The SLC5A6 gene encodes a transmembrane protein responsible for transporting biotin, pantothenic acid, and lipoic acid. Mutations in SLC5A6 have shown a wide spectrum of clinical phenotypes, such as sodium-dependent multivitamin transporter deficiency (SMVTD), childhood-onset biotin-responsive peripheral motor neuropathy (COMNB), and mixed axonal and demyelinating sensory motor neuropathy. The purpose of this study was to identify pathogenic SLC5A6 mutations in the Korean CMT cohort. This study performed whole exome sequencing to identify the genetic cause for two independent patients with early onset axonal sensorimotor polyneuropathy and SMVTD. We also examined the therapeutic effects of multivitamin replenishment on a patient with SLC5A6 mutations. We identified compound heterozygous variants of SLC5A6 in two patients (p.Arg94X and p.Phe522Ser in patient 1; p.Cys443Tyr and p.Phe513_Lys515delinsLeu in patient 2). In patient 2, an oral regimen comprising biotin, lipoic acid, and pantothenic acid demonstrated significant therapeutic effects, including cessation of cyclic vomiting, resolution of skin lesions on the fingers, and improvements in muscle weakness affecting both the upper and lower extremities. This study represents the first report of novel heterozygous SLC5A6 mutations in patients with axonal CMT and SMVTD, expanding the phenotypic spectrum associated with SLC5A6 mutations. Notably, we observed significant therapeutic effects from multivitamin treatment in a patient.

In treatable neurometabolic disorders, early diagnosis and prompt initiation of treatment are key to improved survival and outcomes. Biallelic variants in SLC5A6 cause sodium-dependent multivitamin transporter deficiency (OMIM # 618973), which is treatable with high-dose pantothenic acid, biotin, and alpha lipoic acid. So far, the onset has been postnatal in all reported patients. A review of the prenatal imaging showed ventriculomegaly at 32 weeks of gestation. After birth, the infant exhibited developmental regression. At 6 months of age, he developed acute metabolic shock in the setting of a urinary tract infection. Rapid exome analysis identified compound heterozygous pathogenic variants in SLC5A6 and confirmed the diagnosis of sodium-dependent multivitamin transporter deficiency. After the infant was initiated on treatment with high-dose biotin and pantothenic acid, we noted dramatic improvements in the hematological, cutaneous, cardiac, and gastrointestinal symptoms. Although the infant showed no further regression, he continued to have significant psychomotor disability. A review of the findings during pregnancy showed that the infant already had enlarged ventricles in late pregnancy, and neuroimaging on day 12 of birth showed signs of energy failure in late pregnancy. Our review of previously reported patients suggested no clear genotype-phenotype correlations, but there was little intrafamilial variability in disease onset. The present observation, for the first time, provides clinical evidence of a fetal onset in sodium-dependent multivitamin transporter deficiency. The high risk of recurrence and the low intrafamilial variability in disease onset suggest that identification and prenatal treatment in the high-risk group may be of significance.

The sodium-dependent multivitamin transporter (SMVT) is a ubiquitously expressed sodium-solute symporter that transports pantothenic acid, biotin, and α-lipoic acid across the intestinal epithelia and blood-brain barrier. Severe biallelic loss-of-function variants in SLC5A6 (MIM #604024) lead to SMVT deficiency (SMVTD, MIM #618973), which classically presents with developmental delay, brain atrophy, epilepsy, sensorineural hearing loss, peripheral neuropathy, and gastrointestinal, cutaneous, and immunologic abnormalities. We describe a 25-year-old female with autism spectrum disorder (ASD), intellectual disability, agenesis of the corpus callosum (ACC), and epilepsy who presented at 15 years of age with a severe metabolic crisis characterized by hyperammonemia, lactic acidosis, and rhabdomyolysis. Trio exome sequencing (ES) identified compound heterozygous variants in SLC5A6 . Plasma untargeted metabolomics analysis demonstrated reduced pantothenate and coenzyme A with elevated long-chain fatty acids, indicating impaired fatty acid oxidation, functionally validating ES results, and confirming a diagnosis of SMVTD. Targeted replacement with biotin, lipoic acid, and pantothenic acid improved her neurocognitive function and metabolic control. Our patient, the oldest reported at diagnosis, expands the phenotype of SMVTD to include rhabdomyolysis, ACC, and ASD. Our study suggests that integrating ES and untargeted metabolomics in undiagnosed patients with suspected inborn errors of metabolism may help identify this ultra-rare disorder.

This case report describes a 3-year-old girl who presented with progressive pruritic, palmoplantar plaques, and periorifical exudative erythema who experienced hair loss, recurrent episodes of pneumonia, and transient thrombocytopenia.

SLC5A6 encodes the sodium-dependent multivitamin transporter, a transmembrane protein that uptakes biotin, pantothenic acid, and lipoic acid. Biallelic SLC5A6 variants cause sodium-dependent multivitamin transporter deficiency (SMVTD) and childhood-onset biotin-responsive peripheral motor neuropathy (COMNB), which both respond well to replacement therapy with the above three nutrients. SMVTD usually presents with various symptoms in multiple organs, such as gastrointestinal hemorrhage, brain atrophy, and global developmental delay, at birth or in infancy. Without nutrient replacement therapy, SMVTD can be lethal in early childhood. COMNB is clinically milder and has a later onset than SMVTD, at approximately 10 years of age. COMNB symptoms are mostly limited to peripheral motor neuropathy. Here we report three patients from one Japanese family harboring novel compound heterozygous missense variants in SLC5A6, namely NM_021095.4:c.[221C>T];[642G>C] p.[(Ser74Phe)];[(Gln214His)]. Both variants were predicted to be deleterious through multiple lines of evidence, including amino acid conservation, in silico predictions of pathogenicity, and protein structure considerations. Drosophila analysis also showed c.221C>T to be pathogenic. All three patients had congenital brain cysts on neonatal cranial imaging, but no other morphological abnormalities. They also had a mild motor developmental delay that almost completely resolved despite no treatment. In terms of severity, their phenotypes were intermediate between SMVTD and COMNB. From these findings we propose a new SLC5A6-related disorder, spontaneously remitting developmental delay with brain cysts (SRDDBC) whose phenotypic severity is between that of SMVTD and COMNB. Further clinical and genetic evidence is needed to support our suggestion.