High penetrance and pronounced variation in expressivity of GCH1 mutations in five families with dopa‐responsive dystonia

Abstract

We performed a clinical and molecular genetic analysis in members of five families with dopa-responsive dystonia. Four mutations were detected in the gene GCH1 that codes for GTP cyclohydrolase I. Two of these mutations, a delG309 in exon 1 and a C544T transition in exon 5, have not been described before. They result in inactivation of the enzyme by truncation. The remaining two mutations, both A to G transitions, a(-2)g in intron 1 and a(-2)g in intron 2, cause truncation by abnormal splicing. The genotype of family members was correlated to their clinical phenotype (obtained before molecular analysis). Clinical symptoms observed in the families included generalized and focal dystonia, abnormal gait, and subtle signs such as an abnormal writing test. High penetrance (0.8-1.0) was observed in four of five families if minor symptoms and signs were considered. A given mutation was more likely to cause symptoms in females than in males, thus confirming the well-established higher incidence of dopa-responsive dystonia in females than in males.

The genetics of the dystonias – a review based on the new classification of the dystonias

“…In DRD patients, various mutations have been identified in all the exons and also in the introns. Penetrance is low (approximately 30%), but if atypical clinical presentations are taken into account, it can vary from 38% to 100% 32,33 . Penetrance is higher in females (87% to 100%) than in males (38% to 55%), and the disease is also more common in females 34 .…”

Study of the genetic basis of dystonia in Serbian population

“…To je distonija plus sindrom koji se karakteriše dnevnom fluktuacijom simptoma u oko 75% slučajeva, parkinsonizmom i dramatičnim odgovorom na terapiju L-dopom (Segawa et al, 1976;Nygaard, 1993a;Nygaard et al, 1993b). Klinička slika DYT5a može da varira od generalizovane, segmentne i multifokalne distonije, preko abnormalnosti u položaju tela, parkinsonizma, abnormalnosti u hodu i blagog tremora do subjektivnih smetnji i simptoma koje je moguće uočiti samo prilikom indukcije tokom neurološkog pregleda (Nygaard et al, 1990;Furukawa et al, 1998a;Steinberger et al, 1998;. Distonija DYT5a obično počinje u detinjstvu, ali godine početka prvih simptoma vrlo variraju, pa bolest može početi i u adolescenciji ili čak u adultnom dobu.…”

“…Tako je u jednoj velikoj severnoameričkoj porodici penetrabilnost prvobitno izračunata i iznosila je 30% (Nygaard et al, 1990), ali kada su kasnije uzeti u ubzir i manje primetni simptomi, penetrabilnost je procenjena na 60%. Studija na pet DYT5a porodica dala je prosečnu penetrabilnost od 80%, odnosno 100% kod žena i 55% kod muškaraca (Steinberger et al, 1998). Druge dve studije dobile su međusobno slične vrednosti: 87% kod žena, 38% kod muškaraca (Furukawa et al 1998a) i 87% kod žena, 35% kod muškaraca (Segawa et al 2003).…”

“…Tačnije, opisuje se postojanje široke inter-i intrafamilijarne varijabilnosti u ekspresiji kod nosilaca mutacija u GCH1 genu (Nygaard et al, 1993a;Bandmann et al, 1998;Steinberger et al, 1998;Tassin et al, 2000;Grimes et al, 2002b;Klein et al, 2002b;Uncini et al 2004;Furukawa et al, 2005;Wu et al, 2008;Trender-Gerhard et al, 2009;Ling et al 2011).…”

“…Ova porodica, gde su 3 od 4 člana sa mutacijom obolela, je primer i visoke penetrabilnost DYT5a mutacije koja se opisuje u literaturi (Steinberger et al, 1998).…”