The proband was a 63-year-old woman who suffered of a severe depressive episode at 46 years of age, then she slowly developed gait ataxia with falls and dysfunction of fine finger movements. She is the second child of unrelated Italian parents. The father died at 82 years of age with cognitive deterioration starting at 70; the mother is 87 years old and healthy. The patient has three healthy siblings and a son (34 years old) who is reported to suffer of epilepsy since his childhood and showing a wide-based gait in the last two years.
When she was 54, the patient's relatives noticed personality changes (aggressiveness, hyperphagia, inappropriate shopping) and increased frequency of falls. Brain magnetic resonance imaging (MRI) showed bilateral and symmetric moderate atrophy of frontal and parietal cortex and clear atrophy of both cerebellum hemispheres and vermis. At that time a tentative diagnosis of olivo-ponto-cerebellar atrophy was made in another hospital. At 55 years of age neuropsychological tests (including Stroop color-word, Wisconsin Card Sorting, Rey auditory verbal learning, Clock drawing, Digit symbol, and Trail Making A and B tests) showed executive attention and visuospatial deficit. The mini-mental state examination (MMSE) score was 29/30. At the age of 59 the patient developed dysarthria. When she was 61 she suffered from generalized tonic-clonic seizures but the interictal electroencephalogram (EEG) was normal. There was progressive cognitive worsening and at the age of 62 the neuropsychological assessment showed deficit in verbal memory, language and attention, and the MMSE scored 15/30. The neurological examination showed moderate gait ataxia, dysdiadochokinesia and dysmetria, dysphagia, dysarthria and abnormal saccadic pursuit, severe axial asynergy during postural changes, choreiform dyskinesias involving upper limbs, face, and tongue. She had no muscle weakness or sensory deficits, deep tendon reflexes were normal and pyramidal signs were absent. At the time of the last examination when the patient was 63, she required assistance for everyday activities. Brain MRI showed advanced cerebellar atrophy, involving both hemispheres and vermis, with brainstem sparing (Fig. 1a). Brain single photon emission computed tomography (SPECT) using the Dopamine Transporter (DAT) ligand I-123 Ioflupane (DAT-SPECT) showed mild reduced uptake in left posterior putamen but was otherwise normal (Fig. 1b). F-18 Fluorodeoxyglucose positron emission tomography (FDG-PET) showed severely decreased glucose metabolism of both cerebellar hemispheres and putamen (Fig. 1c).
The genetic analysis for HD, DRPLA and TBP was performed on genomic DNA extracted from peripheral blood sample by standard methods. The polymerase chain reaction (PCR) was performed by using the published primers and PCR products were separated by capillary electrophoresis ABIPrism 3130XL Genetic Analyzer. The size of each allele was established by comparison with control DNAs previously determined by direct sequencing.