P 233. Thiamine Pyrophosphokinase Deficiency due to Mutations in the TPK1 Gene: A Rare, Treatable Neurodegenerative Disorder

Background: Thiamine or vitamin B1 is an essential nutrient absorbed in the small intestine. The cytosolic thiamine pyrophosphokinase (TPK) phosphorylates thiamine to the active form thiamine pyrophosphate (TPP). TPP acts as cofactor for the cytosolic transketolase and mitochondrial enzymes involved in the oxidative decarboxylation, as well as for peroxisomal enzymes.

Several defects in the thiamine transport and metabolism is known to cause distinct diseases, such as thiamine responsive megaloblastic anemia syndrome or biotin thiamine responsive basal ganglia disease. Only in 2011, a severe neurodegenerative, Leigh-like syndrome due to TPK deficiency caused by TPK1 gene mutations was identified. Since then, less than 20 patients with TPK deficiency were reported. These patients presented after an initial normal development with episodic ataxia, psychomotor regression, dystonia, and spasticity in their first year of life. Symptoms were often triggered by febrile illness. Biochemical studies revealed elevated serum and CSF lactate, and increased urinary α-ketoglutarate excretion. Magnetic resonance imaging (MRI) showed mostly lesions of the basal ganglia and dentate nuclei, and in addition lesions of the thalami, cerebellum, brain stem, and spinal cord. Some patients with TPK deficiency have been treated with thiamine. These patients stabilized or even improved clinically and survived longer compared with patients without thiamine supplementation.

Case Report: Our patient is the first child of nonconsanguineous parents. She was born at term via cesarean section after an uneventful pregnancy. Initial development appeared normal. Triggered by febrile infections at the age of 6 and 9 months, the girl became lethargic, hypotonic, and atactic, and showed psychomotor regression with loss of previously acquired developmental milestones. Recovery from these episodes was slow and only partial. Neurological examination at the age of 20 months showed a global developmental delay, elevated muscle tone of the extremities, and ataxia. Cerebral MRI demonstrated bilateral focal T2 hyperintense lesions with diffusion restriction in the basal ganglia, thalami, dentate nuclei, and centrally in the intraorbital optic nerves. Serum and cerebrospinal fluid lactate was slightly elevated. Urine organic acids analysis showed increased α-ketoglutarate. Due to the clinical presentation and the abnormalities in the MRI, a mitochondrial disease was suspected.

Exome sequencing revealed two variants in the TPK1 gene (NM_022445.3), a previously unreported, highly conserved missense variant (c.576T>G, p.Cys192Trp) and a previously as pathogenic described near-splice variant (c.501+4A>T, p>). Both parents were heterozygous carriers of one variant each. High-dose oral thiamine supplementation was initiated to increase the substrate concentration for the residual TPK and TPP production. Marked and sustained improvement of the muscle tone, alertness, and ataxia was observed within days to several weeks following thiamine supplementation with continuous developmental progress up to the last follow-up investigation at the age of 31 months.

Conclusion: TPK deficiency is a rare, but potentially treatable disorder of the thiamine metabolism. Our case outlines the importance of considering the group of thiamine responsive disorders and conducting appropriate genetic tests when patients present with acute-onset encephalopathy, ataxia, and other signs suggesting a mitochondrial disorder. High-dose thiamine supplementation may ameliorate the course of TPK deficiency and should be initiated promptly after diagnosis or even upon suspicion.

No conflict of interest has been declared by the author(s).