Dementia, ataxia, extrapyramidal features, and epilepsy: phenotype spectrum in two Italian families with spinocerebellar ataxia type 17

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).     

常染色体显性遗传成人癫癎、震颤伴共济失调临床及致病基因定位研究

目的探讨常染色体显性遗传成人癫癎、震颤伴共济失调的临床特征并排除已知的致病基因。方法对可追溯6代130人的一家系的30名成员（包括11例患者）进行详细的神经系统检查，通过查询人类孟德尔遗传病数据库（OMIM）及表型鉴别、突变筛查和连锁分析验证方法排除已知致病基因；采用模拟连锁分析软件对该家系进行评估。结果该家系患者临床表现为多种形式的癫癎发作、震颤、肌阵挛小脑协调障碍和锥体束征。通过3种方法排除了已知基因致病可能，模拟连锁分析显示重组率为零时LOD值为6．03。结论该家系可能为尚未报道的常染色体显性遗传癫癎、震颤伴共济失调综合征，模拟分析证实它可为连锁分析提供足够的遗传信息，为定位克隆奠定了基础。     

Autosomal recessive ataxia, slow eye movements, dementia and extrapyramidal disturbances

An Arab family with an autosomal recessive form of spinocerebellar degeneration with slow eye movements is reported. Hitherto all the reported cases were either sporadic or of autosomal dominant inheritance. Associated are progressive intellectual impairment and extrapyramidal dysfunction as well as peripheral neuropathy and skeletal abnormalities. Muscle biopsy revealed non-specific mitochondrial abnormalities. The spectrum of eye movement abnormalities is discussed and the literature is reviewed. It is concluded that the hallmark of this syndrome (slow or even absent saccades) is one of a group of oculomotor abnormalities, all being characterized by delayed initiation and slow velocity. The syndrome seems to be related to the olivopontocerebellar degenerations, but differs in that there is in addition selective degeneration of certain tracts and nuclei in the mesencephalon and probably more rostral structures.     

Clinical features and neuropathology of autosomal dominant spinocerebellar ataxia (SCA17)

Autosomal dominant spinocerebellar ataxias (SCAs) are a group of neurodegenerative disorders clinically characterized by late-onset ataxia and variable other manifestations. Genetically and clinically, SCA is highly heterogeneous. Recently, CAG repeat expansions in the gene encoding TATA-binding protein (TBP) have been found in a new form of SCA, which has been designated SCA17. To estimate the frequency of SCA17 among white SCA patients and to define the phenotypic variability, we determined the frequency of SCA17 in a large sample of 1,318 SCA patients. In total, 15 patients in four autosomal dominant SCA families had CAG/CAA repeat expansions in the TBP gene ranging from 45 to 54 repeats. The clinical features of our SCA17 patients differ from other SCA types by manifesting with psychiatric abnormalities and dementia. The neuropathology of SCA17 can be classified as a "pure cerebellar" or "cerebello-olivary" form of ataxia. However, intranuclear neuronal inclusion bodies with immunoreactivity to anti-TBP and antipolyglutamine were much more widely distributed throughout the brain gray matter than in other SCAs. Based on clinical and genetic data, we conclude that SCA17 is rare among white SCA patients. SCA17 should be considered in sporadic and familial cases of ataxia with accompanying psychiatric symptoms and dementia.     

An autosomal dominant disorder with episodic ataxia, vertigo, and tinnitus.

The authors report an autosomal dominant episodic ataxia that is clinically distinct from the other episodic ataxias. Vestibular ataxia, vertigo, tinnitus, and interictal myokymia are prominent; attacks are diminished by acetazolamide. Linkage analyses of markers flanking the EA1 and EA2 loci demonstrate genetic exclusion from the other autosomal dominant episodic ataxias. The authors suggest EA3 for periodic vestibulocerebellar ataxia and EA4 for the disorder described here.     

Late onset autosomal dominant cerebellar ataxia. A family description and linkage analysis with the HLA system.

A family suffering an autosomal dominant form of late onset hereditary cerebellar ataxia is described. Eight affected family members were personally studied, and data from another four were obtained through anamnesis. The mean age of onset was 37.1 +/- 5.4 years (27-47 years). The clinical picture consisted basically of a pure ataxic cerebellar syndrome. CT-scan disclosed diffuse cerebellar atrophy with relative sparing of the brainstem and no involvement of supratentorial structures. Neurophysiological studies (nerve conduction, VEP and BAEP) were normal. Twenty-six individuals were typed for HLA histocompatibility antigens. Lod scores were calculated with the computer program LINKMAP. Close linkage of the ataxia gene with the HLA system in this family could be excluded--0 = 0.02, z = (-2.17)--and the overall analysis of the lod scores suggest another chromosomal location than chromosome 6.     

Novel LGI1 mutation in a family with autosomal dominant partial epilepsy with auditory features

Autosomal dominant partial epilepsy with auditory features (ADPEAF) is a rare idiopathic epilepsy syndrome caused by mutations in the leucine-rich, glioma-inactivated 1 (LGI1) gene. The authors report that molecular genetic studies in seven affected family members identified a novel F318C substitution that alters a highly conserved residue in a predicted repeat domain of unknown function. This report suggests that this domain may participate in the development of the ADPEAF phenotype.     

Neuroimaging study in autosomal dominant cerebellar ataxia, deafness, and narcolepsy

Four patients affected with autosomal dominant cerebellar ataxia, deafness, and narcolepsy underwent brain CT and MRI. Radiologic findings were supratentorial atrophy (more pronounced than infratentorial atrophy), pronounced dilatation of the third ventricle, low T2 signal intensity in the basal ganglia, loss of cerebral cortex-white matter differentiation, and periventricular high-signal rims. 2-[18F]Fluoro-2-deoxy-D-glucose PET was done with one patient, without specific findings. Genetic analyses excluded SCA-1, SCA-2, SCA-3, SCA-6, SCA-7, DRPLA, and huntingtin gene mutations.     

Early onset parkinsonism in dementia lacking distinct histopathological features

Dementia lacking distinct histopathological features (DLDHF) belongs to the frontotemporal dementia syndromes. Behavioral, cognitive and motor symptoms are its usual clinical manifestations. However, considerable heterogeneity exists and no evident clinicopathological correlations can be performed. We report a patient who presented with a very unusual combination of behavioral abnormalities and prominent early parkinsonism progressing to a severe dementia. Pathological studies confirmed DLDHF with severe frontal and striatal neuronal loss and gliosis.     

Clinical features of chromosome 16q22.1 linked autosomal dominant cerebellar ataxia in Japanese

Chromosome 16q22.1-linked autosomal dominant cerebellar ataxia (16q-ADCA) is strongly associated with a substitution in the puratrophin-1 gene. This locus overlaps with spinocerebellar ataxia type 4 (SCA4) which shows ataxia with prominent sensory axonal neuropathy. We found that 16q-ADCA is a common ADCA subtype in the Tohoku District of Japan. The clinical feature of Japanese 16q-ADCA is characterized as late-onset pure cerebellar ataxia.     

Genetic heterogeneity of autosomal dominant nonprogressive congenital ataxia

We studied a family with nonprogressive congenital ataxia (NPCA) previously reported in 1985. Follow-up evaluation documented a nonprogressive course. Older family members developed ataxic spells and vertical oscillopsia triggered by stress and exercise. Linkage analysis using a 10K single-nucleotide polymorphism array found suggestive linkage to four loci on chromosomes 1q44, 5q35.1-35.3, 7q36.2-36.3, and 9q31.2-32 and ruled out linkage to the NPCA locus on 3p, proving genetic heterogeneity for autosomal dominant NPCA.     

A new autosomal dominant pure cerebellar ataxia.

A kindred is described with a dominantly inherited "pure" cerebellar ataxia in which the currently known spinocerebellar ataxias have been excluded. In the eight subjects studied, a notable clinical feature is slow progression, with the three least affected having only a mild degree of gait ataxia after three or more decades of disease duration. Pending an actual chromosomal locus discovery, the name spinocerebellar ataxia (SCA)15 is expectantly applied.     

Clinical study of large kindreds with autosomal dominant HLA-linked spinocerebellar ataxia (SCA1) of late onset

Six families with SCA1 were studied. The clinical data on 35 patients are reported. Cerebellar and pyramidal system involvement was invariably found in association with brainstem, spinal cord and/or peripheral nervous system disorders. In our patients the clinical features appeared concordant when the patients with the same disease duration were compared. Previous reports of SCA1 families had shown great variability in clinical phenotype both interfamilial and intrafamilial. We suggest that the phenotype might appear more homogeneous if disease duration is taken into account.

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Sommario Sono state studiate 6 famiglie con atassia spinocerebellare autosomica domiinante ad esordio tardivo, in linkage con l'HLA e con il marker D6S89 (SCA1). I dati clinici su 35 pazienti hanno permesso di stabilire che la malattia è caratterizzata da deficit cerebellari e piramidali associati a segni di interessamento del tronco dell'encefalo, del midollo spinale e del sistema nervoso periferico. Nella valutazione clinica dei pazienti si è tenuto conto della durata della malattia e ciò ha permesso di evidenziare un fenotipo clinico abbastanza omogeno nei differenti stadi della malattia. è possibile che la variabilità intra- e inter-familiare nel fenotipo di altre famiglie SCA1 sia da attribuire al fatto di confrontare soggetti in fasi diverse della malattia.

     

Saccade velocity in idiopathic and autosomal dominant cerebellar ataxia.

Slow saccades are often found in degenerative ataxia. Experimental studies have shown that horizontal saccades are generated in the paramedian pontine reticular formation and that lesions in this area produce slow saccades. Based on these findings, saccade slowing should be a frequent feature of olivopontocerebellar atrophy, a type of cerebellar degeneration with prominent involvement of the pons. To test this hypothesis, saccade velocity was measured in 31 patients with autosomal dominant cerebellar ataxia (ADCA) and 17 patients with idiopathic cerebellar ataxia (IDCA). Saccade velocity was reduced in most patients with ADCA whereas it was normal in IDCA although olivopontocerebellar atrophy occurred in both groups. Saccade velocities correlated with pontine size in ADCA but not in IDCA. The data disprove the hypothesis that saccadic slowing is a clinical hallmark of olivopontocerebellar atrophy. Instead, only patients with ADCA and morphological features of olivopontocerebellar atrophy have slow saccades.     

Rapidly progressive autosomal dominant parkinsonism and dementia with pallido-ponto-nigral degeneration.

We describe a family with nearly 300 members over 8 generations with 32 affected individuals who have an autosomal dominant neurodegenerative disease characterized by progressive parkinsonism with dystonia unrelated to medications, dementia, ocular motility abnormalities, pyramidal tract dysfunction, frontal lobe release signs, perseverative vocalizations, and urinary incontinence. The course is exceptionally aggressive; symptom onset and death consistently occur in the fifth decade. Positron emission tomographic studies with [18F]6-fluoro-L-dopa (6FD) were performed in 4 patients and 7 individuals at risk for development of the disease. All affected subjects had markedly reduced striatal uptake of 6FD (p less than 0.001). All individuals at risk had normal striatal uptake, but high 6FD uptake rate constants were noted in 3 of the 7 studied. Autopsy findings revealed severe neuronal loss with gliosis in substantia nigra, pontine tegmentum, and globus pallidus, with less involvement of the caudate and the putamen. There were no plaques, tangles, Lewy bodies, or amyloid bodies. This kindred appears to represent a neurodegenerative disease not heretofore described. We propose the following name for this new genetic disease: autosomal dominant parkinsonism and dementia with pallido-ponto-nigral degeneration.     

Early onset autosomal dominant spastic paraplegia caused by novel mutations in SPG3A

Hereditary spastic paraplegia (HSP) is a group of neurodegenerative disorders mainly characterized by progressive spasticity of the lower limbs. The major features of HSP are a marked phenotypic variability both among and within families and an extended genetic heterogeneity. More than 20 HSP loci and 10 spastic paraplegia genes ( SPG) have been identified to date, including the genes responsible for the two most frequent forms of autosomal dominant spastic paraplegia (AD-HSP), encoding spastin ( SPG4) and atlastin ( SPG3A), respectively. To date, only eight mutations have been described in the atlastin gene, which was reported to account for about 10% of all AD-HSP families. We investigated 15 German and French AD-HSP families, including the 3 large pedigrees that allowed the mapping and subsequent refinement of the SPG3A locus. Three novel mutations were found in exons 4, 9, and 12 of the atlastin gene and the common R239C mutation located in exon 7 was confirmed in a 7th family of European origin. Overall, the comparison of the clinical data for all SPG3A-HSP families reported to date failed to reveal any genotype/phenotype correlation as demonstrated for other forms of AD-HSP. However, it confirmed the early onset of this form of HSP, which was observed in almost all affected individuals with a mutation in the atlastin gene.