TPK1 Deficiency—A Vitamin-Responsive Encephalopathy with a Suggestive MRI Pattern
Acute or subacute encephalopathy, with or without febrile illness, is an emergency that warrants quick recognition of the underlying disease. Cranial imaging, preferably by cranial magnetic resonance imaging (MRI), is a cornerstone of diagnostic workup. Symmetric lesions of gray or white matter should always prompt the suspicion of a metabolic disorder. Affection of the basal ganglia often leads to the annotation of a Leigh-like disease and the assumption of an untreatable mitochondrial disease. Additional MRI features, such as subcortical lesions or cerebellar findings, have to be looked for thoroughly, as they may give important clues toward the underlying etiology such as genetic defects in thiamine metabolism. Recently, a nomenclature was established, assigning gene defects in thiamine metabolism to thiamine dysfunction syndromes 1 to 5. Thiamine is a water-soluble vitamin and several genes are involved in its transport and activation. Genetic defects have been described for the two transporter genes SLC19A2 and SLC19A3, responsible for cellular uptake of thiamine, as well as for its mitochondrial uptake by a transporter encoded by SLC25A19. TPK1, in contrast, is an enzyme that phosphorylates thiamine to its active form, namely thiamine pyrophosphate (TPP). Thiamine is an important cofactor in carbohydrate metabolism and deficiency of TPP may lead to elevated lactate in plasma and cerebrospinal fluid (CSF). In defects of SLC19A3 concentrations of free thiamine are reduced in plasma and CSF, while in TPK1, concentrations of TPP are decreased in plasma, but measurement of these biomarkers is restricted to very few specialized laboratories. Interestingly, defects in the different genes involved in thiamine metabolism cause quite distinct phenotypes, all inherited by autosomal recessive traits. Defects in the high affinity thiamine transporter SLC19A2 cause Rogers syndrome (OMIM # 249270 megaloblastic anemia with diabetes and sensorineural deafness), while defects in the low affinity thiamine transporter SLC19A3 lead to biotin-thiamine-responsive basal ganglia disease (BTBGD) (OMIM # 607483) and defects in the mitochondrial thiamine transporter SLC25A19 cause Amish lethal microcephaly or bilateral striatal necrosis (OMIM # 607196). Defects in TPK1 were first described in 2011and the 15 patients published to date show some overlap with presentations of BTBGD. In this issue of neuropediatrics, Eckenweiler et al and Rüsch et al publish two patients with typical presentations of episodic encephalopathy in previously healthy children. Both children underwent extensive metabolic workup with very mild elevation of CSF lactate in one of them. Rüsch et al present a useful summary of findings of all hitherto published patients with TPK1 deficiency illustrating that only 9 out of 14 patients had elevated lactate levels in plasma and 3 out of 7 had elevated lactate levels in CSF. In the here reported cases, diagnostic workup was guided by findings of cranial imaging, suggesting a mitochondrial disorder, including defects in thiamine metabolism. One patient was immediately treated with high-dose biotin and thiamine based on imaging findings with very quick recovery. The patient published by Rüsch et al received additional magnesium, which is a known cofactor of TPK1, but has not been tried in previous cases. Biallelic variants in TPK1 were identified in both patients by next-generation sequencing, whereby the variant c.576T > G, p.Cys192Trp reported by Rüsch et al is novel and probably damaging by prediction programs.
Defects in thiamine metabolism represent an important cohort among the growing group of vitamin-responsive encephalopathies. Therefore, child neurologists should have “vitamins in their pockets.” The two reports on TPK1 deficiency in this issue of neuropediatrics nicely outline that pediatricians should think of defects in thiamine metabolism in patients presenting with a Leigh-like encephalopathy. Early recognition of thiamine responsive disorders is especially rewarding for oral treatment options and prevention of irreversible brain damage by a timely diagnosis. In the absence of quickly available biomarkers, a treatment trial with biotin and thiamine should be considered generously even before results of whole exome sequencing are available.
24 February 2021 (online)
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