Whole Exome Sequencing Identifies a Novel Mutation of TPK1 in a Chinese Family with Recurrent Ataxia

Zhu, Bizhen; Wu, Jinzhun; Chen, Guobing; Chen, Ling; Yao, Yonghua

doi:10.1007/s12031-020-01568-x

Cited by 7 publications

(6 citation statements)

References 15 publications

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“…The brain MRI were abnormal in most cases (17/21). The principal manifestations of the MRI include abnormal signal in the basal ganglia, cerebellum, brainstem and global atrophy [ 14 ]. It is symmetric or asymmetric.…”

Section: Discussionmentioning

confidence: 99%

Case report of two affected siblings in a family with thiamine metabolism dysfunction syndrome 5: a rare, but treatable neurodegenerative disease

Huang

Chen

et al. 2022

BMC Neurol

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Background Thiamine metabolism dysfunction syndrome 5 (THMD5) is a rare inherited metabolic disorder due to thiamine pyrophosphokinase 1(TPK1) deficiency, caused by mutations in TPK1. The core symptoms of the disease is acute or subacute onset encephalopathy, ataxia, muscle hypotonia, and regression of developmental milestones in early infancy, repeatedly triggered by acute infectious illness. However, we report two brothers of THMD5 with compound heterozygous for the mutations c.614-1G > A,c.224 T > A p.(Ile75Asn), but the prognosis is quite different if thiamine suppled. According to our current knowledge, the missense variant c.224 T > A p.(Ile75Asn) was not published previously. Case presentation Here, we describe two affected siblings in a Chinese family, after an uneventful pregnancy to non-consanguineous and healthy parents. The older brother presented with normal development during the first 6 months of life, but developed regression of developmental milestones after, accompanied with muscle hypotonia, and chronic encephalopathy, and died at 1 year and 6 months old. The younger brother presented with acute onset encephalopathy, ataxia, muscle hypotonia, repeatedly triggered by acute infectious illness. He was compound heterozygous for the mutations c.614-1G > A,c.224 T > A p.(Ile75Asn) identified by whole exome sequencing. He was diagnosed of THMD5 when he was 11 month. Oral supplementation of thiamine 100 mg/day, the symptoms gradually disappeared. At the age of 2 years and 4 months, he stoped thiamine, his symptoms returned and were once again relieved by oral supplementation of thiamine 100 mg/day. Conclusions THMD5 is a rare, but treatable neurodegenerative disease, the clinical phenotype ranges from mild to severe. Massive-dose of thiamine supplementation may ameliorate the course of TPK1 deficiency. When similar clinical cases appear, gene detection is particularly important, which is conducive to early diagnosis. Treatment with thiamine while awaiting the outcome of diagnostic tests may be a good choice.

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Section: Discussionmentioning

confidence: 99%

Case report of two affected siblings in a family with thiamine metabolism dysfunction syndrome 5: a rare, but treatable neurodegenerative disease

Huang

Chen

et al. 2022

BMC Neurol

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“…In summary, functional loss of the C-terminus of CHAMP1 alters the localization to chromosomes and spindles and disrupts the microtubule attachment complex, which results in kinetochore-microtubule-related syndromic ID. WES is a powerful tool for the diagnosis of neurodevelopmental disorders; however, the analysis of massive amounts of data has been a major challenge (16). MRD40 was first described and the phenotype was linked to CHAMP1 in the DDD study (4).…”

Section: Discussionmentioning

confidence: 99%

“…WES is a powerful tool for the diagnosis of neurodevelopmental disorders; however, the analysis of massive amounts of data has been a major challenge ( 16 ). MRD40 was first described and the phenotype was linked to CHAMP1 in the DDD study ( 4 ).…”

Section: Discussionmentioning

confidence: 99%

First Chinese patient with mental retardation‑40 due to a de novo CHAMP1 frameshift mutation: Case report and literature review

Dong

Shi

et al. 2021

Exp Ther Med

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Mental retardation-40 (MRD40) is a rare autosomal dominant neurodevelopmental disorder with a poor prognosis that is caused by a heterozygous mutation in chromosome alignment maintaining phosphoprotein 1 (CHAMP1). It was previously considered a non-syndromic disease due to the lack of specific external features. Only limited international reports describing CHAMP1 mutations are currently available. The present case study was the first to report on a Chinese patient with MRD40. The patient presented with severe global development delay with significant craniofacial dysmorphia. Using trio whole-exome sequencing, a novel de novo frameshift mutation in CHAMP1, NM_032436.2: c.530delCinsTTT, was identified, which expands the spectrum of the known pathogenic variants. The present case report helps to improve the syndromic profile of the rare MRD40 disorder and provides an example for the clinical diagnosis of MRD40.

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“…The majority of thiamine absorption occurs in the small intestine and is taken in by cells and tissues. Afterward, it is transformed into thiamine pyrophosphate (TPP) through the action of cytosolic enzyme thiamine pyrophosphokinase (TPK) [ 1 ]. TPP plays a key role in various metabolic processes occurring in cytosol, peroxisome, and mitochondria, accounting for eighty percent of thiamine present in the body.…”

Section: Introductionmentioning

confidence: 99%

“…The TPK1 gene exhibits intense activity in the small intestine, where it is linked to the assimilation of thiamine, and in the kidney, where it plays a role in the re-absorption of thiamine. Additionally, it is also present in the liver, brain, placenta, and spleen [ 1 ]. THMD2 is a rare metabolic condition inherited in an autosomal recessive manner and caused by SLC19A3 gene mutations.…”

Section: Introductionmentioning

confidence: 99%

Identification of novel mutations in TPK1 and SLC19A3 genes in families exhibiting thiamine metabolism dysfunction syndrome

Norouzi Rostami,

Sadeghi,

Hashemi-Gorji

et al. 2024

Heliyon

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Whole Exome Sequencing Identifies a Novel Mutation of TPK1 in a Chinese Family with Recurrent Ataxia

Cited by 7 publications

References 15 publications

Case report of two affected siblings in a family with thiamine metabolism dysfunction syndrome 5: a rare, but treatable neurodegenerative disease

Case report of two affected siblings in a family with thiamine metabolism dysfunction syndrome 5: a rare, but treatable neurodegenerative disease

First Chinese patient with mental retardation‑40 due to a de novo CHAMP1 frameshift mutation: Case report and literature review

Identification of novel mutations in TPK1 and SLC19A3 genes in families exhibiting thiamine metabolism dysfunction syndrome

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