Expanding the clinical and molecular spectrum of thiamine pyrophosphokinase deficiency: A treatable neurological disorder caused by TPK1 mutations

Banka, Siddharth; Goede, Christian de; Yue, Wyatt W.; Morris, Andrew A. M.; Bremen, Beate von; Chandler, Kate; Feichtinger, René G.; Hart, Claire; Khan, Nasaim; Lunzer, Verena; Mataković, Lavinija; Marquardt, Thorsten; Makowski, Christine; Prokisch, Holger; Debus, O.; Nosaka, Kazuto; Sonwalkar, Hemant; Zimmermann, Franz; Sperl, Wolfgang; Mayr, Johannes A.

doi:10.1016/j.ymgme.2014.09.010

Cited by 56 publications

(44 citation statements)

References 13 publications

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“…Since the first description of five individuals from three families reported by Mayr et al, 109 a total of 15 patients have been reported. [109][110][111][112][113][114] All described patients had onset of symptoms in childhood (range: 1 month to 4 years and 8 months). Children may exhibit a normal or delayed psychomotor development until they present with recurrent episodes of encephalopathy, ataxia, dysarthria, dystonia, seizures, ophthalmoplegia, nystagmus, and psychomotor regression.…”

Section: Clinical Phenotypementioning

confidence: 99%

“…Thiamine pyrophosphokinase deficiency (TPK1; #606370) is associated with episodic encephalopathy triggered by infections or dehydration. Since the first description of five individuals from three families reported by Mayr et al, a total of 15 patients have been reported . All described patients had onset of symptoms in childhood (range: 1 month to 4 years and 8 months).…”

Section: Inborn Errors Of Metabolism Leading To Thiamine Dysfunction mentioning

confidence: 99%

“…Recessive defects within TPK1 sequence result in thiamine metabolism dysfunction due to thiamine pyrophosphokinase deficiency . Up to date, 11 different variants have been reported . Most of them are missense variants but there is also a frameshift variant which truncates the protein (c.179_182delGAGA), two deletions of exon 3 and 4, and the splicing variant c.501+4A>T that results in a complete deletion of exon 6 (Figure ).…”

Section: Inborn Errors Of Metabolism Leading To Thiamine Dysfunction mentioning

confidence: 99%

“…109 It has also proven to prevent further metabolic decompensations 113 and ameliorate brain MRI lesions. 110,113 Authors conclude that dosage of thiamine should be sufficient to provide adequate substrate concentration for residual TPK activity and to prevent any depletion of this vitamin. Recently, Huang et al 112 reported a Chinese girl with a novel homozygous TPK1 mutation (p.L28S) who was treated with thiamine early in disease evolution.…”

Section: Treatmentmentioning

confidence: 99%

“…112 The implementation of a ketogenic diet has shown controversial results, with one patient manifesting clinical improvement 111 and other patient presenting clinical deterioration. 110 Deep pallidal stimulation in a patient with TPK1 SLC25A19 c.373G>A c.580T>C c.530G>C F I G U R E 4 SLC25A19 gene structure including all described patients' variants. Homozygous variants causing THMD4 in black and homozygous variant in orange cause a different phenotype (MCPHA).…”

Section: Treatmentmentioning

confidence: 99%

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Genetic defects of thiamine transport and metabolism: A review of clinical phenotypes, genetics, and functional studies

Marcé‐Grau

Martí-Sánchez

Baide‐Mairena

et al. 2019

J of Inher Metab Disea

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Thiamine is a crucial cofactor involved in the maintenance of carbohydrate metabolism and participates in multiple cellular metabolic processes within the cytosol, mitochondria, and peroxisomes. Currently, four genetic defects have been described causing impairment of thiamine transport and metabolism: SLC19A2 dysfunction leads to diabetes mellitus, megaloblastic anemia and sensory‐neural hearing loss, whereas SLC19A3, SLC25A19, and TPK1‐related disorders result in recurrent encephalopathy, basal ganglia necrosis, generalized dystonia, severe disability, and early death. In order to achieve early diagnosis and treatment, biomarkers play an important role. SLC19A3 patients present a profound decrease of free‐thiamine in cerebrospinal fluid (CSF) and fibroblasts. TPK1 patients show decreased concentrations of thiamine pyrophosphate in blood and muscle. Thiamine supplementation has been shown to improve diabetes and anemia control in Rogers' syndrome patients due to SLC19A2 deficiency. In a significant number of patients with SLC19A3, thiamine improves clinical outcome and survival, and prevents further metabolic crisis. In SLC25A19 and TPK1 defects, thiamine has also led to clinical stabilization in single cases. Moreover, thiamine supplementation leads to normal concentrations of free‐thiamine in the CSF of SLC19A3 patients. Herein, we present a literature review of the current knowledge of the disease including related clinical phenotypes, treatment approaches, update of pathogenic variants, as well as in vitro and in vivo functional models that provide pathogenic evidence and propose mechanisms for thiamine deficiency in humans.

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Section: Clinical Phenotypementioning

confidence: 99%

Section: Inborn Errors Of Metabolism Leading To Thiamine Dysfunction mentioning

confidence: 99%

Section: Inborn Errors Of Metabolism Leading To Thiamine Dysfunction mentioning

confidence: 99%

Section: Treatmentmentioning

confidence: 99%

Section: Treatmentmentioning

confidence: 99%

See 3 more Smart Citations

Genetic defects of thiamine transport and metabolism: A review of clinical phenotypes, genetics, and functional studies

Marcé‐Grau

Martí-Sánchez

Baide‐Mairena

et al. 2019

J of Inher Metab Disea

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Thiamine metabolism dysfunction syndrome 5 (THMD5) mimicking acute disseminated encephalomyelitis

Thompson,

Boyd,

Khoshnood

et al. 2023

American J of Med Genetics Pt A

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Thiamine pyrophosphate (TPP), the substrate of Thiamine pyrophosphate kinase (TPK), is an important cofactor in carbohydrate metabolism, specifically as a cofactor of the Pyruvate dehydrogenase complex (PDH) complex. The nervous system is particularly dependent on TPP due to its reliance on glucose metabolism. In this case, a four‐year‐old girl had a previously unreported pathogenic variant of the gene encoding TPK (TPK1) which presented as Thiamine metabolism dysfunction syndrome 5 (THMD5; OMIM 614458). She had been diagnosed with acute disseminated encephalomyelitis and autism spectrum disorder (ASD), and initially presented with fever and agitation following vaccinations. After follow‐up with genetic testing, our patient was found to have compound heterozygous pathogenic variants of TPK1. After treatment with biotin and thiamine her clinical status improved, and her ASD features resolved. The presentation of our patient was consistent with previous reports and adds to the evidence that thiamine and biotin are effective treatments of TPK1 related metabolic deficiencies. The improvement of neurobehavioral symptoms in this case was marked, highlighting the importance of early identification and therapeutic intervention in this condition.

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Thiamine deficiency in childhood with attention to genetic causes: Survival and outcome predictors

Ortigoza‐Escobar

Alfadhel

Molero-Luís

et al. 2017

Annals of Neurology

119

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Primary and secondary conditions leading to thiamine deficiency have overlapping features in children, presenting with acute episodes of encephalopathy, bilateral symmetric brain lesions, and high excretion of organic acids that are specific of thiamine-dependent mitochondrial enzymes, mainly lactate, alpha-ketoglutarate, and branched chain keto-acids. Undiagnosed and untreated thiamine deficiencies are often fatal or lead to severe sequelae. Herein, we describe the clinical and genetic characterization of 79 patients with inherited thiamine defects causing encephalopathy in childhood, identifying outcome predictors in patients with pathogenic SLC19A3 variants, the most common genetic etiology. We propose diagnostic criteria that will aid clinicians to establish a faster and accurate diagnosis so that early vitamin supplementation is considered. Ann Neurol 2017;82:317-330.

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Expanding the clinical and molecular spectrum of thiamine pyrophosphokinase deficiency: A treatable neurological disorder caused by TPK1 mutations

Cited by 56 publications

References 13 publications

Genetic defects of thiamine transport and metabolism: A review of clinical phenotypes, genetics, and functional studies

Genetic defects of thiamine transport and metabolism: A review of clinical phenotypes, genetics, and functional studies

Thiamine metabolism dysfunction syndrome 5 (THMD5) mimicking acute disseminated encephalomyelitis

Thiamine deficiency in childhood with attention to genetic causes: Survival and outcome predictors

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