Recessive SLC19A2 mutations are a cause of neonatal diabetes mellitus in thiamine-responsive megaloblastic anaemia

Abstract

Permanent neonatal diabetes mellitus (PNDM) is diagnosed within the first 6 months of life, and is usually monogenic in origin. Heterozygous mutations in ABCC8, KCNJ11, and INS genes account for around half of cases of PNDM; mutations in 10 further genes account for a further 10%, and the remaining 40% of cases are currently without a molecular genetic diagnosis. Thiamine-responsive megaloblastic anaemia (TRMA), due to mutations in the thiamine transporter SLC19A2, is associated with the classical clinical triad of diabetes, deafness, and megaloblastic anaemia. Diabetes in this condition is well described in infancy but has only very rarely been reported in association with neonatal diabetes. We used a combination of homozygosity mapping and evaluation of clinical information to identify cases of TRMA from our cohort of patients with PNDM. Homozygous mutations in SLC19A2 were identified in three cases in which diabetes presented in the first 6 months of life, and a further two cases in which diabetes presented between 6 and 12 months of age. We noted the presence of a significant neurological disorder in four of the five cases in our series, prompting us to examine the incidence of these and other non-classical clinical features in TRMA. From 30 cases reported in the literature, we found significant neurological deficit (stroke, focal, or generalized epilepsy) in 27%, visual system disturbance in 43%, and cardiac abnormalities in 27% of cases. TRMA should be considered in the differential diagnosis of diabetes presenting in the neonatal period.

Pharmacogenomics in diabetes: outcomes of thiamine therapy in TRMA syndrome

“…At the time of referral for genetic testing, the age of the individuals in the cohort ranged from 3 months to 28 years (median age 4 years [IQR 1-9]). We describe 20 previously unreported individuals with TRMA syndrome and present follow-up data for 12 individuals reported previously [16,26].…”

“…If the phenotype was suggestive of TRMA syndrome, direct sequencing of SLC19A2 was performed. The six coding exons of the SLC19A2 gene were screened by Sanger sequencing as described previously [16] (primers available on request). Sequencing reactions were run on an ABI3730 capillary machine (Applied Biosystems, Warrington, UK) and analysed using Mutation Surveyor v3.98 (SoftGenetics, State College, PA, USA) (SLC19A2 nucleotide reference NM_006996.2).…”

“…In some individuals additional features such as thrombocytopenia, neurological symptoms, cardiac anomalies, visual disturbances and short stature have also been reported [14][15][16][17].…”

A Case of Early-Onset Thiamine-Responsive Megaloblastic Anemia Syndrome

“…TRMA'nın yenidoğan döneminde tanı alan diyabet olgularının ayırıcı tanısında akılda tutulması gerektiği bilinmektedir. 11 Nitekim olgumuz da iki ay gibi küçük bir yaşta tanı almıştır. Tiamin tedavisi ile insülin ihtiyacı kaybolan olgumuzun izlemine devam edilmektedir.…”

“…Yine Shaw-Smith ve ark.nın yaptıkları çalışmada, TRMA hastalarının %27'sinde inme, fokal veya jeneralize epilepsi gibi nörolojik defisit saptanmıştır. 11 Olgumuzda ise herhangi bir nörolojik semptom yoktu.…”