SLC5A6 – Infantile-Onset Biotin-Responsive Neurodegeneration

Biallelic pathogenic variants in SLC5A6 cause Neurodegeneration, infantile-onset, biotin-responsive (SMVT deficiency), an autosomal recessive disorder characterized by early-onset neurodevelopmental arrest, metabolic crises, and multisystem involvement. To date, 10 affected individuals from 8 unrelated pedigrees have been reported (PMID:35217562; PMID:39898461; PMID:40396389; PMID:31754459; PMID:38816490). Experimental data uniformly demonstrate loss-of-function through impaired biotin uptake or mis-splicing, supporting a null mechanism. Collectively, these data support a Strong gene–disease association.

Inheritance is autosomal recessive with compound heterozygous or homozygous variants identified in all cases. Segregation analysis in two pedigrees showed concordant genotype–phenotype co-segregation in two affected siblings (PMID:31754459) and an affected uncle (PMID:38816490).

Clinical case series and single-patient reports describe a spectrum of compound heterozygous splice-site, nonsense, frameshift, and missense variants. The recurrent nonsense allele c.280C>T (p.Arg94Ter) exemplifies a canonical LoF variant seen in multiple unrelated cases (PMID:27904971; PMID:31754459). Other examples include c.1005+1G>A and c.1865_1866del (p.Gln622fs) in infants presenting with failure to thrive and metabolic acidosis (PMID:35217562), and missense variants c.1328G>A (p.Cys443Tyr) and c.1565T>C (p.Phe522Ser) in neuropathy cases with SMVT deficiency (PMID:40396389).

Functional assays demonstrate that truncating mutants (e.g., p.Arg94Ter, p.Gln277Ter) severely disrupt 3H-biotin uptake in human intestinal and neural cell lines (PMID:27904971; PMID:31754459). Splicing assays revealed that c.393+2C>T induces mis-splicing and ~50% SMVT mRNA reduction with ~90% loss of biotin transport in patient fibroblasts (PMID:38816490).

No studies have refuted this relationship, although milder intermediate phenotypes (e.g., spontaneously remitting developmental delay with brain cysts) have been proposed. Integration of robust genetic segregation, diverse LoF variant classes with functional validation, and consistent clinical response to targeted multivitamin therapy establishes a strong association between SLC5A6 and infantile-onset biotin-responsive neurodegeneration. Key take-home: Early molecular diagnosis of SLC5A6 deficiency enables timely initiation of biotin, pantothenate, and lipoate therapy to mitigate neurodegeneration and metabolic crises.

References

• Cold Spring Harbor molecular case studies • 2022 • A mild case of sodium-dependent multivitamin transporter (SMVT) deficiency illustrating the importance of treatment response in variant classification. PMID:35217562
• American journal of medical genetics. Part A • 2025 • Expanded Clinical Phenotype and the Role of Untargeted Metabolomics Analysis in Confirming the Diagnosis of Sodium-Dependent Multivitamin Transporter Deficiency. PMID:39898461
• Journal of the peripheral nervous system : JPNS • 2025 • SLC5A6 Mutations in Axonal Sensorimotor Polyneuropathy Patients Concurrent With Sodium Dependent Multivitamin Transporter Deficiency and Improved Effects by Multivitamin Therapy. PMID:40396389
• Human genetics • 2017 • Mutations in SLC5A6 associated with brain, immune, bone, and intestinal dysfunction in a young child. PMID:27904971
• NPJ genomic medicine • 2019 • Identification and targeted management of a neurodegenerative disorder caused by biallelic mutations in SLC5A6. PMID:31754459
• European journal of human genetics : EJHG • 2024 • Genome sequencing enables diagnosis and treatment of SLC5A6 neuropathy. PMID:38816490

Evidence Based Scoring (AI generated)