Clinical Presentation and Positive Outcome of Two Siblings with Holocarboxylase Synthetase Deficiency Caused by a Homozygous L216R Mutation

Slavin, Thomas P.; Zaidi, S. Javed; Neal, Charles R.; Nishikawa, B.; Seaver, Laurie H.

doi:10.1007/8904_2013_252

Cited by 11 publications

(7 citation statements)

References 11 publications

(29 reference statements)

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“…Patients with HLCS deficiency presenting abnormal BAEPs have rarely been reported, and the reason is worthy of discussion. Slavin et al reported a girl with HLCS deficiency presenting conductive hearing loss as a result of cerumen impaction [7], but this is different from the situation with our patient. Additionally, our patient's hearing impairment recovered after 43 days of biotin therapy, which is different from the irreversible hearing loss of biotinidase deficiency.…”

Section: Discussioncontrasting

confidence: 99%

Clinical, biochemical, and genetic analysis of a Chinese Han pedigree with holocarboxylase synthetase deficiency: a case report

et al. 2020

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Background: Holocarboxylase synthetase (HLCS) deficiency is a rare inborn disorder of biotin metabolism, which results in defects in several biotin-dependent carboxylases and presents with metabolic ketoacidosis and skin lesions. Case presentation: In this paper, we report a Chinese Han pedigree with HLCS deficiency diagnosed by using next-generation sequencing and validated with Sanger sequencing of the HLCS and BTD genes. The Chinese proband carries the common missense mutation c.1522C > T (p.Arg508Trp) in exon 9 of the HLCS gene, which generates an increased K m value for biotin. A novel frameshift mutation c.1006_1007delGA (p.Glu336Thrfs*15) in exon 6 of the HLCS gene is predicted to be deleterious through PROVEAN and MutationTaster. A novel heterozygous mutation, c.638_642delAACAC (p.His213Profs*4), in the BTD gene is also identified. Conclusions: The Chinese proband carries the reported Arg508Trp variant, the novel 2-bp frameshift mutation c.1006_1007delGA (p.Glu336Thrfs*15), which expands the mutational spectrum of the HLCS gene, and the novel heterozygous mutation c.638_642delAACAC (p.His213Profs*4), which expands the mutational spectrum of the BTD gene. Furthermore, reversible hearing damage is rarely reported in patients with HLCS deficiency, which deserves further discussion.

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Section: Discussioncontrasting

confidence: 99%

Clinical, biochemical, and genetic analysis of a Chinese Han pedigree with holocarboxylase synthetase deficiency: a case report

et al. 2020

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“…As the exact mechanisms for biotin responsiveness have yet to be fully elucidated, an alternative classification is not readily apparent. Our case, in combination with the recent report by Slavin et al (2014), provides evidence that large doses of biotin can ameliorate some symptoms even when the detected mutations suggest severe disruption in the production of a functional protein. These individuals, however, will require closer observation, especially during periods of stress and illness.…”

Section: Discussionsupporting

confidence: 78%

“…In line with this observation, very large doses of biotin (i.e. 1.2 g daily) have been found to ameliorate symptoms in individuals homozygous for the p.L216R variant, a non-K m -variant which causes one of the most severe forms of HLCS deficiency (Slavin et al 2014).…”

Section: Discussionmentioning

confidence: 60%

“…His clinical presentation included tachypnea and poor feeding but no significant skin involvement. Cranial ultrasound also demonstrated subependymal cysts, a finding observed in most reported cases of holocarboxylase deficiency due to the p.L216R pathogenic variant (Wilson et al 2005;Slavin et al 2014). His partial response to high dose biotin (60 mg daily) is evident by the age-appropriate developmental skills and normal physical examination but with persistently elevated lactic acid concentration and abnormal metabolites on urine organic acids.…”

Section: Discussionmentioning

confidence: 76%

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Paracentric Inversion of Chromosome 21 Leading to Disruption of the HLCS Gene in a Family with Holocarboxylase Synthetase Deficiency

et al. 2016

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Holocarboxylase synthetase (HLCS) deficiency is a rare autosomal recessive disorder that presents with multiple life-threatening metabolic derangements including metabolic acidosis, ketosis, and hyperammonemia. A majority of HLCS deficiency patients respond to biotin therapy; however, some patients show only a partial or no response to biotin therapy. Here, we report a neonatal presentation of HLCS deficiency with partial response to biotin therapy. Sequencing of HLCS showed a novel heterozygous mutation in exon 5, c.996G>C (p.Gln332His), which likely abolishes the normal intron 6 splice donor site. Cytogenetic analysis revealed that the defect of the other allele is a paracentric inversion on chromosome 21 that disrupts HLCS. This case illustrates that in addition to facilitating necessary family testing, a molecular diagnosis can optimize management by providing a better explanation of the enzyme's underlying defect. It also emphasizes the potential benefit of a karyotype in cases in which molecular genetic testing fails to provide an explanation.

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“…And the reason is worthy of discussion. Slavin et al have reported a girl with HLCS deficiency presenting conductive hearing loss due to cerumen impaction(7), which is different from the situation of our patient. Otherwise, our patient's hearing impairment has recovered after 43 days of biotin therapy, which is different with the irreversible hearing loss of biotinidase deficiency.…”

contrasting

confidence: 96%

Clinical, biochemical and genetic analysis of a Chinese Han pedigree with holocarboxylase synthetase deficiency: a case report

Zheng

Yuan

Zheng

et al. 2020

Preprint

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Background: Holocarboxylase synthetase (HLCS) deficiency is a rare inborn disorder of biotin metabolism, which results in the defect of several biotin-dependent carboxylases and presents with metabolic ketoacidosis and skin lesions. Case presentation : In this study, we have reported a Chinese Han pedigree with HLCS deficiency diagnosed using next-generation sequencing and validated with Sanger sequencing of HLCS and BTD gene. The Chinese proband carries a common missense mutation c.1522C>T (p.Arg508Trp) in exon 9 of HLCS gene, which generates an increased K m for biotin. A novel frameshift mutation c.1006_1007delGA (p.Glu336Thrfs*15) in exon 6 of H L CS gene produces a low Vmax and is predicted to be deleterious through PROVEAN and MutationTaster. A novel heterozygous mutation c.638_642delAACAC (p.His213Profs*4) in BTD gene is also identified. Otherwise, the proband presents abnormal BAEP suggesting hearing damage in the acute episode. Conclusions: A Chinese proband carries a reported Arg508Trp variant, a novel 2-bp frameshift mutation c.1006_1007delGA (p.Glu336Thr) expanding mutational spectrum of HLCS gene, and a novel heterozygous mutation c.638_642delAACAC (p.His213Profs*4) expanding mutational spectrum of BTD gene. Furthermore, the reversible hearing damage is rarely reported in the patients with HLCS deficiency, which deserves for further discussion.

show abstract

Clinical Presentation and Positive Outcome of Two Siblings with Holocarboxylase Synthetase Deficiency Caused by a Homozygous L216R Mutation

Cited by 11 publications

References 11 publications

Clinical, biochemical, and genetic analysis of a Chinese Han pedigree with holocarboxylase synthetase deficiency: a case report

Clinical, biochemical, and genetic analysis of a Chinese Han pedigree with holocarboxylase synthetase deficiency: a case report

Paracentric Inversion of Chromosome 21 Leading to Disruption of the HLCS Gene in a Family with Holocarboxylase Synthetase Deficiency

Clinical, biochemical and genetic analysis of a Chinese Han pedigree with holocarboxylase synthetase deficiency: a case report

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