A RARE CASE OF THIAMINE-RESPONSIVE MEGALOBLASTIC ANAEMIA SYNDROME : A DISORDER OF HIGH-AFFINITY THIAMINE TRANSPORT

J Ayub Med Coll Abbottabad 2008;20(3)
CASE REPORT
A RARE CASE OF THIAMINE-RESPONSIVE MEGALOBLASTIC ANAEMIA
SYNDROME: A DISORDER OF HIGH-AFFINITY THIAMINE TRANSPORT
Naeem MA, Shabaz A*, Shoaib A, Usman M,
Combined Military Hospital Abbottabad,*Armed Forces Institute of Pathology, Rawalpindi, Pakistan.
A three years old boy presented with sensory neural hearing loss since birth, Diabetes mellitus and
anaemia .On investigation he was found to be suffering from Thiamine Responsive Megaloblastic
Anaemia (TRMA) a very rare condition diagnosed in our settings.
Keywords: TRMA, Megaloblastic Anaemia, Thiamine, Haemoglobin, Bone Marrow, Prenatal Testing
INTRODUCTION
anaemia. The physical and systemic examination
The condition is caused by a deficiency of a thiamine
revealed an anaemic child with sensory neural
(vitamin B
hearing loss. Initial Lab investigations showed
1) transporter protein which means that the
body is unable to effectively utilize thiamine from the
anaemia (Hb 6.1 gm/dl) and peripheral blood
diet. Thiamine responsive megaloblastic anaemia
macrocytosis (MCV 110 fl/l). Bone marrow
syndrome is listed as a ‘rare disease’ by the Office of
examination was performed to determine the cause of
Rare Diseases (ORD) of the National Institutes of
macrocytosis. Megaloblastosis with hypercellur
Health (NIH) USA. Consortium of European
marrow was seen. The bone marrow iron was
partners, currently defines a condition rare when if
increased with moderate number of sidrocytes and
affects 1 person per 2,000. They list Thiamine
sideroblasts. On the basis of bone marrow
responsive megaloblastic anaemia syndrome as a
examination a diagnosis of Megaloblastic anaemia
‘rare disease’. Twenty-five affected individuals
was made. Here the child’s father gave a valuable
reported to date have been diagnosed.1 The diagnosis
clue that two of the child’s paternal first cousins
of TRMA should be suspected in patients with
suffered from exactly similar condition. This led to a
syndrome of diabetes including hearing loss and
bit of brain storming by the authors and a differential
anaemia, even if the latter is only very mild and
diagnosis of Thiamine-Responsive Megaloblastic
particularly in the case of consanguinity. The bone
Anaemia Syndrome was kept in mind. The diagnosis
marrow aspirate usually shows megaloblastic
of TRMA should is suspected in patients with
changes and ringed sideroblasts.2 TRMA syndrome
syndrome of diabetes including hearing loss and
gene maps to a region on chromosome 1q23.2–23.3.3
anaemia. The fasting blood glucose levels done two
The clinical features of TRMA, resembling in part
weeks apart revealed a very high glucose content
those found in typical mitochondrial disorders with
(16.2 mmol/l). We decided to get the molecular
complex deficiency, may be caused by a secondary
diagnosis. The child was taken to the United States
defect
in
mitochondrial
energy
production.4
where his DNA analysis confirmed the1q23.2–23.3
Designated ‘SLC19A2’ as a member of the solute
mutation. The child has been on Thiamine therapy for
carrier gene super family, this gene is mutated in all
the past six months. His anaemia has significantly
TRMA kindred’s studied to date. The product of the
improved (Hb 10.6 gm/dl). The child is transfusion
SLC19A2 gene is a membrane protein which
independent since the start of therapy. The patient is
transports
thiamine
(vitamin
B1)
with
sub-
on insulin therapy at the moment.
micromolar affinity.5 Cells from TRMA patients are
DISCUSSION
uniquely sensitive to thiamine depletion to the
Thiamine
responsive
megaloblastic
anaemia
nanomolar range, while pharmacologic doses of
vitamin B
syndrome (TRMA), an autosomal recessive disorder
1 ameliorate the anaemia and Diabetes.6
caused by the deficiency of thiamine transporter
CASE REPORT
protein, is the association of diabetes mellitus,
A three years old boy was referred to us by our
anaemia and deafness.7
worthy hospital Paediatrician for the diagnosis and
The water-soluble micronutrient thiamine is
management
of
anaemia.
On
taking
of
required for normal tissue growth and development in
comprehensive history from his father, the boy was
humans. Thiamine is accumulated into cells through
the only child of their parents. He was born at a local
the activity of two cell surface thiamine transporters
hospital and had hearing loss since birth. He was
(hTHTR1 and hTHTR2), which are differentially
observed to have developed gradual pallor about a
targeted in polarized tissues. Mutational dysfunction
year and a half after birth. The child was transfused
of hTHTR1 is associated with the clinical condition
twice with red cell concentrates for correction of
of thiamine-responsive megaloblastic anaemia: the
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J Ayub Med Coll Abbottabad 2008;20(3)
symptoms of which are alleviated by thiamine
in TRMA patients that is most marked under
supplementation.8
thiamine-deprived culture conditions and is partially
Diabetes in this syndrome is due to an
restored by thiamine supplementation, explaining the
insulin insufficiency that initially responds to
clinical responsiveness of TRMA patients to high
thiamine supplements; however, most patients
doses of thiamine. Use of the powerful tools provided
become fully insulin dependent after puberty.9
by SIDMAP and related techniques that use even
Cochlear histological analysis showed a
more sensitive accelerator mass spectrometry with
pattern uncommon for sensor neural hearing loss:
ultra-low-dose labelling techniques provides the
selective loss of inner hair cells after 1–2 weeks on
promise to address, perhaps in vivo, similar
low thiamine and significantly greater inner than
unanswered questions involving the molecular basis
outer hair cell loss after longer low-thiamine
for disease. Applying these methods to the study of
challenges. Such a pattern is consistent with the
the
more
common
conditions
that
cause
observed discrepancy between ABR and OAE
megaloblastic anaemia, but that are still shrouded in
threshold shifts. The possible role of thiamine
mystery, could ultimately shed similar light on their
transport in other reported cases of selective inner
mechanism.
hair cell loss is confirmed.10 Retinal abnormality and
The diagnosis of TRMA is based on an
visual disturbances occur in thiamine-responsive
obligate triad of clinical features described above.15
megaloblastic anaemia.11
Examination of the bone marrow reveals megaloblastic
Megaloblastic changes in the bone marrow
anaemia with erythroblasts often containing iron-filled
are morphologically quite distinctive, and the several
mitochondria (ringed sideroblasts). SLC19A2, which
causes of this condition, including specific nutrient
encodes the high-affinity thiamine transporter, is the
deficiencies, metabolic errors, and certain drugs, are
only gene known to be associated with TRMA. All
well described.12 Among the more obscure causes of
individuals with the diagnostic phenotypic triad
megaloblastic anaemia is the acronymic curiosity
evaluated by sequence analysis have identifiable
thiamine-responsive megaloblastic anaemia, the use
mutations in the SLC19A2 gene.16 Sequence analysis
of mass spectrometry in conjunction with stable
of SLC19A2 DNA is available clinically. That reduced
isotope-labelling techniques has made it possible to
nucleic acid production through impaired transketolase
unlock doors along previously inaccessible hallways
catalysis is the underlying biochemical disturbance that
of gene function analysis in the metabolomic maze.
likely induces cell cycle arrest or apoptosis in bone
The door to TRMA was thus opened by Boros et al,13
marrow cells and leads to the TRMA syndrome in
who have pioneered the use of Stable Isotope-based
patients
with
defective
high-affinity
thiamine
Dynamic Metabolic Profiling (SIDMAP) as a key to
transport.17 Pharmacological dose thiamine normalizes
better understanding of changes in substrate flow as a
haematological abnormalities and their effects on the
basis for drug mechanisms and disease. Teaming up
course of diabetes mellitus. Thiamine induces a
with the Boston group who first identified the loss of
remarkable haematological response and improvement
function mutation in the high-affinity, low-capacity
in the diabetic control but has no effect on deafness.18
thiamine transporter in TRMA, the authors have
Treatment of TRMA focuses on lifelong use
pinpointed the cause of disruption of nucleic acid
of pharmacologic doses (25–75 mg per day) of
synthesis that leads ultimately to premature apoptosis
thiamine (Vitamin B1) in affected individuals.19
in this intriguing genetic disorder. Through tracking
Surveillance to monitor the efficacy of the oral
the stable13 C-labelled glucose in fibroblasts from
thiamine therapy as well as disease progression
patients with TRMA, these authors concluded that
should be performed at least yearly and includes:
the underlying lesion in this condition resides in the
haematologic tests (CBC, reticulocyte count),
pentose cycle, specifically the transketolase enzyme,
assessment for glucose intolerance (fasting serum
which requires thiamine pyro-phosphate as a
glucose concentration, OGTT, urine analysis), and
cofactor14. Through a consideration of the several
hearing, ophthalmologic, and cardiac evaluations.20
interconnected
pathways
of
glycolysis,
the
TRMA is inherited in an autosomal recessive
tricarboxylic acid cycle, and ribose synthesis, the
manner. At conception, the sibs of an affected
authors defined substrate flux in TRMA and normal
individual have a 25% chance of being affected, a 50%
wild-type fibroblasts grown in both low- and high-
chance of being an asymptomatic carrier, and a 25%
thiamine medium. They concluded that defective
chance of being unaffected and not a carrier. Once an
high-affinity thiamine transport in TRMA leads to a
at-risk sib is known to be unaffected, the risk of his/her
critical reduction in de novo generation of ribose with
being a carrier is 2/3. Prenatal testing is available for
consequent cell-cycle arrest that triggers precocious
families in which the disease-causing mutations have
apoptosis. Their results clearly demonstrate a
been identified.21
selective and time-dependent loss of ribose synthesis
http://www.ayubmed.edu.pk/JAMC/PAST/20-3/AbdulNaeem.pdf
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J Ayub Med Coll Abbottabad 2008;20(3)
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Address for Correspondence:
Dr. Mohammad Abdul Naeem, Classified Haematologist, CMH Abbottabad.
E-mail: bugsgallian@yahoo.com
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