Genetic defect of the sodium‐dependent multivitamin transporter: A treatable disease, mimicking biotinidase deficiency

Abstract

The sodium‐dependent multivitamin transporter that facilitates the uptake of the water‐soluble vitamins biotin, pantothenic acid, and the vitamin‐like substance lipoate is coded by the SLC5A6 gene. Variants in this gene cause a relatively novel treatable metabolic disorder. Here we describe the second case. A 17‐month‐old girl presented with hypoglycemia (2.0 mmol/L) and severe metabolic acidosis (pH 6.87), leading to resuscitation. Her history revealed feeding problems from birth and poor weight gain. Metabolic investigation showed elevated plasma C3‐carnitine and C5‐OH‐carnitine. Urine analysis showed persistently elevated excretion of 3‐OH‐isovaleric acid. Biochemically, the combination of elevated C5‐OH‐carnitine and increased excretion of 3‐OH‐isovaleric acid seemed compatible with biotinidase deficiency. Supplementation with biotin was started. Biotinidase activity in plasma showed only marginally decreased activity, which was considered insufficient explanation for her clinical symptoms. Subsequent trio‐based whole exome sequencing revealed compound heterozygosity for variants in the SLC5A6 gene. Upon increasing the dosage of biotin supplementation and introduction of pantothenic acid supplementation, a striking clinical improvement was seen.

Novel biallelic variants expand the SLC5A6-related phenotypic spectrum

“…In retrospect, this patient likely had biallelic SLC5A6 variants although SLC5A6 cDNA sequencing did not reveal variants affecting function [ 20 ]. A previously reported patient with biallelic SLC5A6 variants had a severe metabolic crisis with encephalopathy [ 10 ]. These data suggest that patients carrying biallelic SLC5A6 variants with a severe impact on SMVT function can present with a state of precarious biotin homeostasis that can lead to life-threatening metabolic crises.…”

“…Biotin and pantothenic acid supplementation rescued the phenotype [ 23 ]. Two previously reported patients with biallelic SLC5A6 variants also showed failure to thrive [ 9 , 10 ] and triple vitamin replacement therapy, likely via a simple diffusion mechanism, had beneficial effects in the three live patients [ 9 – 11 ]. In our cohort, patient 2–1 showed unequivocal improvement with vitamin therapy; the patients in families 1 and 3 did not show consistent improvements, indicating that responses to vitamin therapy are not uniform.…”

“…Four of the nine patients with biallelic SLC5A6 variants reported to date (including the current cohort) carry early nonsense or frameshift variants together with a missense variant [ 9 , 11 ]. One patient has an early frameshift in combination with a late frameshift variant [ 10 ], and four patients reported here are homozygous for the same missense variant. Is there any possible correlation between genotypes and phenotypes?…”

“…A 3-year-old girl with compound heterozygous SLC5A6 p.(Val141Alafs*34) and p.(Gln622Argfs*51) variants had failure to thrive and delayed motor development in infancy. At 17 months, she developed a severe metabolic crisis with hypoglycemia during gastroenteritis requiring resuscitation [ 10 ]. Two siblings with c.422_423del and c.1199 G > C/p.…”

Effect of chronic alcohol exposure on gut vitamin B7 uptake: involvement of epigenetic mechanisms and effect of alcohol metabolites

“…In recent years, evidence has mounted showing functions for biotin beyond its role as cofactor, including regulation of immune response (2)(3)(4)(5)(6), gene expression (7)(8)(9), and mitochondrial function (10). Biotin deficiency and suboptimal levels occur in a variety of conditions including chronic alcoholism (11), IBD (12,13), in patients with mutations in the SLC5A6 gene and other inborn errors of biotin metabolism (14)(15)(16)(17), and those on long-term therapy with certain anticonvulsant drugs (18,19). Biotin deficiency leads to a variety of clinical abnormalities including immune dysfunction and cutaneous and neurological features (19)(20)(21).…”