Whole exome sequencing reveals compound heterozygous mutations in SLC19A3 causing biotin-thiamine responsive basal ganglia disease

Sremba, Leighann; Chang, Richard Y.; Elbalalesy, Naser; Cambray-Forker, E.J.; Abdenur, José E.

doi:10.1016/j.ymgmr.2014.07.008

Cited by 15 publications

(20 citation statements)

References 11 publications

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“…The follow-up MRI after 1-6 months showed resolved lesions after treatment. Genetic testing in those patients revealed mutation of the SLC19A gene in agreement with Karimzadeh [4], Alabdulqader et al [5], and Sremba et al [7] who reported similar MRI imaging findings and genetic testing results and concluded that the typical MRI finding, lack of clinical improvement, and the clinical suspicion should raise the possibility of BTBGD, so empirical treatment should started.…”

Section: Discussionsupporting

confidence: 73%

“…The disease is characterized by early onset encephalopathy (usually below the age of 4 years). In many case reports, febrile illness preceded the manifestation disease; this febrile illness progresses to severe disability, dystonia, ataxia, seizures, and death if the patients were not treated with biotin and thiamine supplements [4][5][6][7].…”

Section: Introductionmentioning

confidence: 99%

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Reliability of MRI in detection and differentiation of acute neonatal/pediatric encephalopathy causes among neonatal/pediatric intensive care unit patients

Hassan

Mohey

2020

Egypt J Radiol Nucl Med

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Background: Causes of encephalopathy in neonates/pediatrics include hypoxic-ischemic injury (which is the most frequent cause and is defined as any impairment to the brain caused by insufficient blood flow and oxygenation), trauma, metabolic disorders, and congenital and infectious diseases. The aim of this study is to evaluate the value of MRI in detection and possible differentiation of different non-traumatic, non-infectious causes of acute neonatal/ pediatric encephalopathy among NICU/PICU patients. Results: This retrospective study included 60 selected patients according to the study inclusion and exclusion criteria; all presented with positive MRI findings for non-traumatic, non-infectious acute brain injury. Females (32, 53.3%) were affected more than males (28, 46.7%) with a mean age of 1.1 ± 1.02 years; all presented with variable neurological symptoms and signs that necessitate neonatal intensive care unit/pediatric intensive care unit (NICU/ PICU) admission. The final diagnosis of the study group patients were hypoxic ischemia injury (HII) in 39 patients (65%), metachromatic leukodystrophy in 6 patients (10%), biotin-thiamine-responsive basal ganglia disease (BTBGD) and Leigh disease each in 4 patients (6.7%), periventricular leukomalacia (PVL) in 3 patients (5%), and mitochondrial encephalopathy with lactic acidosis and stroke-like episodes syndrome (MELAS) and non-ketotic hyperglycinemia (NKH) each in 2 patients (3.3%). Conclusion: Much attention should be paid to pediatric non-traumatic brain injuries. MRI is a safe modality and should be the first radiological investigation if neurological causes are suggested but should be aided by meticulous clinical evaluation and dedicated laboratory investigations for better characterization and differentiation of various causes of non-traumatic, non-infective brain encephalopathy among NICU/PICU patients. When interpreting MRI, it is essential to have thorough relevant clinical data, gestational age at birth which is prognostic of the pattern of hypoxic-ischemic injury, and the time lag between the onset of HII and the time of performing the MR study.

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Section: Discussionsupporting

confidence: 73%

Section: Introductionmentioning

confidence: 99%

Reliability of MRI in detection and differentiation of acute neonatal/pediatric encephalopathy causes among neonatal/pediatric intensive care unit patients

Hassan

Mohey

2020

Egypt J Radiol Nucl Med

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“…The infantile-onset progressive neurodegeneration and bilateral, symmetrical abnormalities in the basal ganglia found in HIBCH deficiency are typical of Leigh syndrome, which is a genetically and clinically heterogeneous entity [4,20]. In addition to HIBCH, other inborn errors of metabolism, including pyruvate dehydrogenase complex (PDHC) deficiency [8], biotin-thiamine basal ganglia disease [21], pyruvate carboxylase [22,23] and SCEH deficiencies [10], mirror the radiological findings associated with Leigh syndrome. These clinical similarities caused by multiple independent genetic etiologies highlight the importance of comprehensive diagnostic testing, including acylcarnitine analysis, in the clinical work-up of patients presenting with Leigh’s disease.When biochemical investigations are negative or inconclusive, NGS gene panels that include HIBCH or WES may be reasonable approaches.…”

Section: Discussionmentioning

confidence: 99%

Successful diagnosis of HIBCH deficiency from exome sequencing and positive retrospective analysis of newborn screening cards in two siblings presenting with Leigh's disease

Stiles

Ferdinandusse

Besse

et al. 2015

Molecular Genetics and Metabolism

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Purpose 3-hydroxyisobutryl-CoA hydrolase (HIBCH) deficiency is a rare disorder of valine metabolism. We present a family with the oldest reported subjects with HIBCH deficiency and provide support that HIBCH deficiency should be included in the differential for elevated hydroxy-C4-carnitine in newborn screening (NBS). Methods Whole exome sequencing (WES) was performed on one affected sibling. HIBCH enzymatic activity was measured in patient fibroblasts. Acylcarnitines were measured by electrospray ionization tandem mass spectrometry (ESI-MS/MS). Disease incidence was estimated using a cohort of 61,434 individuals. Results Two siblings presented with infantile-onset, progressive neurodegenerative disease. WES identified a novel homozygous variant in HIBCH c.196C>T; p.Arg66Trp. HIBCH enzymatic activity was significantly reduced in patients’ fibroblasts. Acylcarnitine analysis showed elevated hydroxy-C4-carnitine in blood spots of both affected siblings, including in their NBS cards, while plasma acylcarnitines were normal. Estimates show HIBCH deficiency incidence as high as 1 in ~130,000 individuals. Conclusion We describe a novel family with HIBCH deficiency at the biochemical, enzymatic and molecular level. Disease incidence estimates indicate HIBCH deficiency may be under-diagnosed. This together with the elevated hydroxy-C4-carnitine found in the retrospective analysis of our patient’s NBS cards suggests that this disorder could be screened by NBS programs and should be added to the differential diagnosis for elevated hydroxy-C4-carnitine which is already measured in most NBS programs using MS/MS.

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“…5 Most of the patients with this category were unresponsive to biotin and thiamine supplementation and died early. [29][30][31][32][33] However, two reports in the literature showed favorable response to biotin and thiamine administration from this subtype. 5 B. Atypical infantile spasms: In 2010, Yamada et al 6 reported four Japanese patients whom neurological symptoms started to appear at 1 to 2 months and started to have atypical infantile spasms at the age ranging from 2 to 11 months.…”

Section: Metabolic Pathwaymentioning

confidence: 95%

“…22 Patients with the early-onset Leigh-like form suffer from homozygous nonsense mutations, homozygous missense mutations, compound heterozygous deletions or duplications. 5,29,[31][32][33]36 Genotype-phenotype correlations for SLC19A3 gene defects are poor and incomplete. However, it seems that the founder Middle Eastern mutation is associated with the milder phenotype and late onset (i.e., the classical childhood BTBGD form).…”

Section: Geneticsmentioning

confidence: 99%

SLC19A3 Gene Defects Sorting the Phenotype and Acronyms: Review

Alfadhel

Tabarki

2017

Neuropediatrics

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Thiamine metabolism dysfunction syndrome type 2 is also known by other terms including: " gene defect," "biotin-responsive basal ganglia disease" (BBGD), and "biotin-thiamine-responsive basal ganglia disease" (BTBGD). The worldwide incidence and prevalence of this disorder are unknown, but the syndrome has primarily been reported in Saudi Arabia (52% of reported cases). It is caused by a defect in thiamine transporter 2 (hTHTR2), which is encoded by the gene. The clinical presentations of these syndromes are heterogeneous and are likely related to the age of onset. They can be classified into three major categories: classical childhood BBGD; early-infantile Leigh-like syndrome/atypical infantile spasms; and adult Wernicke's-like encephalopathy. These variable phenotypes have common features in that all are triggered by stressors, such as fever, trauma, or vaccinations. Affected brain areas include the basal ganglia, cerebral cortex, thalamus, and periaqueductal regions. Free thiamine is a potential biomarker for diagnosis and monitoring of treatment. Definitive diagnosis is usually made by molecular testing for the gene defect, and treatment consists of thiamine alone or in combination with biotin for life. In this report, we review all reported cases of the gene defect, discuss the history, epidemiology, metabolic pathways, clinical phenotypes, biochemical abnormalities, brain pathology, diagnosis, genetic issues, and treatment of this devastating disorder. Finally, we recommend instituting an international registry to further the basic scientific and clinical research to elucidate multiple unanswered questions about gene syndromes.

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Whole exome sequencing reveals compound heterozygous mutations in SLC19A3 causing biotin-thiamine responsive basal ganglia disease

Cited by 15 publications

References 11 publications

Reliability of MRI in detection and differentiation of acute neonatal/pediatric encephalopathy causes among neonatal/pediatric intensive care unit patients

Reliability of MRI in detection and differentiation of acute neonatal/pediatric encephalopathy causes among neonatal/pediatric intensive care unit patients

Successful diagnosis of HIBCH deficiency from exome sequencing and positive retrospective analysis of newborn screening cards in two siblings presenting with Leigh's disease

SLC19A3 Gene Defects Sorting the Phenotype and Acronyms: Review

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