We identified nine novel mutations and one previously known mutation among seven TRMA kindreds. Six of these were missense mutations, three nonsense and one insertion; these can be added to the prior 19 distinct mutations in SLC19A2 (). These mutations are spread across the first four exons. Among 28 SLC19A2 mutations now known in about 70 total reported patients, only four variants appear in multiple families and of these only two, 484C>T and 515G>A likely arose independently in different ethnic populations (), while others are potentially from single founders or limited geographic regions. The majority of the mutations are null mutations as a consequence of nonsense or frameshift mutations.
Known Mutations in SLC19A2 Leading to TRMA
Although missense mutations could conceivably yield interesting structure/function relationships, or correspond to variable phenotype, not enough data exist to make these correlations. Only five of the previously described mutations are missense, and some of those five impair proper processing and cellular localization4
, and may be “functionally null”. In prior reports, all TRMA kindreds had homozygous mutations in SLC19A2
, usually due to consanguinity or ethnic isolation and homozygosity by descent. However four patients in this group are compound heterozygotes (). Two of these patients present with less severe hearing phenotypes. Patient 2 has normal hearing at age 15, while Patient 5 had a first observation of mild hearing loss at age 30. It remains unclear if these milder phenotypes can be explained by compound heterozygous missense mutations that are not functionally null.
Although the clinical triad of anemia, diabetes and deafness defines the syndrome of TRMA, other clinical signs or symptoms are often observed in TRMA patients (). These associated findings also add difficulties to attempts to correlate genotype and phenotype: for example, optic atrophy, retinal changes, and stroke (or stroke-like episodes) are certainly features of TRMA, but seen only in a minority of cases, even with homozygous null mutations. Although the clinical presentation of TRMA shares some features with Wolfram Syndrome (DIDMOAD, OMIM # 222300) and a variety of mitochondrial disorders, these are known to be distinct.5
The pathophysiology of TRMA syndrome has been elucidated in metabolic studies in fibroblasts from patients, and in a mouse model deficient in Slc19a2
, the murine homolog of SLC19A2
: Megaloblastosis is due to defective de novo
synthesis of nucleic acids, because limited intracellular thiamine affects the pentose phosphate pathway and production of ribose-5-P.6
Observed ringed sideroblasts and ineffective erythropoiesis in TRMA are most likely due to a decrease in succinyl-CoA, which is needed for heme biosynthesis and generated by the action of a thiamine-requiring mitochondrial enzyme, α-ketoglutarate dehydrogenase.7
deficient mice become deaf due to a loss of cochlear inner hair cells.8
Although patients’ cochleae cannot be examined as for the mice, this spatial distribution of transporters as a cause of the particular pathology is both plausible and likely. Most tissues of normal mammals express two high-affinity thiamine transporters, both SLC19A2 and SlC19A3, so that if one is missing, it is supposed that the other protects those tissues (brain, heart, liver, skeletal muscle, intestine, for example). However, SLC19A2 is the sole transporter in marrow, pancreatic beta cells, and a subset of cochlear cells8, 9
, and therefore deafness, diabetes and anemia are the consequences of deficiency.
A potential limitation of this survey of mutations is one of ascertainment bias. When the TRMA gene was under study in the late 1990s, investigators intentionally accumulated kindreds from consanguineous backgrounds for homozygosity mapping.2
More recently, clinicians identify TRMA when confronted with the full TRMA syndrome (diabetes, macrocytic/thiamine-responsive anemia, and hearing loss). We predict that more mildly affected patients, either
with later onset of manifestations or without the cardinal clinical triad, remain to be discovered. We predict that to some degree, less severely affected patients may be expected to have less drastic mutations in the SLC19A2
gene. Many adult patients are now known, but only a few presented as adults. Our study remains open to evaluate research samples from full blown TRMA, but also from subjects with only two suggestive symptoms (e.g. hearing loss and thiamine-responsive anemia, anemia with diabetes, or diabetes and deafness). It is likely that the age-range and spectrum of clinical findings in SLC19A2
-related disorders will continue to widen as we learn more about the disorder.