adult Refsum disease

Summary

adult Refsum disease (MONDO:0009958) is a disease caused by PHYH (GenCC Definitive), with 2 cohort genes and 4 clinical trials.

At a glance

• Prevalence: 1-9 / 1 000 000 (Europe) [Orphanet-validated]
• Causal gene: PHYH (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 109
• Phenotypes (HPO): 38
• Clinical trials: 4

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		60	Worldwide	Validated
Point prevalence	1-9 / 1 000 000	0.1	Europe	Validated

Signs & symptoms

Clinical features (HPO)

38 HPO clinical features (Orphanet curated; top 38 by frequency):

HPO ID	Term	Frequency
HP:0000458	Anosmia	Very frequent (80-99%)
HP:0000478	Abnormality of the eye	Very frequent (80-99%)
HP:0000488	Retinopathy	Very frequent (80-99%)
HP:0000504	Abnormality of vision	Very frequent (80-99%)
HP:0000518	Cataract	Very frequent (80-99%)
HP:0000958	Dry skin	Very frequent (80-99%)
HP:0001251	Ataxia	Very frequent (80-99%)
HP:0001638	Cardiomyopathy	Very frequent (80-99%)
HP:0000407	Sensorineural hearing impairment	Very frequent (80-99%)
HP:0001760	Abnormal foot morphology	Very frequent (80-99%)
HP:0001939	Abnormality of metabolism/homeostasis	Very frequent (80-99%)
HP:0002164	Nail dysplasia	Very frequent (80-99%)
HP:0002652	Skeletal dysplasia	Very frequent (80-99%)
HP:0004374	Hemiplegia/hemiparesis	Very frequent (80-99%)
HP:0007256	Abnormal pyramidal sign	Very frequent (80-99%)
HP:0007703	Abnormality of retinal pigmentation	Very frequent (80-99%)
HP:0008064	Ichthyosis	Very frequent (80-99%)
HP:0009830	Peripheral neuropathy	Very frequent (80-99%)
HP:0000496	Abnormality of eye movement	Frequent (30-79%)
HP:0000505	Visual impairment	Frequent (30-79%)
HP:0000508	Ptosis	Frequent (30-79%)
HP:0000662	Nyctalopia	Frequent (30-79%)
HP:0001744	Splenomegaly	Frequent (30-79%)
HP:0000616	Miosis	Frequent (30-79%)
HP:0001252	Hypotonia	Frequent (30-79%)
HP:0001765	Hammertoe	Frequent (30-79%)
HP:0002376	Developmental regression	Frequent (30-79%)
HP:0003202	Skeletal muscle atrophy	Frequent (30-79%)
HP:0005930	Abnormality of epiphysis morphology	Frequent (30-79%)
HP:0010049	Short metacarpal	Frequent (30-79%)
HP:0010864	Intellectual disability, severe	Frequent (30-79%)
HP:0000083	Renal insufficiency	Occasional (5-29%)
HP:0000529	Progressive visual loss	Occasional (5-29%)
HP:0000568	Microphthalmia	Occasional (5-29%)
HP:0000639	Nystagmus	Occasional (5-29%)
HP:0001761	Pes cavus	Occasional (5-29%)
HP:0002093	Respiratory insufficiency	Occasional (5-29%)
HP:0012722	Heart block	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	adult Refsum disease
Mondo ID	MONDO:0009958
MeSH	C535517, D012035
OMIM	266500, 600964
Orphanet	773
DOID	DOID:10582
ICD-10-CM	G60.1
SNOMED CT	25362006
UMLS	C0034960
MedGen	11161
GARD	0005691
MedDRA	10038275
NORD	1654
Is cancer (heuristic)	no

Also known as: adult Refsum disease · adult Refsum disease due to PHYH · classic Refsum disease · disorder of cornification 11 (phytanic acid type) · DOC 11 (phytanic acid type) · hereditary motor and sensory neuropathy 4 · hereditary motor and sensory neuropathy type 4 · hereditary sensory and motor neuropathy type 4 · heredopathia atactica polyneuritiformis · HMSN 4 · HMSN type IV · HSMN IV · hypertrophic neuropathy of Refsum · phytanic acid oxidase deficiency · phytanic-CoA hydroxylase deficiency · RDPA · Refsum Disease · Refsum disease · Refsum disease with increased pipecolic acidemia · Refsum disease, adult, 1 (+2 more)

Data availability: 109 ClinVar variants · 7 GenCC gene-disease records · 6 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › peroxisomal disease › peroxisomal single enzyme/protein defect › disorder of peroxisomal alpha oxidation › phytanoyl-CoA hydroxylase deficiency › adult Refsum disease

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

109 retrieved; paginated sample, class counts are floors:

34 uncertain significance, 26 likely pathogenic, 14 conflicting classifications of pathogenicity, 12 pathogenic/likely pathogenic, 8 pathogenic, 6 benign/likely benign, 5 benign, 4 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1454975	NM_006214.4(PHYH):c.42_60dup (p.Ser21fs)	LOC130003374	Pathogenic	criteria provided, multiple submitters, no conflicts
188975	NM_000288.4(PEX7):c.188+1G>C	PEX7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
370682	NM_000288.4(PEX7):c.277C>T (p.Gln93Ter)	PEX7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
7780	NM_000288.4(PEX7):c.875T>A (p.Leu292Ter)	PEX7	Pathogenic	criteria provided, multiple submitters, no conflicts
7781	NM_000288.4(PEX7):c.653C>T (p.Ala218Val)	PEX7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
7788	NM_000288.4(PEX7):c.120C>G (p.Tyr40Ter)	PEX7	Pathogenic	criteria provided, multiple submitters, no conflicts
1404181	NM_006214.4(PHYH):c.679-1dup	PHYH	Pathogenic	criteria provided, multiple submitters, no conflicts
1698840	NM_006214.4(PHYH):c.811del (p.Thr271fs)	PHYH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1973968	NM_006214.4(PHYH):c.675G>A (p.Trp225Ter)	PHYH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2136846	NM_006214.4(PHYH):c.457del (p.Ala153fs)	PHYH	Pathogenic	criteria provided, multiple submitters, no conflicts
2576187	NM_006214.4(PHYH):c.520dup (p.Leu174fs)	PHYH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2677764	NM_006214.4(PHYH):c.426del (p.Lys141_Tyr142insTer)	PHYH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3359073	NM_006214.4(PHYH):c.336del (p.Pro113fs)	PHYH	Pathogenic	criteria provided, single submitter
7580	NM_006214.4(PHYH):c.823C>T (p.Arg275Trp)	PHYH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
7581	NM_006214.4(PHYH):c.135-2A>G	PHYH	Pathogenic	criteria provided, multiple submitters, no conflicts
7588	NM_006214.4(PHYH):c.824G>A (p.Arg275Gln)	PHYH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
812375	NM_006214.4(PHYH):c.135-1G>C	PHYH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
853270	NM_006214.4(PHYH):c.497-2A>G	PHYH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
872163	NM_006214.4(PHYH):c.830C>A (p.Ala277Glu)	PHYH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
962882	NM_006214.4(PHYH):c.375_376del (p.Glu126fs)	PHYH	Pathogenic	criteria provided, multiple submitters, no conflicts
2677760	NM_006214.4(PHYH):c.50dup (p.Gly18fs)	LOC130003374	Likely pathogenic	criteria provided, single submitter
3591466	NM_006214.4(PHYH):c.7C>T (p.Gln3Ter)	LOC130003374	Likely pathogenic	criteria provided, single submitter
38871	NM_000288.4(PEX7):c.-45C>T	PEX7	Likely pathogenic	criteria provided, single submitter
1474610	NM_006214.4(PHYH):c.497-1G>A	PHYH	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1724882	NM_006214.4(PHYH):c.549_550delinsT (p.Arg184fs)	PHYH	Likely pathogenic	criteria provided, single submitter
1724932	NM_006214.4(PHYH):c.684del (p.Val229fs)	PHYH	Likely pathogenic	criteria provided, single submitter
1725221	NM_006214.4(PHYH):c.502A>T (p.Lys168Ter)	PHYH	Likely pathogenic	criteria provided, single submitter
1725332	NM_006214.4(PHYH):c.640A>T (p.Lys214Ter)	PHYH	Likely pathogenic	criteria provided, single submitter
1725861	NM_006214.4(PHYH):c.488del (p.Pro163fs)	PHYH	Likely pathogenic	criteria provided, single submitter
1726812	NM_006214.4(PHYH):c.686_687del (p.Val229fs)	PHYH	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 16 · Orphanet: 3 · 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
PHYH	Definitive	Autosomal recessive	adult Refsum disease	7
PEX7	Supportive	Autosomal recessive	adult Refsum disease	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PEX7	Orphanet:309789	Rhizomelic chondrodysplasia punctata type 1
PEX7	Orphanet:773	Adult Refsum disease
PHYH	Orphanet:773	Adult Refsum disease

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
PEX7	HGNC:8860	ENSG00000112357	O00628	Peroxisomal targeting signal 2 receptor	gencc,clinvar
PHYH	HGNC:8940	ENSG00000107537	O14832	Phytanoyl-CoA dioxygenase, peroxisomal	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PEX7	Peroxisomal targeting signal 2 receptor	Receptor required for the peroxisomal import of proteins containing a C-terminal PTS2-type peroxisomal targeting signal.
PHYH	Phytanoyl-CoA dioxygenase, peroxisomal	Catalyzes the 2-hydroxylation of not only racemic phytanoyl-CoA and the isomers of 3-methylhexadecanoyl-CoA, but also a variety of other mono-branched 3-methylacyl-CoA esters (with a chain length of at least seven carbon atoms) and straigh…

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.5

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
Scaffold/PPI	1	8.6×	0.160
Enzyme (other)	1	6.0×	0.160

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PEX7	Scaffold/PPI	no		WD40_rpt, WD40/YVTN_repeat-like_dom_sf, WD40_repeat_CS
PHYH	Enzyme (other)	yes	1.14.11.18	Phytyl_CoA_dOase-like, PhyH

Expression context

Cohort genes with no expression data: 0.

2 cohort genes 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
esophagus squamous epithelium	1
pigmented layer of retina	1
sperm	1
biceps brachii	1
quadriceps femoris	1
vastus lateralis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PEX7	276	ubiquitous	marker	pigmented layer of retina, sperm, esophagus squamous epithelium
PHYH	296	ubiquitous	marker	vastus lateralis, biceps brachii, quadriceps femoris

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PHYH	1,777
PEX7	1,356

Intra-cohort edges

A	B	Sources
PEX7	PHYH	biogrid_interaction, intact, string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PHYH	O14832	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PEX7	O00628	95.54

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. 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
Peroxisomal protein import	2	173.0×	1e-04	PEX7, PHYH
Alpha-oxidation of phytanate	1	951.7×	0.001	PHYH
TYSND1 cleaves peroxisomal proteins	1	713.8×	0.001	PHYH

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
2-oxobutyrate catabolic process	1	8426.0×	0.001	PHYH
methyl-branched fatty acid metabolic process	1	2808.7×	0.002	PHYH
isoprenoid metabolic process	1	1685.2×	0.002	PHYH
fatty acid alpha-oxidation	1	1203.7×	0.002	PHYH
ether lipid biosynthetic process	1	936.2×	0.002	PEX7
protein targeting to peroxisome	1	842.6×	0.002	PEX7
protein import into peroxisome matrix	1	702.2×	0.002	PEX7
2-oxoglutarate metabolic process	1	468.1×	0.003	PHYH
peroxisome organization	1	401.2×	0.003	PEX7
endochondral ossification	1	271.8×	0.004	PEX7
fatty acid beta-oxidation	1	187.2×	0.006	PEX7
neuron migration	1	66.9×	0.015	PEX7

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PEX7	0	0
PHYH	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PHYH	1.14.11.18	phytanoyl-CoA dioxygenase

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	1	PHYH
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	PEX7

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)
PEX7	0	—
PHYH	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 4.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	4

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01668186	Not specified	RECRUITING	Longitudinal Natural History Study of Patients With Peroxisome Biogenesis Disorders (PBD)
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT03047369	Not specified	RECRUITING	The Myelin Disorders Biorepository Project
NCT02699190	Not specified	COMPLETED	LeukoSEQ: Whole Genome Sequencing as a First-Line Diagnostic Tool for Leukodystrophies