Sodium-dependent multivitamin transporter deficiency

What is sodium-dependent multivitamin transporter deficiency?

Sodium-dependent multivitamin transporter (SMVT) deficiency is a very rare, multisystem, genetic disorder. It results from impaired uptake of three essential nutrients: biotin (vitamin B7), pantothenic acid (vitamin B5), and α-lipoic acid (lipoate).

SMVT deficiency often presents with characteristic skin changes, including dermatitis, keratoderma, alopecia, and nail changes. It was first described in 2017 and can be classified as a vitamin-responsive inborn error of metabolism.

Who gets sodium-dependent multivitamin transporter deficiency?

SMVT deficiency is exceedingly rare, with only a few cases reported worldwide. It follows an autosomal recessive inheritance pattern, meaning individuals must inherit two defective SLC5A6 gene copies to develop the condition.

Symptoms usually become apparent shortly after birth, though its rarity can delay diagnosis. The age at diagnosis has been reported to range from 19 months to 20 years.

What causes sodium-dependent multivitamin transporter deficiency?

Biallelic pathogenic variants in the SLC5A6 gene, located on chromosome 2p23.3, result in a defective sodium-dependent multivitamin transporter. SMVT is a transmembrane protein expressed throughout the body that facilitates the uptake of essential vitamins biotin (B7) and pantothenic acid (B5), as well as α-lipoic acid, particularly in the gastrointestinal tract and across the blood-brain barrier.

SMVT deficiency therefore leads to impaired intestinal absorption and intracellular deficiencies of those substrates, which are critical to normal metabolism and development.

• Biotin: involved in various metabolic pathways eg, gluconeogenesis, amino acid catabolism, and fatty acid synthesis. Defective fatty acid synthesis disrupts skin barrier formation and contributes to characteristic dermatoses (Also see: Biotin responsive dermatoses).
• Pantothenic acid: precursor to Coenzyme A, which is essential to the Krebs cycle and fatty acid metabolism.
• α-Lipoic acid: cofactor in mitochondrial energy production with anti-inflammatory and antioxidant properties; deficiency is associated with reduced bone density and neurological disorders.
• Iodide: SMVT can also transport iodide, but its role in iodide homeostasis remains poorly understood.

What are the clinical features of sodium-dependent multivitamin transporter deficiency?

Sodium-dependent multivitamin transporter deficiency presents variably across individuals with a broad phenotypic spectrum.

Cutaneous Features

Cutaneous features of SMVT deficiency resemble other biotin-responsive dermatoses and may include:

• Dermatitis: exudative, well-demarcated erythematous rash, typically in a periorificial distribution (around the mouth, eyes, and genitals)
• Diffuse alopecia
• Palmoplantar keratoderma; associated tapering and flexion contractions of the fingers
• Angular cheilitis
• Brittle nails.

Non-cutaneous features

• Neurological features: peripheral neuropathy, ataxia, seizures, optic atrophy, microcephaly, and global developmental delays.
• Gastrointestinal symptoms: severe early-onset feeding problems with chronic diarrhoea, cyclic vomiting, and gastro-oesophageal reflux.
• Other: immunodeficiency (hypogammaglobulinemia), osteopenia, osteoporosis, and cardiac dysfunction.

SMVT presentation across different Fitzpatrick skin types is unclear due to limited data.

What are the complications of sodium-dependent multivitamin transporter deficiency?

• Recurrent infections
• Failure to thrive and growth retardation
• Permanent neurological impairment
• Pathologic fractures
• Gastrointestinal haemorrhage
• Metabolic crises (eg, acute metabolic acidosis, hypoglycaemia, hyperammonaemia), typically precipitated by an infection or other stressor
• Cardiac failure

How is sodium-dependent multivitamin transporter deficiency diagnosed?

The combination of neurological, gastrointestinal, dermatological, and other systemic features in an infant or child should prompt consideration of SMVT deficiency. If suspected, an initial screen for inborn errors of metabolism should be performed with readily available tests, such as:

• Blood glucose
• Blood gas analysis
• Serum lactate and ammonia
• Urinalysis, including ketones.

Abnormal screening results should be followed by consultation with a paediatric metabolic specialist and specialised testing:

• Qualitative urine organic acids
  • Increased excretion of 3-hydroxyisovaleric acid (3-HIA), a sensitive predictor of biotin deficiency that is elevated in both SMVT deficiency and biotinidase deficiency
• Blood tests
  • Abnormal plasma acylcarnitines profile
  • Low serum levels of biotin, pantothenic acid, and lipoate
  • Normal or only marginally decreased biotinidase activity — markedly low activity would indicate a biotinidase deficiency.

A positive response to high-dose supplementation of biotin and pantothenic acid is indicative of the diagnosis. A definitive diagnosis is made by identifying biallelic mutations of the SLC5A6 gene through genetic sequencing.

What is the differential diagnosis for sodium-dependent multivitamin transporter deficiency?

• Inborn errors of biotin metabolism ie, biotinidase deficiency and holocarboxylase synthetase deficiency
• Acquired biotin deficiency
• Acrodermatitis enteropathica (inherited zinc deficiency)
• Acrodermatitis dysmetabolica (acrodermatitis enteropathica-like eruption associated with metabolic disorders)
• Acquired zinc deficiency
• Fatty acid oxidation disorders
• Essential fatty acid deficiency
• Pellagra (vitamin B3 deficiency)
• Leiner disease
• Psoriasis
• Atopic eczema
• Seborrhoeic dermatitis
• Other inborn errors of metabolisms eg, biotin-thiamine-responsive basal ganglia disease

What is the treatment for sodium-dependent multivitamin transporter deficiency?

Sodium-dependent multivitamin transporter deficiency is responsive to high-dose supplementation of biotin and pantothenic acid, leading to clinically significant improvements.

At high concentrations, these nutrients may enter cells via simple diffusion, partially compensating for the defective SMVT. Lipoate may also be supplemented, though its necessity remains unclear.

If SMVT deficiency is suspected, vitamin supplementation should begin immediately without awaiting genetic confirmation.

How do you prevent sodium-dependent multivitamin transporter deficiency?

There are no primary prevention strategies due to the genetic nature of the disease. Couples with an affected child and identified SLC5A6 mutations may be offered pre-implantation genetic testing for subsequent pregnancies.

What is the outcome for sodium-dependent multivitamin transporter deficiency?

Without treatment, sodium-dependent multivitamin transporter deficiency is a genetic disorder that can lead to irreversible neurological damage and early demise. Early diagnosis and supplementation can resolve most symptoms and prevent complications, allowing individuals to lead relatively normal lives. Lifelong supplementation and monitoring are key to improved outcomes.