Mucopolysaccharidosis type I due to maternal uniparental disomy of chromosome 4 with partial isodisomy of 4p16.3p15.2

Kloth, Katja; Vater, Inga; Ramona, L. Walls; Caliebe, Almuth; Maria, Muschol Nicole

doi:10.1016/j.ymgmr.2020.100660

Cited by 2 publications

(1 citation statement)

References 26 publications

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“…To improve recognition of childhood dementia and outcomes for patients, consistent language and definitions are needed for this group of disorders. The term ‘childhood dementia’ has not been widely adopted despite being described in medical literature since the mid-20th century 68 and the term being increasingly associated with individual conditions, especially Batten disease, 69 Sanfilippo syndrome, 70 Lafora disease, 71 Hurler syndrome 72 and Alexander disease. 73 Patient organizations are adopting the term and individual families are using it to raise awareness and understanding of their child’s condition on social media and in the community.…”

Section: Conclusion and Future Prospectsmentioning

confidence: 99%

The collective burden of childhood dementia: a scoping review

Elvidge,

Christodoulou,

Farrar

et al. 2023

Brain

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Childhood dementia is a devastating and under-recognised group of disorders with a high level of unmet need. Typically monogenic in origin, this collective of individual neurodegenerative conditions are defined by a progressive impairment of neurocognitive function, presenting in childhood and adolescence. This scoping review aims to clarify definitions and conceptual boundaries of childhood dementia and quantify the collective disease burden. A literature review identified conditions that met the case definition. An expert clinical working group reviewed and ratified inclusion. Epidemiological data were extracted from published literature and collective burden modelled. One hundred and seventy genetic childhood dementia disorders were identified. Of these, 25 were analysed separately as treatable conditions. Collectively, currently untreatable childhood dementia was estimated to have an incidence of 34.5 per 100,000 (1 in 2,900 births), median life expectancy of 9 years and prevalence of 5.3 per 100,000 persons. The estimated number of premature deaths per year is similar to childhood cancer (0-14 years) and approximately 70% of those deaths will be prior to adulthood. An additional 49.8 per 100,000 births are attributable to treatable conditions that would cause childhood dementia if not diagnosed early and stringently treated. A relational database of the childhood dementia disorders has been created and will be continually updated as new disorders are identified (https://knowledgebase.childhooddementia.org/). We present the first comprehensive overview of monogenic childhood dementia conditions and their collective epidemiology. Unifying these conditions, with consistent language and definitions, reinforces motivation to advance therapeutic development and health service supports for this significantly disadvantaged group of children and their families.

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Section: Conclusion and Future Prospectsmentioning

confidence: 99%

The collective burden of childhood dementia: a scoping review

Elvidge,

Christodoulou,

Farrar

et al. 2023

Brain

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Whole paternal uniparental disomy of chromosome 4 with a novel homozygous IDUA splicing variant, c.159‐9T>A, in a Chinese patient with mucopolysaccharidosis type I

Yan,

Ding,

et al. 2024

Molec Gen & Gen Med

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BackgroundMucopolysaccharidosis type I (MPS‐I) is a rare autosomal recessive genetic lysosomal storage disorder that is caused by pathogenic variants of the α‐L‐iduronidase (IDUA) gene. This study aimed to identify the genetic causes of MPS‐I in a Chinese patient and construct a minigene of IDUA to analyze its variants upon splicing.MethodsWhole‐exome sequencing (WES) and Sanger sequencing were used to confirm the potential causative variants. Single‐nucleotide polymorphism (SNP) array was subsequently performed to confirm uniparental disomy (UPD). Minigene assay was performed to analyze the effect on splicing of mRNA. We meanwhile explored the conservative analysis and protein homology simulation.ResultsA novel homozygous splicing mutation of IDUA, c.159‐9T>A, was identified in an individual presenting with overlapping features of MPS‐I. Interestingly, only the father and sisters, but not the mother, carried the variant in a heterozygous state. WES and SNP array analyses validated paternal UPD on chromosome 4. Minigene splicing revealed two aberrant splicing events: exon 2 skipping and intron 1 retention. Moreover, the specific structure of the mutant protein obviously changed according to the results of the homologous model.ConclusionsThis study describes a rare autosomal recessive disorder with paternal UPD of chromosome 4 leading to the homozygosity of the IDUA splicing variant in patients with MPS‐I for the first time. This study expands the variant spectrum of IDUA and provides insights into the splicing system, facilitating its enhanced diagnosis and treatment.

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Mucopolysaccharidosis type I due to maternal uniparental disomy of chromosome 4 with partial isodisomy of 4p16.3p15.2

Cited by 2 publications

References 26 publications

The collective burden of childhood dementia: a scoping review

The collective burden of childhood dementia: a scoping review

Whole paternal uniparental disomy of chromosome 4 with a novel homozygous IDUA splicing variant, c.159‐9T>A, in a Chinese patient with mucopolysaccharidosis type I

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