Dementia, ataxia, extrapyramidal features, and epilepsy: phenotype spectrum in two Italian families with spinocerebellar ataxia type 17 G. De Michele 1 () • F. Maltecca 2 • M. Carella 3 G. Volpe 1 • M. Orio 1 • A. De Falco 1 • S. Gombia 1 A. Servadio 4 • G. Casari 2 • A. Filla 1 • A. Bruni 5 1 Dipartimento di Scienze Neurologiche Università Federico II, via Pansini 5, Naples, Italy 2 DIBIT-Istituto Scientifico San Raffaele, Milan, Italy 3 TIGEM Naples, Italy 4 Laboratorio di Medicina Molecolare, Università di Milano-Bicocca, Italy 5 Centro Regionale Neurogenetica, Lamezia Terme, Italy Abstract We observed two families with a dominantly inher- ited complex neurological syndrome with onset in adult- hood. Family F included 9 affected in four generations. One patient showed prominent anticipation of onset age. Onset was with cerebellar signs followed by dementia, psychiatric symptoms, seizures, and extrapyramidal features. Family M included 14 affected individuals in five generations. Presenting symptoms were either psychiatric and cognitive impairment or a cerebellar syndrome. Extrapyramidal fea- tures, dysphagia, incontinence, seizures, and myoclonus may occur. In both families magnetic resonance imaging showed marked atrophy of the brain and cerebellum. Molecular analyses demonstrated an expanded CAG/CAA repeat in the in the TATAbox-binding protein (TBP) gene (SCA17). There is a wide genetic heterogeneity within autosomal dom- inant spinocerebellar ataxias (SCAs), and 19 different loci have been identified. An expanded trinucleotide cytosine- adenine-guanine (CAG) repeat has been shown in most of the cloned genes [1]. An expanded CAG repeat has been described in the TATAbox-binding protein (TBP) gene [2], a general transcription initiation factor, in four Japanese pedi- grees (SCA17). We describe the phenotype of two Italian families with this mutation. The first kindred (Family F) originated from Campania and included 9 patients in four generations. The clinical fea- tures of the four personally examined patients are shown in Table 1. The patients in III generations had disease onset in the 3rd to 4th decade, whereas in the only patient in the IV gener- ation the disease began at 3 years. The mean age at death was 54 years in 7 deceased patients. Cerebellar signs, such as gait ataxia, dysarthria, and dysmetria, were the first symptoms in all patients. Dementia was early and severe; psychiatric symp- toms, such as mood depression, insomnia, and delusions, were frequent. Increased tendon reflexes, abnormal involuntary movements, seizures, and hypoacusia may occur. Incontinence and dysphagia were late features. Magnetic resonance imaging (MRI) showed atrophy of the cerebrum and cerebellum in all patients. Peripheral nerve conduction studies demonstrated a mild sensorimotor axonal neuropathy. The clinical picture of patient 4 was peculiar, with ataxia and dysarthria presenting at the age of 3 years, fast progres- sion with loss of independent gait and sphincter control, dys- phagia, spasticity, growth delay, grand mal seizures, and death at the age of 15 years. The second pedigree (Family M) originated from Calabria and included 14 patients in five generations. The clinical features of the 7 personally examined patients are shown in Table 1. The age at onset was usually in the 3rd-4th decade. No differences in age at onset were found between generations. The mean age at death was 56 years in 7 deceased patients. Psychiatric features, such as depression, personality changes, aggressiveness, negligence of personal hygiene, delusional thoughts, hallucinations, and alcoholism, were present in the majority of patients at onset. Cognitive impairment was an early feature. Ataxia, dysarthria, rigidity, and dystonia developed successively. Perioral dyskinesia, brisk tendon reflexes, and seizures may occur and late stages were characterized by anarthria, dysphagia, and inconti- nence. In some cases the disease began with a cerebellar syn- drome followed by dementia and other neurological features. MRI showed marked atrophy of the brain and cerebellum. Genomic DNA was prepared from peripheral blood according to standard procedures after informed consent. The presence of a CAG repeat in HD, SCA1, SCA2, SCA3, SCA6, SCA7, SCA12, and DRPLA genes was excluded by polymerase chain reaction (PCR), as previously described [3]. In addition, we excluded linkage to other autosomal dominant spinocerebellar ataxias (SCA4, SCA5, SCA6, SCA11, SCA13, and SCA14 loci), familial Alzheimer dis- ease (APP, PS-1, PS-2, FTDP-17, BRI, PI12, FND loci), and parkinsonism (PARK1, PARK2, PARK3 loci). Western blot analyses, with either anti-polyglutamine 1C2 and 1F8 monoclonal antibodies (mAbs), showed in all the analysed patients from both families, beside a normal band corresponding to wild type TBP, a band corresponding to the expanded protein. These findings were confirmed using anti-TBP mAb 3G3. The fragment of the TBP gene containing the CAG/CAA repeat was amplified by PCR and separated by electrophore- sis on a 3% agarose gel, as previously described [2]. PCR analysis of the CAG repeat region within the TBP gene showed an expanded band in all patients. Neuropathological examination of 1 patient from the family M showed cortical, subcortical, and cerebellar atro- phy, Purkinje cell loss and gliosis, degeneration of the infe- rior olive, marked neuronal loss, and gliosis in the caudate nucleus and in medial thalamic nuclei. Neuronal intranuclear Neurol Sci (2003) 24:166–167 DOI 10.1007/s10072-003-0112-4