OBJECTIVE: To determine causative mutations and clinical status of 7 previously unreported kindreds with TRMA syndrome, (thiamine-responsive megaloblastic anemia, online Mendelian inheritance in man, no. 249270), a recessive disorder of thiamine transporter Slc19A2. STUDY DESIGN: Genomic DNA was purified from blood, and SLC19A2 mutations were characterized by sequencing polymerase chain reaction-amplified coding regions and intron-exon boundaries of all probands. Compound heterozygotes were further analyzed by sequencing parents, or cloning patient genomic DNA, to ascertain that mutations were in trans. RESULTS: We detected 9 novel SLC19A2 mutations. Of these, 5 were missense, 3 were nonsense, and 1 was insertion. Five patients from 4 kindreds were compound heterozygotes, a finding not reported previously for this disorder, which has mostly been found in consanguineous kindreds. CONCLUSION: SLC19A2 mutation sites in TRMA are heterogeneous; with no regional "hot spots." TRMA can be caused by heterozygous compound mutations; in these cases, the disorder is found in outbred populations. To the extent that heterozygous patients were ascertained at older ages, a plausible explanation is that if one or more allele(s) is not null, partial function might be preserved. Phenotypic variability may lead to underdiagnosis or diagnostic delay, as the average time between the onset of symptoms and diagnosis was 8 years in this cohort.
OBJECTIVE: To determine causative mutations and clinical status of 7 previously unreported kindreds with TRMA syndrome, (thiamine-responsive megaloblastic anemia, online Mendelian inheritance in man, no. 249270), a recessive disorder of thiamine transporter Slc19A2. STUDY DESIGN: Genomic DNA was purified from blood, and SLC19A2 mutations were characterized by sequencing polymerase chain reaction-amplified coding regions and intron-exon boundaries of all probands. Compound heterozygotes were further analyzed by sequencing parents, or cloning patient genomic DNA, to ascertain that mutations were in trans. RESULTS: We detected 9 novel SLC19A2 mutations. Of these, 5 were missense, 3 were nonsense, and 1 was insertion. Five patients from 4 kindreds were compound heterozygotes, a finding not reported previously for this disorder, which has mostly been found in consanguineous kindreds. CONCLUSION:SLC19A2 mutation sites in TRMA are heterogeneous; with no regional "hot spots." TRMA can be caused by heterozygous compound mutations; in these cases, the disorder is found in outbred populations. To the extent that heterozygous patients were ascertained at older ages, a plausible explanation is that if one or more allele(s) is not null, partial function might be preserved. Phenotypic variability may lead to underdiagnosis or diagnostic delay, as the average time between the onset of symptoms and diagnosis was 8 years in this cohort.
Authors: Christopher J Ricketts; Jayne A Minton; Jacob Samuel; Indra Ariyawansa; Jerry K Wales; Ivan F Lo; Timothy G Barrett Journal: Acta Paediatr Date: 2006-01 Impact factor: 2.299
Authors: E J Neufeld; H Mandel; T Raz; R Szargel; C N Yandava; A Stagg; S Fauré; T Barrett; N Buist; N Cohen Journal: Am J Hum Genet Date: 1997-12 Impact factor: 11.025
Authors: T M Strom; K Hörtnagel; S Hofmann; F Gekeler; C Scharfe; W Rabl; K D Gerbitz; T Meitinger Journal: Hum Mol Genet Date: 1998-12 Impact factor: 6.150
Authors: Beate Karges; Thomas Meissner; Andrea Icks; Thomas Kapellen; Reinhard W Holl Journal: Nat Rev Endocrinol Date: 2011-11-29 Impact factor: 43.330
Authors: Anke K Bergmann; Dean R Campagna; Erin M McLoughlin; Suneet Agarwal; Mark D Fleming; Sylvia S Bottomley; Ellis J Neufeld Journal: Pediatr Blood Cancer Date: 2010-02 Impact factor: 3.167
Authors: Herbert Pichler; Petra Zeitlhofer; Michael N Dworzak; Christopher Diakos; Oskar A Haas; Leo Kager Journal: Eur J Pediatr Date: 2012-05-11 Impact factor: 3.183