Article

Wolfram syndrome: Important implications for pediatricians and pediatric endocrinologists

Department of Pediatrics, Amrita Institute of Medical Sciences, Cochin, Kerala, India.
Pediatric Diabetes (Impact Factor: 2.13). 12/2009; 11(1):28-37. DOI: 10.1111/j.1399-5448.2009.00518.x
Source: PubMed

ABSTRACT Kumar S. Wolfram syndrome: important implications for pediatricians and pediatric endocrinologists.

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    • "Some case series have suggested a higher prevalence of diabetes mellitus and psychiatric disorders among relatives of patients with WS (Kumar, 2010). Furthermore, increased risk of HI has been reported in heterozygous carriers in WS families (Ohata et al, 1998). "
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    ABSTRACT: Abstract Objective: Mutations in the WFS1 gene can cause Wolfram syndrome or nonsyndromic hearing impairment (HI). The objective of this study was to ascertain the presence of mutations in WFS1 among children with HI from unknown causes. Design: We screened 105 Finnish children with HI for mutations in exon 8 in WFS1. Study sample: Children were born in a defined area in Northern Finland and they had sensorineural, mild to profound, syndromic, or nonsyndromic HI. They were negative for GJB2 mutations and for the m.1555A> G and m.3243A> G mutations in mitochondrial DNA. Results: We found three rare variants and the novel p.Gly831Ser variant in WFS1. Segregation analysis suggested that the novel variant had arisen de novo. The p.Gly831Ser variant may be a new member to the group of heterozygous WFS1 mutations that lead to HI, while the pathogenicity of the rare variant p.Gly674Arg remained unclear. The other two rare variants, p.Glu385Lys and p.Glu776Val, did not segregate with HI in the families. Conclusions: WFS1 gene mutations are a rare cause of HI among Finnish children with HI.
    International Journal of Audiology 07/2014; 53(7):446-51. DOI:10.3109/14992027.2014.887230 · 1.43 Impact Factor
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    ABSTRACT: Varajase ehk kõne-eelse KL esinemissagedus arvatakse olevat ligikaudu 1–2 juhtu 1000 lapse kohta. Kuni 60%-l juhtudest on tegemist päriliku ehk geneetilise KL-ga, ülejäänud juhtudel aga omandatud ehk kahjulikest väliskeskkonna faktoritest põhjustatud KL-ga. Hetkel on teada mitusada KL-st põhjustavat geeni, kuid see on siiski vaid umbes 1/3 kõikidest KL-ga seotud geenidest. Geneetiline KL jagatakse omakorda sündroomseks ja mittesündroomseks vormiks. Kõige sagedamini on tegemist autosoom-retsessiivse pärilikkusega mittesündroomse KL-ga. Euroopa erinevates populatsioonides kõige sagedamini esinev pärilikku kuulmislangust põhjustav mutatsioon on GJB2 geenis asuv mutatsioon c.35delG, mida leitakse umbes 30%-l KL-ga patsientidel. Meie töö eesmärkideks oli määrata GJB2 geeni mutatsioonide c.35delG ja p.M34T esinemissagedus Eesti vastsündinute populatsioonis; välja selgitada KL geneetilised põhjused Eesti lastel ja kirjeldada nende fenotüüpi; kirjeldada väikeseid submikroskoopilisi kromosomaalseid ümberkorraldusi ja määrata molekulaarse analüüsiga kaasasündinud tsütomegaloviirusinfektsiooni esinemine KL-ga lastel. Mutatsioonide c.35delG ja p.M34T esinemissageduse skriininggrupis oli 998 anonüümset vastsündinut, kes olid järjestikku sündinud Eesti erinevates piirkondades ühe kuu jooksul. KL-ga laste uuringugruppi kuulus 233 patsienti, kellel oli diagnoositud lapseea algusega KL. Uurisime KL-ga lapsi kuulmislanguse DNA analüüsiga 8 geenis (GJB2, GJB3, GJB6, GJA1, SLC26A4, SLC26A5, 12S-rRNA and tRNA (Ser)) 201 mutatsiooni suhtes APEX meetodil. Töö tulemusena leidsime Eesti vastsündinute anonüümsel skriiningul mutatsiooni c.35delG kandluseks Eestis 1:22 ja mutatsiooni p.M34T kandluseks 1:17. KL-ga laste grupi uuringul leidsime, et GJB2 geeni mutatsioon c.35delG on ka Eestis kõige sagedasem KL-e põhustaja ja teisel kohal on mutatsioon p.M34T. Mutatsioonide c.35delG ja p.M34T esinemissagedus nii KL-ga laste kui ka skriinitud anonüümsete vastsündinute hulgas on Eestis kõrgem kui enamikes Euroopa riikides. Ülegenoomsel genotüpiseerimisel Illumina geenikiipidega leidsime kolmel patsiendil kolm erinevat deleteerunud kromosoomipiirkonda ja kaasasündinud tsütomegaloviirusinfektsioon oli KL-e põhjuseks viiel lapsel. Uuringu tulemusena selgus või täpsustus KL etioloogiline geneetiline faktor 140 patsiendil (60%). Hearing loss (HL) is the most common sensory disorder wordwide, one to two children in 1000 are born with HL. In 50-60% of the cases with HL are hereditary (genetic) and in 40-50% of the cases of hearing loss acquired due to environmental factors. Genetic HL is divided into syndromic and non-syndromic forms. The non-syndromic autosomal-recessive forms of HL are more common. Mutation c.35delG accounts for the vast majority of the GJB2 mutations detected in Caucasian populations. The aim of our study was to establish the prevalence of c.35delG and p.M34T mutations in GJB2 gene among Estonian general population; to investigate genetic background in Estonian children with HL and to describe their phenotype; to evaluate the occurrence of small submicroscopic chromosomal rearrangements and the incidence of cytomegalovirus (CMV) infection in children with HL. The general Estonian population study group consisted of 998 anonymous newborn samples whose were partially dissociated. The study group of children with HL consisted of 233 children. We investigated them by APEX gene array analysis, which covers 201 mutations in eight different genes (GJB2, GJB3, GJB6, GJA1, SLC26A4, SLC26A5, 12S-rRNA and tRNA (Ser)). The results of our study we found carrier frequency for c.35delG mutation 1 in 22 and for p.M34T mutation 1 in 17. The prevalence of the carrier frequencies of the mutations c.35delG and p.M34T in the GJB2 gene in Estonia is the highest of results found in European populations. The mutations found most frequently among Estonian children with early onset HL were c.35delG and p.M34T. Whole genome array analysis was indentified in three patients three potentially pathogenic chromosomal deletions. In five patients the congenital CMV infection was found by DNA analysis. In conclusion the etiology of HL was established or specified in 140 investigated children (60%). Väitekirja elektrooniline versioon ei sisalda publikatsioone.
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