[Some problems on the clinical phenotype of Machado-Joseph disease in relation between their ages at onset]

Abstract

This study proposed that three phenotypes of Machado-Joseph disease (MJD) are closely related to the patients' ages at onset.

Materials: Six patients from two families. Autopsy performed in three of them (case 2, 4, 5). Two patients are a father (case 4) and his son (case 5).

Results: 1. Clinical features. All cases showed cerebellar ataxia and nystagmus. Progressive nuclear oculomotor palsy was common except for one case who killed himself in the early clinical stage. Pyramidal symptom which is increased deep tendon reflexes, spasticity, and extesor plantar response was common for three patients (case 3, 5, 6) whose ages of onset are under 40 years. One case (case 5) developed dystonia of foot at the age of ten and he developed the symptom of type 1 of MJD. However, the other three patients (case 1, 2, 4) who developed ataxia after the middle of the fifth decade showed hypotonia and decreased or absence of deep tendon reflexes from the beginning. The latter did not revealed spasticity or dystonia. Their clinical symptoms were identical with the type 3 of MJD. In spite of ages at onset, they showed general muscular atrophy and sensory disturbance in the advanced clinical course. 2. Neuropathological findings. 1) cerebellar system: Severe degeneration in the spinocerebellar system and mild to moderate one in the pontocerebellar system and dentate nuclei. The inferior olivary nucleus and the cerebellar cortex were almost preserved. 2) extrapyramidal system: Moderate to severe degeneration in the substantia nigra, globus pallidus (prominent in the internal segment) and subthalamic nucleus. 3) Degeneration in the oculomotor nuclei, motor neurons in the anterior horn and dorsal column of the spinal cord.

Conclusion: These clinico-pathological findings indicate the difference of clinical phenotype is not always reflected those of neuropathological findings. The review of our experience and the literature suggests that the clinical features of MJD symptoms are related to the patients' ages at onset and clinical progression of the disease. When the disease begins before the age of ten, dystonia is an initial symptom, followed by pyramidal symptoms and cerebellar ataxia (type 1). In the early adult cases, the onset in which is earlier than forty, cerebellar ataxia and pyramidal symptoms are the initial symptoms, followed by extrapyramidal symptoms such as dystonia or choreoathetoid movements or both (type 2). In both instances however, decreased DTRs, muscular atrophy and sensory disturbance are common clinical manifestations at the advanced clinical stage. In late adult MJD cases with the age at onset after forty, the initial symptom is progressive cerebellar ataxia with hypotonia, followed by muscular atrophy and sensory disturbance (type 3). In spite of a marked degeneration in the extrapyramidal system, few or no extrapyramidal symptoms are detected in the last cases.