spectrum in two Italian families with ... ited complex neurological syndrome with onset in adult- hood. ... The patients in III generations had disease onset in the.
Neurol Sci (2003) 24:166–167 DOI 10.1007/s10072-003-0112-4
Dementia, ataxia, extrapyramidal features, and epilepsy: phenotype spectrum in two Italian families with spinocerebellar ataxia type 17 G. De Michele1 () • F. Maltecca2 • M. Carella3 G. Volpe1 • M. Orio1 • A. De Falco1 • S. Gombia1 A. Servadio4 • G. Casari2 • A. Filla1 • A. Bruni5 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 inherited complex neurological syndrome with onset in adulthood. 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 features, 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 TATA box-binding protein (TBP) gene (SCA17).
There is a wide genetic heterogeneity within autosomal dominant spinocerebellar ataxias (SCAs), and 19 different loci have been identified. An expanded trinucleotide cytosineadenine-guanine (CAG) repeat has been shown in most of the cloned genes [1]. An expanded CAG repeat has been described in the TATA box-binding protein (TBP) gene [2], a general transcription initiation factor, in four Japanese pedigrees (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 features 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 generation 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 symptoms, 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 progression with loss of independent gait and sphincter control, dysphagia, 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 incontinence. In some cases the disease began with a cerebellar syndrome 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 disease (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 electrophoresis 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 atrophy, Purkinje cell loss and gliosis, degeneration of the inferior olive, marked neuronal loss, and gliosis in the caudate nucleus and in medial thalamic nuclei. Neuronal intranuclear
167 Table 1 Clinical features of the patients Family
F
M
Patient
3
2
1
4
5
30
22
18
17
7
10
Sex Age at onset (years) Age at examination (years) Age at death (years) First symptom Ataxia Dysarthria Dementia/psychiatric symptoms Dystonia/rigidity Urinary incontinence Epilepsy Slowing on EEG Atrophy on MRI
F 35 44 – A + + + + + + – +
M 34 44 44 A + + + + + – – +
M 23 32 – A + + + + – + NP +
F 3 14 15 A + + + + + + + +
M 20 60 62 P + + + + + + + NP
F 35 44 – P + + + + – + – +
M 22 51 52 P + + + + + – – +
F 53 63 – D + + + + + + + NP
F 33 54 – P + + + + + + NP +
F 26 40 – P + + + + + + + +
F 33 42 49 A + + + + + + + +
A, ataxia; P, psychiatric symptoms; D, dementia; NP, not performed; MRI, magnetic resonance imaging; EEG, electroencephalogram
inclusions staining with anti-TBP and anti-polyglutamine IC2 mAbs were found. SCA17 appears to be a rare disease since, after the original description [2], two families have been found in a survey of 604 German cases of familial or sporadic ataxia [4], 1 among 162 European families with dominant ataxia [5], and 1 further patient among 202 Portuguese and Brazilian families with ataxia [6]. Both our families showed an expanded CAG repeat within the TBP gene (SCA17). Disease onset was in the 3rd to 4th decade in most cases, but in family F we found a case with a young-onset severe phenotype, with marked anticipation of onset age, not yet described in SCA17. The phenotype of family F is characterized by progressive cerebellar ataxia, dementia, psychiatric and extrapyramidal features, epilepsy, mild axonal neuropathy, and cerebral and cerebellar atrophy. This clinical picture is quite similar to that already described in the other reported families [2, 4, 5, 6]. In family M, behavioral symptoms and frontal impairment dominated the early stages of the disease, preceding ataxia, rigidity, and dystonic movements (Table 1). Since ataxia is not the presenting symptom in most patients, the diagnosis of SCA was difficult. The characteristics of this family broaden the clinical picture of SCA17.
References
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