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Molecular Genetics & Genomic Medicine Feb 2024Biallelic pathogenic variants in SLC5A6 resulting in sodium-dependent multivitamin transporter (SMVT) defect have recently been described as a vitamin-responsive inborn... (Review)
Review
A new case of sodium-dependent multivitamin transporter defect occurring as a life-threatening condition responsive to early vitamin supplementation and literature review.
BACKGROUND
Biallelic pathogenic variants in SLC5A6 resulting in sodium-dependent multivitamin transporter (SMVT) defect have recently been described as a vitamin-responsive inborn error of metabolism mimicking biotinidase deficiency. To our knowledge, only 16 patients have been reported so far with various clinical phenotypes such as neuropathy and other neurologic impairments, gastro-intestinal dysfunction and failure to thrive, osteopenia, immunodeficiency, metabolic acidosis, hypoglycemia, and recently severe cardiac symptoms.
METHODS
We describe a case report of a 5-month-old girl presenting two recurrent episodes of metabolic decompensation and massive cardiac failure in the course of an infectious disease. We compare clinical, biological, and genetic findings of this patient to previous literature collected from Pubmed database (keywords: Sodium-dependent multivitamin transporter (SMVT), SMVT defect/disorder/deficiency, SLC5A6 gene/mutation).
RESULTS
We highlight the life-threatening presentation of this disease, the stagnation of psychomotor development, the severe and persistent hypogammaglobulinemia, and additionally, the successful clinical response on early vitamin supplementation (biotin 15 mg a day and pantothenic acid 100 mg a day). Metabolic assessment showed a persistent increase of urinary 3-hydroxyisovaleric acid (3-HIA) as previously reported in this disease in literature.
CONCLUSION
SMVT deficiency is a vitamin-responsive inborn error of metabolism that can lead to a wide range of symptoms. Increased and isolated excretion of urinary 3-hydroxyisovaleric acid may suggest, in the absence of markedly reduced biotinidase activity, a SMVT deficiency. Prompt supplementation with high doses of biotin and pantothenic acid should be initiated while awaiting results of SLC5A6 sequencing as this condition may be life-threatening.
Topics: Female; Humans; Infant; Biotin; Pantothenic Acid; Vitamins; Dietary Supplements; Sodium; Valerates
PubMed: 38407570
DOI: 10.1002/mgg3.2388 -
Molecular Genetics and Metabolism... Mar 2024Diagnosis of Biotinidase deficiency (BTD) is extremely important to avoid several neurodevelopmental problems in early childhood. Colorimetric and fluorometric methods...
Accurate determination of Biotinidase activity in serum by HPLC and its utilization as second tier test for the confirmation of initial positive newborn screening results.
Diagnosis of Biotinidase deficiency (BTD) is extremely important to avoid several neurodevelopmental problems in early childhood. Colorimetric and fluorometric methods lack specificity and selectivity due to several interferences resulting in a high number of false positive results. We developed an HPLC method for BTD activity in serum with fluorescent detection. In colorimetric assays, biotinidase attacks the amide linkage of the artificial substrate biotinidyl-4-aminobenzoic acid (B-PABA) and releases -aminobenzoic acid (PABA), which is converted to a purple dye by diazotization reaction. The newly developed method injects the reaction mixture directly into the HPLC column and quantifies using a six-point calibration curve without coupling and diazotization reaction. The method is linear over the 5-1000 μmol/L range. The detection and quantitation limits were 2.5 μmol/L and 5.0 μmol/L, respectively. When compared with colorimetric assay, the correlation coefficient (R) was 0.9963. The within-assay and between-assay precision was <10.0% for four levels of quality control samples. No significant variation in BTD activity was detected due to hemolysis, icteric, and lipemic samples. The newly developed method eliminates the potential interference due to the presence of aromatic amines and significantly reduces the false positive results observed with the colorimetric method. It is simple, specific, sensitive, faster in sample preparation, and requires a small sample volume. The newly developed HPLC method was used in our laboratory as a secondary tier test for initial positive BTD samples from newborn screening programs. To our knowledge, no similar HPLC method has been reported to date.
PubMed: 38221916
DOI: 10.1016/j.ymgmr.2023.101045 -
Brain Communications 2023In this study, we have evaluated the underlying aetiologies, yield of genetic testing and long-term outcomes in patients with early-infantile developmental and epileptic...
In this study, we have evaluated the underlying aetiologies, yield of genetic testing and long-term outcomes in patients with early-infantile developmental and epileptic encephalopathies. We have prospectively studied patients with seizure onset before 3 months of age. Based on the clinical details, neuroimaging, metabolic testing and comprehensive genetic evaluation, patients were classified into different aetiological groups. The phenotypic differences between genetic/unknown groups and remaining aetiologies were compared. Factors that could affect seizure control were also assessed. A total of 80 children (M:F ratio-1.5:1) were recruited. The median seizure onset age was 28 days (range, 1-90 days). The aetiologies were confirmed in 66 patients (83%). The patients were further classified into four aetiological groups: genetic (50%), structural (19%), metabolic (14%; all were vitamin responsive) and unknown (17%). On comparing for the phenotypic differences between the groups, children in the 'genetic/unknown' groups were more frequently observed to have severe developmental delay (Odds Ratio = 57; < 0.0001), autistic behaviours (Odds Ratio = 37; < 0.0001), tone abnormalities (Odds Ratio = 9; = 0.0006) and movement disorder (Odds Ratio = 19; < 0.0001). Clonic seizures were more common in the vitamin responsive/structural groups (Risk Ratio = 1.36; = 0.05) as compared to patients with 'genetic/unknown' aetiologies. On the contrary, vitamin responsive/structural aetiology patients were less likely to have tonic seizures (Risk Ratio = 0.66; = 0.04). Metabolic testing was diagnostic in three out of 41 patients tested (all three had biotinidase deficiency). MRI was abnormal in 35/80 patients (malformation observed in 16/35; 19/35 had non-specific changes that did not contribute to underlying aetiology). A molecular diagnosis was achieved in 53 out of 77 patients tested (69%). Next-generation sequencing had a yield of 51%, while microarray had a yield of 14%. was the most common (five patients) single-gene defect identified. There were 24 novel variants. The mean follow-up period was 30 months (range, 4-72 months). On multivariate logistic regression for the important factors that could affect seizure control (seizure onset age, time lag of first visit to paediatric neurologist and aetiologies), only vitamin responsive aetiology had a statistically significant positive effect on seizure control ( = 0.02). Genetic aetiologies are the most common cause of early-infantile developmental and epileptic encephalopathies. Patients in the genetic/unknown groups had a more severe phenotype. Patients with vitamin responsive epilepsies had the best probability of seizure control.
PubMed: 38074073
DOI: 10.1093/braincomms/fcad243 -
Clinical Immunology (Orlando, Fla.) Dec 2023We characterized a family diagnosed with immunodeficiency disease presenting with low immunoglobulin levels and skin dyskeratosis. Exome sequencing revealed compound...
We characterized a family diagnosed with immunodeficiency disease presenting with low immunoglobulin levels and skin dyskeratosis. Exome sequencing revealed compound heterozygous missense variants in SLC5A6, the gene encoding a cellular sodium-dependent multivitamin transporter (SMVT) responsible for transporting vitamins, including biotin (vitamin B7). We showed that the biotin deficiency was caused by the SLC5A6 variants resulting in defective B cell differentiation and antibody deficiency. Altered cellular metabolic profiles, including aberrant mitochondrial respiration and reliance on glycolysis, may underlie the failure in plasma cell maturation. Replenishment of biotin improved plasma cell maturation and recovered the antibody producing activity in the patient and in a CRISPR-Cas9 gene-edited mouse model bearing a patient-specific SLC5A6 variant. Our results demonstrate the critical role of metabolic reprogramming in the maturation of plasma cells and nominate SLC5A6 as a causative gene for immunodeficiency that may be treated by biotin replenishment.
Topics: Animals; Humans; Mice; B-Lymphocytes; Biotin; Biotinidase Deficiency; Mutation
PubMed: 38036278
DOI: 10.1016/j.clim.2023.109855 -
Annals of Indian Academy of Neurology 2023
PubMed: 38022461
DOI: 10.4103/aian.aian_697_23 -
ACS Omega Oct 2023Biotinidase deficiency (BD) is an autosomal recessive inherited disorder of biotin recycling that leads to neurological and cutaneous consequences if left untreated. The...
Biotinidase deficiency (BD) is an autosomal recessive inherited disorder of biotin recycling that leads to neurological and cutaneous consequences if left untreated. The clinical features of BD can be ameliorated or prevented by the administration of pharmacological doses of the vitamin biotin. Since it is a treatable disorder, BD is included in the newborn screening program in Türkiye as in many other countries. Therefore, monitoring of biotinidase enzyme activity (BEA) is of vital importance, especially for patients. The aim of this study was to develop a simple and reliable colorimetric method based on digital imaging for the analysis of BEA in serum samples. To determine the optimum distance and LED light source in the analyzer box that we fabricated in the laboratory, images of the solutions in a 96-well microplate were taken with a mobile phone camera, and each color space was examined. The most reliable relationship was between blank subtracted intensities of green channel and analyte concentrations, which was in the range of 35-400 ng/mL -aminobenzoic acid ( = 0.999). The limit of detection and limit of quantification were 11 and 35 ng/mL, respectively. The proposed method was successfully applied to serum samples of 60 patients with BD and 60 healthy controls. We claim that the method can be easily performed for determination of BEA anywhere without needing expensive instruments.
PubMed: 37901531
DOI: 10.1021/acsomega.3c05759 -
Genes Oct 2023Whole-exome DNA sequencing is a rich source of clinically useful information for specialists, patients, and their families, as well as elucidating the genetic basis of...
Whole-exome DNA sequencing is a rich source of clinically useful information for specialists, patients, and their families, as well as elucidating the genetic basis of monogenic and complex diseases in clinical diagnosis. However, interpreting and reporting variants encompassing exome and genome sequence analysis outcome data are one of the greatest challenges of the genomic era. In this study, we aimed to investigate the frequency and allele frequency spectrum of single nucleotide variants accepted as recessive disease carrier status in Turkish Cypriot exomes. The same sequencing platform and data processing line were used for the analysis of data from 100 Turkish Cypriot whole-exome sequence analysis. Identified variants were classified according to ACMG guidelines, and pathogenic variants were confirmed in other databases such as ClinVar, HGMD, Varsome, etc. Pathogenic variants were detected in 68 genes out of 100 whole-exome sequence data. The carriage rate was the highest in the gene, causing 21-hydroxylase deficiency (14.70%), 11.76% in the gene causing β-thalassemia, 10.29% in the gene causing biotinidase deficiency, 8.82% in the gene causing cystic fibrosis, 8.82% in the gene causing thrombocytopenia-absent radius syndrome, which is an ultra-rare disease, and 5.88% in the gene causing glycogen storage disease II. The carriage of pathogenic variants in other genes causing the disease (, , , , , , etc.) was determined as less than 5.00%. Also, the identified variations in the mentioned gene within the examined population were reported. The most prevalent mutation in North Cyprus was a missense variant (c.1360 C>T, p.Pro454Ser) detected in the gene (rs6445), and the most frequently seen variant in the gene was c.93-21G>A (rs35004220). We investigated reported pathogenic variants by estimating the lower and upper limits of carrier and population frequencies for autosomal recessive diseases, for which exome sequencing may reveal additional medically relevant information. Determining the lower and upper limits of these frequencies will shed light on preventive medicine practices and governmental actions.
Topics: Humans; Mutation; Gene Frequency; Genomics; Adrenal Hyperplasia, Congenital; Cystic Fibrosis; Steroid 21-Hydroxylase
PubMed: 37895316
DOI: 10.3390/genes14101967 -
Bioinformation 2022The process of testing newborn infants for hormonal, genetic, metabolic, and other disorders is known as newborn screening (NSB). Newborn screening is essential for...
The process of testing newborn infants for hormonal, genetic, metabolic, and other disorders is known as newborn screening (NSB). Newborn screening is essential for detecting, diagnosing, and treating disorders that could save serious consequences for a newborn's health. Congenital Hypothyroidism (CH), Cystic Fibrosis (CF), Glucose-6-phosphate dehydrogenase (G6PD) deficiency, and Profound Biotinidase deficiency (BD) are common disorders in India. A retrospective analysis of the results of NBS by Cord blood spots was performed at the department of Obstetrics and Gynecology, 7 Airforce Hospital, Kanpur, Uttar Pradesh, from June 2022 to September 2022. During this period, 26 newborns were screened for four disorders, including CH, CF, G6PD deficiency, and BD. In this investigation, no cases of CH, CF, G6PD deficiency, or BD were found to be positive. The results of the current data provide a distinct opportunity to investigate the birth prevalence of inborn metabolic disorders in the area close to the city of Kanpur.
PubMed: 37701517
DOI: 10.6026/973206300181122 -
Revista Paulista de Pediatria : Orgao... 2023To evaluate quality indicators of the Neonatal Screening Referral Service of the state of Mato Grosso (NSRS-MT) from 2005 to 2019. (Observational Study)
Observational Study
OBJECTIVE
To evaluate quality indicators of the Neonatal Screening Referral Service of the state of Mato Grosso (NSRS-MT) from 2005 to 2019.
METHODS
Cross-sectional, retrospective, exploratory, descriptive, and observational study from 2005 to 2019. The following parameters were analyzed: age of newborns at the first collection, time between sample collection and arrival at the laboratory, time between the arrival and release of results and time between requesting the second sample and arrival at the NSRS. The population coverage of the program and the incidence of each clinical situation screened were also analyzed.
RESULTS
NSRS-MT coverage was analyzed and recorded as 76%. The incidence was analyzed for congenital hypothyroidism (CH) 1:1867, phenylketonuria (PKU) 1:33,311, sickle cell disease (SCD) 1:2004, cystic fibrosis (CF) 1:12,663, congenital adrenal hyperplasia (CAH) 1:15,843, and biotinidase deficiency (DB) 1:25,349. The median age (days) at the first consultation was: 44 for HC, 22 for PKU, 60 for DF, 52 for FC, 79 for HAC and 79 for DB. The mean time between exam collection and delivery to the NSRS was 8.4 days; between the arrival and release of results, 9 days; and for the return of recalls, 59 days.
CONCLUSIONS
Regarding the coverage of the target population and collection at the ideal age, the NSRS-MT presents values below the national average. However, regarding the mean age at the time of the first consultation, the state's performance is better than the national.
Topics: Infant, Newborn; Humans; Neonatal Screening; Cross-Sectional Studies; Retrospective Studies; Phenylketonurias; Anemia, Sickle Cell
PubMed: 37646746
DOI: 10.1590/1984-0462/2024/42/2022161 -
Advanced Biomedical Research 2023Biotinidase deficiency is a rare autosomal recessive neurometabolic disorder resulting in biotin deficiency. Our patient presented with seizures and developmental delay...
Biotinidase deficiency is a rare autosomal recessive neurometabolic disorder resulting in biotin deficiency. Our patient presented with seizures and developmental delay since infancy and was started on megavitamin supplements. At 14 years, she presented with motor regression with encephalopathy after discontinuation of vitamins. There were no skin and hair changes. Magnetic resonance imaging (MRI) of the brain showed bilateral symmetrical posterior putamen signal changes. Tandem mass spectroscopy showed increased methyl malonyl carnitine and 3-OH isovaleryl carnitine. There was a low biotinidase level, and a pathogenic variant in the gene in the next-generation sequencing was identified. Special importance is placed on the unusual symmetric posterior putamen involvement seen in MRI of the brain.
PubMed: 37564434
DOI: 10.4103/abr.abr_98_22