Review Paper

NeuroMolecular Medicine

, Volume 13, Issue 1, pp 27-30

First online:

Markesbery Disease: Autosomal Dominant Late-Onset Distal Myopathy: From Phenotype to ZASP Gene Identification

  • Robert C. GriggsAffiliated withDepartment of Neurology, University of Rochester School of Medicine and Dentistry Email author 
  • , Bjarne A. UddAffiliated withNeuromuscular Research Unit, University of Tampere

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In 1974, Markesbery et al. thoroughly characterized and reported a large kindred with distal muscle weakness of late adult-onset that was autosomal dominantly inherited. Clinical evidence supported myopathy rather than the usual neuropathy expected with distal weakness. Postmortem examination of two patients documented myopathy and excluded anterior horn cell disease or peripheral neuropathy as the cause. Distinctive morphologic changes were present in muscle. Widely accepted as a distinct disease entity, this disorder has recently been characterized as one of a group of myofibrillar myopathies resulting from mutations in several muscle proteins. Studies of members of the original family have now identified the molecular defect to be a mutation in ZASP, Z-band alternatively spliced PDZ-motif-containing protein. The specific mutation, A165V, was identified in all clinical affected family members by direct sequencing. Thus, Markesbery disease is a zaspopathy. Other families have been identified with the same mutation and a shared haplotype indicating a founder effect.


Myopathy Muscular dystrophy ZASP Myofibrillar Myofibrillar myopathology