Significant phenotype variability of congenital central hypoventilation syndrome in a family with polyalanine expansion mutation of the PHOX2B gene

Klásková, Eva; Drábek, Jir̆ı́; Hobzová, Milada; Smolka, Vratislav; Šeda, Miroslav; Hyjánek, Jiří; Slavkovský, Rastislav; Stránská, Jana; Procházka, Martin

doi:10.5507/bp.2016.038

Cited by 8 publications

(5 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Therefore, mutations associated with homeobox genes can lead to devastating neurological defects. Two such genes, ARX and SOX3 , are involved in development of the central nervous system and function as transcription factors containing several poly-Ala stretches [ 71 , 72 ]. Expansion of the poly-Ala stretch in SOX3 protein is associated with X-linked mental retardation with growth hormone deficiency as well as X-linked hypopituitarism [ 72 , 74 ].…”

Section: Polyalanine Repeat Expansionsmentioning

confidence: 99%

Intrinsic Disorder in Proteins with Pathogenic Repeat Expansions

Darling

Uversky

2017

Molecules

View full text Add to dashboard Cite

Intrinsically disordered proteins and proteins with intrinsically disordered regions have been shown to be highly prevalent in disease. Furthermore, disease-causing expansions of the regions containing tandem amino acid repeats often push repetitive proteins towards formation of irreversible aggregates. In fact, in disease-relevant proteins, the increased repeat length often positively correlates with the increased aggregation efficiency and the increased disease severity and penetrance, being negatively correlated with the age of disease onset. The major categories of repeat extensions involved in disease include poly-glutamine and poly-alanine homorepeats, which are often times located in the intrinsically disordered regions, as well as repeats in non-coding regions of genes typically encoding proteins with ordered structures. Repeats in such non-coding regions of genes can be expressed at the mRNA level. Although they can affect the expression levels of encoded proteins, they are not translated as parts of an affected protein and have no effect on its structure. However, in some cases, the repetitive mRNAs can be translated in a non-canonical manner, generating highly repetitive peptides of different length and amino acid composition. The repeat extension-caused aggregation of a repetitive protein may represent a pivotal step for its transformation into a proteotoxic entity that can lead to pathology. The goals of this article are to systematically analyze molecular mechanisms of the proteinopathies caused by the poly-glutamine and poly-alanine homorepeat expansion, as well as by the polypeptides generated as a result of the microsatellite expansions in non-coding gene regions and to examine the related proteins. We also present results of the analysis of the prevalence and functional roles of intrinsic disorder in proteins associated with pathological repeat expansions.

show abstract

Section: Polyalanine Repeat Expansionsmentioning

confidence: 99%

Intrinsic Disorder in Proteins with Pathogenic Repeat Expansions

Darling

Uversky

2017

Molecules

View full text Add to dashboard Cite

show abstract

“…Approximately 10% of patients have a non-polyalanine repeat mutation (NPARM) in the PHOX2B gene, which is generally reported to be associated with a more severe phenotype. 1 Only a few familial cases of CCHS with confirmed PHOX2B gene mutations have been previously reported in the literature, [2][3][4][5][6][7] only two of which involve the PHOX2B NPARM mutation. 4,5 In these two familial cases, Hirschsprung disease as well as respiratory control symptoms were prominent.…”

Section: Introductionmentioning

confidence: 99%

Three-Generation Family With Congenital Central Hypoventilation Syndrome and Novel PHOX2B Gene Non-Polyalanine Repeat Mutation

Kasi

Jurgensen

Yen

et al. 2017

Journal of Clinical Sleep Medicine

View full text Add to dashboard Cite

PHOX2B non-polyalanine repeat mutation (NPARM) in patients with congenital central hypoventilation syndrome (CCHS) is generally considered to be associated with full-time ventilator dependence and severe autonomic nervous system dysfunction. We report a three-generation family with four individuals possessing a novel PHOX2B NPARM (c.245C > T) with variable phenotypes. This mutation was inherited in an autosomal dominant pattern with variable penetrance. The affected family members with CCHS have a milder phenotype than is typically expected with a NPARM. Two family members are ventilator dependent only during sleep and do not have Hirschsprung disease or neural crest tumors. One family member was asymptomatic until systemic hypertension developed during adulthood and another family member remains asymptomatic as an adult. Our findings emphasize the importance of monitoring adults with a PHOX2B NPARM who are considered asymptomatic in childhood.

show abstract

“…This highlights the importance of screening family members of patients with CCHS to minimize the future incidence of pulmonary compromise. Abnormalities on the PSG findings in 5 of the remaining 27 undiagnosed patients in group B were observed, 10,[15][16][17][18] but the abnormal findings of PSG in patient #B-16 were not detected. 10 This might suggest that usual overnight PSG (ie, without monitoring for CO 2 ) will not sufficiently detect the alveolar hypoventilation associated with CCHS.…”

Section: Discussionmentioning

confidence: 83%

“…Five of the PHOX2B-mutation carriers were treated with NPPV or CPAP for obstructive sleep apnea syndrome or other unreported reasons. 15,16,18 However, since these carriers are at risk of developing CCHS, close monitoring, investigation, and early initiation of the therapy (particularly with illness or exposure to sedative medications) are warranted. In addition, although CPAP has been introduced for the treatment of OSA in some carriers, we think that its use would be insufficient to treat hypoventilation (ie, no increase in minute ventilation with hypercapnia and hypoxia; no backup rate) if an association with CCHS is likely.…”

Section: Discussionmentioning

confidence: 99%

Adult cases of late-onset congenital central hypoventilation syndrome and paired-like homeobox 2B-mutation carriers: an additional case report and pooled analysis

Hino

Terada

Kasai

et al. 2020

Journal of Clinical Sleep Medicine

View full text Add to dashboard Cite

Study Objectives: Congenital central hypoventilation syndrome (CCHS) is caused by the paired-like homeobox 2B (PHOX2B) mutation and predominantly diagnosed during the neonatal period. Although late-onset CCHS and PHOX2B mutation carriers have been reported, the features of these disease states in adults remain uncertain. This study aimed to identify the characteristics of adult-onset CCHS and PHOX2B-mutation carriers in adult. Methods: We mainly searched the PubMed/Medline and Cochrane Databases and classified our target patients into 2 groups: group A, symptomatically diagnosed with late-onset CCHS in adulthood; group B, adult PHOX2B-mutation carriers. Then, clinical characteristics, including the onset, treatment, long-term course, and pattern of the PHOX2B mutation in both groups were analyzed. Additionally, a new adult-case of late-onset CCHS was added to the analysis. Results: Group A was comprised of 12 patients. The onset triggers of illness included a history of respiratory compromise following general anesthesia and respiratory tract infections. All patients in group A had 20/25 polyalanine repeat mutations and required some chronic ventilatory support at least during sleep, including portable positive pressure ventilator via tracheostomy or noninvasive positive pressure ventilation. In these patients with ventilatory support during sleep, sudden death or poor prognosis was not reported. Group B was comprised of 33 adults from 24 families with PHOX2B mutations. Nine patients in group B were confirmed with the diagnosis of CCHS. Although polyalanine repeat mutations 20/25 represented the most common gene mutation, diverse mutations, including mosaicism, were observed. Hypoventilation of several cases in group B were underdiagnosed by overnight polysomnography without monitoring for CO 2 . Conclusion: Alveolar hypoventilation with unknown origin can be caused by the PHOX2B mutation even in adult cases. Both the identification of the PHOX2B mutation and the incorporation of capnography in polysomnography are important for adult cases with unexplained alveolar hypoventilation or asymptomatic mutation carriers.

show abstract

Significant phenotype variability of congenital central hypoventilation syndrome in a family with polyalanine expansion mutation of the PHOX2B gene

Cited by 8 publications

References 21 publications

Intrinsic Disorder in Proteins with Pathogenic Repeat Expansions

Intrinsic Disorder in Proteins with Pathogenic Repeat Expansions

Three-Generation Family With Congenital Central Hypoventilation Syndrome and Novel PHOX2B Gene Non-Polyalanine Repeat Mutation

Adult cases of late-onset congenital central hypoventilation syndrome and paired-like homeobox 2B-mutation carriers: an additional case report and pooled analysis

Contact Info

Product

Resources

About