Dataset Information

Clinical Spectrum Associated with Wolfram Syndrome Type 1 and Type 2: A Review on Genotype-Phenotype Correlations.

ABSTRACT: Wolfram syndrome is a rare neurodegenerative disorder that is typically characterized by diabetes mellitus and optic atrophy. Other common features are diabetes insipidus and hearing loss, but additional less-frequent findings may also be present. The phenotype spectrum is quite wide, and penetrance may be incomplete. The syndrome is progressive, and thus, the clinical picture may change during follow-up. Currently, two different subtypes of this syndrome have been described, and they are associated with two different disease-genes, wolframin (WFS1) and CISD2. These genes encode a transmembrane protein and an endoplasmic reticulum intermembrane protein, respectively. These genes are detected in different organs and account for the pleiotropic features of this syndrome. In this review, we describe the phenotypes of both syndromes and discuss the most pertinent literature about the genotype-phenotype correlation. The clinical presentation of Wolfram syndrome type 1 suggests that the pathogenic variant does not predict the phenotype. There are few papers on Wolfram syndrome type 2 and, thus, predicting the phenotype on the basis of genotype is not yet supported. We also discuss the most pertinent approach to gene analysis.

SUBMITTER: Delvecchio M

PROVIDER: S-EPMC8124476 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Clinical Spectrum Associated with Wolfram Syndrome Type 1 and Type 2: A Review on Genotype-Phenotype Correlations.

Delvecchio Maurizio M Iacoviello Matteo M Pantaleo Antonino A Resta Nicoletta N

International journal of environmental research and public health 20210430 9

Wolfram syndrome is a rare neurodegenerative disorder that is typically characterized by diabetes mellitus and optic atrophy. Other common features are diabetes insipidus and hearing loss, but additional less-frequent findings may also be present. The phenotype spectrum is quite wide, and penetrance may be incomplete. The syndrome is progressive, and thus, the clinical picture may change during follow-up. Currently, two different subtypes of this syndrome have been described, and they are associ ...[more]

PMID: 33946243

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Project description:The GGGGCC (G4C2) repeat expansion in C9ORF72 is the most common cause of familial amyotrophic lateral sclerosis (ALS), frontotemporal lobar dementia (FTLD) and ALS-FTLD, as well as contributing to sporadic forms of these diseases. Screening of large cohorts of ALS and FTLD cohorts has identified that C9ORF72-ALS is represented throughout the clinical spectrum of ALS phenotypes, though in comparison with other genetic subtypes, C9ORF72 carriers have a higher incidence of bulbar onset disease. In contrast, C9ORF72-FTLD is predominantly associated with behavioural variant FTD, which often presents with psychosis, most commonly in the form of hallucinations and delusions. However, C9ORF72 expansions are not restricted to these clinical phenotypes. There is a higher than expected incidence of parkinsonism in ALS patients with C9ORF72 expansions, and the G4C2 repeat has also been reported in other motor phenotypes, such as primary lateral sclerosis, progressive muscular atrophy, corticobasal syndrome and Huntington-like disorders. In addition, the expansion has been identified in non-motor phenotypes including Alzheimer's disease and Lewy body dementia. It is not currently understood what is the basis of the clinical variation seen with the G4C2 repeat expansion. One potential explanation is repeat length. Sizing of the expansion by Southern blotting has established that there is somatic heterogeneity, with different expansion lengths in different tissues, even within the brain. To date, no correlation with expansion size and clinical phenotype has been established in ALS, whilst in FTLD only repeat size in the cerebellum was found to correlate with disease duration. Somatic heterogeneity suggests there is a degree of instability within the repeat and evidence of anticipation has been reported with reducing age of onset in subsequent generations. This variability/instability in expansion length, along with its interactions with environmental and genetic modifiers, such as TMEM106B, may be the basis of the differing clinical phenotypes arising from the mutation.

Dataset Information

Clinical Spectrum Associated with Wolfram Syndrome Type 1 and Type 2: A Review on Genotype-Phenotype Correlations.

Publications

Clinical Spectrum Associated with Wolfram Syndrome Type 1 and Type 2: A Review on Genotype-Phenotype Correlations.

Similar Datasets

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