løkkegaard1, J E Nielsen, L Hasholt
1Institute of Medical Biochemistry and Genetics, The Panum Institute, University of Copenhagen, Denmark.
Abstract:
Machado-Joseph disease (MJD) is an autosomal dominantly inherited neurodegenerative disorder characterized by varying age of onset and pronounced phenotypic heterogeneity. The clinical core features include gait ataxia, external ophthalmoplegia, nystagmus, and bulging eyes. Recently, Kawagushi et al. (1994) cloned the MJD1 gene on chromosome 14 and MJD turned out to be the fifth neurodegenerative disease caused by an unstable CAG repeat expansion. We have studied two large Danish families and one Norwegian family with MJD. Three features not previously associated with MJD are reported: dementia, generalized muscle and joint pain, and in one case neuropathological examination revealed atrophy of the inferior olives. We found a significant inverse correlation between age of onset and the length of the CAG repeat expansion, and anticipation is described through four succeeding generations. Instability of the CAG repeat expansion was most pronounced at paternal transmission.
Insights
Machado-Joseph disease (MJD), an inherited neurodegenerative disorder, is linked to unstable CAG repeat expansions. This study identified new symptoms and confirmed anticipation, with repeat instability most prominent in paternal transmission.
Area of Science:
- Genetics
- Neuroscience
- Molecular Biology
Background:
- Machado-Joseph disease (MJD) is an autosomal dominant neurodegenerative disorder.
- It is characterized by genetic instability, specifically an expanding CAG trinucleotide repeat in the MJD1 gene.
- Phenotypic heterogeneity and variable age of onset are hallmarks of MJD.
Observation:
- This study investigated two Danish and one Norwegian family affected by MJD.
- New clinical features observed include dementia and generalized muscle/joint pain.
- Neuropathological findings revealed atrophy of the inferior olives in one patient.
Findings:
- A significant inverse correlation was found between age of onset and CAG repeat length.
- Anticipation, the phenomenon of earlier onset in successive generations, was observed across four generations.
- CAG repeat expansion instability was most pronounced during paternal transmission.
Implications:
- These findings expand the known clinical spectrum of Machado-Joseph disease.
- Understanding the correlation between repeat length and age of onset aids in predicting disease progression.
- The observed paternal instability may offer insights into the mechanisms of repeat expansion in MJD.