Hereditary spastic paraplegia and hereditary ataxia - Part 2: A family demonstrating various phenotypic manifestations with the SCA3 genotype

Background: Clinical descriptions of the dominantly inherited ataxic motor syndromes in a 7-generation family of German origin were first reported in 1951. Objective: To provide follow-up clinical, pathological, and genetic data fo r 9 patients in this family. Design: Clinical histories and neurologic findings, gross and microscopic p athological features, and DNA analysis. Results: Clinical presentations in this closely followed. up portion of the family include fairly uniform ataxic and upper motor neuron symptoms. Nyst agmus was a conspicuous and early sign, but generational anticipation was n ot evident. Although often present, amyotrophy was not a major source of di sability. Major pathological degeneration was noted in the pens, spinal cor d, and upper brainstem, where ubiquitin-immunoreactive intranuclear inclusi on bodies were demonstrated. The diagnosis of Machado-Joseph disease (SCA3 [spinocerebellar ataxia type 3] genotype) was established from autopsy tiss ue in 1 patient and from blood specimens in 6 others. Conclusions: Clinical variation within this family and between this family and families with the SCAI and SCA3 genotypes is so broad as to make the ge netic diagnosis From clinical criteria alone practically impossible. The pa thological definition of Machado-Joseph disease is more reliable, but some findings do overlap those of other genotypes. To our knowledge, the basis f or the phenotypic variations in Machado-Joseph disease, genetic or otherwis e, has not been established.