Thiamine-responsive megaloblastic anemia: identification of novel compound heterozygotes and mutation update.
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.


METHODS
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.


CONCLUSIONS
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.
Bergmann
Anke K
AK
Division of Hematology and Oncology, Children's Hospital Boston and Harvard Medical School, Boston, MA 02115, USA.
Sahai
Inderneel
I
Falcone
Jill F
JF
Fleming
Judy
J
Bagg
Adam
A
Borgna-Pignati
Caterina
C
Casey
Robin
R
Fabris
Luca
L
Hexner
Elizabeth
E
Mathews
Lulu
L
Ribeiro
Maria Leticia
ML
Wierenga
Klaas J
KJ
Neufeld
Ellis J
EJ
D000328:Adult; D000749:Anemia, Megaloblastic / Q000150:complications / Q000188:drug therapy / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003638:Deafness / Q000209:etiology; D003920:Diabetes Mellitus / Q000209:etiology; D005260:Female; D006579:Heterozygote; D006801:Humans; D007223:Infant; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D013831:Thiamine / Q000627:therapeutic use*; D014803:Vitamin B Complex / Q000627:therapeutic use*
D026901:Membrane Transport Proteins; C120043:SLC19A2 protein, human; D014803:Vitamin B Complex; D013831:Thiamine