Adult Refsum Disease

Genetic MONDO:0009958 Pathograph 52 Peroxisomal Disease Hereditary Neuropathy

Adult Refsum disease is an autosomal recessive peroxisomal metabolic disorder caused by biallelic pathogenic variants in PHYH or, less commonly, PEX7. Impaired peroxisomal phytanic acid alpha-oxidation causes phytanic acid accumulation in plasma and tissues, leading to retinitis pigmentosa, anosmia, peripheral neuropathy, ataxia, hearing impairment, ichthyosis, skeletal findings, and potentially severe cardiomyopathy or arrhythmia.

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1
Inheritance
8
Pathophys.
38
Phenotypes
52
Pathograph
2
Genes
2
Treatments
11
References
1
Deep Research
👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
Adult Refsum disease is inherited in an autosomal recessive manner and is caused by biallelic pathogenic variants in PHYH or PEX7.
Autosomal recessive inheritance
Show evidence (2 references)
ORPHA:773 SUPPORT Other
"Autosomal recessive"
Orphanet lists autosomal recessive inheritance.
PMID:20301527 SUPPORT Human Clinical
"ARD is inherited in an autosomal recessive manner."
GeneReviews states autosomal recessive inheritance.
⚙

Pathophysiology

8
PHYH Phytanoyl-CoA Hydroxylase Deficiency
Biallelic PHYH variants impair phytanoyl-CoA 2-hydroxylase, the peroxisomal enzyme catalyzing the first alpha-oxidation step in phytanic acid degradation.
PHYH link
fatty acid alpha-oxidation link ↓ DECREASED
phytanoyl-CoA dioxygenase activity link
peroxisome link
Downstream
Phytanic Acid Catabolic Block Loss of PHYH enzymatic activity blocks the initial peroxisomal alpha-oxidation step.
Show evidence (2 references)
PMID:16186124 SUPPORT In Vitro
"mutations in phytanoyl-CoA 2-hydroxylase (PAHX), an Fe(II) and 2-oxoglutarate (2OG)-dependent oxygenase that catalyzes the initial alpha-oxidation step in the degradation of phytenic acid in peroxisomes."
Structural enzymology paper identifies the affected enzyme and reaction.
PMID:14974078 SUPPORT Other
"the accumulation of phytanic acid (3,7,11,15-tetramethylhexadecanoic acid) caused by an alpha-oxidation deficiency of this branched chain fatty acid in peroxisomes."
Review links peroxisomal alpha-oxidation deficiency to phytanic acid accumulation.
PEX7 Peroxisomal Matrix Import Defect
Biallelic PEX7 variants impair peroxisomal import of PTS2-containing proteins, causing a Refsum phenotype in a subset of patients by disrupting peroxisomal alpha-oxidation machinery.
PEX7 link
protein import into peroxisome matrix link ↓ DECREASED
protein transporter activity link
peroxisome link
Downstream
Phytanic Acid Catabolic Block PEX7 import defects reduce peroxisomal localization of PTS2-containing enzymes required for phytanic acid alpha-oxidation.
Show evidence (2 references)
PMID:12522768 SUPPORT Human Clinical
"PEX7 gene, which codes for the peroxin 7 receptor protein required for peroxisomal import of proteins containing a peroxisomal targeting signal type 2."
Patient genetic study states the PEX7 import function.
PMID:12522768 SUPPORT Human Clinical
"Biochemical analyses of the patients with RD revealed defects not only in phytanic acid alpha-oxidation but also in plasmalogen synthesis and peroxisomal thiolase."
PEX7-linked Refsum cases show broader peroxisomal functional defects including alpha-oxidation impairment.
Phytanic Acid Catabolic Block
Defective peroxisomal alpha-oxidation prevents normal degradation of exogenous phytanic acid and related branched-chain fatty acids.
fatty acid alpha-oxidation link ↓ DECREASED
Downstream
Plasma and Tissue Phytanic Acid Accumulation Reduced degradation causes phytanic acid accumulation.
Show evidence (2 references)
PMID:4164676 SUPPORT Human Clinical
"patients with Refsum's disease have a relative block in the degradation of phytanic acid and possibly other similar branched-chain compounds."
Human tracer study supports impaired degradation of phytanic acid.
PMID:14974078 SUPPORT Other
"The mechanism of phytanic acid alpha-oxidation and the enzymes involved had long remained mysterious, but they have been resolved in recent years."
Review connects disease mechanism to resolved alpha-oxidation enzymes.
Plasma and Tissue Phytanic Acid Accumulation
Phytanic acid from dietary phytol and animal-derived foods accumulates in plasma, adipose tissue, and other tissues.
Downstream
Elevated plasma and tissue phytanic acid Phytanic acid accumulation is the diagnostic biochemical hallmark in plasma and tissues.
Exogenous phytanic acid retention Dietary phytol-derived phytanic acid persists in plasma because degradation is blocked.
Retinal and Olfactory Neurodegeneration Phytanic acid storage affects special sensory tissues, producing retinitis pigmentosa and anosmia.
Peripheral Nerve and Cerebellar Dysfunction Phytanic acid storage affects peripheral nerve and cerebellar pathways, producing neuropathy and ataxia.
Cardiac Conduction and Myocardial Disease Later disease can involve arrhythmia and cardiomyopathy.
Ichthyosis and Skeletal Manifestations Adult Refsum disease summaries associate the phytanic acid storage phenotype with dermatologic and skeletal manifestations.
Abnormality of metabolism/homeostasis Adult Refsum disease is associated with broad metabolic or homeostatic abnormality.
Renal insufficiency Adult Refsum disease is occasionally associated with renal insufficiency.
Splenomegaly Adult Refsum disease is associated with splenomegaly in Orphanet phenotype data.
Respiratory insufficiency Adult Refsum disease is occasionally associated with respiratory insufficiency.
Show evidence (2 references)
PMID:20301527 SUPPORT Human Clinical
"Adult Refsum disease (ARD) is associated with elevated plasma phytanic acid levels"
GeneReviews identifies elevated plasma phytanic acid as a core biochemical feature.
PMID:4164676 SUPPORT Human Clinical
"This labeled phytanic acid had disappeared almost completely from the plasma of the seven control subjects by 24 to 48 hours, whereas it persisted at high concentrations in the plasma of the two patients for many days."
Human tracer study supports prolonged phytanic acid retention in patients.
Retinal and Olfactory Neurodegeneration
Phytanic acid accumulation is associated with early-onset retinitis pigmentosa, progressive visual impairment, and anosmia.
Downstream
Anosmia Adult Refsum disease is associated with anosmia in Orphanet phenotype data.
Abnormality of the eye Adult Refsum disease is associated with broad ocular abnormalities in Orphanet phenotype data.
Retinopathy Retinal neurodegeneration includes retinopathy/retinitis pigmentosa.
Abnormality of eye movement Adult Refsum disease is associated with abnormal eye movement in Orphanet phenotype data.
Abnormality of vision Adult Refsum disease is associated with broad visual abnormalities in Orphanet phenotype data.
Visual impairment Adult Refsum disease is associated with visual impairment in Orphanet phenotype data.
Ptosis Adult Refsum disease is associated with ptosis in Orphanet phenotype data.
Cataract Adult Refsum disease is associated with cataract in Orphanet phenotype data.
Progressive visual loss Adult Refsum disease is associated with progressive visual loss in Orphanet phenotype data.
Microphthalmia Adult Refsum disease is associated with microphthalmia in Orphanet phenotype data.
Miosis Adult Refsum disease is associated with miosis in Orphanet phenotype data.
Nystagmus Adult Refsum disease is associated with nystagmus in Orphanet phenotype data.
Nyctalopia Adult Refsum disease is associated with nyctalopia in Orphanet phenotype data.
Abnormal retinal pigmentation Adult Refsum disease is associated with abnormal retinal pigmentation in Orphanet phenotype data.
Show evidence (2 references)
ORPHA:773 SUPPORT Other
"anosmia, cataract, early-onset retinitis pigmentosa"
Orphanet definition identifies anosmia and retinal disease as core features.
PMID:20301527 SUPPORT Human Clinical
"late childhood-onset (or later) retinitis pigmentosa"
GeneReviews supports retinitis pigmentosa as a core manifestation.
Peripheral Nerve and Cerebellar Dysfunction
Adult Refsum disease causes chronic demyelinating peripheral neuropathy, ataxia, weakness, hypotonia, and pyramidal signs.
Downstream
Sensorineural hearing impairment Refsum neurologic involvement can include hearing loss, sometimes localizing to auditory neuropathy.
Ataxia Cerebellar dysfunction manifests clinically as ataxia.
Hypotonia Adult Refsum disease is associated with hypotonia in Orphanet phenotype data.
Developmental regression Adult Refsum disease is associated with developmental regression in Orphanet phenotype data.
Skeletal muscle atrophy Adult Refsum disease is associated with skeletal muscle atrophy in Orphanet phenotype data.
Hemiplegia/hemiparesis Adult Refsum disease is associated with hemiplegia or hemiparesis in Orphanet phenotype data.
Abnormal pyramidal sign Adult Refsum disease is associated with abnormal pyramidal signs in Orphanet phenotype data.
Peripheral neuropathy Peripheral nerve dysfunction manifests as peripheral neuropathy.
Severe intellectual disability Adult Refsum disease is associated with severe intellectual disability in Orphanet phenotype data.
Show evidence (2 references)
PMID:20301527 SUPPORT Human Clinical
"variable combinations of anosmia, polyneuropathy, deafness, ataxia, and ichthyosis."
GeneReviews supports neuropathy and ataxia as common manifestations.
PMID:6170281 SUPPORT Human Clinical
"include pigmentary retinal degeneration, chronic polyneuropathy, ataxia, impaired hearing, and cardiopathy"
Long-term clinical treatment report lists the major neurologic and sensory manifestations.
Cardiac Conduction and Myocardial Disease
Later disease can include arrhythmias, heart block, and cardiomyopathy, which may cause severe morbidity.
Downstream
Cardiomyopathy Myocardial disease can manifest as cardiomyopathy and heart failure.
Heart block Adult Refsum disease is associated with heart block in Orphanet phenotype data.
Show evidence (2 references)
PMID:20301527 SUPPORT Human Clinical
"Cardiac arrhythmia and heart failure caused by cardiomyopathy are potentially severe health problems that develop later in life."
GeneReviews supports later cardiac involvement.
ORPHA:773 SUPPORT Other
"cardiac arrhythmia"
Orphanet definition includes cardiac arrhythmia among possible features.
Ichthyosis and Skeletal Manifestations
Systemic disease includes dry skin or ichthyosis, nail abnormalities, skeletal dysplasia, epiphyseal abnormalities, pes cavus, hammertoes, and short metacarpals.
Downstream
Dry skin Adult Refsum disease is associated with dry skin in Orphanet phenotype data.
Abnormal foot morphology Adult Refsum disease is associated with abnormal foot morphology in Orphanet phenotype data.
Pes cavus Adult Refsum disease is associated with pes cavus in Orphanet phenotype data.
Hammertoe Adult Refsum disease is associated with hammertoe in Orphanet phenotype data.
Nail dysplasia Adult Refsum disease is associated with nail dysplasia in Orphanet phenotype data.
Skeletal dysplasia Adult Refsum disease is associated with skeletal dysplasia in Orphanet phenotype data.
Abnormal epiphysis morphology Adult Refsum disease is associated with epiphyseal morphology abnormalities in Orphanet phenotype data.
Ichthyosis Dermatologic involvement includes ichthyosis.
Short metacarpal Adult Refsum disease is associated with short metacarpals in Orphanet phenotype data.
Show evidence (1 reference)
ORPHA:773 SUPPORT Other
"ichthyosis, skeletal abnormalities"
Orphanet definition includes ichthyosis and skeletal abnormalities.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Adult Refsum Disease Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

38
Cardiovascular 2
Cardiomyopathy VERY_FREQUENT Cardiomyopathy (HP:0001638)
Show evidence (2 references)
ORPHA:773 SUPPORT Other
"HP:0001638 | Cardiomyopathy | Very frequent (99-80%)"
Orphanet provides the phenotype association and frequency band.
PMID:20301527 SUPPORT Human Clinical
"Cardiac arrhythmia and heart failure caused by cardiomyopathy are potentially severe health problems that develop later in life."
GeneReviews supports cardiomyopathy and arrhythmia risk.
Splenomegaly FREQUENT Splenomegaly (HP:0001744)
Show evidence (1 reference)
ORPHA:773 SUPPORT Other
"HP:0001744 | Splenomegaly | Frequent (79-30%)"
Orphanet provides the phenotype association and frequency band.
Ear 1
Sensorineural hearing impairment VERY_FREQUENT Sensorineural hearing impairment (HP:0000407)
Show evidence (2 references)
ORPHA:773 SUPPORT Other
"HP:0000407 | Sensorineural hearing impairment | Very frequent (99-80%)"
Orphanet provides the phenotype association and frequency band.
PMID:11589979 SUPPORT Human Clinical
"Refsum's disease is a disorder of lipid metabolism with pigmentary retinopathy, demyelinating neuropathy, ataxia, and hearing loss."
Case report supports hearing loss as part of Refsum disease.
Eye 10
Retinopathy VERY_FREQUENT Retinopathy (HP:0000488)
Show evidence (2 references)
ORPHA:773 SUPPORT Other
"HP:0000488 | Retinopathy | Very frequent (99-80%)"
Orphanet provides the phenotype association and frequency band.
PMID:20301527 SUPPORT Human Clinical
"late childhood-onset (or later) retinitis pigmentosa"
GeneReviews supports retinitis pigmentosa/retinopathy.
Abnormality of eye movement FREQUENT Abnormality of eye movement (HP:0000496)
Show evidence (1 reference)
ORPHA:773 SUPPORT Other
"HP:0000496 | Abnormality of eye movement | Frequent (79-30%)"
Orphanet provides the phenotype association and frequency band.
Visual impairment FREQUENT Visual impairment (HP:0000505)
Show evidence (1 reference)
ORPHA:773 SUPPORT Other
"HP:0000505 | Visual impairment | Frequent (79-30%)"
Orphanet provides the phenotype association and frequency band.
Ptosis FREQUENT Ptosis (HP:0000508)
Show evidence (1 reference)
ORPHA:773 SUPPORT Other
"HP:0000508 | Ptosis | Frequent (79-30%)"
Orphanet provides the phenotype association and frequency band.
Cataract VERY_FREQUENT Cataract (HP:0000518)
Show evidence (1 reference)
ORPHA:773 SUPPORT Other
"HP:0000518 | Cataract | Very frequent (99-80%)"
Orphanet provides the phenotype association and frequency band.
Progressive visual loss OCCASIONAL Progressive visual loss (HP:0000529)
Show evidence (1 reference)
ORPHA:773 SUPPORT Other
"HP:0000529 | Progressive visual loss | Occasional (29-5%)"
Orphanet provides the phenotype association and frequency band.
Microphthalmia OCCASIONAL Microphthalmia (HP:0000568)
Show evidence (1 reference)
ORPHA:773 SUPPORT Other
"HP:0000568 | Microphthalmia | Occasional (29-5%)"
Orphanet provides the phenotype association and frequency band.
Nystagmus OCCASIONAL Nystagmus (HP:0000639)
Show evidence (1 reference)
ORPHA:773 SUPPORT Other
"HP:0000639 | Nystagmus | Occasional (29-5%)"
Orphanet provides the phenotype association and frequency band.
Nyctalopia FREQUENT Nyctalopia (HP:0000662)
Show evidence (1 reference)
ORPHA:773 SUPPORT Other
"HP:0000662 | Nyctalopia | Frequent (79-30%)"
Orphanet provides the phenotype association and frequency band.
Abnormal retinal pigmentation VERY_FREQUENT Abnormal retinal pigmentation (HP:0007703)
Show evidence (1 reference)
ORPHA:773 SUPPORT Other
"HP:0007703 | Abnormality of retinal pigmentation | Very frequent (99-80%)"
Orphanet provides the phenotype association and frequency band.
Genitourinary 1
Renal insufficiency OCCASIONAL Renal insufficiency (HP:0000083)
Show evidence (1 reference)
ORPHA:773 SUPPORT Other
"HP:0000083 | Renal insufficiency | Occasional (29-5%)"
Orphanet provides the phenotype association and frequency band.
Head and Neck 1
Anosmia VERY_FREQUENT Anosmia (HP:0000458)
Show evidence (2 references)
ORPHA:773 SUPPORT Other
"HP:0000458 | Anosmia | Very frequent (99-80%)"
Orphanet provides the phenotype association and frequency band.
PMID:20301527 SUPPORT Human Clinical
"variable combinations of anosmia, polyneuropathy, deafness, ataxia, and ichthyosis."
GeneReviews supports anosmia as a core feature.
Integument 3
Dry skin VERY_FREQUENT Dry skin (HP:0000958)
Show evidence (1 reference)
ORPHA:773 SUPPORT Other
"HP:0000958 | Dry skin | Very frequent (99-80%)"
Orphanet provides the phenotype association and frequency band.
Nail dysplasia VERY_FREQUENT Nail dysplasia (HP:0002164)
Show evidence (1 reference)
ORPHA:773 SUPPORT Other
"HP:0002164 | Nail dysplasia | Very frequent (99-80%)"
Orphanet provides the phenotype association and frequency band.
Ichthyosis VERY_FREQUENT Ichthyosis (HP:0008064)
Show evidence (2 references)
ORPHA:773 SUPPORT Other
"HP:0008064 | Ichthyosis | Very frequent (99-80%)"
Orphanet provides the phenotype association and frequency band.
PMID:20301527 SUPPORT Human Clinical
"variable combinations of anosmia, polyneuropathy, deafness, ataxia, and ichthyosis."
GeneReviews supports ichthyosis as a core manifestation.
Limbs 2
Pes cavus OCCASIONAL Pes cavus (HP:0001761)
Show evidence (1 reference)
ORPHA:773 SUPPORT Other
"HP:0001761 | Pes cavus | Occasional (29-5%)"
Orphanet provides the phenotype association and frequency band.
Short metacarpal FREQUENT Short metacarpal (HP:0010049)
Show evidence (1 reference)
ORPHA:773 SUPPORT Other
"HP:0010049 | Short metacarpal | Frequent (79-30%)"
Orphanet provides the phenotype association and frequency band.
Musculoskeletal 3
Hypotonia FREQUENT Hypotonia (HP:0001252)
Show evidence (1 reference)
ORPHA:773 SUPPORT Other
"HP:0001252 | Hypotonia | Frequent (79-30%)"
Orphanet provides the phenotype association and frequency band.
Skeletal dysplasia VERY_FREQUENT Skeletal dysplasia (HP:0002652)
Show evidence (1 reference)
ORPHA:773 SUPPORT Other
"HP:0002652 | Skeletal dysplasia | Very frequent (99-80%)"
Orphanet provides the phenotype association and frequency band.
Skeletal muscle atrophy FREQUENT Skeletal muscle atrophy (HP:0003202)
Show evidence (1 reference)
ORPHA:773 SUPPORT Other
"HP:0003202 | Skeletal muscle atrophy | Frequent (79-30%)"
Orphanet provides the phenotype association and frequency band.
Nervous System 4
Ataxia VERY_FREQUENT Ataxia (HP:0001251)
Show evidence (2 references)
ORPHA:773 SUPPORT Other
"HP:0001251 | Ataxia | Very frequent (99-80%)"
Orphanet provides the phenotype association and frequency band.
PMID:6170281 SUPPORT Human Clinical
"include pigmentary retinal degeneration, chronic polyneuropathy, ataxia, impaired hearing, and cardiopathy"
Long-term clinical report supports ataxia among manifestations.
Developmental regression FREQUENT Developmental regression (HP:0002376)
Show evidence (1 reference)
ORPHA:773 SUPPORT Other
"HP:0002376 | Developmental regression | Frequent (79-30%)"
Orphanet provides the phenotype association and frequency band.
Peripheral neuropathy VERY_FREQUENT Peripheral neuropathy (HP:0009830)
Show evidence (2 references)
ORPHA:773 SUPPORT Other
"HP:0009830 | Peripheral neuropathy | Very frequent (99-80%)"
Orphanet provides the phenotype association and frequency band.
PMID:20301527 SUPPORT Human Clinical
"variable combinations of anosmia, polyneuropathy, deafness, ataxia, and ichthyosis."
GeneReviews supports peripheral neuropathy.
Severe intellectual disability FREQUENT Severe intellectual disability (HP:0010864)
Show evidence (1 reference)
ORPHA:773 SUPPORT Other
"HP:0010864 | Intellectual disability, severe | Frequent (79-30%)"
Orphanet provides the phenotype association and frequency band.
Respiratory 1
Respiratory insufficiency OCCASIONAL Respiratory insufficiency (HP:0002093)
Show evidence (1 reference)
ORPHA:773 SUPPORT Other
"HP:0002093 | Respiratory insufficiency | Occasional (29-5%)"
Orphanet provides the phenotype association and frequency band.
Other 10
Abnormality of the eye VERY_FREQUENT Abnormality of the eye (HP:0000478)
Show evidence (1 reference)
ORPHA:773 SUPPORT Other
"HP:0000478 | Abnormality of the eye | Very frequent (99-80%)"
Orphanet provides the phenotype association and frequency band.
Abnormality of vision VERY_FREQUENT Abnormality of vision (HP:0000504)
Show evidence (1 reference)
ORPHA:773 SUPPORT Other
"HP:0000504 | Abnormality of vision | Very frequent (99-80%)"
Orphanet provides the phenotype association and frequency band.
Miosis FREQUENT Miosis (HP:0000616)
Show evidence (1 reference)
ORPHA:773 SUPPORT Other
"HP:0000616 | Miosis | Frequent (79-30%)"
Orphanet provides the phenotype association and frequency band.
Abnormal foot morphology VERY_FREQUENT Abnormal foot morphology (HP:0001760)
Show evidence (1 reference)
ORPHA:773 SUPPORT Other
"HP:0001760 | Abnormal foot morphology | Very frequent (99-80%)"
Orphanet provides the phenotype association and frequency band.
Hammertoe FREQUENT Hammertoe (HP:0001765)
Show evidence (1 reference)
ORPHA:773 SUPPORT Other
"HP:0001765 | Hammertoe | Frequent (79-30%)"
Orphanet provides the phenotype association and frequency band.
Abnormality of metabolism/homeostasis VERY_FREQUENT Abnormality of metabolism/homeostasis (HP:0001939)
Show evidence (1 reference)
ORPHA:773 SUPPORT Other
"HP:0001939 | Abnormality of metabolism/homeostasis | Very frequent (99-80%)"
Orphanet provides the phenotype association and frequency band.
Hemiplegia/hemiparesis VERY_FREQUENT Hemiplegia/hemiparesis (HP:0004374)
Show evidence (1 reference)
ORPHA:773 SUPPORT Other
"HP:0004374 | Hemiplegia/hemiparesis | Very frequent (99-80%)"
Orphanet provides the phenotype association and frequency band.
Abnormal epiphysis morphology FREQUENT Abnormal epiphysis morphology (HP:0005930)
Show evidence (1 reference)
ORPHA:773 SUPPORT Other
"HP:0005930 | Abnormality of epiphysis morphology | Frequent (79-30%)"
Orphanet provides the phenotype association and frequency band.
Abnormal pyramidal sign VERY_FREQUENT Abnormal pyramidal sign (HP:0007256)
Show evidence (1 reference)
ORPHA:773 SUPPORT Other
"HP:0007256 | Abnormal pyramidal sign | Very frequent (99-80%)"
Orphanet provides the phenotype association and frequency band.
Heart block OCCASIONAL Heart block (HP:0012722)
Show evidence (1 reference)
ORPHA:773 SUPPORT Other
"HP:0012722 | Heart block | Occasional (29-5%)"
Orphanet provides the phenotype association and frequency band.
🧬

Genetic Associations

2
PHYH (Biallelic pathogenic variants)
Show evidence (2 references)
ORPHA:773 SUPPORT Other
"PHYH | phytanoyl-CoA 2-hydroxylase | hgnc:8940 | Disease-causing germline mutation(s) in"
Orphanet lists PHYH as a disease-causing gene.
PMID:14974078 SUPPORT Other
"two genes, PHYH (also named PAHX) and PEX7, have been identified to cause Refsum disease"
Review identifies PHYH as one of the two causative genes.
PEX7 (Biallelic pathogenic variants)
Show evidence (2 references)
ORPHA:773 SUPPORT Other
"PEX7 | peroxisomal biogenesis factor 7 | hgnc:8860 | Disease-causing germline mutation(s) in"
Orphanet lists PEX7 as a disease-causing gene.
PMID:12522768 SUPPORT Human Clinical
"Furthermore, we identified mutations in the PEX7 gene."
Human genetic study identified PEX7 mutations in Refsum disease patients.
💊

Treatments

2
Phytanic-acid-restricted diet and fasting avoidance
Action: dietary intervention MAXO:0000088
Long-term management restricts phytanic-acid-rich foods, avoids fasting and sudden weight loss, and maintains adequate calories to reduce mobilization of stored phytanic acid.
Mechanism Target:
INHIBITS Plasma and Tissue Phytanic Acid Accumulation — Dietary restriction lowers exogenous phytanic acid input and limits mobilization from adipose stores.
Show evidence (1 reference)
PMID:20301527 SUPPORT Human Clinical
"Dietary restriction of phytanic acid intake helps resolve ichthyosis, sensory neuropathy, and ataxia."
GeneReviews supports diet as a phytanic-acid-lowering disease management strategy.
Show evidence (2 references)
PMID:6170281 SUPPORT Human Clinical
"can be either kept from worsening or reversed by elimination of foods rich in phytanic acid from patients' diets."
Long-term clinical experience supports a specific phytanic-acid-restricted diet.
PMID:20301527 SUPPORT Human Clinical
"A high-calorie diet and avoidance of fasting prevent mobilization of phytanic acid stored in adipose tissue into the plasma."
GeneReviews supports fasting avoidance and adequate calories.
Plasmapheresis or lipid apheresis for severe acute worsening
Action: Plasmapheresis NCIT:C15304
Plasma exchange or lipid apheresis is reserved for acute arrhythmias, extreme weakness, severe rapidly worsening disease, or failure of dietary control to lower very high phytanic acid levels.
Mechanism Target:
INHIBITS Plasma and Tissue Phytanic Acid Accumulation — Plasma exchange lowers circulating phytanic acid.
Show evidence (1 reference)
PMID:1716665 SUPPORT Human Clinical
"Lowering the plasma phytanic acid by plasma exchange produced a rapid clinical improvement."
Case series supports rapid clinical improvement after lowering phytanic acid by plasma exchange.
Show evidence (2 references)
PMID:20301527 SUPPORT Human Clinical
"Plasmapheresis or lipid apheresis to decrease phytanic acid levels is used only for acute arrhythmias or extreme weakness."
GeneReviews supports restricted use of plasmapheresis/lipid apheresis for severe manifestations.
PMID:10150979 SUPPORT Human Clinical
"Plasma exchange is indicated in Refsum's disease when there is a worsening clinical condition."
Clinical review supports plasma exchange for worsening disease.
🔬

Biochemical Markers

2
Elevated plasma and tissue phytanic acid (Elevated)
Show evidence (2 references)
ORPHA:773 SUPPORT Other
"It is characterized biochemically by accumulation of phytanic acid in plasma and tissues."
Orphanet identifies phytanic acid accumulation as the biochemical hallmark.
PMID:2475586 SUPPORT Human Clinical
"Fourteen patients with heredopathia atactica polyneuritiformis had a plasma phytanic acid level before treatment of 992-6400 mumol/l."
Human clinical study quantifies marked pretreatment plasma phytanic acid elevation.
Exogenous phytanic acid retention (Positive)
Show evidence (2 references)
PMID:4164676 SUPPORT Human Clinical
"establishing phytol in the diet as a potential precursor of phytanic acid."
Tracer study supports dietary phytol as a phytanic acid precursor.
PMID:4164676 SUPPORT Human Clinical
"whereas it persisted at high concentrations in the plasma of the two patients for many days."
Tracer study supports delayed clearance in patients.
{ }

Source YAML

click to show 
name: Adult Refsum Disease
creation_date: "2026-05-07T03:23:42Z"
updated_date: "2026-05-07T21:01:27Z"
category: Genetic
parents:
- Peroxisomal Disease
- Hereditary Neuropathy
synonyms:
- Classic Refsum disease
- HMSN 4
- Hereditary motor and sensory neuropathy type 4
- Heredopathia atactica polyneuritiformis
- Phytanic-CoA hydroxylase deficiency
description: >-
  Adult Refsum disease is an autosomal recessive peroxisomal metabolic disorder
  caused by biallelic pathogenic variants in PHYH or, less commonly, PEX7.
  Impaired peroxisomal phytanic acid alpha-oxidation causes phytanic acid
  accumulation in plasma and tissues, leading to retinitis pigmentosa,
  anosmia, peripheral neuropathy, ataxia, hearing impairment, ichthyosis,
  skeletal findings, and potentially severe cardiomyopathy or arrhythmia.
disease_term:
  preferred_term: adult Refsum disease
  term:
    id: MONDO:0009958
    label: adult Refsum disease
references:
- reference: ORPHA:773
  title: Adult Refsum disease
  found_in:
  - Adult_Refsum_Disease-deep-research-fallback.md
  findings:
  - statement: >-
      Orphanet defines Adult Refsum disease as a metabolic disease with
      anosmia, cataract, early-onset retinitis pigmentosa, neurologic
      manifestations, and phytanic acid accumulation.
    supporting_text: >-
      A metabolic disease characterized by anosmia, cataract, early-onset
      retinitis pigmentosa and possible neurological manifestations
- reference: PMID:20301527
  title: Adult Refsum Disease.
  found_in:
  - Adult_Refsum_Disease-deep-research-fallback.md
  findings:
  - statement: >-
      GeneReviews summarizes the clinical phenotype, diagnostic criteria, diet,
      plasmapheresis/lipid apheresis, and autosomal recessive inheritance of
      Adult Refsum disease.
    supporting_text: >-
      Adult Refsum disease (ARD) is associated with elevated plasma phytanic
      acid levels
- reference: PMID:14974078
  title: "Molecular basis of Refsum disease: sequence variations in phytanoyl-CoA hydroxylase (PHYH) and the PTS2 receptor (PEX7)."
  found_in:
  - Adult_Refsum_Disease-deep-research-fallback.md
  findings:
  - statement: >-
      Review evidence supports Refsum disease as genetically heterogeneous,
      caused by PHYH or PEX7 variants disrupting peroxisomal phytanic acid
      alpha-oxidation.
    supporting_text: >-
      Refsum disease is genetically heterogeneous; two genes, PHYH (also named
      PAHX) and PEX7, have been identified to cause Refsum disease
- reference: PMID:12522768
  title: Identification of PEX7 as the second gene involved in Refsum disease.
  found_in:
  - Adult_Refsum_Disease-deep-research-fallback.md
  findings:
  - statement: >-
      PEX7 variants can cause a milder Refsum phenotype through impaired
      peroxisomal import of PTS2-containing enzymes.
    supporting_text: >-
      Our data show that mutations in the PEX7 gene may result in a broad
      clinical spectrum ranging from severe rhizomelic chondrodysplasia
      punctata to relatively mild RD
- reference: PMID:16186124
  title: Structure of human phytanoyl-CoA 2-hydroxylase identifies molecular mechanisms of Refsum disease.
  found_in:
  - Adult_Refsum_Disease-deep-research-fallback.md
  findings:
  - statement: >-
      Structural enzymology supports PAHX/PHYH mutations as disrupting the
      peroxisomal enzyme that catalyzes the initial alpha-oxidation step.
    supporting_text: >-
      mutations in phytanoyl-CoA 2-hydroxylase (PAHX), an Fe(II) and
      2-oxoglutarate (2OG)-dependent oxygenase that catalyzes the initial
      alpha-oxidation step
- reference: PMID:4164676
  title: Studies on the metabolic error in Refsum's disease.
  found_in:
  - Adult_Refsum_Disease-deep-research-fallback.md
  findings:
  - statement: >-
      Classic metabolic tracer work supports exogenous phytanic acid origin and
      a block in phytanic acid degradation.
    supporting_text: >-
      patients with Refsum's disease have a relative block in the degradation
      of phytanic acid
- reference: PMID:2475586
  title: The significance of plasma phytanic acid levels in adults.
  found_in:
  - Adult_Refsum_Disease-deep-research-fallback.md
  findings:
  - statement: >-
      Plasma phytanic acid measurement distinguishes classic Refsum disease
      from normal controls and many retinitis pigmentosa cases.
    supporting_text: >-
      Fourteen patients with heredopathia atactica polyneuritiformis had a
      plasma phytanic acid level before treatment of 992-6400 mumol/l.
- reference: PMID:6170281
  title: "Heredopathia atactica polyneuritiformis phytanic-acid storage disease, Refsum's disease:\" a biochemically well-defined disease with a specific dietary treatment."
  found_in:
  - Adult_Refsum_Disease-deep-research-fallback.md
  findings:
  - statement: >-
      Dietary elimination of phytanic-acid-rich foods is a disease-specific
      treatment that can improve or stabilize manifestations.
    supporting_text: >-
      can be either kept from worsening or reversed by elimination of foods rich
      in phytanic acid from patients' diets.
- reference: PMID:1716665
  title: "Plasma exchange in the treatment of Refsum's disease (heredopathia atactica polyneuritiformis)."
  found_in:
  - Adult_Refsum_Disease-deep-research-fallback.md
  findings:
  - statement: >-
      Plasma exchange can rapidly lower phytanic acid and improve acute or
      severe worsening disease.
    supporting_text: >-
      Lowering the plasma phytanic acid by plasma exchange produced a rapid
      clinical improvement.
- reference: PMID:10150979
  title: Plasma exchange for Refsum's disease.
  found_in:
  - Adult_Refsum_Disease-deep-research-fallback.md
  findings:
  - statement: >-
      Additional plasma-exchange clinical evidence supports use during worsening
      disease or failure of dietary control.
    supporting_text: >-
      Plasma exchange is indicated in Refsum's disease when there is a worsening
      clinical condition.
- reference: PMID:11589979
  title: The site of the hearing loss in Refsum's disease.
  found_in:
  - Adult_Refsum_Disease-deep-research-fallback.md
  findings:
  - statement: >-
      Case evidence supports hearing loss as part of the Refsum phenotype and
      suggests auditory neuropathy in some cases.
    supporting_text: >-
      Refsum's disease is a disorder of lipid metabolism with pigmentary
      retinopathy, demyelinating neuropathy, ataxia, and hearing loss.
prevalence:
- population: Europe
  percentage: 1-9 per 1,000,000
  notes: Orphanet reports European point prevalence in the 1-9 per million range.
  evidence:
  - reference: ORPHA:773
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "1-9 / 1 000 000 | Europe | Point prevalence | PMID:20301527,EXPERT"
    explanation: Orphanet provides the European point-prevalence estimate.
progression:
- phase: Late childhood to adult-onset multisystem disease
  age_range: Childhood to adulthood
  notes: >-
    Symptoms can begin in late childhood or later, with progressive sensory,
    neurologic, dermatologic, skeletal, and cardiac involvement.
  evidence:
  - reference: ORPHA:773
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Age of onset: Childhood"
    explanation: Orphanet includes childhood among onset categories.
  - reference: PMID:20301527
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Onset of symptoms ranges from age seven months to older than age 50 years."
    explanation: GeneReviews supports broad onset from infancy through adulthood.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Adult Refsum disease is inherited in an autosomal recessive manner and is
    caused by biallelic pathogenic variants in PHYH or PEX7.
  evidence:
  - reference: ORPHA:773
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Autosomal recessive"
    explanation: Orphanet lists autosomal recessive inheritance.
  - reference: PMID:20301527
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ARD is inherited in an autosomal recessive manner."
    explanation: GeneReviews states autosomal recessive inheritance.
genetic:
- name: PHYH
  association: Biallelic pathogenic variants
  presence: Positive
  gene_term:
    preferred_term: PHYH
    term:
      id: hgnc:8940
      label: PHYH
  notes: >-
    PHYH encodes phytanoyl-CoA 2-hydroxylase, the peroxisomal enzyme that
    initiates alpha-oxidation of phytanic acid.
  evidence:
  - reference: ORPHA:773
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "PHYH | phytanoyl-CoA 2-hydroxylase | hgnc:8940 | Disease-causing germline mutation(s) in"
    explanation: Orphanet lists PHYH as a disease-causing gene.
  - reference: PMID:14974078
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "two genes, PHYH (also named PAHX) and PEX7, have been identified to cause Refsum disease"
    explanation: Review identifies PHYH as one of the two causative genes.
- name: PEX7
  association: Biallelic pathogenic variants
  presence: Positive
  gene_term:
    preferred_term: PEX7
    term:
      id: hgnc:8860
      label: PEX7
  notes: >-
    PEX7 encodes the PTS2 receptor required for peroxisomal matrix import of
    PTS2-containing proteins, including enzymes required for phytanic acid
    alpha-oxidation.
  evidence:
  - reference: ORPHA:773
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "PEX7 | peroxisomal biogenesis factor 7 | hgnc:8860 | Disease-causing germline mutation(s) in"
    explanation: Orphanet lists PEX7 as a disease-causing gene.
  - reference: PMID:12522768
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Furthermore, we identified mutations in the PEX7 gene."
    explanation: Human genetic study identified PEX7 mutations in Refsum disease patients.
pathophysiology:
- name: PHYH Phytanoyl-CoA Hydroxylase Deficiency
  description: >-
    Biallelic PHYH variants impair phytanoyl-CoA 2-hydroxylase, the peroxisomal
    enzyme catalyzing the first alpha-oxidation step in phytanic acid
    degradation.
  genes:
  - preferred_term: PHYH
    term:
      id: hgnc:8940
      label: PHYH
  locations:
  - preferred_term: peroxisome
    term:
      id: GO:0005777
      label: peroxisome
  molecular_functions:
  - preferred_term: phytanoyl-CoA dioxygenase activity
    term:
      id: GO:0048244
      label: phytanoyl-CoA dioxygenase activity
  biological_processes:
  - preferred_term: fatty acid alpha-oxidation
    term:
      id: GO:0001561
      label: fatty acid alpha-oxidation
    modifier: DECREASED
  evidence:
  - reference: PMID:16186124
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "mutations in phytanoyl-CoA 2-hydroxylase (PAHX), an Fe(II) and 2-oxoglutarate (2OG)-dependent oxygenase that catalyzes the initial alpha-oxidation step in the degradation of phytenic acid in peroxisomes."
    explanation: Structural enzymology paper identifies the affected enzyme and reaction.
  - reference: PMID:14974078
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "the accumulation of phytanic acid (3,7,11,15-tetramethylhexadecanoic acid) caused by an alpha-oxidation deficiency of this branched chain fatty acid in peroxisomes."
    explanation: Review links peroxisomal alpha-oxidation deficiency to phytanic acid accumulation.
  downstream:
  - target: Phytanic Acid Catabolic Block
    causal_link_type: DIRECT
    description: Loss of PHYH enzymatic activity blocks the initial peroxisomal alpha-oxidation step.
    evidence:
    - reference: PMID:16186124
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "mutations in phytanoyl-CoA 2-hydroxylase (PAHX), an Fe(II) and 2-oxoglutarate (2OG)-dependent oxygenase that catalyzes the initial alpha-oxidation step in the degradation of phytenic acid in peroxisomes."
      explanation: Structural enzymology supports the direct link from impaired PHYH enzymatic activity to alpha-oxidation blockade.
- name: PEX7 Peroxisomal Matrix Import Defect
  description: >-
    Biallelic PEX7 variants impair peroxisomal import of PTS2-containing
    proteins, causing a Refsum phenotype in a subset of patients by disrupting
    peroxisomal alpha-oxidation machinery.
  genes:
  - preferred_term: PEX7
    term:
      id: hgnc:8860
      label: PEX7
  locations:
  - preferred_term: peroxisome
    term:
      id: GO:0005777
      label: peroxisome
  molecular_functions:
  - preferred_term: protein transporter activity
    term:
      id: GO:0140318
      label: protein transporter activity
  biological_processes:
  - preferred_term: protein import into peroxisome matrix
    term:
      id: GO:0016558
      label: protein import into peroxisome matrix
    modifier: DECREASED
  evidence:
  - reference: PMID:12522768
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PEX7 gene, which codes for the peroxin 7 receptor protein required for peroxisomal import of proteins containing a peroxisomal targeting signal type 2."
    explanation: Patient genetic study states the PEX7 import function.
  - reference: PMID:12522768
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Biochemical analyses of the patients with RD revealed defects not only in phytanic acid alpha-oxidation but also in plasmalogen synthesis and peroxisomal thiolase."
    explanation: PEX7-linked Refsum cases show broader peroxisomal functional defects including alpha-oxidation impairment.
  downstream:
  - target: Phytanic Acid Catabolic Block
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - impaired PTS2-dependent peroxisomal enzyme import
    description: PEX7 import defects reduce peroxisomal localization of PTS2-containing enzymes required for phytanic acid alpha-oxidation.
    evidence:
    - reference: PMID:12522768
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Biochemical analyses of the patients with RD revealed defects not only in phytanic acid alpha-oxidation but also in plasmalogen synthesis and peroxisomal thiolase."
      explanation: PEX7-related patient biochemical data support impaired alpha-oxidation as a downstream consequence of the import defect.
- name: Phytanic Acid Catabolic Block
  description: >-
    Defective peroxisomal alpha-oxidation prevents normal degradation of
    exogenous phytanic acid and related branched-chain fatty acids.
  biological_processes:
  - preferred_term: fatty acid alpha-oxidation
    term:
      id: GO:0001561
      label: fatty acid alpha-oxidation
    modifier: DECREASED
  evidence:
  - reference: PMID:4164676
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "patients with Refsum's disease have a relative block in the degradation of phytanic acid and possibly other similar branched-chain compounds."
    explanation: Human tracer study supports impaired degradation of phytanic acid.
  - reference: PMID:14974078
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The mechanism of phytanic acid alpha-oxidation and the enzymes involved had long remained mysterious, but they have been resolved in recent years."
    explanation: Review connects disease mechanism to resolved alpha-oxidation enzymes.
  downstream:
  - target: Plasma and Tissue Phytanic Acid Accumulation
    causal_link_type: DIRECT
    description: Reduced degradation causes phytanic acid accumulation.
    evidence:
    - reference: PMID:4164676
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We conclude that the phytanic acid accumulating in Refsum's disease is primarily of exogenous origin and that patients with Refsum's disease have a relative block in the degradation of phytanic acid and possibly other similar branched-chain compounds."
      explanation: Human tracer data directly link blocked phytanic acid degradation to accumulation.
- name: Plasma and Tissue Phytanic Acid Accumulation
  description: >-
    Phytanic acid from dietary phytol and animal-derived foods accumulates in
    plasma, adipose tissue, and other tissues.
  chemical_entities:
  - preferred_term: phytanic acid
    term:
      id: CHEBI:16285
      label: phytanic acid
    modifier: INCREASED
  evidence:
  - reference: PMID:20301527
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Adult Refsum disease (ARD) is associated with elevated plasma phytanic acid levels"
    explanation: GeneReviews identifies elevated plasma phytanic acid as a core biochemical feature.
  - reference: PMID:4164676
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This labeled phytanic acid had disappeared almost completely from the plasma of the seven control subjects by 24 to 48 hours, whereas it persisted at high concentrations in the plasma of the two patients for many days."
    explanation: Human tracer study supports prolonged phytanic acid retention in patients.
  downstream:
  - target: Elevated plasma and tissue phytanic acid
    description: Phytanic acid accumulation is the diagnostic biochemical hallmark in plasma and tissues.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:773
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "It is characterized biochemically by accumulation of phytanic acid in plasma and tissues."
      explanation: Orphanet directly supports elevated plasma and tissue phytanic acid as the biochemical manifestation of this mechanism.
  - target: Exogenous phytanic acid retention
    description: Dietary phytol-derived phytanic acid persists in plasma because degradation is blocked.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:4164676
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This labeled phytanic acid had disappeared almost completely from the plasma of the seven control subjects by 24 to 48 hours, whereas it persisted at high concentrations in the plasma of the two patients for many days."
      explanation: Human tracer data support retention of exogenous phytanic acid in Refsum disease.
  - target: Retinal and Olfactory Neurodegeneration
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - toxic lipid accumulation in sensory tissues
    description: Phytanic acid storage affects special sensory tissues, producing retinitis pigmentosa and anosmia.
    evidence:
    - reference: PMID:20301527
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Adult Refsum disease (ARD) is associated with elevated plasma phytanic acid levels, late childhood-onset (or later) retinitis pigmentosa, and variable combinations of anosmia, polyneuropathy, deafness, ataxia, and ichthyosis."
      explanation: GeneReviews links elevated phytanic acid with retinal and olfactory manifestations.
  - target: Peripheral Nerve and Cerebellar Dysfunction
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - lipid accumulation affecting peripheral nerve and cerebellar pathways
    description: Phytanic acid storage affects peripheral nerve and cerebellar pathways, producing neuropathy and ataxia.
    evidence:
    - reference: PMID:20301527
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Adult Refsum disease (ARD) is associated with elevated plasma phytanic acid levels, late childhood-onset (or later) retinitis pigmentosa, and variable combinations of anosmia, polyneuropathy, deafness, ataxia, and ichthyosis."
      explanation: GeneReviews links elevated phytanic acid with polyneuropathy and ataxia.
  - target: Cardiac Conduction and Myocardial Disease
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - lipid accumulation affecting cardiac conduction and myocardium
    description: Later disease can involve arrhythmia and cardiomyopathy.
    evidence:
    - reference: PMID:20301527
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Cardiac arrhythmia and heart failure caused by cardiomyopathy are potentially severe health problems that develop later in life."
      explanation: GeneReviews supports cardiac conduction and myocardial disease as later complications.
  - target: Ichthyosis and Skeletal Manifestations
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Adult Refsum disease summaries associate the phytanic acid storage phenotype with dermatologic and skeletal manifestations.
    evidence:
    - reference: ORPHA:773
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Other features can be deafness, ichthyosis, skeletal abnormalities, and cardiac arrhythmia."
      explanation: Orphanet links Adult Refsum disease to ichthyosis and skeletal abnormalities.
  - target: Abnormality of metabolism/homeostasis
    description: Adult Refsum disease is associated with broad metabolic or homeostatic abnormality.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:773
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0001939 | Abnormality of metabolism/homeostasis | Very frequent (99-80%)"
      explanation: Orphanet lists abnormal metabolism/homeostasis as a very frequent phenotype.
  - target: Renal insufficiency
    description: Adult Refsum disease is occasionally associated with renal insufficiency.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:773
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000083 | Renal insufficiency | Occasional (29-5%)"
      explanation: Orphanet supports renal insufficiency as an occasional associated manifestation; the precise intervening mechanism is not specified.
  - target: Splenomegaly
    description: Adult Refsum disease is associated with splenomegaly in Orphanet phenotype data.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:773
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0001744 | Splenomegaly | Frequent (79-30%)"
      explanation: Orphanet supports splenomegaly as an associated manifestation; the precise intervening mechanism is not specified.
  - target: Respiratory insufficiency
    description: Adult Refsum disease is occasionally associated with respiratory insufficiency.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:773
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0002093 | Respiratory insufficiency | Occasional (29-5%)"
      explanation: Orphanet supports respiratory insufficiency as an occasional manifestation; the precise intervening mechanism is not specified.
- name: Retinal and Olfactory Neurodegeneration
  description: >-
    Phytanic acid accumulation is associated with early-onset retinitis
    pigmentosa, progressive visual impairment, and anosmia.
  evidence:
  - reference: ORPHA:773
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "anosmia, cataract, early-onset retinitis pigmentosa"
    explanation: Orphanet definition identifies anosmia and retinal disease as core features.
  - reference: PMID:20301527
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "late childhood-onset (or later) retinitis pigmentosa"
    explanation: GeneReviews supports retinitis pigmentosa as a core manifestation.
  downstream:
  - target: Anosmia
    description: Adult Refsum disease is associated with anosmia in Orphanet phenotype data.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:773
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000458 | Anosmia | Very frequent (99-80%)"
      explanation: Orphanet supports anosmia as a very frequent phenotype.
  - target: Abnormality of the eye
    description: Adult Refsum disease is associated with broad ocular abnormalities in Orphanet phenotype data.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:773
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000478 | Abnormality of the eye | Very frequent (99-80%)"
      explanation: Orphanet supports broad eye abnormalities as very frequent.
  - target: Retinopathy
    description: Retinal neurodegeneration includes retinopathy/retinitis pigmentosa.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301527
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "late childhood-onset (or later) retinitis pigmentosa"
      explanation: GeneReviews directly supports retinitis pigmentosa as the retinal manifestation.
  - target: Abnormality of eye movement
    description: Adult Refsum disease is associated with abnormal eye movement in Orphanet phenotype data.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:773
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000496 | Abnormality of eye movement | Frequent (79-30%)"
      explanation: Orphanet supports abnormal eye movement as a frequent phenotype.
  - target: Abnormality of vision
    description: Adult Refsum disease is associated with broad visual abnormalities in Orphanet phenotype data.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:773
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000504 | Abnormality of vision | Very frequent (99-80%)"
      explanation: Orphanet supports abnormal vision as a very frequent phenotype.
  - target: Visual impairment
    description: Adult Refsum disease is associated with visual impairment in Orphanet phenotype data.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:773
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000505 | Visual impairment | Frequent (79-30%)"
      explanation: Orphanet supports visual impairment as a frequent phenotype.
  - target: Ptosis
    description: Adult Refsum disease is associated with ptosis in Orphanet phenotype data.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:773
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000508 | Ptosis | Frequent (79-30%)"
      explanation: Orphanet supports ptosis as a frequent phenotype.
  - target: Cataract
    description: Adult Refsum disease is associated with cataract in Orphanet phenotype data.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:773
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000518 | Cataract | Very frequent (99-80%)"
      explanation: Orphanet supports cataract as a very frequent phenotype.
  - target: Progressive visual loss
    description: Adult Refsum disease is associated with progressive visual loss in Orphanet phenotype data.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:773
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000529 | Progressive visual loss | Occasional (29-5%)"
      explanation: Orphanet supports progressive visual loss as an occasional phenotype.
  - target: Microphthalmia
    description: Adult Refsum disease is associated with microphthalmia in Orphanet phenotype data.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:773
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000568 | Microphthalmia | Occasional (29-5%)"
      explanation: Orphanet supports microphthalmia as an occasional phenotype.
  - target: Miosis
    description: Adult Refsum disease is associated with miosis in Orphanet phenotype data.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:773
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000616 | Miosis | Frequent (79-30%)"
      explanation: Orphanet supports miosis as a frequent phenotype.
  - target: Nystagmus
    description: Adult Refsum disease is associated with nystagmus in Orphanet phenotype data.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:773
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000639 | Nystagmus | Occasional (29-5%)"
      explanation: Orphanet supports nystagmus as an occasional phenotype.
  - target: Nyctalopia
    description: Adult Refsum disease is associated with nyctalopia in Orphanet phenotype data.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:773
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000662 | Nyctalopia | Frequent (79-30%)"
      explanation: Orphanet supports nyctalopia as a frequent phenotype.
  - target: Abnormal retinal pigmentation
    description: Adult Refsum disease is associated with abnormal retinal pigmentation in Orphanet phenotype data.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:773
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0007703 | Abnormality of retinal pigmentation | Very frequent (99-80%)"
      explanation: Orphanet supports abnormal retinal pigmentation as a very frequent phenotype.
- name: Peripheral Nerve and Cerebellar Dysfunction
  description: >-
    Adult Refsum disease causes chronic demyelinating peripheral neuropathy,
    ataxia, weakness, hypotonia, and pyramidal signs.
  evidence:
  - reference: PMID:20301527
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "variable combinations of anosmia, polyneuropathy, deafness, ataxia, and ichthyosis."
    explanation: GeneReviews supports neuropathy and ataxia as common manifestations.
  - reference: PMID:6170281
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "include pigmentary retinal degeneration, chronic polyneuropathy, ataxia, impaired hearing, and cardiopathy"
    explanation: Long-term clinical treatment report lists the major neurologic and sensory manifestations.
  downstream:
  - target: Sensorineural hearing impairment
    description: Refsum neurologic involvement can include hearing loss, sometimes localizing to auditory neuropathy.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:11589979
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Refsum's disease is a disorder of lipid metabolism with pigmentary retinopathy, demyelinating neuropathy, ataxia, and hearing loss."
      explanation: Case evidence supports hearing impairment as part of the neurologic/sensory disease branch.
  - target: Ataxia
    description: Cerebellar dysfunction manifests clinically as ataxia.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:6170281
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "include pigmentary retinal degeneration, chronic polyneuropathy, ataxia, impaired hearing, and cardiopathy"
      explanation: Long-term clinical report lists ataxia among major manifestations.
  - target: Hypotonia
    description: Adult Refsum disease is associated with hypotonia in Orphanet phenotype data.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:773
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0001252 | Hypotonia | Frequent (79-30%)"
      explanation: Orphanet supports hypotonia as a frequent phenotype.
  - target: Developmental regression
    description: Adult Refsum disease is associated with developmental regression in Orphanet phenotype data.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:773
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0002376 | Developmental regression | Frequent (79-30%)"
      explanation: Orphanet supports developmental regression as a frequent phenotype.
  - target: Skeletal muscle atrophy
    description: Adult Refsum disease is associated with skeletal muscle atrophy in Orphanet phenotype data.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:773
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0003202 | Skeletal muscle atrophy | Frequent (79-30%)"
      explanation: Orphanet supports skeletal muscle atrophy as a frequent phenotype.
  - target: Hemiplegia/hemiparesis
    description: Adult Refsum disease is associated with hemiplegia or hemiparesis in Orphanet phenotype data.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:773
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0004374 | Hemiplegia/hemiparesis | Very frequent (99-80%)"
      explanation: Orphanet supports hemiplegia/hemiparesis as a very frequent listed phenotype.
  - target: Abnormal pyramidal sign
    description: Adult Refsum disease is associated with abnormal pyramidal signs in Orphanet phenotype data.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:773
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0007256 | Abnormal pyramidal sign | Very frequent (99-80%)"
      explanation: Orphanet supports pyramidal signs as a very frequent phenotype.
  - target: Peripheral neuropathy
    description: Peripheral nerve dysfunction manifests as peripheral neuropathy.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301527
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "variable combinations of anosmia, polyneuropathy, deafness, ataxia, and ichthyosis."
      explanation: GeneReviews directly supports polyneuropathy as a core manifestation.
  - target: Severe intellectual disability
    description: Adult Refsum disease is associated with severe intellectual disability in Orphanet phenotype data.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:773
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0010864 | Intellectual disability, severe | Frequent (79-30%)"
      explanation: Orphanet supports severe intellectual disability as a frequent phenotype.
- name: Cardiac Conduction and Myocardial Disease
  description: >-
    Later disease can include arrhythmias, heart block, and cardiomyopathy,
    which may cause severe morbidity.
  evidence:
  - reference: PMID:20301527
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cardiac arrhythmia and heart failure caused by cardiomyopathy are potentially severe health problems that develop later in life."
    explanation: GeneReviews supports later cardiac involvement.
  - reference: ORPHA:773
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "cardiac arrhythmia"
    explanation: Orphanet definition includes cardiac arrhythmia among possible features.
  downstream:
  - target: Cardiomyopathy
    description: Myocardial disease can manifest as cardiomyopathy and heart failure.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301527
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Cardiac arrhythmia and heart failure caused by cardiomyopathy are potentially severe health problems that develop later in life."
      explanation: GeneReviews directly supports cardiomyopathy as a later cardiac manifestation.
  - target: Heart block
    description: Adult Refsum disease is associated with heart block in Orphanet phenotype data.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:773
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0012722 | Heart block | Occasional (29-5%)"
      explanation: Orphanet supports heart block as an occasional phenotype.
- name: Ichthyosis and Skeletal Manifestations
  description: >-
    Systemic disease includes dry skin or ichthyosis, nail abnormalities,
    skeletal dysplasia, epiphyseal abnormalities, pes cavus, hammertoes, and
    short metacarpals.
  evidence:
  - reference: ORPHA:773
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ichthyosis, skeletal abnormalities"
    explanation: Orphanet definition includes ichthyosis and skeletal abnormalities.
  downstream:
  - target: Dry skin
    description: Adult Refsum disease is associated with dry skin in Orphanet phenotype data.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:773
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000958 | Dry skin | Very frequent (99-80%)"
      explanation: Orphanet supports dry skin as a very frequent phenotype.
  - target: Abnormal foot morphology
    description: Adult Refsum disease is associated with abnormal foot morphology in Orphanet phenotype data.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:773
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0001760 | Abnormal foot morphology | Very frequent (99-80%)"
      explanation: Orphanet supports abnormal foot morphology as a very frequent phenotype.
  - target: Pes cavus
    description: Adult Refsum disease is associated with pes cavus in Orphanet phenotype data.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:773
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0001761 | Pes cavus | Occasional (29-5%)"
      explanation: Orphanet supports pes cavus as an occasional phenotype.
  - target: Hammertoe
    description: Adult Refsum disease is associated with hammertoe in Orphanet phenotype data.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:773
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0001765 | Hammertoe | Frequent (79-30%)"
      explanation: Orphanet supports hammertoe as a frequent phenotype.
  - target: Nail dysplasia
    description: Adult Refsum disease is associated with nail dysplasia in Orphanet phenotype data.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:773
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0002164 | Nail dysplasia | Very frequent (99-80%)"
      explanation: Orphanet supports nail dysplasia as a very frequent phenotype.
  - target: Skeletal dysplasia
    description: Adult Refsum disease is associated with skeletal dysplasia in Orphanet phenotype data.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:773
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0002652 | Skeletal dysplasia | Very frequent (99-80%)"
      explanation: Orphanet supports skeletal dysplasia as a very frequent phenotype.
  - target: Abnormal epiphysis morphology
    description: Adult Refsum disease is associated with epiphyseal morphology abnormalities in Orphanet phenotype data.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:773
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0005930 | Abnormality of epiphysis morphology | Frequent (79-30%)"
      explanation: Orphanet supports epiphyseal morphology abnormalities as a frequent phenotype.
  - target: Ichthyosis
    description: Dermatologic involvement includes ichthyosis.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301527
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "variable combinations of anosmia, polyneuropathy, deafness, ataxia, and ichthyosis."
      explanation: GeneReviews supports ichthyosis as a core manifestation.
  - target: Short metacarpal
    description: Adult Refsum disease is associated with short metacarpals in Orphanet phenotype data.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:773
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0010049 | Short metacarpal | Frequent (79-30%)"
      explanation: Orphanet supports short metacarpal as a frequent phenotype.
phenotypes:
- category: Renal
  name: Renal insufficiency
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Renal insufficiency
    term:
      id: HP:0000083
      label: Renal insufficiency
  evidence:
  - reference: ORPHA:773
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000083 | Renal insufficiency | Occasional (29-5%)"
    explanation: Orphanet provides the phenotype association and frequency band.
- category: Auditory
  name: Sensorineural hearing impairment
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: ORPHA:773
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000407 | Sensorineural hearing impairment | Very frequent (99-80%)"
    explanation: Orphanet provides the phenotype association and frequency band.
  - reference: PMID:11589979
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Refsum's disease is a disorder of lipid metabolism with pigmentary retinopathy, demyelinating neuropathy, ataxia, and hearing loss."
    explanation: Case report supports hearing loss as part of Refsum disease.
- category: Neurologic
  name: Anosmia
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Anosmia
    term:
      id: HP:0000458
      label: Anosmia
  evidence:
  - reference: ORPHA:773
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000458 | Anosmia | Very frequent (99-80%)"
    explanation: Orphanet provides the phenotype association and frequency band.
  - reference: PMID:20301527
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "variable combinations of anosmia, polyneuropathy, deafness, ataxia, and ichthyosis."
    explanation: GeneReviews supports anosmia as a core feature.
- category: Ophthalmologic
  name: Abnormality of the eye
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Abnormality of the eye
    term:
      id: HP:0000478
      label: Abnormality of the eye
  evidence:
  - reference: ORPHA:773
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000478 | Abnormality of the eye | Very frequent (99-80%)"
    explanation: Orphanet provides the phenotype association and frequency band.
- category: Ophthalmologic
  name: Retinopathy
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Retinopathy
    term:
      id: HP:0000488
      label: Retinopathy
  evidence:
  - reference: ORPHA:773
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000488 | Retinopathy | Very frequent (99-80%)"
    explanation: Orphanet provides the phenotype association and frequency band.
  - reference: PMID:20301527
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "late childhood-onset (or later) retinitis pigmentosa"
    explanation: GeneReviews supports retinitis pigmentosa/retinopathy.
- category: Ophthalmologic
  name: Abnormality of eye movement
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Abnormality of eye movement
    term:
      id: HP:0000496
      label: Abnormality of eye movement
  evidence:
  - reference: ORPHA:773
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000496 | Abnormality of eye movement | Frequent (79-30%)"
    explanation: Orphanet provides the phenotype association and frequency band.
- category: Ophthalmologic
  name: Abnormality of vision
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Abnormality of vision
    term:
      id: HP:0000504
      label: Abnormality of vision
  evidence:
  - reference: ORPHA:773
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000504 | Abnormality of vision | Very frequent (99-80%)"
    explanation: Orphanet provides the phenotype association and frequency band.
- category: Ophthalmologic
  name: Visual impairment
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Visual impairment
    term:
      id: HP:0000505
      label: Visual impairment
  evidence:
  - reference: ORPHA:773
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000505 | Visual impairment | Frequent (79-30%)"
    explanation: Orphanet provides the phenotype association and frequency band.
- category: Ophthalmologic
  name: Ptosis
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Ptosis
    term:
      id: HP:0000508
      label: Ptosis
  evidence:
  - reference: ORPHA:773
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000508 | Ptosis | Frequent (79-30%)"
    explanation: Orphanet provides the phenotype association and frequency band.
- category: Ophthalmologic
  name: Cataract
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Cataract
    term:
      id: HP:0000518
      label: Cataract
  evidence:
  - reference: ORPHA:773
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000518 | Cataract | Very frequent (99-80%)"
    explanation: Orphanet provides the phenotype association and frequency band.
- category: Ophthalmologic
  name: Progressive visual loss
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Progressive visual loss
    term:
      id: HP:0000529
      label: Progressive visual loss
  evidence:
  - reference: ORPHA:773
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000529 | Progressive visual loss | Occasional (29-5%)"
    explanation: Orphanet provides the phenotype association and frequency band.
- category: Ophthalmologic
  name: Microphthalmia
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Microphthalmia
    term:
      id: HP:0000568
      label: Microphthalmia
  evidence:
  - reference: ORPHA:773
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000568 | Microphthalmia | Occasional (29-5%)"
    explanation: Orphanet provides the phenotype association and frequency band.
- category: Ophthalmologic
  name: Miosis
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Miosis
    term:
      id: HP:0000616
      label: Miosis
  evidence:
  - reference: ORPHA:773
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000616 | Miosis | Frequent (79-30%)"
    explanation: Orphanet provides the phenotype association and frequency band.
- category: Ophthalmologic
  name: Nystagmus
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Nystagmus
    term:
      id: HP:0000639
      label: Nystagmus
  evidence:
  - reference: ORPHA:773
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000639 | Nystagmus | Occasional (29-5%)"
    explanation: Orphanet provides the phenotype association and frequency band.
- category: Ophthalmologic
  name: Nyctalopia
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Nyctalopia
    term:
      id: HP:0000662
      label: Nyctalopia
  evidence:
  - reference: ORPHA:773
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000662 | Nyctalopia | Frequent (79-30%)"
    explanation: Orphanet provides the phenotype association and frequency band.
- category: Dermatologic
  name: Dry skin
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Dry skin
    term:
      id: HP:0000958
      label: Dry skin
  evidence:
  - reference: ORPHA:773
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000958 | Dry skin | Very frequent (99-80%)"
    explanation: Orphanet provides the phenotype association and frequency band.
- category: Neurologic
  name: Ataxia
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
  evidence:
  - reference: ORPHA:773
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001251 | Ataxia | Very frequent (99-80%)"
    explanation: Orphanet provides the phenotype association and frequency band.
  - reference: PMID:6170281
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "include pigmentary retinal degeneration, chronic polyneuropathy, ataxia, impaired hearing, and cardiopathy"
    explanation: Long-term clinical report supports ataxia among manifestations.
- category: Neurologic
  name: Hypotonia
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: ORPHA:773
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001252 | Hypotonia | Frequent (79-30%)"
    explanation: Orphanet provides the phenotype association and frequency band.
- category: Cardiovascular
  name: Cardiomyopathy
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Cardiomyopathy
    term:
      id: HP:0001638
      label: Cardiomyopathy
  evidence:
  - reference: ORPHA:773
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001638 | Cardiomyopathy | Very frequent (99-80%)"
    explanation: Orphanet provides the phenotype association and frequency band.
  - reference: PMID:20301527
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cardiac arrhythmia and heart failure caused by cardiomyopathy are potentially severe health problems that develop later in life."
    explanation: GeneReviews supports cardiomyopathy and arrhythmia risk.
- category: Visceral
  name: Splenomegaly
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Splenomegaly
    term:
      id: HP:0001744
      label: Splenomegaly
  evidence:
  - reference: ORPHA:773
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001744 | Splenomegaly | Frequent (79-30%)"
    explanation: Orphanet provides the phenotype association and frequency band.
- category: Skeletal
  name: Abnormal foot morphology
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Abnormal foot morphology
    term:
      id: HP:0001760
      label: Abnormal foot morphology
  evidence:
  - reference: ORPHA:773
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001760 | Abnormal foot morphology | Very frequent (99-80%)"
    explanation: Orphanet provides the phenotype association and frequency band.
- category: Skeletal
  name: Pes cavus
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Pes cavus
    term:
      id: HP:0001761
      label: Pes cavus
  evidence:
  - reference: ORPHA:773
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001761 | Pes cavus | Occasional (29-5%)"
    explanation: Orphanet provides the phenotype association and frequency band.
- category: Skeletal
  name: Hammertoe
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hammertoe
    term:
      id: HP:0001765
      label: Hammertoe
  evidence:
  - reference: ORPHA:773
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001765 | Hammertoe | Frequent (79-30%)"
    explanation: Orphanet provides the phenotype association and frequency band.
- category: Biochemical
  name: Abnormality of metabolism/homeostasis
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Abnormality of metabolism/homeostasis
    term:
      id: HP:0001939
      label: Abnormality of metabolism/homeostasis
  evidence:
  - reference: ORPHA:773
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001939 | Abnormality of metabolism/homeostasis | Very frequent (99-80%)"
    explanation: Orphanet provides the phenotype association and frequency band.
- category: Respiratory
  name: Respiratory insufficiency
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Respiratory insufficiency
    term:
      id: HP:0002093
      label: Respiratory insufficiency
  evidence:
  - reference: ORPHA:773
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002093 | Respiratory insufficiency | Occasional (29-5%)"
    explanation: Orphanet provides the phenotype association and frequency band.
- category: Dermatologic
  name: Nail dysplasia
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Nail dysplasia
    term:
      id: HP:0002164
      label: Nail dysplasia
  evidence:
  - reference: ORPHA:773
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002164 | Nail dysplasia | Very frequent (99-80%)"
    explanation: Orphanet provides the phenotype association and frequency band.
- category: Neurologic
  name: Developmental regression
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Developmental regression
    term:
      id: HP:0002376
      label: Developmental regression
  evidence:
  - reference: ORPHA:773
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002376 | Developmental regression | Frequent (79-30%)"
    explanation: Orphanet provides the phenotype association and frequency band.
- category: Skeletal
  name: Skeletal dysplasia
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Skeletal dysplasia
    term:
      id: HP:0002652
      label: Skeletal dysplasia
  evidence:
  - reference: ORPHA:773
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002652 | Skeletal dysplasia | Very frequent (99-80%)"
    explanation: Orphanet provides the phenotype association and frequency band.
- category: Musculoskeletal
  name: Skeletal muscle atrophy
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Skeletal muscle atrophy
    term:
      id: HP:0003202
      label: Skeletal muscle atrophy
  evidence:
  - reference: ORPHA:773
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003202 | Skeletal muscle atrophy | Frequent (79-30%)"
    explanation: Orphanet provides the phenotype association and frequency band.
- category: Neurologic
  name: Hemiplegia/hemiparesis
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Hemiplegia/hemiparesis
    term:
      id: HP:0004374
      label: Hemiplegia/hemiparesis
  evidence:
  - reference: ORPHA:773
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0004374 | Hemiplegia/hemiparesis | Very frequent (99-80%)"
    explanation: Orphanet provides the phenotype association and frequency band.
- category: Skeletal
  name: Abnormal epiphysis morphology
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Abnormal epiphysis morphology
    term:
      id: HP:0005930
      label: Abnormal epiphysis morphology
  evidence:
  - reference: ORPHA:773
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0005930 | Abnormality of epiphysis morphology | Frequent (79-30%)"
    explanation: Orphanet provides the phenotype association and frequency band.
- category: Neurologic
  name: Abnormal pyramidal sign
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Abnormal pyramidal sign
    term:
      id: HP:0007256
      label: Abnormal pyramidal sign
  evidence:
  - reference: ORPHA:773
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0007256 | Abnormal pyramidal sign | Very frequent (99-80%)"
    explanation: Orphanet provides the phenotype association and frequency band.
- category: Ophthalmologic
  name: Abnormal retinal pigmentation
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Abnormal retinal pigmentation
    term:
      id: HP:0007703
      label: Abnormal retinal pigmentation
  evidence:
  - reference: ORPHA:773
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0007703 | Abnormality of retinal pigmentation | Very frequent (99-80%)"
    explanation: Orphanet provides the phenotype association and frequency band.
- category: Dermatologic
  name: Ichthyosis
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Ichthyosis
    term:
      id: HP:0008064
      label: Ichthyosis
  evidence:
  - reference: ORPHA:773
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0008064 | Ichthyosis | Very frequent (99-80%)"
    explanation: Orphanet provides the phenotype association and frequency band.
  - reference: PMID:20301527
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "variable combinations of anosmia, polyneuropathy, deafness, ataxia, and ichthyosis."
    explanation: GeneReviews supports ichthyosis as a core manifestation.
- category: Neurologic
  name: Peripheral neuropathy
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Peripheral neuropathy
    term:
      id: HP:0009830
      label: Peripheral neuropathy
  evidence:
  - reference: ORPHA:773
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0009830 | Peripheral neuropathy | Very frequent (99-80%)"
    explanation: Orphanet provides the phenotype association and frequency band.
  - reference: PMID:20301527
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "variable combinations of anosmia, polyneuropathy, deafness, ataxia, and ichthyosis."
    explanation: GeneReviews supports peripheral neuropathy.
- category: Skeletal
  name: Short metacarpal
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Short metacarpal
    term:
      id: HP:0010049
      label: Short metacarpal
  evidence:
  - reference: ORPHA:773
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0010049 | Short metacarpal | Frequent (79-30%)"
    explanation: Orphanet provides the phenotype association and frequency band.
- category: Neurodevelopmental
  name: Severe intellectual disability
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Severe intellectual disability
    term:
      id: HP:0010864
      label: Severe intellectual disability
  evidence:
  - reference: ORPHA:773
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0010864 | Intellectual disability, severe | Frequent (79-30%)"
    explanation: Orphanet provides the phenotype association and frequency band.
- category: Cardiovascular
  name: Heart block
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Heart block
    term:
      id: HP:0012722
      label: Heart block
  evidence:
  - reference: ORPHA:773
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0012722 | Heart block | Occasional (29-5%)"
    explanation: Orphanet provides the phenotype association and frequency band.
biochemical:
- name: Elevated plasma and tissue phytanic acid
  presence: Elevated
  notes: >-
    Elevated phytanic acid in plasma and tissues is the defining biochemical
    abnormality and is used diagnostically and for treatment monitoring.
  evidence:
  - reference: ORPHA:773
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "It is characterized biochemically by accumulation of phytanic acid in plasma and tissues."
    explanation: Orphanet identifies phytanic acid accumulation as the biochemical hallmark.
  - reference: PMID:2475586
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Fourteen patients with heredopathia atactica polyneuritiformis had a plasma phytanic acid level before treatment of 992-6400 mumol/l."
    explanation: Human clinical study quantifies marked pretreatment plasma phytanic acid elevation.
- name: Exogenous phytanic acid retention
  presence: Positive
  notes: >-
    Dietary phytol and phytanic acid are normally cleared, but persist in plasma
    in Adult Refsum disease because degradation is blocked.
  evidence:
  - reference: PMID:4164676
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "establishing phytol in the diet as a potential precursor of phytanic acid."
    explanation: Tracer study supports dietary phytol as a phytanic acid precursor.
  - reference: PMID:4164676
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "whereas it persisted at high concentrations in the plasma of the two patients for many days."
    explanation: Tracer study supports delayed clearance in patients.
diagnosis:
- name: Plasma phytanic acid testing
  description: >-
    Plasma phytanic acid measurement is the core biochemical diagnostic test and
    helps distinguish Adult Refsum disease from isolated retinitis pigmentosa
    and other conditions with only mild phytanic acid elevation.
  results: Markedly elevated plasma phytanic acid supports diagnosis.
  evidence:
  - reference: PMID:2475586
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The presence of phytanic acid in tissues and plasma has been considered diagnostic of heredopathia atactica polyneuritiformis (Refsum's disease)"
    explanation: Human clinical study supports plasma/tissue phytanic acid as diagnostic.
  - reference: PMID:20301527
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Adult Refsum disease (ARD) is associated with elevated plasma phytanic acid levels"
    explanation: GeneReviews supports elevated plasma phytanic acid testing.
- name: PHYH and PEX7 molecular genetic testing
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: MAXO:0000127
      label: genetic testing
  description: >-
    Molecular testing confirms biallelic pathogenic variants in PHYH or PEX7
    and distinguishes PHYH-related disease from PEX7-related disease and other
    peroxisomal disorders.
  results: Biallelic pathogenic variants in PHYH or PEX7 establish the molecular diagnosis.
  evidence:
  - reference: PMID:20301527
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of ARD is established in a proband with suggestive clinical and biochemical findings by identification of biallelic pathogenic variants in either PHYH or PEX7 on molecular genetic testing."
    explanation: GeneReviews states the diagnostic role of PHYH/PEX7 molecular testing.
treatments:
- name: Phytanic-acid-restricted diet and fasting avoidance
  description: >-
    Long-term management restricts phytanic-acid-rich foods, avoids fasting and
    sudden weight loss, and maintains adequate calories to reduce mobilization
    of stored phytanic acid.
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: MAXO:0000088
      label: dietary intervention
  target_mechanisms:
  - target: Plasma and Tissue Phytanic Acid Accumulation
    treatment_effect: INHIBITS
    description: Dietary restriction lowers exogenous phytanic acid input and limits mobilization from adipose stores.
    evidence:
    - reference: PMID:20301527
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Dietary restriction of phytanic acid intake helps resolve ichthyosis, sensory neuropathy, and ataxia."
      explanation: GeneReviews supports diet as a phytanic-acid-lowering disease management strategy.
  evidence:
  - reference: PMID:6170281
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "can be either kept from worsening or reversed by elimination of foods rich in phytanic acid from patients' diets."
    explanation: Long-term clinical experience supports a specific phytanic-acid-restricted diet.
  - reference: PMID:20301527
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A high-calorie diet and avoidance of fasting prevent mobilization of phytanic acid stored in adipose tissue into the plasma."
    explanation: GeneReviews supports fasting avoidance and adequate calories.
- name: Plasmapheresis or lipid apheresis for severe acute worsening
  description: >-
    Plasma exchange or lipid apheresis is reserved for acute arrhythmias,
    extreme weakness, severe rapidly worsening disease, or failure of dietary
    control to lower very high phytanic acid levels.
  treatment_term:
    preferred_term: Plasmapheresis
    term:
      id: NCIT:C15304
      label: Plasmapheresis
  target_mechanisms:
  - target: Plasma and Tissue Phytanic Acid Accumulation
    treatment_effect: INHIBITS
    description: Plasma exchange lowers circulating phytanic acid.
    evidence:
    - reference: PMID:1716665
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Lowering the plasma phytanic acid by plasma exchange produced a rapid clinical improvement."
      explanation: Case series supports rapid clinical improvement after lowering phytanic acid by plasma exchange.
  evidence:
  - reference: PMID:20301527
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Plasmapheresis or lipid apheresis to decrease phytanic acid levels is used only for acute arrhythmias or extreme weakness."
    explanation: GeneReviews supports restricted use of plasmapheresis/lipid apheresis for severe manifestations.
  - reference: PMID:10150979
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Plasma exchange is indicated in Refsum's disease when there is a worsening clinical condition."
    explanation: Clinical review supports plasma exchange for worsening disease.
clinical_trials: []
📚

References & Deep Research

References

11
ORPHA:773
Adult Refsum disease
1 finding
Orphanet defines Adult Refsum disease as a metabolic disease with anosmia, cataract, early-onset retinitis pigmentosa, neurologic manifestations, and phytanic acid accumulation.
"A metabolic disease characterized by anosmia, cataract, early-onset retinitis pigmentosa and possible neurological manifestations"
PMID:20301527
Adult Refsum Disease.
1 finding
GeneReviews summarizes the clinical phenotype, diagnostic criteria, diet, plasmapheresis/lipid apheresis, and autosomal recessive inheritance of Adult Refsum disease.
"Adult Refsum disease (ARD) is associated with elevated plasma phytanic acid levels"
PMID:14974078
Molecular basis of Refsum disease: sequence variations in phytanoyl-CoA hydroxylase (PHYH) and the PTS2 receptor (PEX7).
1 finding
Review evidence supports Refsum disease as genetically heterogeneous, caused by PHYH or PEX7 variants disrupting peroxisomal phytanic acid alpha-oxidation.
"Refsum disease is genetically heterogeneous; two genes, PHYH (also named PAHX) and PEX7, have been identified to cause Refsum disease"
PMID:12522768
Identification of PEX7 as the second gene involved in Refsum disease.
1 finding
PEX7 variants can cause a milder Refsum phenotype through impaired peroxisomal import of PTS2-containing enzymes.
"Our data show that mutations in the PEX7 gene may result in a broad clinical spectrum ranging from severe rhizomelic chondrodysplasia punctata to relatively mild RD"
PMID:16186124
Structure of human phytanoyl-CoA 2-hydroxylase identifies molecular mechanisms of Refsum disease.
1 finding
Structural enzymology supports PAHX/PHYH mutations as disrupting the peroxisomal enzyme that catalyzes the initial alpha-oxidation step.
"mutations in phytanoyl-CoA 2-hydroxylase (PAHX), an Fe(II) and 2-oxoglutarate (2OG)-dependent oxygenase that catalyzes the initial alpha-oxidation step"
PMID:4164676
Studies on the metabolic error in Refsum's disease.
1 finding
Classic metabolic tracer work supports exogenous phytanic acid origin and a block in phytanic acid degradation.
"patients with Refsum's disease have a relative block in the degradation of phytanic acid"
PMID:2475586
The significance of plasma phytanic acid levels in adults.
1 finding
Plasma phytanic acid measurement distinguishes classic Refsum disease from normal controls and many retinitis pigmentosa cases.
"Fourteen patients with heredopathia atactica polyneuritiformis had a plasma phytanic acid level before treatment of 992-6400 mumol/l."
PMID:6170281
Heredopathia atactica polyneuritiformis phytanic-acid storage disease, Refsum's disease:" a biochemically well-defined disease with a specific dietary treatment.
1 finding
Dietary elimination of phytanic-acid-rich foods is a disease-specific treatment that can improve or stabilize manifestations.
"can be either kept from worsening or reversed by elimination of foods rich in phytanic acid from patients' diets."
PMID:1716665
Plasma exchange in the treatment of Refsum's disease (heredopathia atactica polyneuritiformis).
1 finding
Plasma exchange can rapidly lower phytanic acid and improve acute or severe worsening disease.
"Lowering the plasma phytanic acid by plasma exchange produced a rapid clinical improvement."
PMID:10150979
Plasma exchange for Refsum's disease.
1 finding
Additional plasma-exchange clinical evidence supports use during worsening disease or failure of dietary control.
"Plasma exchange is indicated in Refsum's disease when there is a worsening clinical condition."
PMID:11589979
The site of the hearing loss in Refsum's disease.
1 finding
Case evidence supports hearing loss as part of the Refsum phenotype and suggests auditory neuropathy in some cases.
"Refsum's disease is a disorder of lipid metabolism with pigmentary retinopathy, demyelinating neuropathy, ataxia, and hearing loss."

Deep Research

1
Adult Refsum Disease research fallback ▸

Adult Refsum Disease research fallback

Provider attempts

  • Falcon deep-research: attempted with timeout 75s just research-disorder falcon Adult_Refsum_Disease on 2026-05-07 UTC; no artifact was produced before the command timed out.
  • OpenAI deep-research: attempted with timeout 75s just research-disorder openai Adult_Refsum_Disease on 2026-05-07 UTC; no artifact was produced before the command timed out.
  • Perplexity deep-research: not attempted after two bounded provider timeouts; curation proceeded from generated Orphanet and cached PubMed evidence.

Literature scope used for curation

This fallback curation uses generated Orphanet cache ORPHA:773, GeneReviews PMID:20301527, molecular genetics reviews and primary studies for PHYH/PEX7 (PMID:14974078, PMID:12522768), structural enzymology for PAHX/PHYH (PMID:16186124), classic tracer and biochemical diagnostic studies (PMID:4164676, PMID:2475586), and treatment evidence for phytanic-acid dietary restriction and plasma exchange (PMID:6170281, PMID:1716665, PMID:10150979).

Curation synthesis

Adult Refsum disease is a peroxisomal metabolic disorder in which PHYH defects or PEX7-dependent peroxisomal matrix import defects impair phytanic acid alpha-oxidation. Dietary phytol/phytanic acid cannot be cleared normally, causing plasma and tissue phytanic acid accumulation. The modeled consequences include retinal/olfactory disease, peripheral neuropathy with ataxia, cardiac conduction/myocardial involvement, ichthyosis, and skeletal manifestations. Treatment targets the biochemical driver by restricting phytanic-acid-rich foods, avoiding fasting and sudden weight loss, and using plasmapheresis or lipid apheresis only for severe acute worsening or failure of dietary control.

Key references

  • ORPHA:773
  • PMID:20301527
  • PMID:14974078
  • PMID:12522768
  • PMID:16186124
  • PMID:4164676
  • PMID:2475586
  • PMID:6170281
  • PMID:1716665
  • PMID:10150979
  • PMID:11589979