familial isolated deficiency of vitamin E

Summary

familial isolated deficiency of vitamin E (MONDO:0010188) is a disease caused by TTPA (GenCC Definitive), with 2 cohort genes and 3 clinical trials.

At a glance

• Prevalence: 1-9 / 1 000 000 (Europe) [Orphanet-validated]
• Causal gene: TTPA (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 168
• Phenotypes (HPO): 37
• Clinical trials: 3

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000	0.33	Europe	Validated

Signs & symptoms

Clinical features (HPO)

37 HPO clinical features (Orphanet curated; top 37 by frequency):

HPO ID	Term	Frequency
HP:0001251	Ataxia	Very frequent (80-99%)
HP:0001284	Areflexia	Very frequent (80-99%)
HP:0001324	Muscle weakness	Very frequent (80-99%)
HP:0003487	Babinski sign	Very frequent (80-99%)
HP:0007256	Abnormal pyramidal sign	Very frequent (80-99%)
HP:0009830	Peripheral neuropathy	Very frequent (80-99%)
HP:0100513	Low levels of vitamin E	Very frequent (80-99%)
HP:0000639	Nystagmus	Frequent (30-79%)
HP:0000662	Nyctalopia	Frequent (30-79%)
HP:0000763	Sensory neuropathy	Frequent (30-79%)
HP:0001260	Dysarthria	Frequent (30-79%)
HP:0001272	Cerebellar atrophy	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0001310	Dysmetria	Frequent (30-79%)
HP:0001761	Pes cavus	Frequent (30-79%)
HP:0002075	Dysdiadochokinesis	Frequent (30-79%)
HP:0002167	Abnormality of speech or vocalization	Frequent (30-79%)
HP:0002312	Clumsiness	Frequent (30-79%)
HP:0002599	Head titubation	Frequent (30-79%)
HP:0002650	Scoliosis	Frequent (30-79%)
HP:0010831	Impaired proprioception	Frequent (30-79%)
HP:0000012	Urinary urgency	Occasional (5-29%)
HP:0000505	Visual impairment	Occasional (5-29%)
HP:0000649	Abnormality of visual evoked potentials	Occasional (5-29%)
HP:0000819	Diabetes mellitus	Occasional (5-29%)
HP:0001268	Mental deterioration	Occasional (5-29%)
HP:0001276	Hypertonia	Occasional (5-29%)
HP:0001332	Dystonia	Occasional (5-29%)
HP:0001337	Tremor	Occasional (5-29%)
HP:0001639	Hypertrophic cardiomyopathy	Occasional (5-29%)
HP:0002376	Developmental regression	Occasional (5-29%)
HP:0002403	Positive Romberg sign	Occasional (5-29%)
HP:0003202	Skeletal muscle atrophy	Occasional (5-29%)
HP:0004374	Hemiplegia/hemiparesis	Occasional (5-29%)
HP:0007703	Abnormality of retinal pigmentation	Occasional (5-29%)
HP:0011675	Arrhythmia	Occasional (5-29%)
HP:0000580	Pigmentary retinopathy	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	familial isolated deficiency of vitamin E
Mondo ID	MONDO:0010188
MeSH	C535393
OMIM	277460
Orphanet	96
DOID	DOID:0090028
SNOMED CT	702442008
UMLS	C1848533
MedGen	341248
GARD	0008595
MedDRA	10047631
NORD	817
Is cancer (heuristic)	no

Also known as: ataxia with isolated vitamin E deficiency · Ataxia with Vitamin E Deficiency · AVED · familial isolated deficiency of vitamin type E · familial isolated vitamin E deficiency · Friedreich-like ataxia · Friedreich-like ataxia with selective vitamin E deficiency · isolated vitamin E deficiency · VED · vitamin E, familial isolated deficiency OF

Data availability: 168 ClinVar variants · 5 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn vitamin metabolic disorder › familial isolated deficiency of vitamin E

Related subtypes (4): neurodegenerative syndrome due to cerebral folate transport deficiency, disorders of vitamin D metabolism, inborn disorder of cobalamin metabolism and transport, cerebral folate deficiency

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

168 retrieved; paginated sample, class counts are floors:

76 uncertain significance, 31 likely pathogenic, 18 pathogenic/likely pathogenic, 11 pathogenic, 10 benign, 9 likely benign, 9 conflicting classifications of pathogenicity, 3 not provided, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1027489	NM_000370.3(TTPA):c.553-1G>T	TTPA	Pathogenic	criteria provided, multiple submitters, no conflicts
1073498	NM_000370.3(TTPA):c.84_91dup (p.Leu31fs)	TTPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076433	NM_000370.3(TTPA):c.19C>T (p.Gln7Ter)	TTPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1371154	NM_000370.3(TTPA):c.652dup (p.Ile218fs)	TTPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1452309	NM_000370.3(TTPA):c.663+1G>A	TTPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1459425	NM_000370.3(TTPA):c.218_219dup (p.Tyr74fs)	TTPA	Pathogenic	criteria provided, multiple submitters, no conflicts
188951	NM_000370.3(TTPA):c.487del (p.Trp163fs)	TTPA	Pathogenic	criteria provided, multiple submitters, no conflicts
189186	NM_000370.3(TTPA):c.2T>C (p.Met1Thr)	TTPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2044146	NM_000370.3(TTPA):c.74del (p.Gln25fs)	TTPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2074456	NM_000370.3(TTPA):c.588del (p.Leu196_Ile197insTer)	TTPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
208623	NM_000370.3(TTPA):c.19del (p.Gln7fs)	TTPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
267261	NM_000370.3(TTPA):c.205-1G>T	TTPA	Pathogenic	criteria provided, single submitter
2679385	NM_000370.3(TTPA):c.302_309del (p.His101fs)	TTPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
370311	NM_000370.3(TTPA):c.13C>T (p.Arg5Ter)	TTPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
370407	NM_000370.3(TTPA):c.205-1G>C	TTPA	Pathogenic	criteria provided, multiple submitters, no conflicts
370950	NM_000370.3(TTPA):c.205-2A>G	TTPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
371454	NM_000370.3(TTPA):c.2T>A (p.Met1Lys)	TTPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
374211	NM_000370.3(TTPA):c.552G>A (p.Thr184=)	TTPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
550204	NM_000370.3(TTPA):c.88_118del (p.Ala30fs)	TTPA	Pathogenic	criteria provided, single submitter
551293	NM_000370.3(TTPA):c.227_229delinsATT (p.Trp76_Arg77delinsTyrTer)	TTPA	Pathogenic	criteria provided, multiple submitters, no conflicts
557555	NM_000370.3(TTPA):c.1A>T (p.Met1Leu)	TTPA	Pathogenic	criteria provided, single submitter
65591	NM_000370.3(TTPA):c.358G>A (p.Ala120Thr)	TTPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
65592	NM_000370.3(TTPA):c.421G>A (p.Glu141Lys)	TTPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
65597	NM_000370.3(TTPA):c.661C>T (p.Arg221Trp)	TTPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
840876	NM_000370.3(TTPA):c.182del (p.Phe61fs)	TTPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
9136	NM_000370.3(TTPA):c.744del (p.Glu249fs)	TTPA	Pathogenic	criteria provided, multiple submitters, no conflicts
9137	NM_000370.3(TTPA):c.303T>G (p.His101Gln)	TTPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
9139	NM_000370.3(TTPA):c.513_514insTT (p.Thr172fs)	TTPA	Pathogenic	criteria provided, multiple submitters, no conflicts
9141	NM_000370.3(TTPA):c.400C>T (p.Arg134Ter)	TTPA	Pathogenic	criteria provided, multiple submitters, no conflicts
1256475	NM_000370.3(TTPA):c.173C>A (p.Ala58Asp)	TTPA	Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
TTPA	Definitive	Autosomal recessive	familial isolated deficiency of vitamin E	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TTPA	Orphanet:96	Ataxia with vitamin E deficiency
HLCS	Orphanet:79242	Holocarboxylase synthetase deficiency

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TTPA	HGNC:12404	ENSG00000137561	P49638	Alpha-tocopherol transfer protein	gencc,clinvar
HLCS	HGNC:4976	ENSG00000159267	P50747	Biotin–protein ligase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TTPA	Alpha-tocopherol transfer protein	Binds alpha-tocopherol, enhances its transfer between separate membranes, and stimulates its release from liver cells.
HLCS	Biotin–protein ligase	Biotin–protein ligase catalyzing the biotinylation of the 4 biotin-dependent carboxylases acetyl-CoA-carboxylase, pyruvate carboxylase, propionyl-CoA carboxylase, and methylcrotonyl-CoA carboxylase.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TTPA	Other/Unknown	no		CRAL-TRIO_dom, CRAL/TRIO_N_dom, CRAL/TRIO_N_dom_sf
HLCS	Other/Unknown	no		BPL_C, BPL_LPL_catalytic, Biotin_CoA_COase_ligase

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
buccal mucosa cell	1
liver	1
right lobe of liver	1
frontal pole	1
middle frontal gyrus	1
paraflocculus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TTPA	135	broad	yes	right lobe of liver, liver, buccal mucosa cell
HLCS	205	ubiquitous	marker	paraflocculus, frontal pole, middle frontal gyrus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HLCS	2,554
TTPA	1,060

Structural data

PDB: 1 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TTPA	P49638	6

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
HLCS	P50747	77.33

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Vitamin E transport	1	5710.0×	0.002	TTPA
Defects in biotin (Btn) metabolism	1	1142.0×	0.004	HLCS
Defective HLCS causes multiple carboxylase deficiency	1	815.7×	0.004	HLCS
Biotin transport and metabolism	1	519.1×	0.005	HLCS
Defects in vitamin and cofactor metabolism	1	300.5×	0.007	HLCS
Metabolism of water-soluble vitamins and cofactors	1	90.6×	0.018	HLCS
Metabolism of vitamins and cofactors	1	58.3×	0.024	HLCS
Diseases of metabolism	1	40.2×	0.031	HLCS
Disease	1	6.5×	0.163	HLCS
Metabolism	1	5.8×	0.165	HLCS

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of establishment of blood-brain barrier	1	8426.0×	0.001	TTPA
response to biotin	1	4213.0×	0.001	HLCS
biotin metabolic process	1	2106.5×	0.002	HLCS
vitamin E metabolic process	1	1685.2×	0.002	TTPA
vitamin transport	1	1404.3×	0.002	TTPA
positive regulation of amyloid-beta clearance	1	1053.2×	0.002	TTPA
intermembrane lipid transfer	1	601.9×	0.003	TTPA
embryonic placenta development	1	383.0×	0.004	TTPA
post-translational protein modification	1	210.7×	0.006	HLCS
response to toxic substance	1	105.3×	0.010	TTPA
lipid metabolic process	1	45.8×	0.022	TTPA

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TTPA	0	0
HLCS	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
HLCS	8	Binding:8
TTPA	5	Binding:5

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	TTPA, HLCS

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
TTPA	5	—
HLCS	8	—

Clinical trials & evidence

Clinical trials

Clinical trials: 3.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	3

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening