Autosomal dominant cerebellar ataxia with pigmentary macular dystrophy. A clinical and genetic study of eight familes

Enevoldson, T P; Sanders, M. D.; Harding, A. E.

doi:10.1093/brain/117.3.445

Cited by 128 publications

(91 citation statements)

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“…13 The normal range is 7 to 19 CAG repeats, with 72% of the normal population having 10 repeats. The pathological range is represented by 37 to more than 220 CAG 14,15 In no other disease caused by trinucleotide expansion are such large repeat sequences observed.…”

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confidence: 99%

Massive SCA7 expansion detected in a 7‐month‐old male with hypotonia, cardiomegaly, and renal compromise

Whitney

Lim

Kanabar

et al. 2007

Develop Med Child Neuro

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Infantile spinocerebellar ataxia type 7 (SCA7) is phenotypically different from the child‐onset and adult‐onset cases, presenting as a multisystem disorder associated with pathologically large CAG trinucleotide repeat sequences. We describe a case study of a male who presented at 5 months of age with marked motor delay, failure to thrive, and a patent ductus arteriosus. He later developed renal failure of uncertain aetiology. The infant became progressively hypotonic, and cardiac and renal function deteriorated further; he died at the age of 11 months of multisystem failure. Family history revealed a diagnosis of SCA7 in the infant's father, paternal grandfather, and aunt. DNA analysis confirmed an expanded trinucleotide repeat in the SCA7 locus of about 240 repeats, suggesting a diagnosis of infantile SCA7. Striking anticipation is seen in SCA7, particularly with paternal transmission. The underlying pathophysiological processes seem to involve alteration in transcriptional regulation and a selective neuronal vulnerability to the widely distributed abnormal protein product. This case report reviews the current literature relating to infantile SCA7 and raises awareness of this rare but important phenotype.

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mentioning

confidence: 99%

Massive SCA7 expansion detected in a 7‐month‐old male with hypotonia, cardiomegaly, and renal compromise

Whitney

Lim

Kanabar

et al. 2007

Develop Med Child Neuro

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“…SCA7 is clinically unique in that it is the only polyglutamine disorder in which the retina is affected, eventually resulting in blindness (Enevoldson et al 1994). Insight into the molecular basis of SCA7 has come largely from studies on the function of ataxin-7 in rod-photoreceptors.…”

Section: Sca 7: a Role In Cell-specific Chromatin Structurementioning

confidence: 99%

Polyglutamine neurodegenerative diseases and regulation of transcription: assembling the puzzle

Riley¹,

Orr²

2006

Genes Dev.

132

106

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The polyglutamine disorders are a class of nine neurodegenerative disorders that are inherited gain-of-function diseases caused by expansion of a translated CAG repeat. Even though the disease-causing proteins are widely expressed, specific collections of neurons are more susceptible in each disease, resulting in characteristic patterns of pathology and clinical symptoms. One hypothesis poses that altered protein function is fundamental to pathogenesis, with protein context of the expanded polyglutamine having key roles in diseasespecific processes. This review will focus on the role of the disease-causing polyglutamine proteins in gene transcription and the extent to which the mutant proteins induce disruption of transcription.One of the intriguing developments in human genetics is the identification of a mutational mechanism apparently unique to the human genome, the expansion of unstable nucleotide repeats (Gatchel and Zoghbi 2005). Depending on the genetic context of the unstable repeat, the pathogenic mechanism underlying the disorder can be either a loss-of-function or gain-of-function mutation operating at either the RNA or protein level. A subclass of the unstable repeat disorders is caused by the expansion of an unstable CAG trinucleotide repeat located within the protein encoding region such that the repeat is translated into a stretch of glutamine residues; i.e., the polyglutamine diseases. Although rare as a group, the polyglutamine disorders represent the most common form of inherited neurodegenerative disease. At present, nine disorders make up this class of neurodegenerative disease (Table 1). Initially, it was argued that the genetic similarities among these disorders strongly supported the hypothesis that these disorders shared a common mechanism of pathogenesis entirely dependent on the toxic properties of the polyglutamine tract. This typically centered on the enhanced ability of polyglutamine peptides to form intranuclear aggregates/inclusions (Ross and Poirer 2004). The presence of these aggregates/ inclusions within the nuclei of affected neurons focused attention on the nucleus as the subcellular site important in pathogenesis. After much study, the concept of large aggregates/inclusions of mutant polyglutamine as the pathogenic species has become suspect (Arrasate et al. 2004). However, for many of the polyglutamine disorders, understanding events in the nucleus still remains crucial for comprehending pathogenesis.Expansion of the polyglutamine tract is the trigger for pathogenesis. Yet, it likely does so by acting in concert with the other amino acids of the "host" protein (Orr 2001). This point is nicely illustrated by studies on SCA1 and AR/SBMA. In the case of SCA1, replacing single amino acids in ataxin-1 outside of its polyglutamine tract dramatically reduced the ability of mutant ataxin-1 (ataxin-1[82Q]) to cause disease in vivo (Klement et al. 1998;Emamian et al. 2003). In SBMA, androgen binding to the ligand-binding region in AR is critical for pathogenesis (Katsuno et al. 2002(K...

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“…Enevoldson et al 22 descreveram 54 membros afetados de 8 famílias. A idade de início da doença é extremamente variável (6 meses -60 anos), com progressão mais rápida nos casos de início mais precoce.…”

Section: Ataxia Espinocerebelar VII (Sca7)unclassified

“…Observa-se o fenômeno de antecipação em descendentes de pais afetados (transmissão paterna). Além de um início mais precoce, o curso da doença é mais grave em descendentes paternos 22 . Inicialmente demonstrou-se que locus gênico desta forma de ACAD não possui ligação com os locus SCAl no cromossomo 6p e SCA2 no cromossomo 12q 33 .…”

Section: Ataxia Espinocerebelar VII (Sca7)unclassified

Ataxias cerebelares hereditárias: do martelo ao gen

Arruda

Teive²

1997

Arq. Neuro-Psiquiatr.

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RESUMO -As heredoataxias constituem grupo complexo de doenças neurodegenerativas hereditárias, para o qual várias formas de classificação clínica e patológica foram propostas com sucesso variável. O desenvolvimento das técnicas de biologia molecular trouxe informações importantes que têm permitido caracterizar geneticamente as ataxias cerebelares hereditárias. O reconhecimento das doenças causadas por expansões de trinucleotídeos abre novo capítulo para a pesquisa sobre outros mecanismos de doenças, como na ataxia de Friedreich e nas várias formas de ataxia cerebelar autossômica dominante(SCAl a SCA7), das quais a doença de MachadoJoseph / SCA3 parece ser a mais comum no nosso meio. A deficiência familial de vitamina E (cromossomo 8q) leva a quadro semelhante ao da ataxia de Friedreich (cromossomo 9p), mas responde à reposição oral de tocoferol. Formas familiais de ataxia periódica com (cromossomo 12p) ou sem (cromossomo 19p) mioquimia foram caracterizadas, a primeira resultado de mutações dos gens de canais de potássio. Os portadores do gen da ataxiateleangiectasia (cromossomo 1 lq) representam 1-3% da população e são suscetíveis aos efeitos oncogênicos da radiação iônica. Sem olvidar da importância da avaliação clínica neurológica, a avaliação genética laboratorial passa a ser valiosa ferramenta para o diagnóstico e aconselhamento genético, além do melhor entendimento da patogênese dessas doenças. PALAVRAS-CHAVE: ataxia cerebelar, doenças cerebelares, trinucleotídeos, genética. Hereditary cerebellar ataxias from neurological hammer to geneticsABSTRACT -The hereditary ataxias comprise a complex group of neurological disorders involving the cerebellum and its connections. Several classifications based on clinical and/or pathological data have been only partially successful. Recent progress in molecular genetics has identified the genic loci of hereditary ataxias and has allowed a more precise diagnosis of distinct genetic diseases. Trinucleotide repeat expansions has been recognized as a mechanism of disease in some autosomal dominant spinocerebellar ataxias (ADCA) (SCA1 to SCA7), including Machado-Joseph disease / SCA3, probably the most common form of ADCA in South Brazil, and Friedreich ataxia (GAA expansion -chromosome 9p). Familial alpha-tocopherol deficiency (chromosome 8q) may have a Friedreich ataxia phenotype and responds to the oral supplementaion with vitamin E. Familial episodic ataxias with (EA1 -chromosome 12p) and without (chromosome 19p -EA2) myokimia were identified, the first one caused by point mutations in the gene encoding the KCNA1 potassium voltage-gated channel. The gene responsible for ataxia-teleangiectasia (chromosome 1 lq) was found to encode a putative DNA binding protein kinase (ATM), related to the cell cycle control. One to 3% of the population are heterozygotic ATM gen carry and pose a higher risk of cancer when exposed to ionizing radiation. Molecular biology has provided us with useful tools to diagnosis and genetic counseling and, hopefully, will provide us with a better under...

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Autosomal dominant cerebellar ataxia with pigmentary macular dystrophy. A clinical and genetic study of eight familes

Cited by 128 publications

References 0 publications

Massive SCA7 expansion detected in a 7‐month‐old male with hypotonia, cardiomegaly, and renal compromise

Massive SCA7 expansion detected in a 7‐month‐old male with hypotonia, cardiomegaly, and renal compromise

Polyglutamine neurodegenerative diseases and regulation of transcription: assembling the puzzle

Ataxias cerebelares hereditárias: do martelo ao gen

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