J Inherit Metab Dis
DOI 10.1007/s10545-014-9712-9
ICIEM SYMPOSIUM 2013
Defects of thiamine transport and metabolism
Garry Brown
Received: 13 February 2014 / Revised: 25 March 2014 / Accepted: 31 March 2014
# SSIEM and Springer Science+Business Media Dordrecht 2014
Abstract Thiamine, in the form of thiamine pyrophosphate,
is a cofactor for a number of enzymes which play important
roles in energy metabolism. Although dietary thiamine defi-
ciency states have long been recognised, it is only relatively
recently that inherited defects in thiamine uptake, activation
and the attachment of the active cofactor to target enzymes
have been described, and the underlying genetic defects iden-
tified. Thiamine is transported into cells by two carriers,
THTR1 and THTR2, and deficiency of these results in
thiamine-responsive megaloblastic anaemia and biotin-
responsive basal ganglia disease respectively. Defective syn-
thesis of thiamine pyrophosphate has been found in a small
number of patients with episodic ataxia, delayed development
and dystonia, while impaired transport of thiamine pyrophos-
phate into the mitochondrion is associated with Amish lethal
microcephaly in most cases. In addition to defects in thiamine
uptake and metabolism, patients with pyruvate dehydrogenase
deficiency and maple syrup urine disease have been described
who have a significant clinical and/or biochemical response to
thiamine supplementation. In these patients, an intrinsic struc-
tural defect in the target enzymes reduces binding of the
cofactor and this can be overcome at high concentrations. In
most cases, the clinical and biochemical abnormalities in these
conditions are relatively non-specific, and the range of
recognised presentations is increasing rapidly at present as
new patients are identified, often by genome sequencing.
These conditions highlight the value of a trial of thiamine
Communicated by: John Christodoulou
Presented at the 12th International Congress of Inborn Errors of
Metabolism, Barcelona, Spain, September 36, 2013.
G. Brown (*)
Department of Biochemistry, University of Oxford, South Parks
Road, Oxford OX1 3QU, UK
e-mail: garry.brown@bioch.ox.ac.uk
supplementation in patients whose clinical presentation falls
within the spectrum of documented cases.
Introduction
Thiamine is an important vitamin in human nutrition and, in
the form of thiamine pyrophosphate (TPP), is the cofactor for
a number of enzymes which play major roles in energy
metabolism, including the -ketoacid dehydrogenase com-
plexes. Defects in thiamine transport or the biosynthesis of
thiamine pyrophosphate can lead to deficiency of these en-
zymes, as can structural abnormalities in the enzymes them-
selves which impair cofactor binding. Patients have now been
described with defects in all of these aspects of thiamine
metabolism and they present with a much wider range of
clinical and biochemical manifestations than might be expect-
ed from shared involvement in common biochemical path-
ways. In this review, an outline of the biochemistry of thia-
mine will be presented, together with a summary of the
manifestations of the different conditions in which this is
abnormal.
Thiamine is a dicyclic compound with thiazole and
aminopyrimidine rings joined by a methylene bridge (Fig. 1).
There is an alcohol side chain on the thiazole ring and in the
activation of thiamine to its active cofactor derivative, this is
esterified with pyrophosphate. Thiamine is an essential vitamin
in humans and is found in most foods, albeit at relatively low
levels. The most important source of thiamine in most diets is
unrefined cereal grains. Dietary thiamine is mainly in the form
of phosphate derivatives and, before absorption, these are con-
verted to free thiamine by intestinal phosphatases. Although
normal requirements for thiamine can be met by a daily intake
of 12 mg, there is no evidence of adverse effects of much
higher, pharmacological doses, and this is an important

Fig. 1 Structure of thiamine. The
vitamin precursor, thiamine (top)
and the active cofactor derived
from it, thiamine pyrophosphate
(below) are shown
consideration in providing supplementation for patients with
defects in the bioavailability of the active cofactor.
Thiamine transport and activation
Thiamine is absorbed into the body in the upper small intes-
tine by two transporters, THTR1 and THTR2, the products of
the SLC19A2 and SLC19A3 genes respectively (Ganapathy
et al 2004; Zhao and Goldman 2013). These transporters are
closely related, with 48 % identity, and both facilitate a high
affinity, pH dependent saturable transport across cell mem-
branes. Both carriers are widely distributed in the body, but the
levels differ in different tissues and they have different kinetic
properties. They are also differentially distributed in polarised
cells, such as those in the intestinal mucosa and renal tubule
(Boulware et al 2003; Rindi and Laforenza 2000). At very
high concentrations, there is evidence that some thiamine may
also be absorbed by diffusion.
While thiamine is mainly absorbed in the free form, there is
a mechanism for absorption of thiamine monophosphate
(TMP), as this is a substrate for the reduced folate carrier
(RFC1) (Zhao et al 2002). This is the product of the
SLC19A1 gene and is very closely related to the two thiamine
carriers. The biological significance of this mechanism is
unclear and it may actually provide a means for exporting
thiamine from cells. In addition, there is also some evidence
for direct uptake of TPP produced by gut bacteria into colonic
epithelial cells (Nabokina and Said 2012). The main mecha-
nisms for intestinal uptake of thiamine are shown in Fig. 2. At
the luminal surface, THTR2 is the major transporter and this
delivers thiamine into the cell in exchange for hydrogen ions.
At the basal surface, THTR1 is mainly responsible for release
of free thiamine into the circulation. Within the mucosal cells,
some thiamine can be converted to TPP and TMP and
exported into the circulation by RFC1.
J Inherit Metab Dis
+
The active cofactor of thiamine in animal cells, thiamine
pyrophosphate (Fig. 1), is a cofactor for the -ketoacid dehy-
drogenase complexes (pyruvate dehydrogenase, -
ketoglutarate dehydrogenase and the branched chain -
ketoacid dehydrogenase), transketolase, an enzyme of the pen-
tose phosphate cycle, and, as recently described, 2-hydroxyacyl
CoA lyase, a peroxisomal enzyme involved in the -oxidation
of branched fatty acids, such as phytanic acid (Casteels et al
2007). The active TPP cofactor is generated within cells from
free thiamine by the enzyme thiamine pyrophosphokinase
(TPK) (Fig. 3). Biochemical studies indicate that TPP can be
converted to TMP by a thiamine pyrophosphatase and this can
be further hydrolysed back to free thiamine by a thiamine
monophosphatase, however genes for these enzymes have not
yet been identified. The formation of TPP takes place in the
cytoplasm of the cell and the cofactor is immediately available
for association with transketolase. To provide active cofactor
for the -ketoacid dehydrogenases, which are located in the
mitochondrial matrix, there is a TPP transporter in the
inner mitochondrial membrane (Kang and Samuels 2008;
RFC
TMP
TPP
THTR2 THTR1
T+ T+
H+ H+
LUMEN BLOOD
Fig. 2 Uptake of thiamine in the small intestine. Free thiamine is gener-
ated in the intestinal lumen from various phosphate derivatives present in
the diet. Thiamine is transported across the apical membrane by THTR2
in exchange for hydrogen ions. At the basal membrane, thiamine is
released into the circulation by THTR1 in a similar exchange reaction.
In addition, some thiamine is converted by intestinal epithelial cells to
TMP and this can be released from the cell by the reduced folate carrier, a
transporter which is closely related to the thiamine carriers
J Inherit Metab Dis
Fig. 3 Intra-cellular thiamine
metabolism. Thiamine is
transported into cells by THTR1
and/or THTR2, depending on
their tissue distribution. Within
the cell, it is activated to TPP by
thiamine pyrophosphokinase. The
active cofactor can bind to
transketolase in the cytoplasm. It
is also attached to 2-hydroxyacyl
CoA lyase (HACL1) in the
cytoplasm before this enzyme is
transported into the peroxisome. T T
TPP is transported into the THTR1
mitochondrion by a specific THTR2
transporter for attachment to the
-ketoacid dehydrogenase
apoenzymes
Lindhurst et al 2006). TPP is attached to the hydroxyacyl
CoA lyase apoprotein before it is transported into the
peroxisome (Casteels et al 2007).
Defects in the thiamine transporters
THTR1 deficiency
THTR1 deficiency results in thiamine-responsive megaloblas-
tic anaemia, also known as Rogers syndrome (Neufeld et al
2001; Ricketts et al 2006, OMIM 249270). This condition is
characterised by a core triad of megaloblastic anaemia, diabe-
tes mellitus and sensorineural deafness. Patients usually pres-
ent in infancy or early childhood and often the anaemia is the
first recognised feature. The anaemia is often accompanied by
thrombocytopaenia, and ringed sideroblasts are prominent in
bone marrow aspirates (Bazarbachi et al 1998). While the
diabetes usually develops during childhood, a number of
patients with neonatal diabetes have been reported (Shaw-
Smith et al 2012). In addition to the core features, a number
of other manifestations are associated with this condition,
including cardiac abnormalities, optic atrophy, retinal abnor-
malities, stroke-like episodes and short stature. Cardiac in-
volvement appears to be relatively common, and patients have
been described with various arrhythmias, congenital
malformations and cardiomyopathy (Lorber et al 2003).
A variety of different mutations in the SLC19A2 gene have
been identified in these patients confirming the deficiency of
the THTR1 transporter. However, as the focus of investigation
has been on the haematological aspects in most cases, the
biochemical consequences are rather poorly defined. The blood
thiamine concentration is normal, suggesting that THTR1 is
RFC1
TMP TPP
TMPase TPPase
TPP TPP transporter
TPK
HACL1 TPP TPP
not of major importance for intestinal absorption. The addition-
al clinical features show considerable overlap with mitochon-
drial diseases and this would be consistent with the important
roles of the -ketoacid dehydrogenase complexes in energy
metabolism. One patient has been described with raised blood
and cerebrospinal fluid lactate concentration. In this patient, a
muscle biopsy was morphologically normal, but there were
reduced activities of complex I of the respiratory chain and
pyruvate dehydrogenase, which returned to normal with thia-
mine supplementation (Scharfe et al 2000). Now that the
biochemical basis of this condition has been established, it is
anticipated that more systematic investigation of mitochondrial
function will be performed in future patients.
There has been some investigation of possible pathogenic
mechanisms responsible for the megaloblastic anaemia in
THTR1 deficiency. The role of imbalance in DNA and RNA
biosynthesis in megaloblastic erythropoiesis has led to a con-
sideration of the activity of the pentose phosphate cycle in
general, and the enzyme transketolase in particular, in provi-
sion of ribose-5-phosphate for these processes (Fig. 4).
Ribose-5-phosphate can be formed from glucose either via
ribulose-5-phosphate, the product of the oxidative branch of
the pathway, or from glycolytic intermediates through a
series of carbohydrate interconversions. These interconver-
sions depend upon the activity of transketolase, with its
TPP cofactor. In vitro studies of ribose synthesis from
glucose have been performed in cultured fibroblasts from
patients with THTR1 deficiency (Boros et al 2003). These
show that RNA ribose synthesis is significantly reduced in
thiamine-depleted medium and that this is due to enhanced
reliance on the oxidative branch of the pathway. The
biochemical abnormalities are reversed when the cells are
grown in thiamine-supplemented medium.

Fig. 4 Role of TPP in ribose GLUCOSE
metabolism. The pentose
phosphate shunt is an important
source of ribose-5-phosphate for
glucose-6-P
RNA and DNA biosynthesis.
This product can be generated
from ribulose-5-phosphate in the
oxidative part of this pathway, or
via a series of carbohydrate
interconversions involving the
enzymes transketolase (TK) and
transaldolase. The reactions
involving transketolase are fructose-6-P
dependent on the availability of
its cofactor, TPP
TK-TPP
glyceraldehyde-3-P
Although this is a thiamine-responsive disorder, the differ-
ent elements of the syndrome respond to a greater or lesser
extent to thiamine supplementation. The anaemia and diabetes
usually respond very well initially to doses of thiamine be-
tween 2550 mg/day (although some patients have been treat-
ed with considerably higher doses), and cardiac arrythmias
also generally respond well (Borgna-Pignatti et al 2009;
Ricketts et al 2006). On the other hand, the deafness and other
neurological manifestations respond poorly, although there
may be a better outcome with early diagnosis and treatment
(Onal et al 2009). There is also evidence that thiamine-
responsiveness decreases after puberty and adult patients
may become transfusion- and insulin-dependent in spite of
previously adequate thiamine supplementation (Ricketts et al
2006).
THTR2 deficiency
This was initially described in patients from Saudi Arabia as
biotin-responsive basal ganglia disease (Ozand et al 1998).
Patients presented in childhood with a subacute encephalop-
athy and symmetrical lesions in the basal ganglia, particularly
the caudate nucleus and putamen. Clinical manifestations
included confusion, difficulties with speech and swallowing,
dystonia and rigidity. These responded very rapidly to biotin
supplementation at doses of 510 mg/day and the patients did
not have neurological sequelae if recognised early and treated
continuously. The genetic defect in SLC19A3, the gene for
THTR2 was identified in studies on this group of patients, in
which there is a high degree of parental consanguinity and a
common missense mutation, p.thr422ala (Zeng et al 2005).
Although the clinical presentation and brain MRI changes
in patients with biotin-responsive basal ganglia disease have
J Inherit Metab Dis
2NADP+
ribulose-5-P
2NADPH
xylulose-5-P RIBOSE-5-P
TK-TPP
glyceraldehyde-3-P sedoheptulose-7-P
erythrose-4-P fructose-6-P
now been well defined (Alfadhel et al 2013; Tabarki et al 2013),
a number of additional patients with SLC19A3 mutations have
been described with different clinical presentations, so that the
recognised spectrum of this disorder has now expanded signif-
icantly and a new designation, thiamine metabolism dysfunc-
tion syndrome 2 (OMIM 607483) has been proposed. Four
patients from Japan have been described with atypical infantile
spasms and delayed development, progressive cerebral atrophy
and bilateral lesions in the thalami and basal ganglia (Yamada
et al 2010). One patient has been reported with severe neonatal
lactic acidosis and acute encephalopathy which responded im-
mediately to thiamine and biotin (Perez-Duenas et al 2013).
Although metabolic abnormalities in this patient were con-
trolled with continuing thiamine supplementation, some neuro-
logical sequelae remained. Several patients have presented later
in life in adolescence or as adults, including a 15 year old girl
with a Leigh-like encephalopathy (Fassone et al 2013), two
adult brothers with a Wernicke-like encephalopathy (Kono et al
2009), and two adult sisters with generalised dystonia and
seizures (Debs et al 2010).
Recently, there have been two reports of SLC19A3 muta-
tions in patients from eight unrelated families with an early
onset, fatal encephalopathy and a characteristic pattern of brain
MRI abnormalities with cerebral atrophy and symmetrical le-
sions in the thalami, basal ganglia and brain stem (Gerards et al
2013; Kevelam et al 2013). In some of these patients, various
biochemical abnormalities have been documented, including
raised blood and cerebrospinal fluid lactate concentration and
reduced activity of pyruvate and -ketoglutarate dehydroge-
nase in muscle. In patients who received thiamine supplemen-
tation, there was improved survival.
In early-onset patients, the most effective treatment appears
to be a combination of biotin and thiamine. The range of doses
J Inherit Metab Dis
used has been quite wide, with biotin doses between 2 and
10 mg/day and thiamine doses of 100400 mg/day being the
most common (Alfadhel et al 2013; Tabarki et al 2013). In the
Japanese patients with infantile spasms and delayed develop-
ment, biotin was ineffective and they were treated with thia-
mine alone. Similarly, the patients presenting with a
Wernicke-like encephalopathy also responded to thiamine
alone. A significant number of different mutations in the
SLC19A3 gene have been identified and there is no clear
genotype-phenotype correlation to inform treatment.
The most striking aspect of this condition is the response
to biotin supplementation, given that THTR2 does not trans-
port biotin (Subramanian et al 2006). An explanation for the
responsiveness may come from studies of the role of biotin
in gene expression. In addition to being a cofactor for
various biotin-containing enzymes, biotin is also involved
in the expression of a number of genes including those for
enzymes involved in glucose metabolism, biotin transport,
carboxylase apoenzymes, cytokines and oncogenes
(Dakshinamurti 2005; Rodriguez-Melendez and Zempleni
2003). The mechanism for the regulation of gene expression
involves activation of cGMP signalling pathways by
biotinyl-AMP and biotinylation of histones H3 and H4 by
holocarboxylase synthase (Rodriguez-Melendez and
Zempleni 2003). In a study of human subjects made mar-
ginally biotin deficient, Vlasova et al demonstrated a signif-
icant reduction in expression of the SLC19A3 gene (Vlasova
et al 2005). In patients with THTR2 deficiency due to
mutations in this gene, limited availability of biotin may
be sufficient to aggravate the basic defect and this could be
overcome by dietary supplementation.
Thiamine pyrophosphokinase deficiency
This condition has only recently been reported in five patients
from three families (Mayr et al 2011, OMIM 606370). Onset
was during early childhood, in some cases after a period of
normal development. Common features were episodic ataxia,
psychomotor retardation and dystonia, with additional spas-
ticity and seizures in one of the patients. Brain MRI changes
were quite variable with global atrophy, and abnormal signal
in the basal ganglia, cerebellum and brain stem. While two
patients died in childhood, three are currently being treated
with thiamine 100200 mg/day and a high fat diet. One of
these attends normal school and has normal development. All
patients have mutations in the TPK1 gene.
These patients have all had extensive biochemical investi-
gation which revealed consistent elevation of blood and cere-
brospinal fluid lactate concentration during episodes of ataxia,
and enhanced excretion of -ketoglutarate in urine. All pa-
tients had reduced TPP concentration in both blood and mus-
cle and measurement of the concentration in blood provides a
simple screening test for this condition. While the primary
defect should theoretically affect all enzymes which have TPP
as cofactor, the most significant effects appear to be on pyru-
vate dehydrogenase and -ketoglutarate dehydrogenase.
When assayed in the presence of TPP, pyruvate dehydroge-
nase activity in muscle was normal.
Mitochondrial TPP transporter deficiency
The mitochondrial TPP transporter is the product of the
SLC25A19 gene and was originally described as the mito-
chondrial deoxynucleotide carrier (Dolce et al 2001; Kang and
Samuels 2008). Deficiency of this carrier was first described
in the condition of Amish lethal microcephaly (OMIM
607196), a condition with a characteristic facial appearance,
brain MRI findings and increased urinary excretion of -
ketoglutarate. All patients from the Amish community have
a common missense mutation, p.Gly177Ala (Rosenberg et al
2002). While this condition is usually associated with early
lethality, there is one report of a patient of Amish ancestry who
has survived into late childhood (Siu et al 2010).
Subsequent identification of mutations in the SLC25A19
gene in patients outside of this inbred community suggests
that the spectrum of this condition is likely to be much
broader. Four siblings have been described with a similar
presentation of acute episodes of flaccid paralysis and enceph-
alopathy precipitated by intercurrent illness (Spiegel et al
2009). During acute episodes, they developed a motor and
sensory neuropathy, with a raised cerebrospinal fluid lactate
concentration. Between episodes, there was some residual
weakness, and a progressive polyneuropathy. There was no
cognitive impairment. Brain MRI revealed basal ganglia
changes affecting the caudate nucleus and putamen, with
sparing of the globus pallidus. Excretion of -ketoglutarate
was not increased, and in one patient, activity of respiratory
chain complexes and pyruvate dehydrogenase in muscle were
normal. This condition has been designated thiamine metab-
olism syndrome 4 (bilateral striatal degeneration and progres-
sive polyneuropathy type, OMIM 613710).
Thiamine-responsive -ketoacid dehydrogenase
deficiencies
A clinical and/or biochemical response to pharmacological
doses of thiamine has been reported in a small number of
pyruvate dehydrogenase deficiency (OMIM 312170) and ma-
ple syrup urine disease (OMIM 248600) patients. This respon-
siveness suggests a structural abnormality in the complexes
which impairs TPP binding, but which can be overcome in the
presence of a high concentration of the cofactor. From the
published reports, it is difficult to assess the significance of the

thiamine-responsiveness, as thiamine supplementation
alone has usually been insufficient to control symptoms and
has had to be combined with other therapeutic measures. An
extremely wide range of doses, 501200 mg/day, has been
used, and only in about half of the cases has a clear and
sustained response been demonstrated, either clinically or
biochemically. There are very few reports of long term follow
up, but several patients have survived to late childhood and are
attending normal school.
Thiamine-responsive pyruvate dehydrogenase deficiency
has been reported in over 20 patients (Di Rocco et al 2000;
Lee et al 2006; Naito et al 2002a, 2002b; Pastoris et al 1996;
Sedel et al 2008). These patients are usually at the less severe
end of the spectrum of this condition, presenting typically in
late infancy with hypotonia and delayed development, or
episodes of ataxia associated with intercurrent illness. Blood
and cerebrospinal fluid lactate concentrations are usually
raised during acute episodes, but may be normal or moderate-
ly elevated at other times. In almost all cases, brain MRI
imaging reveals symmetrical lesions in basal ganglia and brain
stem, typical of Leigh syndrome. Several patients have been
described with prolonged survival, well preserved cognitive
function, and a clinical presentation dominated by peripheral
neuropathy, rather than the more common central neurological
deficits (Bachmann-Gagescu et al 2009; Lee et al 2006;
Marsac et al 1997).
Because of variability in the clinical and biochemical re-
sponse to thiamine, underlying biochemical defects in these
patients have been investigated in vitro in an attempt to
confirm that there is impaired cofactor binding to the complex
and that this can be overcome by increasing the thiamine
I87M, R88S, R88C, G89S
Y118, R119
Fig. 5 Amino acid substitutions associated with thiamine-responsive
pyruvate dehydrogenase deficiency. The region of the E1 subunit sur-
rounding the thiamine pyrophosphate binding site is shown. The cofactor
(shown in ball and stick form) is bound in the interface between the E1
and E1 subunits, with the thiamine attached primarily to the E1
J Inherit Metab Dis
concentration. Initial reports suggested that assaying the com-
plex from cultured cells with a range of TPP concentrations
was sufficient to differentiate responsive and non-responsive
patients (Naito et al 2002b). In our experience, this is often not
the case, and patient fibroblasts may have normal activity even
when cultured and assayed in very low thiamine concentra-
tions (van Dongen et al 2014). In these cases, the diagnosis
may be missed unless more extensive investigations to expose
impaired cofactor binding are performed.
As thiamine responsiveness is not easily demonstrated by
biochemical analysis, attempts have also been made to iden-
tify specific mutations which are associated with the respon-
sive phenotype. Although the TPP binding site is in the
interface between the and subunits of the E1 component
of the complex, so far all mutations in thiamine-responsive
patients have been located in the PDHA1 gene which encodes
the E1 subunit. In general, these mutations do not involve
amino acid residues which form the actual TPP binding site,
instead, most are located in one of two adjacent regions. These
mutations presumably affect cofactor binding indirectly,
through interactions with the amino acids which form the site
itself (Fig. 5). While most cases of thiamine-responsive pyru-
vate dehydrogenase deficiency have mutations in these re-
gions, other mutations in the PDHA1 gene which are well
away from the TPP binding site have also been implicated in
some patients. These may result in altered stability of the
complex which may be overcome by high concentrations of
the cofactor.
Thiamine-responsive maple syrup urine disease has been
reported in over ten patients (Simon et al 2006). These again
usually present in late infancy with delayed development and
TPP
F205L, M210V, L216F
D196, G197, A198
N225, Y227
subunit and the pyrophosphate attached to the E1 subunit by the amino
acid residues highlighted in black. The majority of amino acid substitu-
tions which are associated with thiamine responsiveness involve residues
adjacent to the binding site on either side (shown in red)
J Inherit Metab Dis
episodes of ketoacidosis or ataxia. Again a wide range of
thiamine doses has been administered, up to 1000 mg/day,
and patients have also received dietary branched chain amino
acid restriction. Several patients remain healthy as adults,
without episodes of ketoacidosis and with normal cognitive
function on this regimen. Although the TPP binding site of the
branched chain -ketoacid dehydrogenase is in the interface
between the E1 and E1 subunits, as in pyruvate dehydro-
genase, almost all thiamine-responsive maple syrup urine
disease patients have been found to have mutations in the
DBT gene for the E2 component of the complex (Chuang
et al 2006). While the E2 protein is not directly involved in
TPP binding, in vitro studies suggest that the affinity of the
E1 subunit for TPP is influenced by binding to this compo-
nent, which forms the core of the complex (Chuang et al
2004). No responsive patients with mutations in the
BCKDHA gene for the E1 subunit have been described,
but there is a recent report of a responsive patient with a
mutation in the BCKDHB gene which codes for the E1
subunit (Yang et al 2012).
Conclusion
The two thiamine transporters, THTR1 and THTR2, are both
widely distributed, however, differences in their expression
may account for the different manifestations of deficiencies.
Thiamine is converted to the active thiamine pyrophosphate
cofactor in the cytoplasm of the cell, and a specific transporter
then delivers this to the mitochondrion. Apart from THTR1
deficiency, which results in a well-defined condition of
thiamine-responsive megaloblastic anaemia, consequences
of defects in thiamine transport and metabolism are quite
variable and often non-specific, with considerable overlap
with various mitochondrial disorders. Biochemical abnormal-
ities are inconstant, although raised blood and cerebrospinal
fluid lactate concentrations and increased urinary excretion of
-ketoglutarate are among the most frequent findings. In the
absence of specific diagnostic features, patients with this
group of conditions are increasingly being recognised by
genome sequencing.
In addition to defects in thiamine transport and activation,
there are also defects in the binding of TPP to some of the
enzymes for which this is a cofactor. Patients with thiamine-
responsive pyruvate dehydrogenase deficiency and maple
syrup urine disease have been described, but it is often diffi-
cult to correlate a clinical response with the results of either
biochemical or genetic analysis. In general, responsive pa-
tients have less severe illness and a more prolonged course,
however follow up studies are very limited and it is not known
if long term problems may still develop. Few of these patients
have been fully normal, or have reached adulthood. Genetic
heterogeneity, great variation in the dose of thiamine
administered and the requirement for additional dietary ma-
nipulation, all make it difficult to determine the extent to
which true thiamine responsiveness exists in these conditions.
It is anticipated that the spectrum of the thiamine metabo-
lism dysfunction syndromes will continue to expand as new
patients are identified, either by biochemical or genetic anal-
ysis and that a clearer idea of the true incidence will be
obtained. Although, at present, it appears that the individual
disorders of thiamine metabolism are quite rare, they all
emphasise the importance of a trial of thiamine supplementa-
tion in appropriate patients, both for potential therapy and to
indicate possible diagnoses for specific investigation.
Compliance with Ethics Guidelines
Conflict of interest None.
Animal Rights This article does not contain any studies with human or
animal subjects performed by the author.
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