Thiamine Pyrophosphokinase Deficiency in Indian origin Siblings - Expanding the phenotype

Introduction: Thiamine metabolism dysfunction syndrome (THMD) is a group of heterogeneous disorders with autosomal recessive inheritance. THMD due to SLC19A3, SLC25A19 and TPK1 mutations present as episodic encephalopathies. Thiamine pyrophosphokinase (TPK) produces thiamine pyrophosphate which is a coenzyme for pyruvate dehydrogenase and 2-ketoglutarate dehydrogenase. We discuss Indian siblings presenting with the TPK deficiency/THMD5. Case Report: An 11-month-old boy born of 3rd degree consanguineous marriage with normal birth and developmental history presented to us with appendicular as well as axial dystonia. The dystonia progressed rapidly and persisted despite all medications. He stopped walking but cognition remained preserved. He also had episodes of irritability and swallowing difficulty during intercurrent illness. There was history of similar complaints in all his three elder siblings. Two of them passed away at the age of 2 years, the surviving brother - 6 years old, had dystonia spasticity and neuroregression. Nerve conduction velocity performed in older brother was normal. MRI brain of the younger child showed bilaterally symmetrical T1, T2 hyperintensities with restricted diffusion in putamen & globus pallidus. Molecular analysis revealed a novel homozygous missense variant c.620A>T (p.Asp207Val) in TPK1 gene in both the brothers and parents were carriers. High dose thiamine supplementation in the younger child did not show any clinical benefit. Conclusions: Thiamine and biotin supplementation showed improved outcomes in most cases of SLC19A3 deficiency and in few with SLC25A19 and TPK1. Hence early suspicion and diagnosis can impact neurological prognosis. In absence of commercial biochemical tests, molecular testing is indispensable for establishing diagnosis.
Keywords: Thiamine metabolism, Dystonia, Basal ganglia, THMD5, TPK1 gene