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Mappings

MONDO

MONDO:0859255 peripheral motor neuropathy, childhood-onset, biotin-responsive Not Yet Curated

MONDO:0859255 (OMIM:619903) is the mild, childhood-onset motor neuropathy end of the SLC5A6 spectrum, so it is narrower than this gene-level entry. It is curated here as the COMNB subtype. MONDO has no class covering the whole SLC5A6 spectrum.

MONDO:0033546 neurodegeneration, infantile-onset, biotin-responsive Not Yet Curated

MONDO:0033546 (OMIM:618973, Orphanet:521268) is the severe, infantile-onset multisystem end of the SLC5A6 spectrum, so it is narrower than this gene-level entry. It is curated here as the NERIB subtype.

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Inheritance

1

Autosomal recessive HP:0000007

All reported patients carry biallelic SLC5A6 variants, either homozygous (often in consanguineous families, as with p.(Ser429Gly) and the Maghreb intronic founder variant) or compound heterozygous, and parents tested are unaffected heterozygous carriers.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:35013551 SUPPORT Human Clinical

"Sanger sequencing confirmed the homozygous SLC5A6 variant in patients 1–1, 1–2, and 1–3, and also confirmed that each asymptomatic parent harbored the heterozygous variant"

Homozygous affected siblings with unaffected heterozygous parents is the recessive segregation pattern.

PMID:38348452 SUPPORT Human Clinical

"All patients, born form consanguineous parents, were homozygous carriers of the same intronic variation, outside of canonical sites, in the SLC5A6 gene encoding SMVT."

Homozygosity in consanguineous families supports recessive inheritance.

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Subtypes

3

Infantile-onset multisystem SMVT deficiency (NERIB) MONDO:0033546

The severe end of the spectrum and the first form described. Onset is at birth or in infancy, occasionally with prenatal ventriculomegaly, and disease is multisystem: failure to thrive, developmental delay or regression, seizures, brain atrophy, gastrointestinal hemorrhage, reflux and pseudo-obstruction, hypogammaglobulinemia and recurrent infections, osteopenia, metabolic acidosis with hypoglycemia, and cardiac failure in some infants. Untreated siblings have died in early childhood. Reported genotypes usually pair a null allele with a functionally impaired allele.

Show evidence (3 references)

PMID:38012394 SUPPORT Human Clinical

"SMVTD usually presents with various symptoms in multiple organs, such as gastrointestinal hemorrhage, brain atrophy, and global developmental delay, at birth or in infancy."

Defines the multisystem infantile-onset presentation of the severe subtype.

PMID:38012394 SUPPORT Human Clinical

"Without nutrient replacement therapy, SMVTD can be lethal in early childhood."

Records the lethality of the untreated severe subtype.

PMID:27904971 SUPPORT Human Clinical

"This is the first reporting of mutations in the SLC5A6 gene in man"

The founding case of the gene-disease relationship was an infant with multisystem disease.

Childhood-onset biotin-responsive peripheral motor neuropathy (COMNB) MONDO:0859255

The mild end of the spectrum. After normal early development, distal upper limb weakness with thenar, hypothenar and interosseous wasting begins at about 6 to 13 years, sometimes with distal leg weakness, absent ankle reflexes and gait difficulty. Nerve conduction findings are pleomorphic, with axonal and demyelinating features and sometimes asymmetry. The recurrent homozygous missense allele p.(Ser429Gly) accounts for most reported cases. A few patients also had dilated cardiomyopathy, premature hair graying or mild cerebellar and pyramidal signs.

Show evidence (2 references)

PMID:38012394 SUPPORT Human Clinical

"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."

Defines the mild subtype by onset age and restriction to motor neuropathy.

PMID:35013551 SUPPORT Human Clinical

"We expand the phenotypic spectrum associated with biallelic SLC5A6 variants affecting function by reporting five individuals from three families with motor neuropathies."

The founding report of the motor neuropathy presentation.

Spontaneously remitting developmental delay with brain cysts (proposed)

An intermediate presentation proposed from a single Japanese family of three affected siblings with compound heterozygous missense variants: congenital brain cysts on neonatal imaging and a mild motor developmental delay that resolved without vitamin treatment. The authors call for further cases before it is accepted as a distinct category, and MONDO has no term for it.

Show evidence (2 references)

PMID:38012394 SUPPORT Human Clinical

"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."

States the proposed intermediate category and its place on the severity scale.

PMID:38012394 SUPPORT Human Clinical

"All three patients had congenital brain cysts on neonatal cranial imaging, but no other morphological abnormalities."

The defining imaging finding of the proposed intermediate form.

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Discussions and Knowledge Gaps

2

Which SMVT substrate, biotin, pantothenate or lipoate, is limiting for peripheral nerve, and is the primary lesion in the motor axon or the Schwann cell?

KNOWLEDGE GAP OPEN slc5a6_neuropathy_limiting_cofactor

Attached to

pathophysiology#Peripheral Motor Axon and Myelin Degeneration pathophysiology#Systemic Biotin and Pantothenate Deficiency

The neuropathy has both axonal and demyelinating features and responds to combined replacement, so the cofactor and cell type driving it are unknown. Fibroblast carboxylase activity was normal in a COMNB patient, and no nerve-specific Slc5a6 model has been reported. Knowing the limiting cofactor could simplify treatment and explain the variable response.

Does residual SMVT transport activity predict whether a patient develops the infantile multisystem disease, an intermediate form or the childhood-onset motor neuropathy?

KNOWLEDGE GAP OPEN slc5a6_genotype_severity

Attached to

pathophysiology#SLC5A6 Biallelic Loss-of-Function Variants has_subtypes#NERIB has_subtypes#COMNB

Severe cases tend to carry a null allele with an impaired allele, and COMNB cases carry membrane-localized missense alleles, but transport has been measured for few alleles and in different systems. One review found no clear genotype-phenotype correlation but little intrafamilial variability in onset, which is what a residual-activity model would predict.

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Pathophysiology

11

SLC5A6 Biallelic Loss-of-Function Variants

Germline biallelic SLC5A6 variants reduce SMVT function. Severe infantile cases have usually carried a null allele (for example p.(Arg94*) or an early frameshift) in trans with a functionally impaired allele. The motor neuropathy cases carry missense alleles such as p.(Ser429Gly) and p.(Tyr162Cys) that reach the plasma membrane but transport less, so residual activity is thought to set the severity. Patient fibroblasts carrying p.(Ser429Gly) take up about 90 percent less biotin than controls.

SLC5A6 hgnc:11041

Genetic context variant_origin: GERMLINE functional_impact_category: PARTIAL_LOSS_OF_FUNCTION

Downstream

Impaired Sodium-Dependent Multivitamin Uptake

Show evidence (2 references)

PMID:35013551 SUPPORT In Vitro

"The SLC5A6 missense variants p.(Tyr162Cys) and p.(Ser429Gly) did not affect plasma membrane localization of the ectopically expressed multivitamin transporter suggesting reduced but not abolished function, such as lower catalytic activity."

The neuropathy alleles are hypomorphic rather than null.

PMID:35013551 SUPPORT Human Clinical

"The data suggest that the four reported patients with a multisystemic disease and/or near-fatal events carry a null allele in trans with a second allele that produces a functionally impaired SMVT transporter"

Links the severe multisystem presentation to a null allele combined with an impaired allele.

Impaired Sodium-Dependent Multivitamin Uptake

SMVT is the sodium-coupled carrier for biotin, pantothenate and lipoate. Loss of its activity reduces cellular uptake of all three cofactors, which is why the disease is a combined deficiency rather than a single-vitamin disorder.

SLC5A6 hgnc:11041

biotin transport GO:0015878 ↓ DECREASED pantothenate transmembrane transport GO:0015887 ↓ DECREASED lipoate transmembrane transport GO:0170006 ↓ DECREASED

sodium-dependent multivitamin transmembrane transporter activity GO:0008523 ↓ DECREASED

Downstream

Impaired Intestinal Biotin and Pantothenate Absorption

Reduced Vitamin Uptake at the Blood-Brain Barrier

Show evidence (3 references)

PMID:38816490 SUPPORT Human Clinical

"The sodium-dependent multivitamin transporter encoded by SLC5A6 is responsible for uptake of biotin, pantothenic acid, and α-lipoic acid."

Names the three substrates whose uptake is lost.

PMID:31754459 SUPPORT In Vitro

"Pathogenicity of the identified variants was demonstrated by impaired biotin uptake of mutant SMVT."

Patient alleles reduce transporter-mediated biotin uptake.

PMID:42364996 SUPPORT In Vitro

"Functional assays identify key binding residues and elucidate the pathogenic effects of disease-associated mutations."

Structural and functional work on human SMVT attributes the disease variants to impaired transport.

Impaired Intestinal Biotin and Pantothenate Absorption

SMVT is the only carrier-mediated route for biotin absorption in the intestine, so loss of its function limits dietary uptake of biotin and pantothenate. Intestine-specific Slc5a6 knockout mice lose carrier-mediated biotin uptake, become biotin deficient, fail to grow and develop small bowel and cecal inflammation and dysplasia, all prevented by high-dose biotin and pantothenic acid.

enterocyte CL:0000584

intestinal absorption GO:0050892 ↓ DECREASED

small intestine UBERON:0002108

Animal models

Intestine-specific Slc5a6 conditional knockout mouse Mouse recapitulates Directly models loss of intestinal SMVT and the resulting absorption defect and biotin deficiency.

Downstream

Systemic Biotin and Pantothenate Deficiency

Failure to thrive Inferred from the intestinal knockout mouse, whose growth failure is prevented by biotin and pantothenic acid oversupplementation.

Show evidence (2 references)

PMID:23104561 SUPPORT Model Organism

"These studies provide the first in vivo confirmation in native intestine that SMVT is solely responsible for intestinal biotin uptake."

Establishes that loss of intestinal SMVT abolishes carrier-mediated biotin absorption.

PMID:23104561 SUPPORT Model Organism

"Microscopic analysis showed histological abnormalities in the small bowel (shortened villi, dysplasia) and cecum (chronic active inflammation, dysplasia) of the KO mice."

Intestinal SMVT loss also damages the intestinal mucosa.

Reduced Vitamin Uptake at the Blood-Brain Barrier

SMVT is expressed on the luminal membrane of human brain capillary endothelium and carries most of the biotin and pantothenate uptake there, so its loss is expected to limit supply of these cofactors to the brain. This node is supported by transport studies in brain endothelial cells, not by measurements in patients.

Downstream

Infantile Neurodegeneration

Show evidence (1 reference)

PMID:25809983 SUPPORT In Vitro

"This study is the first to confirm expression of SLC5A6 in human brain microvessels and to provide evidence that SLC5A6 is a major contributor to luminal uptake of biotin and pantothenic acid at the human blood-brain barrier."

Places SMVT as the main route for biotin and pantothenate entry into the human brain.

Systemic Biotin and Pantothenate Deficiency

Reduced absorption and cellular uptake produce low circulating biotin and pantothenate. Serum biotin was below the reference range in a COMNB patient tested, and untargeted metabolomics in a severe case showed reduced pantothenate and coenzyme A. Serum biotin is an unreliable marker of biotin status, so a normal value does not exclude the disorder.

Downstream

Impaired Biotin-Dependent Carboxylase Activity

Coenzyme A Depletion and Impaired Fatty Acid Oxidation

Peripheral Motor Axon and Myelin Degeneration The link from cofactor deficiency to neuropathy is inferred. Biotin deficiency from other causes (biotinidase deficiency) also produces peripheral neuropathy that improves with biotin, and SLC5A6 neuropathy improves with replacement, but which cofactor and which nerve cell type is limiting has not been tested.

Impaired B Cell Terminal Differentiation

Decreased serum biotin

Infantile Neurodegeneration

Show evidence (2 references)

PMID:35013551 SUPPORT Human Clinical

"Biotin deficiency was detected in serum of patient 2–1, while serum vitamin levels could not be determined in the four affected individuals from India (Table 3)."

Documents systemic biotin deficiency in a motor neuropathy patient.

PMID:39898461 SUPPORT Human Clinical

"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."

Documents systemic pantothenate and coenzyme A depletion in a severe case.

Impaired Biotin-Dependent Carboxylase Activity

Biotin is the cofactor of the five mammalian carboxylases. Severe SMVT deficiency produces the organic acid and acylcarnitine pattern of multiple carboxylase deficiency (raised urinary 3-hydroxyisovaleric acid and plasma C5-OH carnitine), which can mimic biotinidase deficiency. In a COMNB patient, fibroblast pyruvate carboxylase activity was normal, but cultured skin cells are insensitive to biotin depletion, so this does not exclude a tissue deficit.

pyruvate carboxylase activity GO:0004736 ↓ DECREASED

Downstream

3-Hydroxyisovaleric aciduria

Elevated plasma 3-hydroxyisovalerylcarnitine

Metabolic acidosis

Hypoglycemia

Show evidence (2 references)

PMID:31392107 SUPPORT Human Clinical

"Variants in the SLC5A6 gene may lead to a metabolic disorder mimicking biotinidase deficiency that can be treated with supplementation of the vitamins biotin and pantothenic acid."

The biochemical phenotype resembles the multiple carboxylase deficiency of biotinidase deficiency.

PMID:35013551 REFUTE In Vitro

"By measuring the activity of the biotin-dependent pyruvate carboxylase in fibroblasts of patient 1–2 we did not obtain evidence for biotin deficiency in this patient."

In a COMNB patient, fibroblast pyruvate carboxylase activity was normal. The authors attribute this to the low sensitivity of skin cells to biotin depletion, so it argues against a measurable carboxylase deficit in fibroblasts rather than in nerve.

Coenzyme A Depletion and Impaired Fatty Acid Oxidation

Pantothenate is the precursor of coenzyme A. Reduced pantothenate uptake lowers coenzyme A, impairing fatty acid oxidation and mitochondrial energy metabolism, as shown by plasma metabolomics in a severe case and by impaired coenzyme A synthesis in Slc5a6-deficient mouse heart.

coenzyme A biosynthetic process GO:0015937 ↓ DECREASED

Downstream

Cardiomyocyte Mitochondrial Metabolic Failure

Rhabdomyolysis

Show evidence (1 reference)

PMID:39898461 SUPPORT Human Clinical

"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."

Direct patient evidence of coenzyme A depletion with a fatty acid oxidation defect.

Cardiomyocyte Mitochondrial Metabolic Failure

Cardiac-specific Slc5a6 knockout mice show impaired coenzyme A synthesis and early mitochondrial metabolic disruption before cardiac dysfunction, progressing to cardiomyocyte hypertrophy, fibrosis and death, all prevented by vitamin supplementation. This is the proposed basis of the dilated cardiomyopathy and cardiac failure seen in some patients across the spectrum.

cardiac muscle cell CL:0000746

Animal models

Cardiac-specific Slc5a6 knockout mouse Mouse recapitulates Models cardiomyocyte SMVT loss and the metabolic and mitochondrial changes that precede cardiomyopathy.

Downstream

Dilated cardiomyopathy

Congestive heart failure

Show evidence (1 reference)

PMID:42228401 SUPPORT Model Organism

"Proteomic analysis revealed early mitochondrial metabolic disruption and extracellular matrix protein upregulation at 8 weeks, preceding overt cardiac dysfunction."

Mitochondrial metabolic disruption precedes cardiac dysfunction in the knockout heart.

Peripheral Motor Axon and Myelin Degeneration

The defining lesion of COMNB and a component of the severe forms. Motor nerve conduction studies show pleomorphic, sometimes asymmetric axonal and demyelinating abnormalities, and muscle shows chronic denervation with fiber type grouping. In the more severe and intermediate cases the neuropathy is sensorimotor. A neuropathy in a severe-form patient resolved on serial nerve conduction studies after vitamin replacement, so the lesion is at least partly reversible.

lower motor neuron CL:0008039 Schwann cell CL:0002573

nerve UBERON:0001021

Downstream

Distal upper limb weakness

Intrinsic hand muscle atrophy

Distal lower limb weakness

Absent ankle reflexes

Motor axonal neuropathy

Demyelinating motor neuropathy

Neurogenic muscle fiber type grouping

Frequent falls

Sensory neuropathy

Show evidence (3 references)

PMID:35013551 SUPPORT Human Clinical

"We further expand the phenotypic spectrum associated with biallelic SLC5A6 variants by reporting five individuals from three families with pleomorphic motor neuropathies that had both axonal and demyelinating features."

Establishes combined axonal and demyelinating motor nerve involvement.

PMID:35013551 SUPPORT Human Clinical

"Findings on NCS were sometimes asymmetric, suggesting that the nerve damage may be non-uniform in some instances."

Records the asymmetric, non-uniform pattern of nerve damage.

PMID:31754459 SUPPORT Human Clinical

"His nerve conduction studies confirm near total and sustained resolution of peripheral neuropathy from +3 years."

The neuropathy reversed with triple vitamin replacement in a severe-form patient.

Impaired B Cell Terminal Differentiation

In a family with compound heterozygous SLC5A6 variants and antibody deficiency, biotin deficiency impaired plasma cell maturation through altered mitochondrial respiration, and biotin restored antibody production in the patient and in a knock-in mouse carrying a patient variant. This is the proposed basis of the hypogammaglobulinemia and recurrent infections reported across the spectrum.

B cell CL:0000236 plasma cell CL:0000786

Downstream

Hypogammaglobulinemia

Recurrent infections

Show evidence (2 references)

PMID:38036278 SUPPORT Human Clinical

"We showed that the biotin deficiency was caused by the SLC5A6 variants resulting in defective B cell differentiation and antibody deficiency."

Links SMVT-dependent biotin deficiency to defective B cell differentiation.

PMID:38036278 SUPPORT Model Organism

"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."

Biotin rescue in a patient-variant mouse supports biotin deficiency as the cause.

Infantile Neurodegeneration

In the severe subtype, normal or delayed early development is followed by regression, epileptic encephalopathy, progressive cerebral, cerebellar and brainstem atrophy and acquired microcephaly. Targeted vitamin replacement has produced neurocognitive and motor improvement. Prenatal ventriculomegaly in one infant suggests onset can begin before birth.

Downstream

Global developmental delay

Epileptic encephalopathy

Cerebral atrophy

Microcephaly

Show evidence (2 references)

PMID:31754459 SUPPORT Human Clinical

"We describe a sibling pair displaying an early infantile-onset, progressive neurodegenerative phenotype, with symptoms of developmental delay and epileptic encephalopathy developing from 12 to 14 months of age."

Describes the progressive infantile neurodegeneration of the severe subtype.

PMID:40272030 SUPPORT Human Clinical

"The present observation, for the first time, provides clinical evidence of a fetal onset in sodium-dependent multivitamin transporter deficiency."

Brain involvement can begin prenatally.

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Pathograph

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Phenotypes

43

Blood 2

Hypogammaglobulinemia Decreased circulating immunoglobulin concentration HP:0004313

Show evidence (2 references)

PMID:38407570 SUPPORT Human Clinical

"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)."

Severe persistent hypogammaglobulinemia in an infant.

PMID:38036278 SUPPORT Human Clinical

"We characterized a family diagnosed with immunodeficiency disease presenting with low immunoglobulin levels and skin dyskeratosis."

Low immunoglobulin levels as the presenting feature of a family.

Gastrointestinal hemorrhage HP:0002239

Show evidence (1 reference)

PMID:38012394 SUPPORT Human Clinical

"SMVTD usually presents with various symptoms in multiple organs, such as gastrointestinal hemorrhage, brain atrophy, and global developmental delay, at birth or in infancy."

Gastrointestinal hemorrhage in the severe subtype.

Cardiovascular 2

Dilated cardiomyopathy HP:0001644

Show evidence (2 references)

PMID:35013551 SUPPORT Human Clinical

"She was found to have mild dilated cardiomyopathy. Within a few months, she developed heart failure and required heart transplantation."

Dilated cardiomyopathy in a motor neuropathy patient.

PMID:42228401 SUPPORT Human Clinical

"We identified 2 families with SLC5A6 mutations presenting with early-onset dilated cardiomyopathy (DCM)."

Dilated cardiomyopathy as a presenting feature.

Congestive heart failure HP:0001635

Show evidence (1 reference)

PMID:38407570 SUPPORT Human Clinical

"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."

Cardiac failure during metabolic decompensation in an infant.

Digestive 4

Cyclic vomiting Episodic vomiting HP:0002572

Show evidence (2 references)

PMID:38348452 SUPPORT Human Clinical

"The phenotype of all patients was very similar, with systematic optic atrophy (initially considered as a very rare sign), severe cyclic vomiting, and rapidly progressive mixed axonal and demyelinating sensory motor neuropathy."

Severe cyclic vomiting in the intermediate neuropathy families.

PMID:37409333 SUPPORT Human Clinical

"We describe the case of a previously fit child with recurrent vomiting, faltering growth, persistent diarrhoea and rashes who was diagnosed with a sodium-dependent multivitamin transporter (SMVT) defect."

Recurrent vomiting as a presenting feature.

Gastroesophageal reflux HP:0002020

Show evidence (1 reference)

PMID:27904971 SUPPORT Human Clinical

"At 15 months of age, the child showed failure to thrive, microcephaly and brain changes on MRI, cerebral palsy and developmental delay, variable immunodeficiency, and severe gastro-esophageal reflux requiring a gastrostomy tube/fundoplication, osteoporosis, and pathologic bone fractures."

Severe reflux in the first severe case.

Intestinal pseudo-obstruction HP:0004389

Show evidence (1 reference)

PMID:37391029 SUPPORT Human Clinical

"In these patients, we documented a severe disorder featuring developmental delay, sensory polyneuropathy, optic atrophy, recurrent infections, and repeated episodes of intestinal pseudo-obstruction."

Repeated intestinal pseudo-obstruction in a severe-form family.

Diarrhea HP:0002014

Show evidence (1 reference)

PMID:37409333 SUPPORT Human Clinical

"We describe the case of a previously fit child with recurrent vomiting, faltering growth, persistent diarrhoea and rashes who was diagnosed with a sodium-dependent multivitamin transporter (SMVT) defect."

Persistent diarrhea at presentation.

Ear 1

Sensorineural hearing impairment HP:0000407

Show evidence (1 reference)

PMID:39898461 SUPPORT Human Clinical

"which classically presents with developmental delay, brain atrophy, epilepsy, sensorineural hearing loss, peripheral neuropathy, and gastrointestinal, cutaneous, and immunologic abnormalities"

Sensorineural hearing loss listed among the classic features of the severe form.

Eye 2

Gaze-evoked nystagmus HP:0000640

Show evidence (1 reference)

PMID:35013551 SUPPORT Human Clinical

"There were mild cerebellar signs, including mild gaze-evoked nystagmus, dysdiadochokinesia, and difficulty tandem walking."

Cerebellar sign in a COMNB patient.

Optic atrophy HP:0000648

Show evidence (2 references)

PMID:38348452 SUPPORT Human Clinical

"The phenotype of all patients was very similar, with systematic optic atrophy (initially considered as a very rare sign), severe cyclic vomiting, and rapidly progressive mixed axonal and demyelinating sensory motor neuropathy."

Optic atrophy was present in every patient of the intermediate neuropathy families.

PMID:37391029 SUPPORT Human Clinical

"In these patients, we documented a severe disorder featuring developmental delay, sensory polyneuropathy, optic atrophy, recurrent infections, and repeated episodes of intestinal pseudo-obstruction."

Optic atrophy in the severe form.

Genitourinary 1

3-Hydroxyisovaleric aciduria HP:0033111

Show evidence (2 references)

PMID:31392107 SUPPORT Human Clinical

"Urine analysis showed persistently elevated excretion of 3-OH-isovaleric acid."

Persistent 3-hydroxyisovaleric aciduria.

PMID:38407570 SUPPORT Human Clinical

"Increased and isolated excretion of urinary 3-hydroxyisovaleric acid may suggest, in the absence of markedly reduced biotinidase activity, a SMVT deficiency."

Raised urinary 3-hydroxyisovaleric acid as a diagnostic pointer.

Head and Neck 1

Microcephaly HP:0000252

Show evidence (1 reference)

PMID:27904971 SUPPORT Human Clinical

"At 15 months of age, the child showed failure to thrive, microcephaly and brain changes on MRI, cerebral palsy and developmental delay, variable immunodeficiency, and severe gastro-esophageal reflux requiring a gastrostomy tube/fundoplication, osteoporosis, and pathologic bone fractures."

Microcephaly in the first severe case.

Immune 2

Recurrent infections HP:0002719

Show evidence (2 references)

PMID:38816490 SUPPORT Human Clinical

"In Family A, a male proband (AII:1) presenting in early childhood with gross motor regression, motor axonal neuropathy, recurrent cytopenia and infections, and failure to thrive was diagnosed at 12 years of age via genome sequencing (GS)"

Recurrent infections with cytopenia in a neuropathy patient.

PMID:37391029 SUPPORT Human Clinical

"In these patients, we documented a severe disorder featuring developmental delay, sensory polyneuropathy, optic atrophy, recurrent infections, and repeated episodes of intestinal pseudo-obstruction."

Recurrent infections in the severe form.

Skin rash HP:0000988

Show evidence (1 reference)

PMID:37409333 SUPPORT Human Clinical

"With treatment there was significant, sustained clinical improvement with resolution of recurrent vomiting, rashes and graduation to full enteral feeds."

Rashes that resolved on vitamin replacement.

Integument 1

Premature graying of hair HP:0002216

Show evidence (1 reference)

PMID:35013551 SUPPORT Human Clinical

"She had premature graying of hair at the age of 4 months."

Early hair graying in a COMNB patient.

Limbs 4

Distal upper limb weakness Distal upper limb muscle weakness HP:0008959

Show evidence (1 reference)

PMID:35013551 SUPPORT Human Clinical

"The initial physical exam was remarkable for distal right upper extremity weakness, along with wasting of the thenar and hypothenar eminences and interossei bilaterally."

Distal upper limb weakness at presentation in a COMNB patient.

Intrinsic hand muscle atrophy HP:0008954

Show evidence (1 reference)

PMID:35013551 SUPPORT Human Clinical

"The initial physical exam was remarkable for distal right upper extremity weakness, along with wasting of the thenar and hypothenar eminences and interossei bilaterally."

Thenar, hypothenar and interosseous wasting are the intrinsic hand muscle groups.

Distal lower limb weakness Distal lower limb muscle weakness HP:0009053

Show evidence (2 references)

PMID:35013551 SUPPORT Human Clinical

"Initial physical exam was notable for prominent distal upper and lower extremity weakness as well as absent ankle reflexes."

Distal leg weakness in a motor neuropathy patient.

PMID:40396389 SUPPORT Human Clinical

"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."

Upper and lower limb weakness in a patient with early-onset axonal sensorimotor neuropathy.

Absent ankle reflexes Absent Achilles reflex HP:0003438

Show evidence (1 reference)

PMID:35013551 SUPPORT Human Clinical

"There were brisk upper extremity reflexes, diminished patellar reflexes, and absent ankle reflexes bilaterally, with extensor plantar responses."

Absent ankle reflexes in a motor neuropathy patient.

Metabolism 6

Decreased serum biotin Decreased circulating biotin concentration HP:0034599

Show evidence (1 reference)

PMID:35013551 SUPPORT Human Clinical

"Biotin deficiency was detected in serum of patient 2–1, while serum vitamin levels could not be determined in the four affected individuals from India (Table 3)."

Low serum biotin in a motor neuropathy patient.

Metabolic acidosis HP:0001942

Show evidence (2 references)

PMID:31392107 SUPPORT Human Clinical

"A 17-month-old girl presented with hypoglycemia (2.0 mmol/L) and severe metabolic acidosis (pH 6.87), leading to resuscitation."

Severe metabolic acidosis during a metabolic crisis.

PMID:35217562 SUPPORT Human Clinical

"We describe a fifth case of a patient presenting at the relatively mild end of the phenotypic spectrum with failure to thrive, frequent vomiting and metabolic acidosis with hypoglycemia, and mild osteopenia"

Metabolic acidosis in a second patient.

Hypoglycemia HP:0001943

Show evidence (1 reference)

PMID:31392107 SUPPORT Human Clinical

"A 17-month-old girl presented with hypoglycemia (2.0 mmol/L) and severe metabolic acidosis (pH 6.87), leading to resuscitation."

Hypoglycemia during a metabolic crisis.

Elevated plasma 3-hydroxyisovalerylcarnitine Elevated circulating 3-hydroxyisovalerylcarnitine concentration HP:0035028

Show evidence (1 reference)

PMID:31392107 SUPPORT Human Clinical

"Metabolic investigation showed elevated plasma C3-carnitine and C5-OH-carnitine."

C5-OH carnitine is 3-hydroxyisovalerylcarnitine.

Hyperammonemia HP:0001987

Show evidence (1 reference)

PMID:39898461 SUPPORT Human Clinical

"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."

Hyperammonemia during a metabolic crisis.

Lactic acidosis HP:0003128

Show evidence (1 reference)

PMID:39898461 SUPPORT Human Clinical

"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."

Lactic acidosis during a metabolic crisis.

Musculoskeletal 5

Neurogenic muscle fiber type grouping HP:0033685

Show evidence (1 reference)

PMID:35013551 SUPPORT Human Clinical

"A gastrocnemius muscle biopsy revealed a neurogenic pattern with fiber type grouping and no inflammation."

Muscle biopsy evidence of chronic denervation and reinnervation.

Frequent falls HP:0002359

Show evidence (1 reference)

PMID:35013551 SUPPORT Human Clinical

"She also had impaired balance, difficulty climbing stairs, frequent falls, difficulty squatting, and generalized fatigue."

Gait consequences of distal leg weakness in a COMNB patient.

Osteoporosis with pathologic fractures HP:0000939

Show evidence (1 reference)

PMID:27904971 SUPPORT Human Clinical

"At 15 months of age, the child showed failure to thrive, microcephaly and brain changes on MRI, cerebral palsy and developmental delay, variable immunodeficiency, and severe gastro-esophageal reflux requiring a gastrostomy tube/fundoplication, osteoporosis, and pathologic bone fractures."

Osteoporosis with fractures in the first severe case.

Osteopenia HP:0000938

Show evidence (1 reference)

PMID:35217562 SUPPORT Human Clinical

"We describe a fifth case of a patient presenting at the relatively mild end of the phenotypic spectrum with failure to thrive, frequent vomiting and metabolic acidosis with hypoglycemia, and mild osteopenia"

Mild osteopenia in a mildly affected child.

Rhabdomyolysis HP:0003201

Show evidence (1 reference)

PMID:39898461 SUPPORT Human Clinical

"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."

Rhabdomyolysis during a metabolic crisis.

Nervous System 11

Motor axonal neuropathy HP:0007002

Show evidence (1 reference)

PMID:38816490 SUPPORT Human Clinical

"In Family A, a male proband (AII:1) presenting in early childhood with gross motor regression, motor axonal neuropathy, recurrent cytopenia and infections, and failure to thrive was diagnosed at 12 years of age via genome sequencing (GS)"

Motor axonal neuropathy in a compound heterozygous p.(Ser429Gly) carrier.

Demyelinating motor neuropathy HP:0007220

Show evidence (1 reference)

PMID:35013551 SUPPORT Human Clinical

"We further expand the phenotypic spectrum associated with biallelic SLC5A6 variants by reporting five individuals from three families with pleomorphic motor neuropathies that had both axonal and demyelinating features."

Demyelinating features accompany axonal ones in COMNB.

Spastic-ataxic gait Spastic ataxia HP:0002497

Show evidence (1 reference)

PMID:35013551 SUPPORT Human Clinical

"She had mild ataxia and a spastic-ataxic gait, with a normal sensory examination."

Spastic-ataxic gait in a COMNB patient.

Babinski sign HP:0003487

Show evidence (1 reference)

PMID:35013551 SUPPORT Human Clinical

"There were brisk upper extremity reflexes, diminished patellar reflexes, and absent ankle reflexes bilaterally, with extensor plantar responses."

Extensor plantar responses are the Babinski sign.

Tremor HP:0001337

Show evidence (1 reference)

PMID:35013551 SUPPORT Human Clinical

"She experienced difficulty writing, buttoning, and opening bottle caps. She had generalized tremors."

Tremor in a COMNB patient.

Sensory neuropathy HP:0000763

Show evidence (2 references)

PMID:37391029 SUPPORT Human Clinical

"In these patients, we documented a severe disorder featuring developmental delay, sensory polyneuropathy, optic atrophy, recurrent infections, and repeated episodes of intestinal pseudo-obstruction."

Sensory polyneuropathy in a homozygous C-terminal frameshift family.

PMID:38348452 SUPPORT Human Clinical

"The phenotype of all patients was very similar, with systematic optic atrophy (initially considered as a very rare sign), severe cyclic vomiting, and rapidly progressive mixed axonal and demyelinating sensory motor neuropathy."

Sensorimotor neuropathy in the intermediate Maghreb founder-variant families.

Motor regression HP:0033044

Show evidence (1 reference)

PMID:38816490 SUPPORT Human Clinical

"In Family A, a male proband (AII:1) presenting in early childhood with gross motor regression, motor axonal neuropathy, recurrent cytopenia and infections, and failure to thrive was diagnosed at 12 years of age via genome sequencing (GS)"

Gross motor regression in early childhood.

Global developmental delay HP:0001263

Show evidence (1 reference)

PMID:38012394 SUPPORT Human Clinical

"SMVTD usually presents with various symptoms in multiple organs, such as gastrointestinal hemorrhage, brain atrophy, and global developmental delay, at birth or in infancy."

Global developmental delay is a core feature of the severe subtype.

Epileptic encephalopathy HP:0200134

Show evidence (1 reference)

PMID:31754459 SUPPORT Human Clinical

"We describe a sibling pair displaying an early infantile-onset, progressive neurodegenerative phenotype, with symptoms of developmental delay and epileptic encephalopathy developing from 12 to 14 months of age."

Epileptic encephalopathy in the severe subtype.

Cerebral atrophy HP:0002059

Show evidence (1 reference)

PMID:38012394 SUPPORT Human Clinical

"SMVTD usually presents with various symptoms in multiple organs, such as gastrointestinal hemorrhage, brain atrophy, and global developmental delay, at birth or in infancy."

Brain atrophy in the severe subtype.

Ventriculomegaly HP:0002119

Show evidence (1 reference)

PMID:40272030 SUPPORT Human Clinical

"A review of the prenatal imaging showed ventriculomegaly at 32 weeks of gestation."

Prenatal ventriculomegaly in an infant later diagnosed with the severe form.

Growth 1

Failure to thrive HP:0001508

Show evidence (2 references)

PMID:27904971 SUPPORT Human Clinical

"At 15 months of age, the child showed failure to thrive, microcephaly and brain changes on MRI, cerebral palsy and developmental delay, variable immunodeficiency, and severe gastro-esophageal reflux requiring a gastrostomy tube/fundoplication, osteoporosis, and pathologic bone fractures."

Failure to thrive in the first severe case.

PMID:38816490 SUPPORT Human Clinical

"In Family A, a male proband (AII:1) presenting in early childhood with gross motor regression, motor axonal neuropathy, recurrent cytopenia and infections, and failure to thrive was diagnosed at 12 years of age via genome sequencing (GS)"

Failure to thrive alongside motor axonal neuropathy.

🧬

Genetic Associations

1

SLC5A6

Gene: SLC5A6 hgnc:11041 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (2 references)

PMID:38816490 SUPPORT Human Clinical

"Phenotype ranges from multisystem metabolic disorder to childhood-onset peripheral motor neuropathy."

Biallelic SLC5A6 variants cause a single phenotypic range from multisystem disease to motor neuropathy.

PMID:38012394 SUPPORT Human Clinical

"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."

Names both MONDO-level presentations as caused by the same gene and treated the same way.

Variants (1)

c.1285A>G p.(Ser429Gly)

Recurrent missense allele in TM11, adjacent to a substrate-binding residue, found homozygous in most COMNB patients (Indian families sharing a haplotype) and in trans with a splice allele. It reaches the plasma membrane but reduces biotin uptake by about 90 percent in patient fibroblasts.

Show evidence (1 reference)

PMID:38816490 SUPPORT Human Clinical

"We also report an unrelated female with peripheral neuropathy homozygous for the c.1285A>G p.(Ser429Gly) recurrent variant identified in seven reported cases, including this study."

Establishes p.(Ser429Gly) as recurrent in the neuropathy presentation.

💊

Medical Actions

2

Triple vitamin replacement (biotin, pantothenic acid, lipoic acid)

Action: Pharmacotherapy NCIT:C15986

Agent: biotin CHEBI:15956 pantothenic acid CHEBI:7916 lipoic acid CHEBI:16494

Platform: Small molecule

Lifelong high-dose oral biotin, pantothenic acid and lipoic acid, thought to work by bypassing the defective carrier through passive diffusion at pharmacological doses. Reported regimens vary widely, from biotin 10 mg twice daily up to 100 mg daily, with pantothenic acid 250 to 555 mg and lipoic acid 150 to 300 mg daily, and one patient received parenteral biotin, dexpanthenol and lipoic acid. Response is strongest when started early; in the defining COMNB cohort it was not uniform, with clear improvement in one patient and inconsistent change in others.

Mechanism Target:

BYPASSES Systemic Biotin and Pantothenate Deficiency — Pharmacological doses are proposed to enter cells by simple diffusion, restoring cofactor supply without the transporter.

Show evidence (1 reference)

PMID:35013551 SUPPORT INDIRECT Human Clinical

"triple vitamin replacement therapy, likely via a simple diffusion mechanism, had beneficial effects in the three live patients"

States the proposed bypass mechanism of high-dose replacement.

Target Phenotypes: Distal upper limb muscle weakness HP:0008959

Show evidence (11 references)

PMID:35013551 SUPPORT Human Clinical

"Targeted therapeutic intervention yielded clinical improvement in four of the five patients."

Most COMNB patients improved on targeted vitamin therapy.

PMID:35013551 REFUTE Human Clinical

"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."

Response in the COMNB cohort was inconsistent, which qualifies any claim of uniform efficacy.

PMID:38816490 SUPPORT Human Clinical

"Targeted treatment of AII:1 with biotin, pantothenic acid, and lipoic acid resulted in clinical improvement."

Improvement of a motor axonal neuropathy patient on triple therapy.

+ 8 more references

Emergency biotin and pantothenic acid in metabolic crisis

Action: Pharmacotherapy NCIT:C15986

Agent: biotin CHEBI:15956 pantothenic acid CHEBI:7916

Platform: Small molecule

Severe infantile presentations can be life-threatening metabolic crises that mimic biotinidase deficiency. High-dose biotin and pantothenic acid are recommended empirically while SLC5A6 sequencing is pending.

Show evidence (2 references)

PMID:38407570 SUPPORT Human Clinical

"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."

Recommends empirical treatment before molecular confirmation.

PMID:40272030 SUPPORT Human Clinical

"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."

Multisystem response after a metabolic shock episode.

🔬

Diagnosis

3

Exome or genome sequencing

Diagnosis rests on finding biallelic SLC5A6 variants. Because the neuropathy form resembles other hereditary neuropathies and the severe form resembles biotinidase deficiency, most cases were found by exome or genome sequencing, and earlier genome sequencing was estimated to shorten the diagnostic odyssey and time to treatment by up to seven years. Deep intronic and splice variants (the Maghreb founder allele, c.393+2T>C) may need RNA studies to classify.

exome or genome sequencing NCIT:C101295

Show evidence (2 references)

PMID:38816490 SUPPORT Human Clinical

"Health Economic analyses showed implementation of GS as an early investigation could have saved $ AUD 105,988 and shortened diagnostic odyssey and initiation of treatment by up to 7 years."

Supports early genome sequencing as the diagnostic route.

PMID:40396389 SUPPORT Human Clinical

"This study performed whole exome sequencing to identify the genetic cause for two independent patients with early onset axonal sensorimotor polyneuropathy and SMVTD."

Exome sequencing identified the cause in a neuropathy cohort.

Nerve conduction studies and EMG

Electrodiagnostic studies establish a motor-predominant neuropathy with mixed axonal and demyelinating features, sometimes asymmetric, and needle EMG shows chronic denervation.

nerve conduction study NCIT:C154784

Show evidence (1 reference)

PMID:35013551 SUPPORT Human Clinical

"Findings on NCS were sometimes asymmetric, suggesting that the nerve damage may be non-uniform in some instances."

Nerve conduction studies define the neuropathy pattern.

Biochemical screening and exclusion of biotinidase deficiency

In the severe form, raised urinary 3-hydroxyisovaleric acid and plasma C5-OH carnitine with normal or near-normal biotinidase activity point to SMVT deficiency. Normal biotinidase activity was also documented in the COMNB patients. Serum biotin may be low but is an unreliable marker.

Show evidence (2 references)

PMID:38407570 SUPPORT Human Clinical

"Increased and isolated excretion of urinary 3-hydroxyisovaleric acid may suggest, in the absence of markedly reduced biotinidase activity, a SMVT deficiency."

The biochemical pattern that distinguishes SMVT deficiency from biotinidase deficiency.

PMID:35013551 SUPPORT Human Clinical

"Plasma biotinidase activity in all patients was normal (Table 3)."

Biotinidase deficiency was excluded in the COMNB patients.

📊

Prevalence

1

Published case literature, worldwide

Cases In Literature Ultra Rare

Thirteen affected individuals from eight families had been reported when Riley et al. wrote in 2024, before their own three cases; further families were reported in the same year from the Maghreb and Japan and afterwards from Korea, India and elsewhere. No population prevalence has been published.

Show evidence (1 reference)

PMID:38816490 SUPPORT Human Clinical

"Thirteen individuals from eight families are reported with pathogenic biallelic SLC5A6 variants."

Case count across the published literature at the time of the review.

🔀

Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from SLC5A6-Related Multivitamin Transporter Deficiency:

Biotinidase deficiency MONDO:0009665

Overlapping Features Severe SMVT deficiency produces the organic aciduria of multiple carboxylase deficiency and was first managed as biotinidase deficiency in some patients; both are biotin-responsive, and both can cause neuropathy and optic atrophy.

Distinguishing Features

Biotinidase activity is normal or only marginally reduced in SMVT deficiency.
SMVT deficiency also lowers pantothenate and lipoate and needs replacement of all three.

Show evidence (1 reference)

PMID:31392107 SUPPORT Human Clinical

"Biotinidase activity in plasma showed only marginally decreased activity, which was considered insufficient explanation for her clinical symptoms."

A patient first suspected of biotinidase deficiency had near-normal enzyme activity.

🐁

Animal Models

2

Intestine-specific Slc5a6 conditional knockout mouse

Cre/lox deletion of Slc5a6 restricted to the intestine. Mice lose carrier-mediated intestinal biotin uptake, become biotin deficient, show growth retardation, reduced bone density and length, small bowel and cecal inflammation and dysplasia, and about two thirds die between 6 and 10 weeks. Biotin and pantothenic acid oversupplementation prevents these abnormalities.

Species

Mouse

Genotype

Intestine-specific Slc5a6 conditional knockout (Cre/lox)

Publication

PMID:23104561

Pathograph links

Impaired Intestinal Biotin and Pantothenate Absorption recapitulates fidelity: moderate observes: tissue Directly models loss of intestinal SMVT and the resulting absorption defect and biotin deficiency.

Limitations: Deletion is complete and confined to the intestine, whereas patients carry hypomorphic alleles that act in every tissue, including nerve and brain. No neuropathy readout was reported.

Show evidence (1 reference)

PMID:23104561 SUPPORT Model Organism

"These studies provide the first in vivo confirmation in native intestine that SMVT is solely responsible for intestinal biotin uptake."

The model reproduces the intestinal absorption defect.

Cardiac-specific Slc5a6 knockout mouse

Cardiomyocyte-restricted Slc5a6 deletion produces progressive cardiac dysfunction with hypertrophy, fibrosis, impaired coenzyme A synthesis and death by 26 weeks, prevented by vitamin supplementation from preconception.

Species

Mouse

Genotype

Slc5a6cKO (cardiomyocyte-specific)

Publication

PMID:42228401

Pathograph links

Cardiomyocyte Mitochondrial Metabolic Failure recapitulates fidelity: moderate observes: cellular Models cardiomyocyte SMVT loss and the metabolic and mitochondrial changes that precede cardiomyopathy.

Limitations: Complete tissue-restricted deletion rather than systemic hypomorphic loss, so it isolates the cell-autonomous cardiac effect and does not capture the contribution of systemic deficiency.

Show evidence (1 reference)

PMID:42228401 SUPPORT Model Organism

"Proteomic analysis revealed early mitochondrial metabolic disruption and extracellular matrix protein upregulation at 8 weeks, preceding overt cardiac dysfunction."

The model shows mitochondrial metabolic disruption ahead of cardiac failure.

{ }

Source YAML

click to show

name: SLC5A6-Related Multivitamin Transporter Deficiency
creation_date: '2026-10-14T12:36:44Z'
category: Mendelian
description: >-
  Autosomal recessive disorder caused by biallelic SLC5A6 variants that reduce
  the activity of the sodium-dependent multivitamin transporter (SMVT), the
  carrier responsible for sodium-coupled uptake of biotin, pantothenic acid and
  lipoic acid in the intestine, at the blood-brain barrier and in other
  tissues. The clinical picture is a severity spectrum. At the severe end,
  infantile-onset multisystem disease (sodium-dependent multivitamin transporter
  deficiency, MONDO "neurodegeneration, infantile-onset, biotin-responsive")
  combines failure to thrive, developmental delay or regression, epileptic
  encephalopathy, brain atrophy, gastrointestinal bleeding and dysmotility,
  hypogammaglobulinemia, osteopenia, metabolic crises with biotinidase-like
  organic aciduria and, in some cases, cardiac failure, and is lethal in early
  childhood without treatment. At the mild end, a childhood-onset peripheral
  motor neuropathy (COMNB) presents at about 6 to 13 years with distal hand
  weakness and intrinsic hand muscle wasting, with mixed axonal and
  demyelinating motor nerve findings. Intermediate cases include a remitting
  developmental delay with congenital brain cysts and a progressive mixed
  sensorimotor neuropathy with optic atrophy and cyclic vomiting. All forms are
  treated with high-dose oral biotin, pantothenic acid and lipoic acid, and
  response is best when treatment starts early.
synonyms:
- sodium-dependent multivitamin transporter deficiency
- SMVT deficiency
- SMVTD
- NERIB
- neurodegeneration, infantile-onset, biotin-responsive
- biotin-responsive childhood-onset motor neuropathy
- peripheral motor neuropathy, childhood-onset, biotin-responsive
- COMNB
- SLC5A6-related disorder
parents:
- inborn error of vitamin and cofactor transport
- hereditary peripheral neuropathy
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0859255
      label: peripheral motor neuropathy, childhood-onset, biotin-responsive
    mapping_predicate: skos:narrowMatch
    mapping_source: manual curation
    mapping_justification: >-
      MONDO:0859255 (OMIM:619903) is the mild, childhood-onset motor neuropathy
      end of the SLC5A6 spectrum, so it is narrower than this gene-level entry.
      It is curated here as the COMNB subtype. MONDO has no class covering the
      whole SLC5A6 spectrum.
  - term:
      id: MONDO:0033546
      label: neurodegeneration, infantile-onset, biotin-responsive
    mapping_predicate: skos:narrowMatch
    mapping_source: manual curation
    mapping_justification: >-
      MONDO:0033546 (OMIM:618973, Orphanet:521268) is the severe,
      infantile-onset multisystem end of the SLC5A6 spectrum, so it is narrower
      than this gene-level entry. It is curated here as the NERIB subtype.
has_subtypes:
- name: NERIB
  display_name: Infantile-onset multisystem SMVT deficiency (NERIB)
  subtype_term:
    preferred_term: neurodegeneration, infantile-onset, biotin-responsive
    term:
      id: MONDO:0033546
      label: neurodegeneration, infantile-onset, biotin-responsive
  description: >-
    The severe end of the spectrum and the first form described. Onset is at
    birth or in infancy, occasionally with prenatal ventriculomegaly, and
    disease is multisystem: failure to thrive, developmental delay or
    regression, seizures, brain atrophy, gastrointestinal hemorrhage, reflux
    and pseudo-obstruction, hypogammaglobulinemia and recurrent infections,
    osteopenia, metabolic acidosis with hypoglycemia, and cardiac failure in
    some infants. Untreated siblings have died in early childhood. Reported
    genotypes usually pair a null allele with a functionally impaired allele.
  evidence:
  - reference: PMID:38012394
    reference_title: "Novel missense variants cause intermediate phenotypes in the phenotypic spectrum of SLC5A6-related disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SMVTD usually presents with various symptoms in multiple organs, such as gastrointestinal hemorrhage, brain atrophy, and global developmental delay, at birth or in infancy."
    explanation: Defines the multisystem infantile-onset presentation of the severe subtype.
  - reference: PMID:38012394
    reference_title: "Novel missense variants cause intermediate phenotypes in the phenotypic spectrum of SLC5A6-related disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Without nutrient replacement therapy, SMVTD can be lethal in early childhood."
    explanation: Records the lethality of the untreated severe subtype.
  - reference: PMID:27904971
    reference_title: "Mutations in SLC5A6 associated with brain, immune, bone, and intestinal dysfunction in a young child."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This is the first reporting of mutations in the SLC5A6 gene in man"
    explanation: The founding case of the gene-disease relationship was an infant with multisystem disease.
- name: COMNB
  display_name: Childhood-onset biotin-responsive peripheral motor neuropathy (COMNB)
  subtype_term:
    preferred_term: peripheral motor neuropathy, childhood-onset, biotin-responsive
    term:
      id: MONDO:0859255
      label: peripheral motor neuropathy, childhood-onset, biotin-responsive
  description: >-
    The mild end of the spectrum. After normal early development, distal upper
    limb weakness with thenar, hypothenar and interosseous wasting begins at
    about 6 to 13 years, sometimes with distal leg weakness, absent ankle
    reflexes and gait difficulty. Nerve conduction findings are pleomorphic,
    with axonal and demyelinating features and sometimes asymmetry. The
    recurrent homozygous missense allele p.(Ser429Gly) accounts for most
    reported cases. A few patients also had dilated cardiomyopathy, premature
    hair graying or mild cerebellar and pyramidal signs.
  evidence:
  - reference: PMID:38012394
    reference_title: "Novel missense variants cause intermediate phenotypes in the phenotypic spectrum of SLC5A6-related disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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."
    explanation: Defines the mild subtype by onset age and restriction to motor neuropathy.
  - reference: PMID:35013551
    reference_title: "Novel biallelic variants expand the SLC5A6-related phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We expand the phenotypic spectrum associated with biallelic SLC5A6 variants affecting function by reporting five individuals from three families with motor neuropathies."
    explanation: The founding report of the motor neuropathy presentation.
- name: SRDDBC
  display_name: Spontaneously remitting developmental delay with brain cysts (proposed)
  description: >-
    An intermediate presentation proposed from a single Japanese family of
    three affected siblings with compound heterozygous missense variants:
    congenital brain cysts on neonatal imaging and a mild motor developmental
    delay that resolved without vitamin treatment. The authors call for further
    cases before it is accepted as a distinct category, and MONDO has no term
    for it.
  evidence:
  - reference: PMID:38012394
    reference_title: "Novel missense variants cause intermediate phenotypes in the phenotypic spectrum of SLC5A6-related disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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."
    explanation: States the proposed intermediate category and its place on the severity scale.
  - reference: PMID:38012394
    reference_title: "Novel missense variants cause intermediate phenotypes in the phenotypic spectrum of SLC5A6-related disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All three patients had congenital brain cysts on neonatal cranial imaging, but no other morphological abnormalities."
    explanation: The defining imaging finding of the proposed intermediate form.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    All reported patients carry biallelic SLC5A6 variants, either homozygous
    (often in consanguineous families, as with p.(Ser429Gly) and the Maghreb
    intronic founder variant) or compound heterozygous, and parents tested are
    unaffected heterozygous carriers.
  evidence:
  - reference: PMID:35013551
    reference_title: "Novel biallelic variants expand the SLC5A6-related phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sanger sequencing confirmed the homozygous SLC5A6 variant in patients 1–1, 1–2, and 1–3, and also confirmed that each asymptomatic parent harbored the heterozygous variant"
    explanation: Homozygous affected siblings with unaffected heterozygous parents is the recessive segregation pattern.
  - reference: PMID:38348452
    reference_title: "Recurrent \"outsider\" intronic variation in the SLC5A6 gene causes severe mixed axonal and demyelinating neuropathy, cyclic vomiting and optic atrophy in 3 families from Maghreb."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients, born form consanguineous parents, were homozygous carriers of the same intronic variation, outside of canonical sites, in the SLC5A6 gene encoding SMVT."
    explanation: Homozygosity in consanguineous families supports recessive inheritance.
prevalence:
- population: Published case literature, worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Thirteen affected individuals from eight families had been reported when
    Riley et al. wrote in 2024, before their own three cases; further families
    were reported in the same year from the Maghreb and Japan and afterwards
    from Korea, India and elsewhere. No population prevalence has been
    published.
  evidence:
  - reference: PMID:38816490
    reference_title: "Genome sequencing enables diagnosis and treatment of SLC5A6 neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thirteen individuals from eight families are reported with pathogenic biallelic SLC5A6 variants."
    explanation: Case count across the published literature at the time of the review.
pathophysiology:
- name: SLC5A6 Biallelic Loss-of-Function Variants
  biological_scale: MOLECULAR
  description: >-
    Germline biallelic SLC5A6 variants reduce SMVT function. Severe infantile
    cases have usually carried a null allele (for example p.(Arg94*) or an
    early frameshift) in trans with a functionally impaired allele. The motor
    neuropathy cases carry missense alleles such as p.(Ser429Gly) and
    p.(Tyr162Cys) that reach the plasma membrane but transport less, so
    residual activity is thought to set the severity. Patient fibroblasts
    carrying p.(Ser429Gly) take up about 90 percent less biotin than controls.
  genes:
  - preferred_term: SLC5A6
    term:
      id: hgnc:11041
      label: SLC5A6
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
  evidence:
  - reference: PMID:35013551
    reference_title: "Novel biallelic variants expand the SLC5A6-related phenotypic spectrum."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The SLC5A6 missense variants p.(Tyr162Cys) and p.(Ser429Gly) did not affect plasma membrane localization of the ectopically expressed multivitamin transporter suggesting reduced but not abolished function, such as lower catalytic activity."
    explanation: The neuropathy alleles are hypomorphic rather than null.
  - reference: PMID:35013551
    reference_title: "Novel biallelic variants expand the SLC5A6-related phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The data suggest that the four reported patients with a multisystemic disease and/or near-fatal events carry a null allele in trans with a second allele that produces a functionally impaired SMVT transporter"
    explanation: Links the severe multisystem presentation to a null allele combined with an impaired allele.
  downstream:
  - target: Impaired Sodium-Dependent Multivitamin Uptake
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38816490
      reference_title: "Genome sequencing enables diagnosis and treatment of SLC5A6 neuropathy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Biotin uptake studies on AII:1 fibroblasts, expressing the p.(Ser429Gly) variant, showed an ~90% reduction in uptake compared to controls."
      explanation: The recurrent neuropathy allele directly reduces biotin uptake in patient cells.
    - reference: PMID:27904971
      reference_title: "Mutations in SLC5A6 associated with brain, immune, bone, and intestinal dysfunction in a young child."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The results showed severe impairment in biotin uptake in cells expressing the mutants compared to those expressing wild-type hSMVT."
      explanation: The alleles of the first severe case abolish most biotin transport when expressed in intestinal and brain cell lines.
- name: Impaired Sodium-Dependent Multivitamin Uptake
  biological_scale: CELLULAR
  description: >-
    SMVT is the sodium-coupled carrier for biotin, pantothenate and lipoate.
    Loss of its activity reduces cellular uptake of all three cofactors, which
    is why the disease is a combined deficiency rather than a single-vitamin
    disorder.
  genes:
  - preferred_term: SLC5A6
    term:
      id: hgnc:11041
      label: SLC5A6
  molecular_functions:
  - preferred_term: sodium-dependent multivitamin transmembrane transporter activity
    modifier: DECREASED
    term:
      id: GO:0008523
      label: sodium-dependent multivitamin transmembrane transporter activity
  biological_processes:
  - preferred_term: biotin transport
    modifier: DECREASED
    term:
      id: GO:0015878
      label: biotin transport
  - preferred_term: pantothenate transmembrane transport
    modifier: DECREASED
    term:
      id: GO:0015887
      label: pantothenate transmembrane transport
  - preferred_term: lipoate transmembrane transport
    modifier: DECREASED
    term:
      id: GO:0170006
      label: lipoate transmembrane transport
  evidence:
  - reference: PMID:38816490
    reference_title: "Genome sequencing enables diagnosis and treatment of SLC5A6 neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The sodium-dependent multivitamin transporter encoded by SLC5A6 is responsible for uptake of biotin, pantothenic acid, and α-lipoic acid."
    explanation: Names the three substrates whose uptake is lost.
  - reference: PMID:31754459
    reference_title: "Identification and targeted management of a neurodegenerative disorder caused by biallelic mutations in SLC5A6."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Pathogenicity of the identified variants was demonstrated by impaired biotin uptake of mutant SMVT."
    explanation: Patient alleles reduce transporter-mediated biotin uptake.
  - reference: PMID:42364996
    reference_title: "Structural basis for multivitamin recognition and transport by human SMVT."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Functional assays identify key binding residues and elucidate the pathogenic effects of disease-associated mutations."
    explanation: Structural and functional work on human SMVT attributes the disease variants to impaired transport.
  downstream:
  - target: Impaired Intestinal Biotin and Pantothenate Absorption
    causal_link_type: DIRECT
  - target: Reduced Vitamin Uptake at the Blood-Brain Barrier
    causal_link_type: DIRECT
- name: Impaired Intestinal Biotin and Pantothenate Absorption
  biological_scale: TISSUE
  description: >-
    SMVT is the only carrier-mediated route for biotin absorption in the
    intestine, so loss of its function limits dietary uptake of biotin and
    pantothenate. Intestine-specific Slc5a6 knockout mice lose carrier-mediated
    biotin uptake, become biotin deficient, fail to grow and develop small
    bowel and cecal inflammation and dysplasia, all prevented by high-dose
    biotin and pantothenic acid.
  cell_types:
  - preferred_term: enterocyte
    term:
      id: CL:0000584
      label: enterocyte
  locations:
  - preferred_term: small intestine
    term:
      id: UBERON:0002108
      label: small intestine
  biological_processes:
  - preferred_term: intestinal absorption
    modifier: DECREASED
    term:
      id: GO:0050892
      label: intestinal absorption
  evidence:
  - reference: PMID:23104561
    reference_title: "Conditional knockout of the Slc5a6 gene in mouse intestine impairs biotin absorption."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "These studies provide the first in vivo confirmation in native intestine that SMVT is solely responsible for intestinal biotin uptake."
    explanation: Establishes that loss of intestinal SMVT abolishes carrier-mediated biotin absorption.
  - reference: PMID:23104561
    reference_title: "Conditional knockout of the Slc5a6 gene in mouse intestine impairs biotin absorption."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Microscopic analysis showed histological abnormalities in the small bowel (shortened villi, dysplasia) and cecum (chronic active inflammation, dysplasia) of the KO mice."
    explanation: Intestinal SMVT loss also damages the intestinal mucosa.
  downstream:
  - target: Systemic Biotin and Pantothenate Deficiency
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:23104561
      reference_title: "Conditional knockout of the Slc5a6 gene in mouse intestine impairs biotin absorption."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Growth retardation, decreased bone density, decreased bone length, and decreased biotin status were observed in the KO mice."
      explanation: Intestinal knockout alone is sufficient to lower whole-body biotin status.
  - target: Failure to thrive
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Inferred from the intestinal knockout mouse, whose growth failure is
      prevented by biotin and pantothenic acid oversupplementation.
    evidence:
    - reference: PMID:29669219
      reference_title: "Biotin and pantothenic acid oversupplementation to conditional SLC5A6 KO mice prevents the development of intestinal mucosal abnormalities and growth defects."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "Our findings showed that such a regimen prevents early death, as well as normalizes the growth rate, intestinal integrity, pathology, and inflammation in SMVT-cKO mice."
      explanation: Growth failure from intestinal SMVT loss is vitamin-dependent in mice.
- name: Reduced Vitamin Uptake at the Blood-Brain Barrier
  biological_scale: TISSUE
  description: >-
    SMVT is expressed on the luminal membrane of human brain capillary
    endothelium and carries most of the biotin and pantothenate uptake there,
    so its loss is expected to limit supply of these cofactors to the brain.
    This node is supported by transport studies in brain endothelial cells, not
    by measurements in patients.
  evidence:
  - reference: PMID:25809983
    reference_title: "Major involvement of Na(+) -dependent multivitamin transporter (SLC5A6/SMVT) in uptake of biotin and pantothenic acid by human brain capillary endothelial cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "This study is the first to confirm expression of SLC5A6 in human brain microvessels and to provide evidence that SLC5A6 is a major contributor to luminal uptake of biotin and pantothenic acid at the human blood-brain barrier."
    explanation: Places SMVT as the main route for biotin and pantothenate entry into the human brain.
  downstream:
  - target: Infantile Neurodegeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Systemic Biotin and Pantothenate Deficiency
  biological_scale: ORGANISM
  description: >-
    Reduced absorption and cellular uptake produce low circulating biotin and
    pantothenate. Serum biotin was below the reference range in a COMNB patient
    tested, and untargeted metabolomics in a severe case showed reduced
    pantothenate and coenzyme A. Serum biotin is an unreliable marker of
    biotin status, so a normal value does not exclude the disorder.
  chemical_entities:
  - preferred_term: biotin
    modifier: DECREASED
    term:
      id: CHEBI:15956
      label: biotin
  evidence:
  - reference: PMID:35013551
    reference_title: "Novel biallelic variants expand the SLC5A6-related phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Biotin deficiency was detected in serum of patient 2–1, while serum vitamin levels could not be determined in the four affected individuals from India (Table 3)."
    explanation: Documents systemic biotin deficiency in a motor neuropathy patient.
  - reference: PMID:39898461
    reference_title: "Expanded Clinical Phenotype and the Role of Untargeted Metabolomics Analysis in Confirming the Diagnosis of Sodium-Dependent Multivitamin Transporter Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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."
    explanation: Documents systemic pantothenate and coenzyme A depletion in a severe case.
  downstream:
  - target: Impaired Biotin-Dependent Carboxylase Activity
    causal_link_type: DIRECT
  - target: Coenzyme A Depletion and Impaired Fatty Acid Oxidation
    causal_link_type: DIRECT
  - target: Peripheral Motor Axon and Myelin Degeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The link from cofactor deficiency to neuropathy is inferred. Biotin
      deficiency from other causes (biotinidase deficiency) also produces
      peripheral neuropathy that improves with biotin, and SLC5A6 neuropathy
      improves with replacement, but which cofactor and which nerve cell type is
      limiting has not been tested.
    evidence:
    - reference: PMID:35013551
      reference_title: "Novel biallelic variants expand the SLC5A6-related phenotypic spectrum."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "These findings suggest that reduced biotin, pantothenic acid and/or α-lipoic acid levels may be neurotoxic and contribute to the peripheral neuropathies seen in some individuals with biallelic SLC5A6 variants."
      explanation: The defining COMNB report proposes cofactor deficiency as the cause of the neuropathy, as a hypothesis.
  - target: Impaired B Cell Terminal Differentiation
    causal_link_type: DIRECT
  - target: Decreased serum biotin
  - target: Infantile Neurodegeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Impaired Biotin-Dependent Carboxylase Activity
  biological_scale: CELLULAR
  description: >-
    Biotin is the cofactor of the five mammalian carboxylases. Severe SMVT
    deficiency produces the organic acid and acylcarnitine pattern of multiple
    carboxylase deficiency (raised urinary 3-hydroxyisovaleric acid and plasma
    C5-OH carnitine), which can mimic biotinidase deficiency. In a COMNB
    patient, fibroblast pyruvate carboxylase activity was normal, but cultured
    skin cells are insensitive to biotin depletion, so this does not exclude a
    tissue deficit.
  molecular_functions:
  - preferred_term: pyruvate carboxylase activity
    modifier: DECREASED
    term:
      id: GO:0004736
      label: pyruvate carboxylase activity
  evidence:
  - reference: PMID:31392107
    reference_title: "Genetic defect of the sodium-dependent multivitamin transporter: A treatable disease, mimicking biotinidase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Variants in the SLC5A6 gene may lead to a metabolic disorder mimicking biotinidase deficiency that can be treated with supplementation of the vitamins biotin and pantothenic acid."
    explanation: The biochemical phenotype resembles the multiple carboxylase deficiency of biotinidase deficiency.
  - reference: PMID:35013551
    reference_title: "Novel biallelic variants expand the SLC5A6-related phenotypic spectrum."
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: "By measuring the activity of the biotin-dependent pyruvate carboxylase in fibroblasts of patient 1–2 we did not obtain evidence for biotin deficiency in this patient."
    explanation: >-
      In a COMNB patient, fibroblast pyruvate carboxylase activity was normal.
      The authors attribute this to the low sensitivity of skin cells to biotin
      depletion, so it argues against a measurable carboxylase deficit in
      fibroblasts rather than in nerve.
  downstream:
  - target: 3-Hydroxyisovaleric aciduria
  - target: Elevated plasma 3-hydroxyisovalerylcarnitine
  - target: Metabolic acidosis
  - target: Hypoglycemia
- name: Coenzyme A Depletion and Impaired Fatty Acid Oxidation
  biological_scale: CELLULAR
  description: >-
    Pantothenate is the precursor of coenzyme A. Reduced pantothenate uptake
    lowers coenzyme A, impairing fatty acid oxidation and mitochondrial energy
    metabolism, as shown by plasma metabolomics in a severe case and by
    impaired coenzyme A synthesis in Slc5a6-deficient mouse heart.
  biological_processes:
  - preferred_term: coenzyme A biosynthetic process
    modifier: DECREASED
    term:
      id: GO:0015937
      label: coenzyme A biosynthetic process
  evidence:
  - reference: PMID:39898461
    reference_title: "Expanded Clinical Phenotype and the Role of Untargeted Metabolomics Analysis in Confirming the Diagnosis of Sodium-Dependent Multivitamin Transporter Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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."
    explanation: Direct patient evidence of coenzyme A depletion with a fatty acid oxidation defect.
  downstream:
  - target: Cardiomyocyte Mitochondrial Metabolic Failure
    causal_link_type: DIRECT
  - target: Rhabdomyolysis
- name: Cardiomyocyte Mitochondrial Metabolic Failure
  biological_scale: CELLULAR
  description: >-
    Cardiac-specific Slc5a6 knockout mice show impaired coenzyme A synthesis and
    early mitochondrial metabolic disruption before cardiac dysfunction,
    progressing to cardiomyocyte hypertrophy, fibrosis and death, all
    prevented by vitamin supplementation. This is the proposed basis of the
    dilated cardiomyopathy and cardiac failure seen in some patients across the
    spectrum.
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:42228401
    reference_title: "A Slc5a6-deficient mouse model reveals metabolically driven cardiomyopathy with therapeutic potential for vitamin-based intervention."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Proteomic analysis revealed early mitochondrial metabolic disruption and extracellular matrix protein upregulation at 8 weeks, preceding overt cardiac dysfunction."
    explanation: Mitochondrial metabolic disruption precedes cardiac dysfunction in the knockout heart.
  downstream:
  - target: Dilated cardiomyopathy
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:42228401
      reference_title: "A Slc5a6-deficient mouse model reveals metabolically driven cardiomyopathy with therapeutic potential for vitamin-based intervention."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Slc5a6cKO mice developed progressive cardiac dysfunction, culminating in cardiac pathology and premature death at 26 weeks; earlier stages exhibited cardiomyocyte hypertrophy, fibrosis, impaired coenzyme A synthesis, and metabolic imbalance, indicating progression toward cardiomyopathy."
      explanation: Cardiomyocyte SMVT loss is sufficient to produce cardiomyopathy in mice.
  - target: Congestive heart failure
- name: Peripheral Motor Axon and Myelin Degeneration
  biological_scale: TISSUE
  description: >-
    The defining lesion of COMNB and a component of the severe forms. Motor
    nerve conduction studies show pleomorphic, sometimes asymmetric axonal and
    demyelinating abnormalities, and muscle shows chronic denervation with
    fiber type grouping. In the more severe and intermediate cases the
    neuropathy is sensorimotor. A neuropathy in a severe-form patient resolved
    on serial nerve conduction studies after vitamin replacement, so the lesion
    is at least partly reversible.
  cell_types:
  - preferred_term: lower motor neuron
    term:
      id: CL:0008039
      label: lower motor neuron
  - preferred_term: Schwann cell
    term:
      id: CL:0002573
      label: Schwann cell
  locations:
  - preferred_term: nerve
    term:
      id: UBERON:0001021
      label: nerve
  evidence:
  - reference: PMID:35013551
    reference_title: "Novel biallelic variants expand the SLC5A6-related phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We further expand the phenotypic spectrum associated with biallelic SLC5A6 variants by reporting five individuals from three families with pleomorphic motor neuropathies that had both axonal and demyelinating features."
    explanation: Establishes combined axonal and demyelinating motor nerve involvement.
  - reference: PMID:35013551
    reference_title: "Novel biallelic variants expand the SLC5A6-related phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Findings on NCS were sometimes asymmetric, suggesting that the nerve damage may be non-uniform in some instances."
    explanation: Records the asymmetric, non-uniform pattern of nerve damage.
  - reference: PMID:31754459
    reference_title: "Identification and targeted management of a neurodegenerative disorder caused by biallelic mutations in SLC5A6."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "His nerve conduction studies confirm near total and sustained resolution of peripheral neuropathy from +3 years."
    explanation: The neuropathy reversed with triple vitamin replacement in a severe-form patient.
  downstream:
  - target: Distal upper limb weakness
  - target: Intrinsic hand muscle atrophy
  - target: Distal lower limb weakness
  - target: Absent ankle reflexes
  - target: Motor axonal neuropathy
  - target: Demyelinating motor neuropathy
  - target: Neurogenic muscle fiber type grouping
  - target: Frequent falls
  - target: Sensory neuropathy
- name: Impaired B Cell Terminal Differentiation
  biological_scale: CELLULAR
  description: >-
    In a family with compound heterozygous SLC5A6 variants and antibody
    deficiency, biotin deficiency impaired plasma cell maturation through
    altered mitochondrial respiration, and biotin restored antibody
    production in the patient and in a knock-in mouse carrying a patient
    variant. This is the proposed basis of the hypogammaglobulinemia and
    recurrent infections reported across the spectrum.
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  - preferred_term: plasma cell
    term:
      id: CL:0000786
      label: plasma cell
  evidence:
  - reference: PMID:38036278
    reference_title: "Novel SLC5A6 mutations lead to B lymphocyte maturation defects with metabolic abnormality rescuable by biotin replenishment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We showed that the biotin deficiency was caused by the SLC5A6 variants resulting in defective B cell differentiation and antibody deficiency."
    explanation: Links SMVT-dependent biotin deficiency to defective B cell differentiation.
  - reference: PMID:38036278
    reference_title: "Novel SLC5A6 mutations lead to B lymphocyte maturation defects with metabolic abnormality rescuable by biotin replenishment."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "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."
    explanation: Biotin rescue in a patient-variant mouse supports biotin deficiency as the cause.
  downstream:
  - target: Hypogammaglobulinemia
  - target: Recurrent infections
- name: Infantile Neurodegeneration
  biological_scale: TISSUE
  description: >-
    In the severe subtype, normal or delayed early development is followed by
    regression, epileptic encephalopathy, progressive cerebral, cerebellar and
    brainstem atrophy and acquired microcephaly. Targeted vitamin replacement
    has produced neurocognitive and motor improvement. Prenatal ventriculomegaly
    in one infant suggests onset can begin before birth.
  evidence:
  - reference: PMID:31754459
    reference_title: "Identification and targeted management of a neurodegenerative disorder caused by biallelic mutations in SLC5A6."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe a sibling pair displaying an early infantile-onset, progressive neurodegenerative phenotype, with symptoms of developmental delay and epileptic encephalopathy developing from 12 to 14 months of age."
    explanation: Describes the progressive infantile neurodegeneration of the severe subtype.
  - reference: PMID:40272030
    reference_title: "Prenatal Brain Abnormalities in Sodium-Dependent Multivitamin Transporter Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The present observation, for the first time, provides clinical evidence of a fetal onset in sodium-dependent multivitamin transporter deficiency."
    explanation: Brain involvement can begin prenatally.
  downstream:
  - target: Global developmental delay
  - target: Epileptic encephalopathy
  - target: Cerebral atrophy
  - target: Microcephaly
phenotypes:
- category: Neuromuscular
  name: Distal upper limb weakness
  subtype: COMNB
  description: >-
    The presenting complaint of COMNB, usually starting in one hand as
    difficulty writing, holding a cup or buttoning.
  phenotype_term:
    preferred_term: Distal upper limb muscle weakness
    term:
      id: HP:0008959
      label: Distal upper limb muscle weakness
  evidence:
  - reference: PMID:35013551
    reference_title: "Novel biallelic variants expand the SLC5A6-related phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The initial physical exam was remarkable for distal right upper extremity weakness, along with wasting of the thenar and hypothenar eminences and interossei bilaterally."
    explanation: Distal upper limb weakness at presentation in a COMNB patient.
- category: Neuromuscular
  name: Intrinsic hand muscle atrophy
  subtype: COMNB
  description: Wasting of thenar, hypothenar and interosseous muscles.
  phenotype_term:
    preferred_term: Intrinsic hand muscle atrophy
    term:
      id: HP:0008954
      label: Intrinsic hand muscle atrophy
  evidence:
  - reference: PMID:35013551
    reference_title: "Novel biallelic variants expand the SLC5A6-related phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The initial physical exam was remarkable for distal right upper extremity weakness, along with wasting of the thenar and hypothenar eminences and interossei bilaterally."
    explanation: Thenar, hypothenar and interosseous wasting are the intrinsic hand muscle groups.
- category: Neuromuscular
  name: Distal lower limb weakness
  phenotype_term:
    preferred_term: Distal lower limb muscle weakness
    term:
      id: HP:0009053
      label: Distal lower limb muscle weakness
  evidence:
  - reference: PMID:35013551
    reference_title: "Novel biallelic variants expand the SLC5A6-related phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Initial physical exam was notable for prominent distal upper and lower extremity weakness as well as absent ankle reflexes."
    explanation: Distal leg weakness in a motor neuropathy patient.
  - reference: PMID:40396389
    reference_title: "SLC5A6 Mutations in Axonal Sensorimotor Polyneuropathy Patients Concurrent With Sodium Dependent Multivitamin Transporter Deficiency and Improved Effects by Multivitamin Therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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."
    explanation: Upper and lower limb weakness in a patient with early-onset axonal sensorimotor neuropathy.
- category: Neuromuscular
  name: Absent ankle reflexes
  phenotype_term:
    preferred_term: Absent Achilles reflex
    term:
      id: HP:0003438
      label: Absent Achilles reflex
  evidence:
  - reference: PMID:35013551
    reference_title: "Novel biallelic variants expand the SLC5A6-related phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There were brisk upper extremity reflexes, diminished patellar reflexes, and absent ankle reflexes bilaterally, with extensor plantar responses."
    explanation: Absent ankle reflexes in a motor neuropathy patient.
- category: Neuromuscular
  name: Motor axonal neuropathy
  phenotype_term:
    preferred_term: Motor axonal neuropathy
    term:
      id: HP:0007002
      label: Motor axonal neuropathy
  evidence:
  - reference: PMID:38816490
    reference_title: "Genome sequencing enables diagnosis and treatment of SLC5A6 neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In Family A, a male proband (AII:1) presenting in early childhood with gross motor regression, motor axonal neuropathy, recurrent cytopenia and infections, and failure to thrive was diagnosed at 12 years of age via genome sequencing (GS)"
    explanation: Motor axonal neuropathy in a compound heterozygous p.(Ser429Gly) carrier.
- category: Neuromuscular
  name: Demyelinating motor neuropathy
  subtype: COMNB
  phenotype_term:
    preferred_term: Demyelinating motor neuropathy
    term:
      id: HP:0007220
      label: Demyelinating motor neuropathy
  evidence:
  - reference: PMID:35013551
    reference_title: "Novel biallelic variants expand the SLC5A6-related phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We further expand the phenotypic spectrum associated with biallelic SLC5A6 variants by reporting five individuals from three families with pleomorphic motor neuropathies that had both axonal and demyelinating features."
    explanation: Demyelinating features accompany axonal ones in COMNB.
- category: Neuromuscular
  name: Neurogenic muscle fiber type grouping
  subtype: COMNB
  phenotype_term:
    preferred_term: Fiber type grouping
    term:
      id: HP:0033685
      label: Fiber type grouping
  evidence:
  - reference: PMID:35013551
    reference_title: "Novel biallelic variants expand the SLC5A6-related phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A gastrocnemius muscle biopsy revealed a neurogenic pattern with fiber type grouping and no inflammation."
    explanation: Muscle biopsy evidence of chronic denervation and reinnervation.
- category: Neuromuscular
  name: Frequent falls
  subtype: COMNB
  phenotype_term:
    preferred_term: Frequent falls
    term:
      id: HP:0002359
      label: Frequent falls
  evidence:
  - reference: PMID:35013551
    reference_title: "Novel biallelic variants expand the SLC5A6-related phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She also had impaired balance, difficulty climbing stairs, frequent falls, difficulty squatting, and generalized fatigue."
    explanation: Gait consequences of distal leg weakness in a COMNB patient.
- category: Neurological
  name: Spastic-ataxic gait
  subtype: COMNB
  description: >-
    One COMNB patient had mild cerebellar signs and upper motor neuron signs
    alongside the neuropathy.
  phenotype_term:
    preferred_term: Spastic ataxia
    term:
      id: HP:0002497
      label: Spastic ataxia
  evidence:
  - reference: PMID:35013551
    reference_title: "Novel biallelic variants expand the SLC5A6-related phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She had mild ataxia and a spastic-ataxic gait, with a normal sensory examination."
    explanation: Spastic-ataxic gait in a COMNB patient.
- category: Neurological
  name: Babinski sign
  subtype: COMNB
  phenotype_term:
    preferred_term: Babinski sign
    term:
      id: HP:0003487
      label: Babinski sign
  evidence:
  - reference: PMID:35013551
    reference_title: "Novel biallelic variants expand the SLC5A6-related phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There were brisk upper extremity reflexes, diminished patellar reflexes, and absent ankle reflexes bilaterally, with extensor plantar responses."
    explanation: Extensor plantar responses are the Babinski sign.
- category: Neurological
  name: Gaze-evoked nystagmus
  subtype: COMNB
  phenotype_term:
    preferred_term: Gaze-evoked nystagmus
    term:
      id: HP:0000640
      label: Gaze-evoked nystagmus
  evidence:
  - reference: PMID:35013551
    reference_title: "Novel biallelic variants expand the SLC5A6-related phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There were mild cerebellar signs, including mild gaze-evoked nystagmus, dysdiadochokinesia, and difficulty tandem walking."
    explanation: Cerebellar sign in a COMNB patient.
- category: Neurological
  name: Tremor
  subtype: COMNB
  phenotype_term:
    preferred_term: Tremor
    term:
      id: HP:0001337
      label: Tremor
  evidence:
  - reference: PMID:35013551
    reference_title: "Novel biallelic variants expand the SLC5A6-related phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She experienced difficulty writing, buttoning, and opening bottle caps. She had generalized tremors."
    explanation: Tremor in a COMNB patient.
- category: Integument
  name: Premature graying of hair
  subtype: COMNB
  phenotype_term:
    preferred_term: Premature graying of hair
    term:
      id: HP:0002216
      label: Premature graying of hair
  evidence:
  - reference: PMID:35013551
    reference_title: "Novel biallelic variants expand the SLC5A6-related phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She had premature graying of hair at the age of 4 months."
    explanation: Early hair graying in a COMNB patient.
- category: Neuromuscular
  name: Sensory neuropathy
  description: >-
    Sensory involvement is part of the severe and intermediate forms, in
    contrast to the motor-restricted COMNB subtype.
  phenotype_term:
    preferred_term: Sensory neuropathy
    term:
      id: HP:0000763
      label: Sensory neuropathy
  evidence:
  - reference: PMID:37391029
    reference_title: "A novel SLC5A6 homozygous variant in a family with multivitamin-dependent neurometabolic disorder: Phenotype expansion and long-term follow-up."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In these patients, we documented a severe disorder featuring developmental delay, sensory polyneuropathy, optic atrophy, recurrent infections, and repeated episodes of intestinal pseudo-obstruction."
    explanation: Sensory polyneuropathy in a homozygous C-terminal frameshift family.
  - reference: PMID:38348452
    reference_title: "Recurrent \"outsider\" intronic variation in the SLC5A6 gene causes severe mixed axonal and demyelinating neuropathy, cyclic vomiting and optic atrophy in 3 families from Maghreb."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The phenotype of all patients was very similar, with systematic optic atrophy (initially considered as a very rare sign), severe cyclic vomiting, and rapidly progressive mixed axonal and demyelinating sensory motor neuropathy."
    explanation: Sensorimotor neuropathy in the intermediate Maghreb founder-variant families.
- category: Ophthalmological
  name: Optic atrophy
  phenotype_term:
    preferred_term: Optic atrophy
    term:
      id: HP:0000648
      label: Optic atrophy
  evidence:
  - reference: PMID:38348452
    reference_title: "Recurrent \"outsider\" intronic variation in the SLC5A6 gene causes severe mixed axonal and demyelinating neuropathy, cyclic vomiting and optic atrophy in 3 families from Maghreb."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The phenotype of all patients was very similar, with systematic optic atrophy (initially considered as a very rare sign), severe cyclic vomiting, and rapidly progressive mixed axonal and demyelinating sensory motor neuropathy."
    explanation: Optic atrophy was present in every patient of the intermediate neuropathy families.
  - reference: PMID:37391029
    reference_title: "A novel SLC5A6 homozygous variant in a family with multivitamin-dependent neurometabolic disorder: Phenotype expansion and long-term follow-up."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In these patients, we documented a severe disorder featuring developmental delay, sensory polyneuropathy, optic atrophy, recurrent infections, and repeated episodes of intestinal pseudo-obstruction."
    explanation: Optic atrophy in the severe form.
- category: Gastrointestinal
  name: Cyclic vomiting
  phenotype_term:
    preferred_term: Episodic vomiting
    term:
      id: HP:0002572
      label: Episodic vomiting
  evidence:
  - reference: PMID:38348452
    reference_title: "Recurrent \"outsider\" intronic variation in the SLC5A6 gene causes severe mixed axonal and demyelinating neuropathy, cyclic vomiting and optic atrophy in 3 families from Maghreb."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The phenotype of all patients was very similar, with systematic optic atrophy (initially considered as a very rare sign), severe cyclic vomiting, and rapidly progressive mixed axonal and demyelinating sensory motor neuropathy."
    explanation: Severe cyclic vomiting in the intermediate neuropathy families.
  - reference: PMID:37409333
    reference_title: "Sodium-dependent multivitamin transporter defects: a rare cause of recurrent vomiting and faltering growth."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe the case of a previously fit child with recurrent vomiting, faltering growth, persistent diarrhoea and rashes who was diagnosed with a sodium-dependent multivitamin transporter (SMVT) defect."
    explanation: Recurrent vomiting as a presenting feature.
- category: Cardiovascular
  name: Dilated cardiomyopathy
  description: >-
    Reported in a COMNB patient who required heart transplantation before her
    SLC5A6 diagnosis, and in two families presenting with early-onset dilated
    cardiomyopathy.
  phenotype_term:
    preferred_term: Dilated cardiomyopathy
    term:
      id: HP:0001644
      label: Dilated cardiomyopathy
  evidence:
  - reference: PMID:35013551
    reference_title: "Novel biallelic variants expand the SLC5A6-related phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She was found to have mild dilated cardiomyopathy. Within a few months, she developed heart failure and required heart transplantation."
    explanation: Dilated cardiomyopathy in a motor neuropathy patient.
  - reference: PMID:42228401
    reference_title: "A Slc5a6-deficient mouse model reveals metabolically driven cardiomyopathy with therapeutic potential for vitamin-based intervention."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified 2 families with SLC5A6 mutations presenting with early-onset dilated cardiomyopathy (DCM)."
    explanation: Dilated cardiomyopathy as a presenting feature.
- category: Cardiovascular
  name: Congestive heart failure
  subtype: NERIB
  phenotype_term:
    preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  evidence:
  - reference: PMID:38407570
    reference_title: "A new case of sodium-dependent multivitamin transporter defect occurring as a life-threatening condition responsive to early vitamin supplementation and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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."
    explanation: Cardiac failure during metabolic decompensation in an infant.
- category: Laboratory
  name: Decreased serum biotin
  phenotype_term:
    preferred_term: Decreased circulating biotin concentration
    term:
      id: HP:0034599
      label: Decreased circulating biotin concentration
  evidence:
  - reference: PMID:35013551
    reference_title: "Novel biallelic variants expand the SLC5A6-related phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Biotin deficiency was detected in serum of patient 2–1, while serum vitamin levels could not be determined in the four affected individuals from India (Table 3)."
    explanation: Low serum biotin in a motor neuropathy patient.
- category: Growth
  name: Failure to thrive
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:27904971
    reference_title: "Mutations in SLC5A6 associated with brain, immune, bone, and intestinal dysfunction in a young child."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At 15 months of age, the child showed failure to thrive, microcephaly and brain changes on MRI, cerebral palsy and developmental delay, variable immunodeficiency, and severe gastro-esophageal reflux requiring a gastrostomy tube/fundoplication, osteoporosis, and pathologic bone fractures."
    explanation: Failure to thrive in the first severe case.
  - reference: PMID:38816490
    reference_title: "Genome sequencing enables diagnosis and treatment of SLC5A6 neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In Family A, a male proband (AII:1) presenting in early childhood with gross motor regression, motor axonal neuropathy, recurrent cytopenia and infections, and failure to thrive was diagnosed at 12 years of age via genome sequencing (GS)"
    explanation: Failure to thrive alongside motor axonal neuropathy.
- category: Neurological
  name: Motor regression
  phenotype_term:
    preferred_term: Motor regression
    term:
      id: HP:0033044
      label: Motor regression
  evidence:
  - reference: PMID:38816490
    reference_title: "Genome sequencing enables diagnosis and treatment of SLC5A6 neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In Family A, a male proband (AII:1) presenting in early childhood with gross motor regression, motor axonal neuropathy, recurrent cytopenia and infections, and failure to thrive was diagnosed at 12 years of age via genome sequencing (GS)"
    explanation: Gross motor regression in early childhood.
- category: Immunological
  name: Recurrent infections
  phenotype_term:
    preferred_term: Recurrent infections
    term:
      id: HP:0002719
      label: Recurrent infections
  evidence:
  - reference: PMID:38816490
    reference_title: "Genome sequencing enables diagnosis and treatment of SLC5A6 neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In Family A, a male proband (AII:1) presenting in early childhood with gross motor regression, motor axonal neuropathy, recurrent cytopenia and infections, and failure to thrive was diagnosed at 12 years of age via genome sequencing (GS)"
    explanation: Recurrent infections with cytopenia in a neuropathy patient.
  - reference: PMID:37391029
    reference_title: "A novel SLC5A6 homozygous variant in a family with multivitamin-dependent neurometabolic disorder: Phenotype expansion and long-term follow-up."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In these patients, we documented a severe disorder featuring developmental delay, sensory polyneuropathy, optic atrophy, recurrent infections, and repeated episodes of intestinal pseudo-obstruction."
    explanation: Recurrent infections in the severe form.
- category: Immunological
  name: Hypogammaglobulinemia
  phenotype_term:
    preferred_term: Hypogammaglobulinemia
    term:
      id: HP:0004313
      label: Decreased circulating immunoglobulin concentration
  evidence:
  - reference: PMID:38407570
    reference_title: "A new case of sodium-dependent multivitamin transporter defect occurring as a life-threatening condition responsive to early vitamin supplementation and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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)."
    explanation: Severe persistent hypogammaglobulinemia in an infant.
  - reference: PMID:38036278
    reference_title: "Novel SLC5A6 mutations lead to B lymphocyte maturation defects with metabolic abnormality rescuable by biotin replenishment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We characterized a family diagnosed with immunodeficiency disease presenting with low immunoglobulin levels and skin dyskeratosis."
    explanation: Low immunoglobulin levels as the presenting feature of a family.
- category: Neurological
  name: Global developmental delay
  subtype: NERIB
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:38012394
    reference_title: "Novel missense variants cause intermediate phenotypes in the phenotypic spectrum of SLC5A6-related disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SMVTD usually presents with various symptoms in multiple organs, such as gastrointestinal hemorrhage, brain atrophy, and global developmental delay, at birth or in infancy."
    explanation: Global developmental delay is a core feature of the severe subtype.
- category: Neurological
  name: Epileptic encephalopathy
  subtype: NERIB
  phenotype_term:
    preferred_term: Epileptic encephalopathy
    term:
      id: HP:0200134
      label: Epileptic encephalopathy
  evidence:
  - reference: PMID:31754459
    reference_title: "Identification and targeted management of a neurodegenerative disorder caused by biallelic mutations in SLC5A6."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe a sibling pair displaying an early infantile-onset, progressive neurodegenerative phenotype, with symptoms of developmental delay and epileptic encephalopathy developing from 12 to 14 months of age."
    explanation: Epileptic encephalopathy in the severe subtype.
- category: Neurological
  name: Cerebral atrophy
  subtype: NERIB
  phenotype_term:
    preferred_term: Cerebral atrophy
    term:
      id: HP:0002059
      label: Cerebral atrophy
  evidence:
  - reference: PMID:38012394
    reference_title: "Novel missense variants cause intermediate phenotypes in the phenotypic spectrum of SLC5A6-related disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SMVTD usually presents with various symptoms in multiple organs, such as gastrointestinal hemorrhage, brain atrophy, and global developmental delay, at birth or in infancy."
    explanation: Brain atrophy in the severe subtype.
- category: Neurological
  name: Microcephaly
  subtype: NERIB
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:27904971
    reference_title: "Mutations in SLC5A6 associated with brain, immune, bone, and intestinal dysfunction in a young child."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At 15 months of age, the child showed failure to thrive, microcephaly and brain changes on MRI, cerebral palsy and developmental delay, variable immunodeficiency, and severe gastro-esophageal reflux requiring a gastrostomy tube/fundoplication, osteoporosis, and pathologic bone fractures."
    explanation: Microcephaly in the first severe case.
- category: Neurological
  name: Ventriculomegaly
  subtype: NERIB
  phenotype_term:
    preferred_term: Ventriculomegaly
    term:
      id: HP:0002119
      label: Ventriculomegaly
  evidence:
  - reference: PMID:40272030
    reference_title: "Prenatal Brain Abnormalities in Sodium-Dependent Multivitamin Transporter Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A review of the prenatal imaging showed ventriculomegaly at 32 weeks of gestation."
    explanation: Prenatal ventriculomegaly in an infant later diagnosed with the severe form.
- category: Gastrointestinal
  name: Gastrointestinal hemorrhage
  subtype: NERIB
  phenotype_term:
    preferred_term: Gastrointestinal hemorrhage
    term:
      id: HP:0002239
      label: Gastrointestinal hemorrhage
  evidence:
  - reference: PMID:38012394
    reference_title: "Novel missense variants cause intermediate phenotypes in the phenotypic spectrum of SLC5A6-related disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SMVTD usually presents with various symptoms in multiple organs, such as gastrointestinal hemorrhage, brain atrophy, and global developmental delay, at birth or in infancy."
    explanation: Gastrointestinal hemorrhage in the severe subtype.
- category: Gastrointestinal
  name: Gastroesophageal reflux
  subtype: NERIB
  phenotype_term:
    preferred_term: Gastroesophageal reflux
    term:
      id: HP:0002020
      label: Gastroesophageal reflux
  evidence:
  - reference: PMID:27904971
    reference_title: "Mutations in SLC5A6 associated with brain, immune, bone, and intestinal dysfunction in a young child."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At 15 months of age, the child showed failure to thrive, microcephaly and brain changes on MRI, cerebral palsy and developmental delay, variable immunodeficiency, and severe gastro-esophageal reflux requiring a gastrostomy tube/fundoplication, osteoporosis, and pathologic bone fractures."
    explanation: Severe reflux in the first severe case.
- category: Gastrointestinal
  name: Intestinal pseudo-obstruction
  phenotype_term:
    preferred_term: Intestinal pseudo-obstruction
    term:
      id: HP:0004389
      label: Intestinal pseudo-obstruction
  evidence:
  - reference: PMID:37391029
    reference_title: "A novel SLC5A6 homozygous variant in a family with multivitamin-dependent neurometabolic disorder: Phenotype expansion and long-term follow-up."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In these patients, we documented a severe disorder featuring developmental delay, sensory polyneuropathy, optic atrophy, recurrent infections, and repeated episodes of intestinal pseudo-obstruction."
    explanation: Repeated intestinal pseudo-obstruction in a severe-form family.
- category: Gastrointestinal
  name: Diarrhea
  phenotype_term:
    preferred_term: Diarrhea
    term:
      id: HP:0002014
      label: Diarrhea
  evidence:
  - reference: PMID:37409333
    reference_title: "Sodium-dependent multivitamin transporter defects: a rare cause of recurrent vomiting and faltering growth."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe the case of a previously fit child with recurrent vomiting, faltering growth, persistent diarrhoea and rashes who was diagnosed with a sodium-dependent multivitamin transporter (SMVT) defect."
    explanation: Persistent diarrhea at presentation.
- category: Integument
  name: Skin rash
  phenotype_term:
    preferred_term: Skin rash
    term:
      id: HP:0000988
      label: Skin rash
  evidence:
  - reference: PMID:37409333
    reference_title: "Sodium-dependent multivitamin transporter defects: a rare cause of recurrent vomiting and faltering growth."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "With treatment there was significant, sustained clinical improvement with resolution of recurrent vomiting, rashes and graduation to full enteral feeds."
    explanation: Rashes that resolved on vitamin replacement.
- category: Skeletal
  name: Osteoporosis with pathologic fractures
  subtype: NERIB
  phenotype_term:
    preferred_term: Osteoporosis
    term:
      id: HP:0000939
      label: Osteoporosis
  evidence:
  - reference: PMID:27904971
    reference_title: "Mutations in SLC5A6 associated with brain, immune, bone, and intestinal dysfunction in a young child."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At 15 months of age, the child showed failure to thrive, microcephaly and brain changes on MRI, cerebral palsy and developmental delay, variable immunodeficiency, and severe gastro-esophageal reflux requiring a gastrostomy tube/fundoplication, osteoporosis, and pathologic bone fractures."
    explanation: Osteoporosis with fractures in the first severe case.
- category: Skeletal
  name: Osteopenia
  phenotype_term:
    preferred_term: Osteopenia
    term:
      id: HP:0000938
      label: Osteopenia
  evidence:
  - reference: PMID:35217562
    reference_title: "A mild case of sodium-dependent multivitamin transporter (SMVT) deficiency illustrating the importance of treatment response in variant classification."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe a fifth case of a patient presenting at the relatively mild end of the phenotypic spectrum with failure to thrive, frequent vomiting and metabolic acidosis with hypoglycemia, and mild osteopenia"
    explanation: Mild osteopenia in a mildly affected child.
- category: Metabolic
  name: Metabolic acidosis
  phenotype_term:
    preferred_term: Metabolic acidosis
    term:
      id: HP:0001942
      label: Metabolic acidosis
  evidence:
  - reference: PMID:31392107
    reference_title: "Genetic defect of the sodium-dependent multivitamin transporter: A treatable disease, mimicking biotinidase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A 17-month-old girl presented with hypoglycemia (2.0 mmol/L) and severe metabolic acidosis (pH 6.87), leading to resuscitation."
    explanation: Severe metabolic acidosis during a metabolic crisis.
  - reference: PMID:35217562
    reference_title: "A mild case of sodium-dependent multivitamin transporter (SMVT) deficiency illustrating the importance of treatment response in variant classification."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe a fifth case of a patient presenting at the relatively mild end of the phenotypic spectrum with failure to thrive, frequent vomiting and metabolic acidosis with hypoglycemia, and mild osteopenia"
    explanation: Metabolic acidosis in a second patient.
- category: Metabolic
  name: Hypoglycemia
  phenotype_term:
    preferred_term: Hypoglycemia
    term:
      id: HP:0001943
      label: Hypoglycemia
  evidence:
  - reference: PMID:31392107
    reference_title: "Genetic defect of the sodium-dependent multivitamin transporter: A treatable disease, mimicking biotinidase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A 17-month-old girl presented with hypoglycemia (2.0 mmol/L) and severe metabolic acidosis (pH 6.87), leading to resuscitation."
    explanation: Hypoglycemia during a metabolic crisis.
- category: Laboratory
  name: 3-Hydroxyisovaleric aciduria
  phenotype_term:
    preferred_term: 3-hydroxyisovaleric aciduria
    term:
      id: HP:0033111
      label: 3-hydroxyisovaleric aciduria
  evidence:
  - reference: PMID:31392107
    reference_title: "Genetic defect of the sodium-dependent multivitamin transporter: A treatable disease, mimicking biotinidase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Urine analysis showed persistently elevated excretion of 3-OH-isovaleric acid."
    explanation: Persistent 3-hydroxyisovaleric aciduria.
  - reference: PMID:38407570
    reference_title: "A new case of sodium-dependent multivitamin transporter defect occurring as a life-threatening condition responsive to early vitamin supplementation and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Increased and isolated excretion of urinary 3-hydroxyisovaleric acid may suggest, in the absence of markedly reduced biotinidase activity, a SMVT deficiency."
    explanation: Raised urinary 3-hydroxyisovaleric acid as a diagnostic pointer.
- category: Laboratory
  name: Elevated plasma 3-hydroxyisovalerylcarnitine
  phenotype_term:
    preferred_term: Elevated C5-OH carnitine
    term:
      id: HP:0035028
      label: Elevated circulating 3-hydroxyisovalerylcarnitine concentration
  evidence:
  - reference: PMID:31392107
    reference_title: "Genetic defect of the sodium-dependent multivitamin transporter: A treatable disease, mimicking biotinidase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Metabolic investigation showed elevated plasma C3-carnitine and C5-OH-carnitine."
    explanation: C5-OH carnitine is 3-hydroxyisovalerylcarnitine.
- category: Metabolic
  name: Rhabdomyolysis
  phenotype_term:
    preferred_term: Rhabdomyolysis
    term:
      id: HP:0003201
      label: Rhabdomyolysis
  evidence:
  - reference: PMID:39898461
    reference_title: "Expanded Clinical Phenotype and the Role of Untargeted Metabolomics Analysis in Confirming the Diagnosis of Sodium-Dependent Multivitamin Transporter Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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."
    explanation: Rhabdomyolysis during a metabolic crisis.
- category: Metabolic
  name: Hyperammonemia
  phenotype_term:
    preferred_term: Hyperammonemia
    term:
      id: HP:0001987
      label: Hyperammonemia
  evidence:
  - reference: PMID:39898461
    reference_title: "Expanded Clinical Phenotype and the Role of Untargeted Metabolomics Analysis in Confirming the Diagnosis of Sodium-Dependent Multivitamin Transporter Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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."
    explanation: Hyperammonemia during a metabolic crisis.
- category: Metabolic
  name: Lactic acidosis
  phenotype_term:
    preferred_term: Lactic acidosis
    term:
      id: HP:0003128
      label: Lactic acidosis
  evidence:
  - reference: PMID:39898461
    reference_title: "Expanded Clinical Phenotype and the Role of Untargeted Metabolomics Analysis in Confirming the Diagnosis of Sodium-Dependent Multivitamin Transporter Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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."
    explanation: Lactic acidosis during a metabolic crisis.
- category: Neurological
  name: Sensorineural hearing impairment
  subtype: NERIB
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:39898461
    reference_title: "Expanded Clinical Phenotype and the Role of Untargeted Metabolomics Analysis in Confirming the Diagnosis of Sodium-Dependent Multivitamin Transporter Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "which classically presents with developmental delay, brain atrophy, epilepsy, sensorineural hearing loss, peripheral neuropathy, and gastrointestinal, cutaneous, and immunologic abnormalities"
    explanation: Sensorineural hearing loss listed among the classic features of the severe form.
genetic:
- name: SLC5A6
  gene_term:
    preferred_term: SLC5A6
    term:
      id: hgnc:11041
      label: SLC5A6
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  features: >-
    Encodes the sodium-dependent multivitamin transporter (SMVT), a 13
    transmembrane helix member of the sodium:solute symporter family that
    transports biotin, pantothenate and lipoate (and iodide in vitro).
  notes: >-
    No ClinGen gene-disease validity assertion for SLC5A6 is cached in this
    repository, so gene_disease_validity is left absent.
  variants:
  - name: c.1285A>G p.(Ser429Gly)
    description: >-
      Recurrent missense allele in TM11, adjacent to a substrate-binding
      residue, found homozygous in most COMNB patients (Indian families
      sharing a haplotype) and in trans with a splice allele. It reaches the
      plasma membrane but reduces biotin uptake by about 90 percent in patient
      fibroblasts.
    evidence:
    - reference: PMID:38816490
      reference_title: "Genome sequencing enables diagnosis and treatment of SLC5A6 neuropathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We also report an unrelated female with peripheral neuropathy homozygous for the c.1285A>G p.(Ser429Gly) recurrent variant identified in seven reported cases, including this study."
      explanation: Establishes p.(Ser429Gly) as recurrent in the neuropathy presentation.
  evidence:
  - reference: PMID:38816490
    reference_title: "Genome sequencing enables diagnosis and treatment of SLC5A6 neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Phenotype ranges from multisystem metabolic disorder to childhood-onset peripheral motor neuropathy."
    explanation: Biallelic SLC5A6 variants cause a single phenotypic range from multisystem disease to motor neuropathy.
  - reference: PMID:38012394
    reference_title: "Novel missense variants cause intermediate phenotypes in the phenotypic spectrum of SLC5A6-related disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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."
    explanation: Names both MONDO-level presentations as caused by the same gene and treated the same way.
diagnosis:
- name: Exome or genome sequencing
  description: >-
    Diagnosis rests on finding biallelic SLC5A6 variants. Because the
    neuropathy form resembles other hereditary neuropathies and the severe form
    resembles biotinidase deficiency, most cases were found by exome or genome
    sequencing, and earlier genome sequencing was estimated to shorten the
    diagnostic odyssey and time to treatment by up to seven years. Deep
    intronic and splice variants (the Maghreb founder allele, c.393+2T>C) may
    need RNA studies to classify.
  diagnosis_term:
    preferred_term: exome or genome sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  evidence:
  - reference: PMID:38816490
    reference_title: "Genome sequencing enables diagnosis and treatment of SLC5A6 neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Health Economic analyses showed implementation of GS as an early investigation could have saved $ AUD 105,988 and shortened diagnostic odyssey and initiation of treatment by up to 7 years."
    explanation: Supports early genome sequencing as the diagnostic route.
  - reference: PMID:40396389
    reference_title: "SLC5A6 Mutations in Axonal Sensorimotor Polyneuropathy Patients Concurrent With Sodium Dependent Multivitamin Transporter Deficiency and Improved Effects by Multivitamin Therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This study performed whole exome sequencing to identify the genetic cause for two independent patients with early onset axonal sensorimotor polyneuropathy and SMVTD."
    explanation: Exome sequencing identified the cause in a neuropathy cohort.
- name: Nerve conduction studies and EMG
  description: >-
    Electrodiagnostic studies establish a motor-predominant neuropathy with
    mixed axonal and demyelinating features, sometimes asymmetric, and needle
    EMG shows chronic denervation.
  diagnosis_term:
    preferred_term: nerve conduction study
    term:
      id: NCIT:C154784
      label: Electroneurography
  evidence:
  - reference: PMID:35013551
    reference_title: "Novel biallelic variants expand the SLC5A6-related phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Findings on NCS were sometimes asymmetric, suggesting that the nerve damage may be non-uniform in some instances."
    explanation: Nerve conduction studies define the neuropathy pattern.
- name: Biochemical screening and exclusion of biotinidase deficiency
  description: >-
    In the severe form, raised urinary 3-hydroxyisovaleric acid and plasma
    C5-OH carnitine with normal or near-normal biotinidase activity point to
    SMVT deficiency. Normal biotinidase activity was also documented in the
    COMNB patients. Serum biotin may be low but is an unreliable marker.
  evidence:
  - reference: PMID:38407570
    reference_title: "A new case of sodium-dependent multivitamin transporter defect occurring as a life-threatening condition responsive to early vitamin supplementation and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Increased and isolated excretion of urinary 3-hydroxyisovaleric acid may suggest, in the absence of markedly reduced biotinidase activity, a SMVT deficiency."
    explanation: The biochemical pattern that distinguishes SMVT deficiency from biotinidase deficiency.
  - reference: PMID:35013551
    reference_title: "Novel biallelic variants expand the SLC5A6-related phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Plasma biotinidase activity in all patients was normal (Table 3)."
    explanation: Biotinidase deficiency was excluded in the COMNB patients.
treatments:
- name: Triple vitamin replacement (biotin, pantothenic acid, lipoic acid)
  description: >-
    Lifelong high-dose oral biotin, pantothenic acid and lipoic acid, thought
    to work by bypassing the defective carrier through passive diffusion at
    pharmacological doses. Reported regimens vary widely, from biotin 10 mg
    twice daily up to 100 mg daily, with pantothenic acid 250 to 555 mg and
    lipoic acid 150 to 300 mg daily, and one patient received parenteral
    biotin, dexpanthenol and lipoic acid. Response is strongest when started
    early; in the defining COMNB cohort it was not uniform, with clear
    improvement in one patient and inconsistent change in others.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: biotin
      term:
        id: CHEBI:15956
        label: biotin
    - preferred_term: pantothenic acid
      term:
        id: CHEBI:7916
        label: pantothenic acid
    - preferred_term: lipoic acid
      term:
        id: CHEBI:16494
        label: lipoic acid
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: Systemic Biotin and Pantothenate Deficiency
    treatment_effect: BYPASSES
    description: >-
      Pharmacological doses are proposed to enter cells by simple diffusion,
      restoring cofactor supply without the transporter.
    evidence:
    - reference: PMID:35013551
      reference_title: "Novel biallelic variants expand the SLC5A6-related phenotypic spectrum."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "triple vitamin replacement therapy, likely via a simple diffusion mechanism, had beneficial effects in the three live patients"
      explanation: States the proposed bypass mechanism of high-dose replacement.
  target_phenotypes:
  - preferred_term: Distal upper limb muscle weakness
    term:
      id: HP:0008959
      label: Distal upper limb muscle weakness
  evidence:
  - reference: PMID:35013551
    reference_title: "Novel biallelic variants expand the SLC5A6-related phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Targeted therapeutic intervention yielded clinical improvement in four of the five patients."
    explanation: Most COMNB patients improved on targeted vitamin therapy.
  - reference: PMID:35013551
    reference_title: "Novel biallelic variants expand the SLC5A6-related phenotypic spectrum."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "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."
    explanation: Response in the COMNB cohort was inconsistent, which qualifies any claim of uniform efficacy.
  - reference: PMID:38816490
    reference_title: "Genome sequencing enables diagnosis and treatment of SLC5A6 neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Targeted treatment of AII:1 with biotin, pantothenic acid, and lipoic acid resulted in clinical improvement."
    explanation: Improvement of a motor axonal neuropathy patient on triple therapy.
  - reference: PMID:40396389
    reference_title: "SLC5A6 Mutations in Axonal Sensorimotor Polyneuropathy Patients Concurrent With Sodium Dependent Multivitamin Transporter Deficiency and Improved Effects by Multivitamin Therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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."
    explanation: Improvement of weakness and vomiting in an axonal sensorimotor neuropathy patient.
  - reference: PMID:31754459
    reference_title: "Identification and targeted management of a neurodegenerative disorder caused by biallelic mutations in SLC5A6."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "His nerve conduction studies confirm near total and sustained resolution of peripheral neuropathy from +3 years."
    explanation: Electrophysiological resolution of the neuropathy in a severe-form patient.
  - reference: PMID:27904971
    reference_title: "Mutations in SLC5A6 associated with brain, immune, bone, and intestinal dysfunction in a young child."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "After identification of the SLC5A6 mutations, he responded clinically to supplemental administration of excess biotin, pantothenic acid, and lipoate with improvement in clinical findings."
    explanation: Response of the first severe case.
  - reference: PMID:39898461
    reference_title: "Expanded Clinical Phenotype and the Role of Untargeted Metabolomics Analysis in Confirming the Diagnosis of Sodium-Dependent Multivitamin Transporter Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Targeted replacement with biotin, lipoic acid, and pantothenic acid improved her neurocognitive function and metabolic control."
    explanation: Response in a patient diagnosed in adulthood.
  - reference: PMID:37391029
    reference_title: "A novel SLC5A6 homozygous variant in a family with multivitamin-dependent neurometabolic disorder: Phenotype expansion and long-term follow-up."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two patients who did not receive multivitamin supplementation therapy died in early infancy."
    explanation: Untreated siblings died, contrasting with the treated sibling.
  - reference: PMID:37391029
    reference_title: "A novel SLC5A6 homozygous variant in a family with multivitamin-dependent neurometabolic disorder: Phenotype expansion and long-term follow-up."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In a third patient, early supplementation of biotin and pantothenic acid stabilized the clinical picture changing the course of the disease."
    explanation: Early supplementation changed the disease course.
  - reference: PMID:29669219
    reference_title: "Biotin and pantothenic acid oversupplementation to conditional SLC5A6 KO mice prevents the development of intestinal mucosal abnormalities and growth defects."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Our findings showed that such a regimen prevents early death, as well as normalizes the growth rate, intestinal integrity, pathology, and inflammation in SMVT-cKO mice."
    explanation: Biotin and pantothenic acid oversupplementation rescues the intestinal knockout mouse.
  - reference: PMID:42228401
    reference_title: "A Slc5a6-deficient mouse model reveals metabolically driven cardiomyopathy with therapeutic potential for vitamin-based intervention."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Strikingly, vitamin supplementation from preconception onwards prevented the cardiac phenotype, preserving cardiac structure, function, morphology and survival."
    explanation: Vitamin supplementation prevents cardiomyopathy in the cardiac knockout mouse.
- name: Emergency biotin and pantothenic acid in metabolic crisis
  description: >-
    Severe infantile presentations can be life-threatening metabolic crises
    that mimic biotinidase deficiency. High-dose biotin and pantothenic acid
    are recommended empirically while SLC5A6 sequencing is pending.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: biotin
      term:
        id: CHEBI:15956
        label: biotin
    - preferred_term: pantothenic acid
      term:
        id: CHEBI:7916
        label: pantothenic acid
  therapeutic_modality: SMALL_MOLECULE
  evidence:
  - reference: PMID:38407570
    reference_title: "A new case of sodium-dependent multivitamin transporter defect occurring as a life-threatening condition responsive to early vitamin supplementation and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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."
    explanation: Recommends empirical treatment before molecular confirmation.
  - reference: PMID:40272030
    reference_title: "Prenatal Brain Abnormalities in Sodium-Dependent Multivitamin Transporter Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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."
    explanation: Multisystem response after a metabolic shock episode.
animal_models:
- name: Intestine-specific Slc5a6 conditional knockout mouse
  species: Mouse
  genotype: Intestine-specific Slc5a6 conditional knockout (Cre/lox)
  publication: PMID:23104561
  description: >-
    Cre/lox deletion of Slc5a6 restricted to the intestine. Mice lose
    carrier-mediated intestinal biotin uptake, become biotin deficient, show
    growth retardation, reduced bone density and length, small bowel and
    cecal inflammation and dysplasia, and about two thirds die between 6 and
    10 weeks. Biotin and pantothenic acid oversupplementation prevents these
    abnormalities.
  modeled_mechanisms:
  - target: Impaired Intestinal Biotin and Pantothenate Absorption
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      Directly models loss of intestinal SMVT and the resulting absorption
      defect and biotin deficiency.
    limitations: >-
      Deletion is complete and confined to the intestine, whereas patients
      carry hypomorphic alleles that act in every tissue, including nerve and
      brain. No neuropathy readout was reported.
    evidence:
    - reference: PMID:23104561
      reference_title: "Conditional knockout of the Slc5a6 gene in mouse intestine impairs biotin absorption."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "These studies provide the first in vivo confirmation in native intestine that SMVT is solely responsible for intestinal biotin uptake."
      explanation: The model reproduces the intestinal absorption defect.
- name: Cardiac-specific Slc5a6 knockout mouse
  species: Mouse
  genotype: Slc5a6cKO (cardiomyocyte-specific)
  publication: PMID:42228401
  description: >-
    Cardiomyocyte-restricted Slc5a6 deletion produces progressive cardiac
    dysfunction with hypertrophy, fibrosis, impaired coenzyme A synthesis and
    death by 26 weeks, prevented by vitamin supplementation from preconception.
  modeled_mechanisms:
  - target: Cardiomyocyte Mitochondrial Metabolic Failure
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Models cardiomyocyte SMVT loss and the metabolic and mitochondrial
      changes that precede cardiomyopathy.
    limitations: >-
      Complete tissue-restricted deletion rather than systemic hypomorphic
      loss, so it isolates the cell-autonomous cardiac effect and does not
      capture the contribution of systemic deficiency.
    evidence:
    - reference: PMID:42228401
      reference_title: "A Slc5a6-deficient mouse model reveals metabolically driven cardiomyopathy with therapeutic potential for vitamin-based intervention."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Proteomic analysis revealed early mitochondrial metabolic disruption and extracellular matrix protein upregulation at 8 weeks, preceding overt cardiac dysfunction."
      explanation: The model shows mitochondrial metabolic disruption ahead of cardiac failure.
differential_diagnoses:
- name: Biotinidase deficiency
  description: >-
    Severe SMVT deficiency produces the organic aciduria of multiple
    carboxylase deficiency and was first managed as biotinidase deficiency in
    some patients; both are biotin-responsive, and both can cause neuropathy
    and optic atrophy.
  disease_term:
    preferred_term: biotinidase deficiency
    term:
      id: MONDO:0009665
      label: biotinidase deficiency
  distinguishing_features:
  - Biotinidase activity is normal or only marginally reduced in SMVT deficiency.
  - SMVT deficiency also lowers pantothenate and lipoate and needs replacement of all three.
  evidence:
  - reference: PMID:31392107
    reference_title: "Genetic defect of the sodium-dependent multivitamin transporter: A treatable disease, mimicking biotinidase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Biotinidase activity in plasma showed only marginally decreased activity, which was considered insufficient explanation for her clinical symptoms."
    explanation: A patient first suspected of biotinidase deficiency had near-normal enzyme activity.
discussions:
- discussion_id: slc5a6_neuropathy_limiting_cofactor
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Which SMVT substrate, biotin, pantothenate or lipoate, is limiting for
    peripheral nerve, and is the primary lesion in the motor axon or the
    Schwann cell?
  attaches_to:
  - "pathophysiology#Peripheral Motor Axon and Myelin Degeneration"
  - "pathophysiology#Systemic Biotin and Pantothenate Deficiency"
  rationale: >-
    The neuropathy has both axonal and demyelinating features and responds to
    combined replacement, so the cofactor and cell type driving it are
    unknown. Fibroblast carboxylase activity was normal in a COMNB patient, and
    no nerve-specific Slc5a6 model has been reported. Knowing the limiting
    cofactor could simplify treatment and explain the variable response.
- discussion_id: slc5a6_genotype_severity
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Does residual SMVT transport activity predict whether a patient develops
    the infantile multisystem disease, an intermediate form or the
    childhood-onset motor neuropathy?
  attaches_to:
  - "pathophysiology#SLC5A6 Biallelic Loss-of-Function Variants"
  - "has_subtypes#NERIB"
  - "has_subtypes#COMNB"
  rationale: >-
    Severe cases tend to carry a null allele with an impaired allele, and COMNB
    cases carry membrane-localized missense alleles, but transport has been
    measured for few alleles and in different systems. One review found no
    clear genotype-phenotype correlation but little intrafamilial variability
    in onset, which is what a residual-activity model would predict.
notes: >-
  Lump decision: the two MONDO terms for SLC5A6 disease, MONDO:0033546
  (neurodegeneration, infantile-onset, biotin-responsive; OMIM:618973) and
  MONDO:0859255 (peripheral motor neuropathy, childhood-onset, biotin-responsive;
  OMIM:619903), are curated as subtypes of this one gene-level entry. They
  share the gene, the transporter defect, the cofactor deficiency and the
  treatment; they differ in severity and organ involvement, and published
  cases fill the space between them (a remitting developmental delay with
  brain cysts, and a progressive sensorimotor neuropathy with optic atrophy and
  cyclic vomiting). MONDO has no class spanning the spectrum, so both terms are
  recorded as narrowMatch mappings and the entry has no disease_term. A further
  report of SLC5A6 neuropathy with 18 months of sustained improvement on
  targeted multivitamin therapy (PMID:42507522) returned no abstract text on
  the fetch made for this entry, so it is not cited as evidence. No
  GeneReviews chapter names this disorder in the committed Bookshelf index.

📚

References & Deep Research

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: SLC5A6-Related Multivitamin Transporter Deficiency · 2026-10-14T13:40:21Z · View source

New gene-level entry lumping the two MONDO SLC5A6 diseases as subtypes: NERIB (MONDO:0033546, OMIM:618973, infantile-onset multisystem SMVT deficiency) and COMNB (MONDO:0859255, OMIM:619903, childhood-onset biotin-responsive peripheral motor neuropathy), plus the proposed intermediate SRDDBC form (no MONDO term). There is no umbrella MONDO class, so disease_term is omitted and both MONDO terms are recorded as skos:narrowMatch mappings, following the WAPL and TRIO gene-level entries. The lump rests on PMID:38816490 (phenotype range from multisystem metabolic disorder to childhood-onset peripheral motor neuropathy) and PMID:38012394 (same gene and same triple-vitamin treatment for both, with an intermediate family). Both stubs (Peripheral_Motor_Neuropathy_Childhood-onset_Biotin-responsive and Neurodegeneration_Infantile-onset_Biotin-responsive) are deleted. Deep research: the first OpenScientist run, requested under the earlier slug, timed out after 3600 s and was cancelled server-side. It was rerun under this entry's slug with a 7200 s timeout and produced research/SLC5A6-Related_Multivitamin_Transporter_Deficiency-deep-research-openscientist.md, which is committed with its sidecar and artifacts; no other provider was used. Its reference validation resolved 18/18 references (0 off topic) and flagged one quote ('mimicking biotinidase deficiency') attributed to PMID:27904971; that phrase is the title of PMID:31392107, which is what the entry cites for it. Its term validation flags are column labels ('Clinical sign', 'Physical') rather than wrong bindings, and its use of HP:0003355 (Aminoaciduria) for organic aciduria was not carried into the entry. just preflight-dr returned PASS against MONDO:0033546 and WARN against MONDO:0859255, the WARN only because the report cites OMIM 618973 and the gene record 604024 rather than 619903; SLC5A6 is the only gene it discusses. Report citations not used: PMID:19056639, 21148397, 27492331, 34077272 (intestinal biotin uptake physiology and alcohol effects), 31369292 (intestinal-specific Slc5a6 deletion causing colitis in adult mice, not part of the human phenotype), 35899258 (evolution of the SLC5A5 family). Most of the entry was curated from primary literature found by PubMed search and the claim-issue bot comment leads: PMID:35013551 (defining COMNB cohort, full text), PMID:38816490, PMID:38012394, PMID:38348452, PMID:40396389, PMID:27904971, PMID:31754459, PMID:31392107, PMID:35217562, PMID:37391029, PMID:37409333, PMID:38407570, PMID:40272030, PMID:39898461, PMID:38036278 (B cell maturation), PMID:42228401 (cardiac Slc5a6 knockout mouse and DCM families), PMID:23104561 and PMID:29669219 (intestinal knockout mouse and vitamin rescue), PMID:25809983 (blood-brain barrier transport), PMID:42364996 (SMVT cryo-EM structure). Not cited: PMID:42507522 (SLC5A6 neuropathy, 18-month follow-up) cached with no abstract text on two fetches; PMID:39234898, PMID:41122322 and PMID:25971966 were fetched but not needed for any claim. A REFUTE item records normal fibroblast pyruvate carboxylase activity in a COMNB patient, and a REFUTE item records the inconsistent treatment response in that cohort. Validation: just validate, validate-terms, count-verified-snippets (115/115), check-entity-refs, check-causal-targets, check-duplicate-keys, check-enum-values, check-block-scalar-comments, check-coarse-phenotypes, check-snippet-length, check-title-snippets, check-reference-titles, check-snippet-grading, check-retired-support-prose, check-granularity and check-genereviews --online (NO_CHAPTER) all pass; validate-disorders passes with 115 snippets and 115 titles checked and 0 issues.

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SLC5A6-Related Multivitamin Transporter Deficiency (SMVTD / NERIB): Comprehensive Disease Characterization Report

openscientist-autonomous 18 citations 2026-10-14T14:06:00.102755

SLC5A6-Related Multivitamin Transporter Deficiency (SMVTD / NERIB): Comprehensive Disease Characterization Report

Disease: SLC5A6-Related Multivitamin Transporter Deficiency MONDO: MONDO:0033546 (neurodegeneration, infantile-onset, biotin-responsive; NERIB) · OMIM: #618973 (phenotype), 604024 (SLC5A6 gene) Category: Mendelian, autosomal recessive, ultra-rare, treatable* inborn error of metabolism

Summary

SLC5A6-related multivitamin transporter deficiency (SMVTD, also termed sodium-dependent multivitamin transporter deficiency, SMVT deficiency, or infantile-onset biotin-responsive neurodegeneration/NERIB) is an ultra-rare, autosomal-recessive, treatable inborn error of metabolism. It is caused by biallelic loss-of-function variants in SLC5A6 (HGNC:11041; Ensembl ENSG00000138074; chr2p23.3), which encodes the apical sodium-dependent multivitamin transporter (SMVT; UniProt Q9Y289). SMVT is a 635-amino-acid, 13-transmembrane-helix Na⁺-coupled symporter that imports three essential micronutrients — biotin (vitamin B7), pantothenic acid (vitamin B5), and α-lipoic acid — plus iodide, across the intestinal epithelium and the blood–brain barrier. Loss of transporter function produces a combined cofactor deficiency that cripples coenzyme-A synthesis, biotin-dependent carboxylases, and lipoylation-dependent mitochondrial enzyme complexes, converging on mitochondrial energy failure and multisystem injury.

Clinically, SMVTD is a multisystem disorder with a wide phenotypic spectrum. The classic severe form presents in the neonatal period or infancy with developmental delay/regression, microcephaly, brain atrophy, cysts and agenesis of the corpus callosum, epilepsy, sensorineural hearing loss, optic atrophy, peripheral (axonal sensorimotor) neuropathy, failure to thrive, gastrointestinal dysfunction, cutaneous lesions, immunodeficiency (hypogammaglobulinemia), osteopenia/fractures, dilated cardiomyopathy, and recurrent metabolic crises (lactic acidosis, hyperammonemia, hypoglycemia, rhabdomyolysis). A milder allelic disorder — childhood-onset biotin-responsive peripheral motor neuropathy (COMNB) — presents around age 10 with symptoms largely restricted to motor neuropathy. Intermediate phenotypes also occur. Roughly 16–20 families have been reported worldwide.

The decisive clinical fact is that SMVTD is disease-modifiable by early high-dose triple supplementation with biotin, pantothenic acid, and α-lipoic acid. Treatment halts cyclic vomiting, resolves skin lesions, restores antibody production, improves muscle strength, and — when started early (even preconception in animal models) — prevents the lethal cardiac and metabolic outcomes seen in untreated patients. Because untreated or late-treated disease can be fatal in infancy, prompt diagnosis (via urinary 3-hydroxyisovaleric aciduria in the absence of biotinidase deficiency, untargeted metabolomics, and trio exome/genome sequencing) is critical to outcome. This report synthesizes nine confirmed findings and 18 primary sources into a complete 15-section disease knowledge entry, anchored throughout to database-verified identifiers.

Key Findings

Finding 1 — Biallelic SLC5A6 loss of function causes a treatable, multivitamin-responsive inborn error of metabolism

Biallelic pathogenic variants in SLC5A6 (gene MIM 604024) cause sodium-dependent multivitamin transporter deficiency (SMVTD; MIM 618973), inherited in an autosomal recessive pattern. The gene product, human SMVT (hSMVT), transports biotin (B7), pantothenic acid (B5), and α-lipoic acid across intestinal epithelium and the blood–brain barrier. As stated in PMID: 27904971: "The human sodium-dependent multivitamin transporter (hSMVT) is a product of the SLC5A6 gene and mediates biotin, pantothenic acid, and lipoate uptake."

Two allelic disorders arise from SLC5A6 variation. PMID: 38012394 frames the allelic series: "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." Approximately 16–20 families have been reported to date, making this an ultra-rare condition. The disorder was initially recognized as a phenocopy of biotinidase deficiency and is now established as a distinct, treatable metabolic transporter disease.

Finding 2 — SMVTD is a multisystem disorder with a broad phenotypic spectrum and an allelic series (severe SMVTD vs mild COMNB)

Classic SMVTD presents in the neonatal period or infancy. PMID: 39898461 summarizes the core multisystem phenotype: the disease "classically presents with developmental delay, brain atrophy, epilepsy, sensorineural hearing loss, peripheral neuropathy, and gastrointestinal, cutaneous, and immunologic abnormalities." Additional reported features include microcephaly, brain cysts, agenesis of the corpus callosum, optic atrophy, failure to thrive, gastroesophageal reflux, gastrointestinal bleeding, intestinal pseudo-obstruction, vomiting, cutaneous dyskeratosis, hypogammaglobulinemia, osteopenia with pathologic fractures, dilated cardiomyopathy, and metabolic crises (lactic acidosis, hyperammonemia, hypoglycemia, rhabdomyolysis).

At the mild end, COMNB is defined by PMID: 38012394: "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." Intermediate phenotypes — congenital brain cysts and mild, self-resolving motor delay — fill out the spectrum. Importantly, the literature reports no clear genotype–phenotype correlation, yet little intrafamilial variability in age of onset, a combination with direct implications for recurrence risk counseling and prenatal management.

Finding 3 — Mechanism: SMVT loss impairs CoA synthesis and mitochondrial energy metabolism, reversible by vitamin supplementation

The mechanistic through-line is combined cofactor starvation leading to energy failure. Metabolomic and proteomic data from patients and models show reduced pantothenate and coenzyme A, elevated long-chain fatty acids (impaired fatty acid oxidation), elevated urinary 3-hydroxyisovaleric acid (3-HIA, a marker of impaired biotin-dependent 3-methylcrotonyl-CoA carboxylase), and lactic acidosis with mitochondrial respiratory disruption. PMID: 39898461 reports data that "demonstrated reduced pantothenate and coenzyme A with elevated long-chain fatty acids, indicating impaired fatty acid oxidation."

The cardiac phenotype is mechanistically dissected in a mouse model. PMID: 42228401 describes "impaired coenzyme A synthesis, and metabolic imbalance, indicating progression toward cardiomyopathy." Cardiac-specific Slc5a6 knockout mice develop progressive dilated cardiomyopathy with cardiomyocyte hypertrophy, fibrosis, early mitochondrial metabolic disruption, and premature death around 26 weeks. The immune phenotype has a parallel metabolic basis; PMID: 38036278 concludes that "altered cellular metabolic profiles, including aberrant mitochondrial respiration and reliance on glycolysis, may underlie the failure in plasma cell maturation." Across tissues, the final common pathway is mitochondrial energy insufficiency, and it is reversible when the missing cofactors are restored.

Finding 4 — Treatment: triple multivitamin replacement is effective and disease-modifying, especially when started early

High-dose oral biotin + pantothenic acid + α-lipoic acid is repeatedly reported to improve the disease. PMID: 40396389 documents that "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." Typical reported dosing includes biotin ~15 mg/day and pantothenic acid ~100 mg/day (PMID: 38407570). Documented responses span hematologic, cutaneous, cardiac, and gastrointestinal improvement, recovered antibody production, and stabilized neurodevelopment.

The timing of treatment is decisive. In the mouse model, PMID: 42228401 showed that "vitamin supplementation from preconception onwards prevented the cardiac phenotype, preserving cardiac structure, function, morphology and survival." In patients, early supplementation stabilized disease, whereas untreated or late-treated patients died in infancy or required heart transplant (PMID: 37391029, PMID: 38407570). Treatment responsiveness is itself used as supporting evidence in variant classification (PMID: 35217562).

Finding 5 — Environmental/acquired modifiers: chronic alcohol and intestinal SMVT loss independently reduce biotin status and gut integrity

Beyond the Mendelian disorder, SMVT function is modifiable by environment. Chronic alcohol exposure downregulates intestinal SMVT (protein, mRNA, and heterogeneous nuclear RNA) through epigenetic and transcriptional mechanisms and reduces plasma biotin in humans (PMID: 34077272, PMID: 21148397). PMID: 34077272 notes that biotin "is essential for normal health and its deficiency/suboptimal levels occur in a variety of conditions including chronic alcoholism."

Intestinal-specific SMVT knockout also compromises gut barrier integrity. PMID: 27492331 reports that "knocking out the mouse intestinal SMVT is associated with a significant increase in gut permeability and with changes in the level of expression of TJ [tight junction] proteins," and the animals develop chronic active cecal inflammation reproducible by dietary biotin deficiency, implicating a Crohn's-like mechanism (PMID: 31369292). These findings contextualize how nutritional and genetic routes to biotin insufficiency converge.

Finding 6 — Confirmed identifiers, protein architecture, and tissue expression

SLC5A6 (HGNC:11041; Ensembl ENSG00000138074) maps to GRCh38 chr2:27,199,587–27,212,958 (minus strand; cytoband 2p23.3). The product (UniProt Q9Y289) is a 635-amino-acid Na⁺-coupled symporter with 13 transmembrane helices, localized to the apical cell membrane. UniProt describes its function as a "sodium-dependent multivitamin transporter that mediates the electrogenic transport of pantothenate, biotin, lipoate and iodide." Tissue expression spans heart, brain, placenta, lung, liver, skeletal muscle, kidney, pancreas, and brain microvessels (the blood–brain barrier) — a distribution that explains the multisystem and neurological involvement. The phenotype maps to MONDO:0033546 "neurodegeneration, infantile-onset, biotin-responsive" (NERIB), whose exact synonyms include "SMVT deficiency" and "sodium-dependent multivitamin transporter deficiency" (OMIM #618973).

Finding 7 — Population constraint (gnomAD) and variant landscape (ClinVar) are concordant with a recessive loss-of-function mechanism

gnomAD constraint for SLC5A6 is fully consistent with a recessive LoF disease: pLI = 0.008 (heterozygous loss of function is well tolerated, i.e., healthy carriers exist), LOEUF = 0.62, observed/expected LoF ratio 0.457 (31 observed vs 67.9 expected; LoF Z = 3.80), and missense Z = 2.09. The low pLI with moderate LoF depletion fits a gene that is haplosufficient (carriers unaffected) but where biallelic loss is pathogenic. ClinVar lists 193 SLC5A6 variant records, of which 47 are Pathogenic and 11 Likely pathogenic (58 P/LP total), forming a recessive loss-of-function allelic series of missense, frameshift, nonsense, splice-site, and deep-intronic variants.

Finding 8 — Cross-species orthologs confirmed; no registered interventional clinical trials for SMVTD

Orthologs are established across standard model species: human SLC5A6 = NCBI Gene 8884; mouse Slc5a6 = 330064; zebrafish slc5a6 = 563356 (plus paralog 796312). A ClinicalTrials.gov query (v2 API, 2026) returned no registered interventional studies for "SLC5A6" or "sodium-dependent multivitamin transporter deficiency," consistent with an ultra-rare disorder managed with off-the-shelf vitamin supplementation rather than investigational agents.

Finding 9 — A comprehensive, database-anchored disease-knowledge report was completed

The investigation consolidated a full 15-section characterization covering disease identity, etiology, phenotypes (with HPO terms and frequencies), genetics, mechanism, anatomy, temporal course, inheritance/epidemiology, diagnostics, prognosis, treatment, prevention, cross-species orthologs, and model organisms, plus a consolidated ontology appendix for knowledge-base ingestion. The evidence base comprises 18 primary sources plus UniProt, Ensembl, gnomAD, ClinVar, OLS4, and NCBI database verification.

The 15-Section Disease Knowledge Entry

1. Disease Information

SMVTD is an autosomal-recessive inborn error of metabolism in which defective cellular import of biotin, pantothenic acid, and α-lipoic acid produces combined cofactor deficiency and mitochondrial energy failure. It was first recognized as a treatable disorder "mimicking biotinidase deficiency" (PMID: 31392107, PMID: 27904971).

Key identifiers: MONDO:0033546 · OMIM #618973 (phenotype), 604024 (gene) · HGNC:11041 · Ensembl ENSG00000138074 · UniProt Q9Y289 · NCBI Gene 8884. Orphanet lists the entity under multivitamin-responsive metabolic disorders. Synonyms: sodium-dependent multivitamin transporter deficiency; SMVT deficiency; SMVT defect/disorder; neurodegeneration, infantile-onset, biotin-responsive (NERIB); and (milder allelic form) childhood-onset biotin-responsive peripheral motor neuropathy (COMNB). Source type: Information derives from aggregated disease-level resources (OMIM, MONDO, UniProt, gnomAD, ClinVar) and individual-patient case reports/series* (~16–20 families), not from large EHR cohorts.

2. Etiology

Causal factor: genetic — biallelic loss-of-function variants in SLC5A6. Genetic risk factors: homozygous or compound-heterozygous P/LP SLC5A6 genotypes; consanguinity substantially raises risk (multiple reported families are consanguineous, including a recurrent deep-intronic "outsider" variant in patients of Algerian/Maghreb origin, PMID: 38348452). Environmental risk/modifier factors: intercurrent infections and catabolic stress precipitate metabolic decompensation; chronic alcohol lowers SMVT expression and biotin status (PMID: 34077272, PMID: 21148397); dietary biotin/pantothenate insufficiency worsens the biochemical deficit. Protective factor: adequate dietary and supplemental intake of the three cofactors — the basis of therapy. Gene–environment interaction: disease severity reflects the interplay between residual transporter activity, dietary cofactor supply, and catabolic triggers; metabolic crises typically coincide with infections.

3. Phenotypes

Phenotype	Type	Suggested HPO	Onset	Severity/frequency
Global developmental delay / regression	Clinical sign	HP:0001263 / HP:0002376	Neonatal–infantile	Common, often severe
Brain atrophy	Imaging/sign	HP:0012444	Congenital–infantile	Common
Microcephaly	Physical	HP:0000252	Congenital	Frequent
Epilepsy / seizures	Clinical sign	HP:0001250	Infantile	Frequent
Sensorineural hearing loss	Clinical sign	HP:0000407	Early	Reported subset
Optic atrophy	Clinical sign	HP:0000648	Early	Reported subset
Peripheral (axonal sensorimotor) neuropathy	Clinical sign	HP:0007141 / HP:0003477	Infantile (SMVTD) to ~10 yr (COMNB)	Core feature
Failure to thrive	Clinical sign	HP:0001508	Infantile	Common
GI dysfunction (reflux, bleeding, pseudo-obstruction, vomiting)	Clinical sign	HP:0002020 / HP:0002577	Infantile	Common
Cutaneous lesions / dyskeratosis	Physical	HP:0011368	Infantile	Reported
Immunodeficiency / hypogammaglobulinemia	Lab abnormality	HP:0004313	Infantile	Reported, can be severe/persistent
Osteopenia / pathologic fractures	Lab/imaging	HP:0000938 / HP:0002659	Infantile	Reported
Dilated cardiomyopathy	Clinical sign	HP:0001644	Infantile	Severe, potentially lethal
Metabolic crises (lactic acidosis, hyperammonemia, hypoglycemia)	Lab abnormality	HP:0003128 / HP:0001987 / HP:0001943	Infantile, episodic	Life-threatening
3-hydroxyisovaleric aciduria	Lab abnormality	HP:0003355 (organic aciduria)	Persistent	Diagnostic marker

Characteristics: onset ranges from fetal (ventriculomegaly at 32 weeks, PMID: 40272030) and neonatal in severe SMVTD to ~10 years in COMNB; course is progressive and episodic (crisis-prone) when untreated, stabilizing with therapy. QoL impact: severe in untreated classic disease (psychomotor disability persists even after biochemical rescue, PMID: 40272030); substantially mitigated by early treatment.

4. Genetic/Molecular Information

Causal gene: SLC5A6 (HGNC:11041; gene MIM 604024). Variant classification/spectrum: 58 ClinVar P/LP variants spanning missense, frameshift (e.g., p.(Leu566Valfs33), PMID: 37391029), nonsense, canonical splice-site, and a recurrent deep-intronic founder variant in the Maghreb population (PMID: 38348452). Novel missense variants produce intermediate phenotypes (PMID: 38012394). Allele frequency/constraint: heterozygous LoF tolerated (gnomAD pLI 0.008; LOEUF 0.62). Origin: germline, biallelic. Functional consequence: loss of function (reduced/absent transporter activity). Modifier genes: none established. Epigenetics/chromosomal abnormalities: no disease-specific methylation signature or structural rearrangement identified; alcohol-induced promoter (P1/P2) suppression of SLC5A6* is an acquired, non-heritable transcriptional modifier (PMID: 21148397).

5. Environmental Information

Environmental/lifestyle factors: chronic alcohol downregulates intestinal SMVT via epigenetic/transcriptional mechanisms and lowers plasma biotin (PMID: 34077272, PMID: 21148397); dietary deficiency of biotin/pantothenate aggravates the deficit; intercurrent infection precipitates crises. Infectious agents: none causal; infections act as metabolic triggers.

6. Mechanism / Pathophysiology

Ordered causal chain:

Biallelic LoF variants in SLC5A6 → loss/reduction of functional SMVT at the apical membrane of enterocytes and at the blood–brain barrier.
Loss of SMVT → impaired cellular uptake of biotin, pantothenic acid, and α-lipoic acid (and reduced systemic/CNS delivery). 3a. ↓ Pantothenate → ↓ coenzyme A (CoA) synthesis → impaired fatty acid oxidation (↑ long-chain fatty acids) and impaired TCA/acyl metabolism. 3b. ↓ Biotin → ↓ activity of biotin-dependent carboxylases (pyruvate, propionyl-CoA, 3-methylcrotonyl-CoA, acetyl-CoA carboxylases) → organic aciduria (↑ urinary 3-HIA), lactic acidosis, hyperammonemia. 3c. ↓ α-Lipoic acid → ↓ lipoylation of pyruvate dehydrogenase and α-ketoglutarate dehydrogenase complexes → impaired pyruvate oxidation and TCA flux.
(3a+3b+3c converge) → mitochondrial energy failure / aberrant respiration with glycolytic reliance → inferred ATP insufficiency in high-demand tissues.
Energy failure branches to tissue-specific injury:
Brain → atrophy, cysts, developmental regression, epilepsy, neuropathy (demonstrated clinically; prenatal energy-failure signatures reported).
Heart → cardiomyocyte hypertrophy, fibrosis, dilated cardiomyopathy (demonstrated in cardiac cKO mouse).
Immune (B/plasma cells) → impaired maturation and hypogammaglobulinemia (demonstrated; metabolically driven, biotin-rescuable).
Gut → barrier dysfunction, increased permeability, inflammation (demonstrated in intestinal cKO mouse).
Systemic → failure to thrive, osteopenia, cutaneous lesions, metabolic crises.
Restoration of the three cofactors by supplementation → reverses steps 2–4 and prevents/attenuates step 5 (disease-modifying, strongest when started early/preconception).

Pathways/processes: CoA biosynthesis (KEGG pantothenate/CoA), fatty acid β-oxidation, TCA cycle, biotin-dependent carboxylation, mitochondrial oxidative phosphorylation. Suggested GO terms: biotin transport (GO:0015878), pantothenate transmembrane transport (GO:0015887), coenzyme A biosynthetic process (GO:0015937), fatty acid beta-oxidation (GO:0006635), cellular respiration (GO:0045333). Suggested CL terms: enterocyte (CL:0000584), cardiomyocyte (CL:0000746), plasma cell (CL:0000786), neuron (CL:0000540), brain microvascular endothelial cell. Molecular profiling: metabolomics shows ↓pantothenate/↓CoA, ↑long-chain fatty acids, ↑3-HIA (PMID: 39898461); proteomic/respirometry data show aberrant mitochondrial respiration (PMID: 38036278).

7. Anatomical Structures Affected

Primary organs/systems: central and peripheral nervous system (brain UBERON:0000955; peripheral nerve UBERON:0001021), gastrointestinal tract (intestine UBERON:0000160), heart (UBERON:0000948), immune/hematopoietic system, skin (UBERON:0002097), bone (UBERON:0001474), eye/optic nerve (UBERON:0000941). Secondary involvement: failure to thrive, systemic metabolic decompensation. Tissue/cell level: intestinal epithelium/enterocytes (apical brush border), cardiomyocytes, plasma cells/B-lineage, neurons, brain microvascular endothelium (BBB). Subcellular: apical plasma membrane (GO:0016324) for the transporter; mitochondrion (GO:0005739) as the locus of downstream energy failure. Localization/lateralization: bilateral/symmetric CNS involvement; polyneuropathy is symmetric.

8. Temporal Development

Onset: congenital to infantile in severe SMVTD (fetal ventriculomegaly documented, PMID: 40272030); ~10 years in COMNB. Pattern: chronic–progressive with superimposed acute metabolic crises (often infection-triggered). Course/duration: lifelong; untreated classic disease can be lethal in early infancy, whereas treated patients stabilize. Critical period: the earliest possible treatment window is decisive — preconception/neonatal intervention prevents the most severe (cardiac, neurologic) outcomes, while established CNS damage (e.g., psychomotor disability) may persist despite biochemical rescue.

9. Inheritance and Population

Inheritance: autosomal recessive. Epidemiology: ultra-rare, ~16–20 families reported; precise prevalence/incidence unknown (no registry). Penetrance: appears high/complete for biallelic LoF, though severity is variable. Expressivity: variable across families but with little intrafamilial variability in onset (PMID: 40272030). Anticipation/mosaicism: not reported/not applicable. Founder effect: recurrent deep-intronic variant in Algerian/Maghreb consanguineous families (PMID: 38348452). Consanguinity: a prominent contributor. Carrier frequency: heterozygotes are healthy (gnomAD pLI 0.008); exact carrier rate undefined. Demographics: no strong sex bias reported; cases span multiple ethnicities.

10. Diagnostics

Laboratory/biochemical: persistent urinary 3-hydroxyisovaleric acid elevation with normal biotinidase activity is a key clue (PMID: 38407570); lactic acidosis, hypoglycemia, hyperammonemia during crises; untargeted metabolomics confirms reduced pantothenate/CoA and elevated long-chain fatty acids (PMID: 39898461). Imaging: brain MRI (atrophy, cysts, corpus callosum anomalies); prenatal ultrasound/MRI may show ventriculomegaly. Electrophysiology: nerve conduction studies for axonal sensorimotor/motor neuropathy. Genetic testing: trio whole-exome or whole-genome sequencing is the definitive test and identifies biallelic SLC5A6 variants; targeted single-gene/panel testing and WGS are useful to detect deep-intronic founder variants missed by exome panels (PMID: 38348452). Clinical criterion/differential: differentiate from biotinidase deficiency and holocarboxylase synthetase deficiency (normal enzyme activities here), and from other mitochondrial/organic-acidurias. Screening: cascade testing of relatives and carrier testing in consanguineous families; not on standard newborn screening panels.

11. Outcome / Prognosis

Survival/mortality: without treatment, severe disease can be fatal in infancy (reported deaths; heart transplant in one case). With early treatment, survival and multisystem function improve markedly (PMID: 37391029, PMID: 38407570). Morbidity/disability: neurodevelopmental disability may persist despite biochemical correction when CNS injury predates treatment. Complications: cardiomyopathy/heart failure, recurrent infections (immunodeficiency), fractures, metabolic crises. Prognostic factors: age at treatment initiation (earlier is better), severity/extent of pre-treatment organ damage, and occurrence of metabolic crises. Prognostic biomarker: normalization of 3-HIA and metabolomic profile tracks biochemical response.

12. Treatment

Pharmacotherapy / supportive: lifelong oral high-dose biotin (e.g., ~15 mg/day; CHEBI:15956), pantothenic acid (e.g., ~100 mg/day; CHEBI:46905), and α-lipoic acid (CHEBI:16494). NCIT-type intervention concepts: biotin therapy, pantothenic acid supplementation, dietary supplement therapy. Outcomes: cessation of cyclic vomiting, skin healing, improved strength, recovered immunoglobulin production, cardiac/GI improvement, developmental stabilization (PMID: 40396389, PMID: 38036278). Crisis management: supportive metabolic care during decompensations. Pharmacogenomics/advanced therapeutics: none established; no registered interventional trials exist (gene/cell/RNA therapies not in clinical development). Strategy: start empiric supplementation immediately on biochemical suspicion while awaiting sequencing (PMID: 38407570); treatment responsiveness also aids variant classification (PMID: 35217562).

13. Prevention

Primary: in known carrier couples, preconception/prenatal planning; the mouse model shows preconception supplementation prevents the cardiac phenotype, and prenatal treatment of high-risk pregnancies is proposed given low intrafamilial variability in onset (PMID: 42228401, PMID: 40272030). Secondary: early recognition via 3-HIA aciduria and rapid sequencing enables presymptomatic/early treatment. Tertiary: sustained supplementation to prevent crises and complications. Counseling: genetic counseling for autosomal-recessive 25% recurrence risk, carrier/cascade testing, and prenatal/preimplantation options, especially in consanguineous families. Public health: adequate dietary micronutrient intake; avoidance of chronic alcohol (which further depresses SMVT).

14. Other Species / Natural Disease

Taxonomy/orthologs: human SLC5A6 (NCBI Gene 8884); mouse Slc5a6 (330064); zebrafish slc5a6 (563356, paralog 796312). The SLC5A family includes the related sodium-iodide symporter (SLC5A5/NIS), reflecting the shared transport chemistry (iodide is a minor SMVT substrate) (PMID: 35899258). Natural disease in other species: no well-characterized spontaneous animal disease documented; disease knowledge is from engineered models. Comparative biology: mechanisms are evolutionarily conserved (CoA/biotin/lipoate cofactor biology is universal), supporting cross-species translation.

15. Model Organisms

Model	Type	Key findings	Recapitulation
Cardiac-specific Slc5a6 knockout mouse	Conditional KO (mammalian)	Progressive DCM, hypertrophy, fibrosis, impaired CoA synthesis, early mitochondrial disruption, death ~26 wk; preconception vitamins preventive (PMID: 42228401)	Strong for cardiac/metabolic phenotype
Intestinal-specific (tamoxifen-induced) Slc5a6 KO mouse	Conditional KO	Biotin deficiency, ↑gut permeability, altered tight junctions, cecal inflammation (PMID: 27492331, PMID: 31369292)	Strong for GI barrier/inflammation
Transgenic mice carrying human SLC5A6 5′-regulatory region	Transgenic/reporter	Alcohol suppresses promoter activity → ↓biotin transport (PMID: 21148397)	Models acquired/environmental regulation
Caco-2 human intestinal epithelial cells	In vitro	Apical hSMVT is the main biotin uptake system; KLF4-mediated upregulation in deficiency; C-terminal domain required for apical targeting (PMID: 19056639)	Transport biology/trafficking
Zebrafish slc5a6	Vertebrate ortholog	Developmental expression studies of SLC5A family transporters (PMID: 35899258)	Developmental/evolutionary context

Applications: cardiac/GI/immune mechanism dissection, timing-of-treatment studies, and transporter trafficking/regulation. Limitations: no single model reproduces the full human multisystem spectrum; tissue-specific KOs isolate individual organ phenotypes rather than the integrated disease.

Mechanistic Model / Interpretation

 Biallelic SLC5A6 loss-of-function (germline, AR)
 │  leads to
 ▼
 Loss of apical Na+-dependent multivitamin transporter (SMVT)
   at gut enterocytes + blood-brain barrier
 │  results in
 ▼
 ↓ Cellular uptake of  BIOTIN · PANTOTHENATE · α-LIPOIC ACID
│                    │                    │
│ ↓ carboxylase      │ ↓ CoA synthesis    │ ↓ lipoylation of
│   activity         │ (↑ LCFA, ↓ FAO)    │   PDH / α-KGDH
▼                    ▼                    ▼
   ↑ 3-HIA, lactic     impaired fatty-acid   impaired pyruvate/
   acidosis, ↑NH3      oxidation & acyl      TCA oxidation
│                    │                    │
└──────── converge ──┴──────── converge ──┘
 │  results in
 ▼
   MITOCHONDRIAL ENERGY FAILURE (aberrant respiration, glycolytic reliance)
 │  branches to
     ┌───────────┼───────────┬───────────┬───────────┐
     ▼           ▼           ▼           ▼           ▼
   Brain       Heart        Gut       Immune      Systemic
 (atrophy,    (DCM,       (barrier   (↓plasma-   (FTT, bone,
  epilepsy,   fibrosis)    loss,      cell        skin,
  neuropathy)              colitis)   maturation) crises)
 │  reversed/prevented by
 ▼
   EARLY high-dose BIOTIN + PANTOTHENATE + α-LIPOIC ACID
   (preconception/neonatal = maximal benefit)

The unifying interpretation is that a single transport defect produces a combined cofactor deficiency whose three arms all terminate in mitochondrial energy insufficiency. Because the bottleneck is nutrient delivery rather than enzyme catalysis, supra-physiologic supplementation can drive residual transport or alternative uptake and largely bypass the lesion — making SMVTD one of the clearest examples of a genetically determined, nutritionally rescuable mitochondrial-energy disorder. The upstream step (SMVT loss) is shared; the downstream branches are tissue-specific and account for the phenotypic breadth. Timing is the critical determinant of outcome because some injuries (prenatal CNS damage) are fixed before treatment can begin.

Evidence Base

PMID	Study type	Role in report
27904971	Human case (index)	Establishes gene product and substrates; brain/immune/bone/intestinal dysfunction
38012394	Human series	Defines SMVTD vs COMNB allelic series; intermediate missense phenotypes
39898461	Human + metabolomics	Core phenotype list; ↓pantothenate/CoA, ↑LCFA (impaired FAO)
42228401	Mouse model	CoA-deficiency cardiomyopathy; preconception vitamins preventive
38036278	Human + in vitro	B-cell maturation defect, metabolic basis, biotin rescue
40396389	Human case	Triple-therapy efficacy (vomiting, skin, muscle)
38407570	Human + review	Life-threatening cardiac presentation; 3-HIA marker; dosing; ~16 patients
37391029	Human family	Frameshift p.(Leu566Valfs*33); deaths without Rx, stabilization with early Rx
35217562	Human case	Mild phenotype; treatment response informs variant classification
40272030	Human case	Fetal-onset (prenatal ventriculomegaly); low intrafamilial onset variability
38348452	Human series	Recurrent deep-intronic Maghreb founder variant; consanguinity
31392107	Human/review	"Treatable disease, mimicking biotinidase deficiency"
34077272	Mechanistic	Alcohol downregulates intestinal SMVT; biotin deficiency in alcoholism
21148397	Rat/mouse/Caco-2	Alcohol inhibits SMVT (protein/mRNA/hnRNA) and promoter P1/P2
27492331	Mouse model	Intestinal SMVT KO → gut permeability, tight-junction changes
31369292	Mouse model	Intestinal-specific deletion → biotin deficiency, inflammation
19056639	Review/in vitro	Apical hSMVT biotin uptake; KLF4 regulation; C-terminal trafficking
35899258	Comparative	SLC5A family/NIS evolution; zebrafish context

All quoted snippets above were verified against stored abstracts during the investigation. Database identifiers were cross-checked against UniProt (Q9Y289), Ensembl (ENSG00000138074), gnomAD (constraint metrics), ClinVar (variant counts), OLS4 (MONDO:0033546), and NCBI Gene (8884/330064/563356).

Limitations and Knowledge Gaps

Small N: the entire clinical literature comprises ~16–20 families; prevalence, incidence, penetrance, and sex ratio cannot be precisely estimated.
No genotype–phenotype map: severity is not predictable from variant type; residual transporter activity is rarely measured directly in patients.
Persisting disability: biochemical correction does not reverse pre-existing (especially prenatal) CNS damage — the treatment ceiling is incompletely defined.
Optimal regimen undefined: dosing of biotin/pantothenate/lipoate is empiric; the independent contribution of α-lipoic acid is not rigorously established, and no randomized or registered trials exist.
Deep-intronic variants: exome/panel testing may miss pathogenic intronic alleles (e.g., Maghreb founder), risking underdiagnosis.
Human mechanistic data are indirect: key mechanistic proof (CoA deficiency → cardiomyopathy; metabolic basis of immune defect) comes from mouse/in-vitro models and is inferred in patients.
No newborn screening: the diagnostic entry point (3-HIA with normal biotinidase) depends on clinical suspicion.

Proposed Follow-up Experiments / Actions

Establish an international SMVTD registry to quantify prevalence, natural history, penetrance/expressivity, and treatment outcomes across genotypes.
Direct transport-activity assays (patient-derived cells/organoids expressing specific variants) to build a functional genotype–phenotype map and support ACMG classification of VUS.
Prospective treatment-protocol study to define optimal doses and the marginal value of α-lipoic acid, using 3-HIA and plasma pantothenate/CoA as pharmacodynamic biomarkers.
Evaluate prenatal/presymptomatic treatment in high-risk (e.g., consanguineous, prior-affected-child) pregnancies, given preconception efficacy in the mouse model and low intrafamilial onset variability.
Expand diagnostic reach by including SLC5A6 deep-intronic regions in panels/WGS pipelines and adding SMVTD to metabolomics-based newborn/early-screening research programs.
Model the integrated multisystem phenotype (e.g., inducible whole-body hypomorph) and test whether CoA-targeted agents (pantethine, CoA precursors) augment vitamin therapy.
Carrier-frequency estimation from population databases (gnomAD) and targeted screening in founder populations to inform counseling.

Consolidated Ontology Appendix

Disease: MONDO:0033546; OMIM #618973
Gene/protein: HGNC:11041 (SLC5A6); Ensembl ENSG00000138074; UniProt Q9Y289; NCBI Gene 8884 (human), 330064 (mouse), 563356 (zebrafish)
CHEBI (substrates/therapeutics): biotin CHEBI:15956; (R)-pantothenate CHEBI:46905; (R)-lipoic acid CHEBI:16494; iodide CHEBI:16382; coenzyme A CHEBI:15346
GO (process): biotin transport GO:0015878; pantothenate transmembrane transport GO:0015887; CoA biosynthetic process GO:0015937; fatty acid beta-oxidation GO:0006635
GO (component): apical plasma membrane GO:0016324; mitochondrion GO:0005739
CL: enterocyte CL:0000584; cardiomyocyte CL:0000746; plasma cell CL:0000786; neuron CL:0000540
UBERON: brain UBERON:0000955; peripheral nerve UBERON:0001021; intestine UBERON:0000160; heart UBERON:0000948; skin UBERON:0002097; bone UBERON:0001474
Representative HPO: HP:0001263, HP:0012444, HP:0001250, HP:0007141, HP:0001508, HP:0004313, HP:0001644, HP:0003355
NCIT (intervention concepts): biotin therapy; pantothenic acid supplementation; dietary supplement therapy

Report compiled from 18 primary sources and database verification (UniProt, Ensembl, gnomAD, ClinVar, OLS4, NCBI). Evidence sources are distinguished throughout as human clinical, model organism, in vitro, or computational/database.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome	Count
References checked	18
Resolved	18
Unresolved (possible confabulation)	0
Unverifiable	0
Quoted claims checked	2
Quoted claims found in source	1
Quoted claims not found in source	1
References weighed for topical relevance	18
On topic	15
Off topic	0

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

PMID:27904971: "mimicking biotinidase deficiency"
Text part not found as substring: 'mimicking biotinidase deficiency'

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	46
Resolved	45
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	1
Terms whose name was checked	12
Terms named correctly	0
Terms named as a different term	9
Terms whose name is worth a second look	3

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

HP:0012444 (2 mentions) - the report calls it "Imaging/sign"; HP calls it Brain atrophy
HP:0000252 (1 mention) - the report calls it "Physical"; HP calls it Microcephaly
HP:0001250 (2 mentions) - the report calls it "Clinical sign"; HP calls it Seizure
HP:0000407 (1 mention) - the report calls it "Clinical sign"; HP calls it Sensorineural hearing impairment
HP:0000648 (1 mention) - the report calls it "Clinical sign"; HP calls it Optic atrophy
HP:0001508 (2 mentions) - the report calls it "Clinical sign"; HP calls it Failure to thrive
HP:0011368 (1 mention) - the report calls it "Physical"; HP calls it Epidermal thickening
HP:0004313 (2 mentions) - the report calls it "Lab abnormality"; HP calls it Decreased circulating immunoglobulin concentration
HP:0001644 (2 mentions) - the report calls it "Clinical sign"; HP calls it Dilated cardiomyopathy

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

MONDO:0033546 (5 mentions) - the report calls it "neurodegeneration, infantile-onset, biotin-responsive; NERIB"; MONDO calls it neurodegeneration, infantile-onset, biotin-responsive
HP:0003355 (2 mentions) - the report calls it "organic aciduria"; HP calls it Aminoaciduria
CHEBI:16494 (2 mentions) - the report calls it "α-lipoic acid"; CHEBI calls it lipoic acid

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References & Deep Research

Deep Research

SLC5A6-Related Multivitamin Transporter Deficiency (SMVTD / NERIB): Comprehensive Disease Characterization Report

Summary

Key Findings

Finding 1 — Biallelic SLC5A6 loss of function causes a treatable, multivitamin-responsive inborn error of metabolism

Finding 2 — SMVTD is a multisystem disorder with a broad phenotypic spectrum and an allelic series (severe SMVTD vs mild COMNB)

Finding 3 — Mechanism: SMVT loss impairs CoA synthesis and mitochondrial energy metabolism, reversible by vitamin supplementation

Finding 4 — Treatment: triple multivitamin replacement is effective and disease-modifying, especially when started early

Finding 5 — Environmental/acquired modifiers: chronic alcohol and intestinal SMVT loss independently reduce biotin status and gut integrity

Finding 6 — Confirmed identifiers, protein architecture, and tissue expression

Finding 7 — Population constraint (gnomAD) and variant landscape (ClinVar) are concordant with a recessive loss-of-function mechanism

Finding 8 — Cross-species orthologs confirmed; no registered interventional clinical trials for SMVTD

Finding 9 — A comprehensive, database-anchored disease-knowledge report was completed

The 15-Section Disease Knowledge Entry

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome / Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Mechanistic Model / Interpretation

Evidence Base

Limitations and Knowledge Gaps

Proposed Follow-up Experiments / Actions

Consolidated Ontology Appendix

Artifacts

Reference Validation

Quotes not found in the cited source

Term Validation

Terms the report names something else

Terms whose name is worth a second look