N279K, P301S N279K, P301S P301L
Modified from Wszolek et al. (13) and Ghetti et al. (16). By permission of Lippincott Williams & Wilkins and ISN Neuropath Press.
a shuffling gait and reduced arm swing. His facial expression also had changed considerably, and drooling became a problem. Subsequently, a resting tremor developed in both legs (in the left more than the right) and occasionally in both hands. His balance deteriorated steadily over the next 2 yr. He experienced many falls throughout the day and had difficulty standing up (see accompanying DVD video 1, segments C and D). His balance was better in the morning than in the evening. Treatment with carbidopa-levodopa was of limited benefit.
At age 44, the patient reported generalized stiffness in the muscles of his neck, tongue, and extremities. The stiffness was more pronounced in the afternoon and after the carbidopa-levodopa effect had worn off (i.e., after 3 h). The tremor in his legs (particularly the left) was also worse several hours after carbidopa-levodopa administration. He complained of frequent and uncontrollable yawning. He chewed gum almost constantly to avoid yawning and excessive drooling. He remained independent in most activities of daily living but needed occasional assistance with cutting food.
When examined at age 44, his Mini-Mental State Examination score was 30/30. His neck was anteroflexed, and he had obvious parkinsonism in the form of facial hypomimia, markedly reduced blinking, prominent drooling, and generalized body bradykinesia. He had severe postural instability, and while walking he needed assistance from at least one person to prevent falls (video 1, segments E-G). Muscle tone was increased and was a mixture of rigidity and spasticity; the tone was more pronounced in axial than in appendicular muscles. Muscle strength was normal. Deep tendon reflexes were exaggerated, with bilateral ankle clonus (right more than left). Bilateral extensor plantar responses were also noted.
At the time of this writing, he was 46 yr old, lived in a skilled nursing facility, and required assistance in all activities of daily living.
The inherited spinocerebellar ataxias (SCAs) are a heterogeneous group of disorders characterized by dysfunction and degeneration of systems involved in motor coordination (24). The clinical phenotypes vary. Additional clinical features include pyramidal signs, eye movement abnormalities, dementia, chorea, and peripheral neuropathy. Currently, 19 SCA loci and mutations have been identified.
Parkinsonism has been recognized as a clinical phenotype in the SCA3 mutation (25,26). The autopsies performed on individuals with the SCA3 mutation demonstrated Purkinje cell loss and torpedo-like structures in the axons of Purkinje cells. Cell loss is also frequently seen in brainstem nuclei, including the substantia nigra, inferior olive, and pontine nuclei.
Recently, several families with the SCA2 mutation were described whose members manifested with either ataxia and parkinsonism or with parkinsonism alone (27-30). However, no autopsies have been reported from these kindreds.
Table 4 outlines clinical data on all known SCA2 families with parkinsonism. Although parkin-sonism is rare with the SCA2 mutation, it can be the only manifestation of the disease in some SCA2 families. For example, before the SCA2 mutation was identified in the Canadian (Alberta) kindred (29), affected individuals in this family were thought to have PD. The parkinsonism in SCA2 is characterized by asymmetrical rigidity, bradykinesia, resting tremor, and responsiveness to levodopa. In a Taiwanese family, two affected individuals had supranuclear gaze palsy (27). The average age at onset of parkinsonian symptoms in SCA2 kindreds is 47 yr (range, 19-86 yr). Because many of the affected individuals in these kindreds are still living, the average disease duration remains unclear.
Table 5 summarizes the clinical signs observed in SCA3 kindreds. In these families, parkinsonism is usually associated not only with ataxia but also with oculomotor dysfunction and upper and lower motor signs. However, in the African-American population, some affected members of families with the SCA3 mutation exhibit a phenotype indistinguishable from that of idiopathic PD (31,32). The
Clinical Features of SCA2 Families With Parkinsonism
Number of affected individuals Age at disease onset, yr Initial symptoms Parkinsonism Bradykinesia Rigidity Resting tremor Postural instability Response to levodopa Ataxic gait Dementia
Length of CAG repeats
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