🏷

Classifications

Harrison's Part

ICIMD (Inherited Metabolic Disorders)

🔗

Mappings

MONDO

MONDO:0030026 retinal dystrophy with leukodystrophy

MONDO:0030026 cross-references OMIM:618863 and names ACBD5 as its causal gene. ClinGen lumped the retinal-dystrophy and ACBD5-deficiency reports into one entity, MONDO:0100112, finding no difference in mechanism, inheritance or phenotype.

👪

Inheritance

1

Autosomal recessive inheritance HP:0000007

Biallelic germline ACBD5 variants cause the disease, homozygous in most reported consanguineous families.

autosomal recessive inheritance

Show evidence (2 references)

CGGV:assertion_8ac052f6-de8d-4c14-adf2-bbecb624defd-2024-06-21T160000.000Z SUPPORT Other

ClinGen records the mode of inheritance as autosomal recessive.

PMID:42343915 SUPPORT BACKGROUND Human clinical

"Its deficiency impairs peroxisomal beta-oxidation of very long-chain fatty acids and causes an autosomal recessive disorder that manifests as retinal dystrophy and leukodystrophy."

Case series restating autosomal recessive inheritance.

?

Discussions and Knowledge Gaps

1

How much of the retinal and white matter disease comes from loss of the peroxisome-ER tether (ether lipid supply, peroxisome positioning, calcium), and how much from loss of very-long-chain acyl-CoA capture?

KNOWLEDGE GAP OPEN acbd5_tether_vs_vlcfa_contribution

Attached to

pathophysiology#Loss of Peroxisome-ER Membrane Contacts pathophysiology#Impaired Peroxisomal Very-Long-Chain Fatty Acid Beta-Oxidation pathophysiology#Disturbed Ether Lipid Synthesis

ACBD5 does both jobs, and patient disease cannot separate them. In cultured cells the tether is not strictly required for VLCFA oxidation, and plasma VLCFA in patients is only mildly raised, while X-linked adrenoleukodystrophy, with much higher VLCFA, has a different clinical picture. The tether's contribution to plasmalogen supply, which myelin depends on, has not been measured in patient neural cells.

Proposed experiments

Separation-of-function ACBD5 alleles in patient iPSC-derived neural cells

acbd5_separation_of_function_ipsc

In ACBD5-null patient iPSC-derived oligodendrocytes, neurons and retinal organoids, re-express wild-type ACBD5, an FFAT-motif mutant that cannot bind VAPB, or an acyl-CoA binding domain mutant. Measure peroxisome-ER contacts and organelle signatures by multispectral imaging, plasmalogen and VLCFA lipidomics, myelin protein expression and synapse number.

Would support

pathophysiology#Disturbed Ether Lipid Synthesis

Supporting outcome

The FFAT mutant fails to restore plasmalogens, myelination or synapses while restoring VLCFA oxidation.

Refuting outcome

The acyl-CoA binding mutant alone reproduces the neural defects and the FFAT mutant rescues them.

Show evidence (1 reference)

PMID:37414147 SUPPORT In vitro / ex vivo

"Overall, our findings suggest that ACBD5 may act as a primary tether and VLCFA recruitment factor, whereas ACBD4 may have regulatory functions in peroxisomal lipid metabolism at the peroxisome-ER interface."

ACBD5 is both a tether and a VLCFA recruitment factor.

⚙

Pathophysiology

9

ACBD5 Loss of Function

Biallelic loss-of-function variants remove ACBD5 from the peroxisomal membrane. The protein does two separable things there, so its loss starts two branches: loss of very-long-chain acyl-CoA capture, and loss of the peroxisome-ER tether.

ACBD5 hgnc:23338

very-long-chain fatty acyl-CoA binding GO:0000062 ↓ DECREASED

peroxisome GO:0005777

Downstream

Impaired Peroxisomal Very-Long-Chain Fatty Acid Beta-Oxidation

Loss of Peroxisome-ER Membrane Contacts

Show evidence (3 references)

PMID:27799409 SUPPORT Human clinical

"We identified a homozygous deleterious indel mutation in ACBD5, leading to complete loss of ACBD5 protein in the patient."

Patient material shows complete loss of ACBD5 protein.

PMID:27899449 SUPPORT In vitro / ex vivo

"We herein report that ACBD5 is a peroxisomal tail-anchored membrane protein exposing its ACBD to the cytosol."

Places the lost protein on the peroxisomal membrane with its acyl-CoA binding domain facing the cytosol.

PMID:27899449 SUPPORT In vitro / ex vivo

"Furthermore, ACBD5 preferentially binds very-long-chain fatty acyl-CoAs (VLC-CoAs)."

The molecular function lost is acyl-CoA binding, with a preference for very-long-chain species. GO has no very-long-chain-specific term (its long-chain term covers shorter chains), so the parent fatty-acyl-CoA binding term is bound.

Impaired Peroxisomal Very-Long-Chain Fatty Acid Beta-Oxidation

Without ACBD5 to capture very-long-chain acyl-CoAs (such as C26:0-CoA) on the cytosolic face of the peroxisome, their transfer into the peroxisome and beta-oxidation slow. The defect is moderate, which fits the mildly raised or normal plasma VLCFA seen in patients. The tethering function is not strictly required for this step in cultured cells, so this branch is modelled separately from the contact-site branch.

very long-chain fatty acid catabolic process GO:0042760 ↓ DECREASED

Downstream

Very-Long-Chain Fatty Acid Accumulation in Membrane Lipids

Show evidence (3 references)

PMID:27799409 SUPPORT Human clinical

"Our studies showed that ACBD5 deficiency leads to accumulation of very long-chain fatty acids (VLCFAs) due to impaired peroxisomal β-oxidation."

Patient material and knockout cells show impaired VLCFA beta-oxidation.

PMID:27899449 SUPPORT In vitro / ex vivo

"we demonstrate that ACBD5 deficiency causes a moderate but significant defect in peroxisomal β-oxidation of very-long-chain fatty acids (VLCFAs)"

Patient fibroblasts and knockout HeLa cells show a moderate oxidation defect.

PMID:37414147 SUPPORT In vitro / ex vivo

"We show that the tethering function of ACBD5 is not absolutely required for efficient peroxisomal β-oxidation of VLCFAs."

Supports treating VLCFA oxidation as a branch distinct from tethering: the oxidation defect is not explained by the loss of contact alone.

Loss of Peroxisome-ER Membrane Contacts

ACBD5 binds ER VAPA and VAPB through its FFAT-like motif and is the main tether holding peroxisomes against the ER. Without it, peroxisome-ER contacts are sharply reduced, and the lipid exchange, calcium uptake and positioning that depend on the contact fail.

organelle localization by membrane tethering GO:0140056 ↓ DECREASED

peroxisome-endoplasmic reticulum membrane contact site GO:0044232

Animal models

ACBD5-deficient mouse Mouse recapitulates Contacts are measured directly in liver.

Downstream

Disturbed Ether Lipid Synthesis

Altered Peroxisome Abundance and Motility

Show evidence (3 references)

PMID:28108524 SUPPORT In vitro / ex vivo

"We show that ACBD5-VAPB interaction regulates PO-ER associations."

Identifies ACBD5-VAPB as the peroxisome-ER tether in mammalian cells.

PMID:28108526 SUPPORT In vitro / ex vivo

"Depletion of either ACBD5 or VAP expression results in increased peroxisome mobility, suggesting that VAP-ACBD5 complex acts as the primary ER-peroxisome tether."

ACBD5 depletion releases peroxisomes from the ER.

PMID:33244184 SUPPORT Model organism

"Liver did not exhibit pathologic changes but increased peroxisome abundance and drastically reduced peroxisome-ER contacts."

The contact loss is seen in vivo in ACBD5-deficient mice.

Disturbed Ether Lipid Synthesis

Ether lipid (plasmalogen) synthesis starts in the peroxisome and is finished in the ER, so it depends on the two organelles being in contact. Loss of the ACBD5 tether lowers plasmalogen synthesis in cultured cells and shifts ether lipid intermediates in ACBD5-deficient mouse liver. Patient fibroblasts with VLCFA oxidation defects, ACBD5-deficient lines among them, have reduced ether phospholipids. Whether this deficit contributes to the leukodystrophy has not been tested (see discussions).

plasmalogen (ether lipid) biosynthesis GO:0008611 ↕ DYSREGULATED

Show evidence (2 references)

PMID:33244184 SUPPORT Model organism

"By contrast, ether lipid formation was perturbed in liver towards an accumulation of alkyldiacylglycerols."

Ether lipid synthesis is perturbed in ACBD5-deficient mouse liver.

PMID:28849344 SUPPORT INDIRECT In vitro / ex vivo

"Remarkably, we found that ether phospholipids, including plasmalogens, were decreased."

Lipidomics of patient fibroblasts with several VLCFA oxidation defects, including ACBD5 deficiency, found reduced plasmalogens. The sentence covers the group of cell lines, not ACBD5 alone.

Altered Peroxisome Abundance and Motility

Untethered peroxisomes move more, fail to expand their membranes normally, and in mouse liver become more numerous. Peroxisomal calcium uptake, which depends on the contact, is also reduced.

peroxisome organization GO:0007031 ⚠ ABNORMAL

Show evidence (2 references)

PMID:28108524 SUPPORT In vitro / ex vivo

"we demonstrate that loss of PO-ER association perturbs PO membrane expansion and increases PO movement"

Loss of the contact changes peroxisome growth and movement.

PMID:42118293 SUPPORT In vitro / ex vivo

"we find that the ACBD5-dependent membrane contact site between peroxisomes and the endoplasmic reticulum (ER) is necessary for efficient peroxisomal Ca2+ uptake"

The ACBD5 contact is needed for peroxisomal calcium uptake.

Very-Long-Chain Fatty Acid Accumulation in Membrane Lipids

Unoxidized very-long-chain fatty acids, including C26:0, ultra-long species above C32 and very-long-chain polyunsaturated fatty acids, are built into phospholipids. In ACBD5-deficient mice the pattern is tissue-specific: ultra-long species rise in cerebellar phosphatidylcholines but not liver, and in the retina VLC-PUFA build up in the plexiform (synaptic) layers rather than in photoreceptor outer segments.

Downstream

CNS Demyelination and Giant Axonopathy

Cerebellar Purkinje Cell Degeneration

Retinal Degeneration with Synaptic and Glial Pathology

Show evidence (2 references)

PMID:33244184 SUPPORT Model organism

"In line with the neurological pathology, unusual ultra-long chain fatty acids (C > 32) were elevated in phosphocholines from cerebelli but not liver indicating an organ-specific imbalance in fatty acid degradation and elongation pathways."

Ultra-long fatty acids accumulate in cerebellar membrane lipids.

PMID:41324649 SUPPORT Model organism

"In contrast, VLC-PUFAs in ACBD5-deficient mice consistently accumulated in the inner retinal region from the outer (OPL) to inner plexiform layer (IPL)."

VLC-PUFA accumulate in the synaptic layers of the retina.

CNS Demyelination and Giant Axonopathy

Progressive leukodystrophy in patients corresponds, in the Acbd5 Gly357* mouse, to demyelination with giant axonal swellings throughout the central nervous system and reactive astrocytes. AAV delivery of Acbd5 reduced the axonopathy and improved myelination.

oligodendrocyte CL:0000128

myelination GO:0042552 ↓ DECREASED

Animal models

Acbd5 Gly357* knock-in mouse Mouse recapitulates Develops CNS demyelination and giant axonopathy, rescued by AAV gene delivery.

Downstream

Spastic paraparesis

Leukodystrophy

Developmental regression

Cognitive decline

Show evidence (2 references)

PMID:38066620 SUPPORT Model organism

"Gly357* mutant mice recapitulated key features of the human disorder, including reduced survival, impaired locomotion and reflexes, loss of photoreceptors, and demyelination."

The mouse model develops demyelination.

PMID:42343915 SUPPORT Human clinical

"Brain MRI revealed diffuse T2 signal abnormality in deep white matter, with involvement of corticospinal tracts."

Patients have deep white matter disease involving the corticospinal tracts.

Cerebellar Purkinje Cell Degeneration

The ataxia of the Acbd5 Gly357* mouse involves loss of cerebellar Purkinje cells, and ACBD5-deficient mice develop progressive cerebellar pathology.

Purkinje cell CL:0000121

Downstream

Cerebellar ataxia

Show evidence (1 reference)

PMID:38066620 SUPPORT Model organism

"The ataxic presentation of Gly357* mice involved the loss of cerebellar Purkinje cells and a giant axonopathy throughout the CNS."

Purkinje cells are lost in the ataxic mouse.

Retinal Degeneration with Synaptic and Glial Pathology

In ACBD5-deficient mice, photoreceptor, bipolar, ganglion and pigment epithelial cells degenerate moderately, photoreceptor ribbon synapses in the outer plexiform layer degenerate, and astroglia and microglia are strongly activated. Inner-retinal signal transmission is severely reduced. This fits the early cone-rod dysfunction seen in patients.

photoreceptor cell CL:0000210 microglial cell CL:0000129

photoreceptor ribbon synapse GO:0097470

Downstream

Cone-rod dystrophy

Retinal dystrophy

Rod monochromatism

Macular dystrophy

Nystagmus

Photophobia

Blindness

Show evidence (2 references)

PMID:41324649 SUPPORT Model organism

"Histological results implied that ACBD5-deficient mice exhibit a moderate degeneration of photoreceptor, bipolar, ganglion and retinal pigment epithelial cells accompanied, however, by a prominent activation of astroglia and microglia."

Retinal neurons degenerate with strong glial activation.

PMID:41324649 SUPPORT Model organism

"Reduced a- and b-wave amplitudes from ffERG point to a severe functional dysregulation of retinal signal transduction with a focus at the level of the information-processing cell of the inner retina."

Electroretinography shows severe loss of retinal signalling.

⬡

Pathograph

Use Group by to collapse related nodes into one box. Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

15

Eye 7

Retinal dystrophy HP:0000556

Show evidence (2 references)

PMID:37789430 SUPPORT BACKGROUND Human clinical

"Presenting features include retinal dystrophy, progressive leukodystrophy, and ataxia."

Retinal dystrophy is a presenting feature.

PMID:27799409 SUPPORT Human clinical

"We studied a girl who presented with progressive leukodystrophy, syndromic cleft palate, ataxia and retinal dystrophy."

The index patient of the VLCFA study had retinal dystrophy.

Cone-rod dystrophy Cone/cone-rod dystrophy HP:0000548

Show evidence (1 reference)

PMID:42343915 SUPPORT Human clinical

"Electroretinogram confirmed severe cone-rod dystrophy."

ERG showed severe cone-rod dystrophy in the Omani series.

Rod monochromatism Achromatopsia HP:0011516

Show evidence (1 reference)

PMID:37789430 SUPPORT Human clinical

"presenting with the common features of rod monochromatism and progressive leukodystrophy with spasticity and ataxia"

Rod monochromatism is described as a common feature.

Macular dystrophy HP:0007754

Show evidence (1 reference)

PMID:38841324 SUPPORT Human clinical

"Macular dystrophy was demonstrated with optical coherence tomography imaging for the first time in the literature in ACBD5 deficiency."

OCT showed macular dystrophy in one patient.

Nystagmus HP:0000639

Onset: INFANTILE

Show evidence (1 reference)

PMID:42343915 SUPPORT Human clinical

"First presentation was in infancy with nystagmus and photophobia and progressed to legal blindness by 10 years of age."

Nystagmus is the presenting sign in infancy.

Photophobia HP:0000613

Show evidence (1 reference)

PMID:42343915 SUPPORT Human clinical

"First presentation was in infancy with nystagmus and photophobia and progressed to legal blindness by 10 years of age."

Photophobia accompanies the infantile presentation.

Blindness HP:0000618

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:42343915 SUPPORT Human clinical

"First presentation was in infancy with nystagmus and photophobia and progressed to legal blindness by 10 years of age."

Vision loss progresses to legal blindness by age 10.

Genitourinary 1

Premature ovarian insufficiency HP:0008209

Show evidence (1 reference)

PMID:37789430 SUPPORT Human clinical

"Additional novel clinical features included head and neck tremor and ovarian insufficiency."

Ovarian insufficiency reported in one adult patient.

Head and Neck 1

Cleft palate HP:0000175

Show evidence (1 reference)

PMID:27799409 SUPPORT Human clinical

"We studied a girl who presented with progressive leukodystrophy, syndromic cleft palate, ataxia and retinal dystrophy."

Cleft palate in the index patient.

Musculoskeletal 1

Spastic paraparesis HP:0002313

Course: PROGRESSIVE

Show evidence (2 references)

PMID:38841324 SUPPORT Human clinical

"He had spastic paraparesis dominated with axial hypotonic posturing and horizontal nystagmus."

Spastic paraparesis in a 6-year-old patient.

PMID:42343915 SUPPORT Human clinical

"This series confirms retinal dystrophy and leukodystrophy as key features of ACBD5 deficiency with main symptoms of early onset visual decline, progressive spasticity, and cerebellar ataxia."

Progressive spasticity is a main symptom across the Omani series.

Nervous System 5

Leukodystrophy HP:0002415

Course: PROGRESSIVE

Show evidence (2 references)

PMID:27799409 SUPPORT Human clinical

"We studied a girl who presented with progressive leukodystrophy, syndromic cleft palate, ataxia and retinal dystrophy."

Progressive leukodystrophy in the index patient.

PMID:42343915 SUPPORT Human clinical

"Brain MRI revealed diffuse T2 signal abnormality in deep white matter, with involvement of corticospinal tracts."

MRI shows deep white matter disease.

Cerebellar ataxia Progressive cerebellar ataxia HP:0002073

Show evidence (1 reference)

PMID:42343915 SUPPORT Human clinical

"Motor neuroregression with variable ages of onset and signs of progressive cerebellar ataxia were seen in all patients, whereas cognitive decline was observed in some."

All five patients had progressive cerebellar ataxia.

Developmental regression HP:0002376

Show evidence (2 references)

PMID:33427402 SUPPORT Human clinical

"Here, we present a 36-year-old female with retinal dystrophy, leukodystrophy, and psychomotor regression due to a novel homozygous variant in ACBD5."

Psychomotor regression in the first reported adult patient.

PMID:38841324 SUPPORT Human clinical

"A 6-year-old male patient was admitted with complaints of neuromotor regression and visual disturbances."

Neuromotor regression was a presenting complaint.

Cognitive decline Mental deterioration HP:0001268

Show evidence (1 reference)

PMID:42343915 SUPPORT Human clinical

"Motor neuroregression with variable ages of onset and signs of progressive cerebellar ataxia were seen in all patients, whereas cognitive decline was observed in some."

Cognitive decline occurred in some patients.

Head tremor HP:0002346

Show evidence (1 reference)

PMID:37789430 SUPPORT Human clinical

"Additional novel clinical features included head and neck tremor and ovarian insufficiency."

Head and neck tremor reported in one adult patient.

🧬

Genetic Associations

1

ACBD5 (Pathogenic Variants)

Gene: ACBD5 hgnc:23338 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (3 references)

CGGV:assertion_8ac052f6-de8d-4c14-adf2-bbecb624defd-2024-06-21T160000.000Z SUPPORT Other

"The mechanism for disease is expected to be loss of function."

ClinGen summary of the disease mechanism.

PMID:23105016 SUPPORT Human clinical

"Additionally, our study revealed six novel candidate disease genes (C21orf2, EMC1, KIAA1549, GPR125, ACBD5, and DTHD1), two of which (ACBD5 and DTHD1) were observed in the context of syndromic forms of RD that are described for the first time."

First report of ACBD5 as a candidate gene for a syndromic retinal dystrophy.

PMID:27799409 SUPPORT Human clinical

"We identified a homozygous deleterious indel mutation in ACBD5, leading to complete loss of ACBD5 protein in the patient."

A null allele with complete protein loss in an affected patient.

💊

Medical Actions

1

AAV-mediated ACBD5 gene delivery (preclinical)

Action: gene therapy Ontology label: Gene Therapy NCIT:C15238

Platform: Gene therapy

No disease-modifying treatment exists for patients; care is supportive. In the Acbd5 Gly357* mouse, adeno-associated virus delivery of Acbd5 improved gait, reduced giant axonopathy, and improved myelination and astrocyte reactivity. This has not been tested in humans.

Mechanism Target:

INHIBITS CNS Demyelination and Giant Axonopathy — Gene delivery reduced axonopathy and improved myelination in mice.

Show evidence (1 reference)

PMID:38066620 SUPPORT Model organism

"We also show that an adeno-associated virus-mediated gene delivery ameliorated the gait phenotypes and the giant axonopathy, also improving myelination and astrocyte reactivity."

Preclinical rescue in the mouse model.

Show evidence (1 reference)

PMID:38066620 SUPPORT Model organism

"We also show that an adeno-associated virus-mediated gene delivery ameliorated the gait phenotypes and the giant axonopathy, also improving myelination and astrocyte reactivity."

Preclinical efficacy in mice only.

🔬

Biochemical Markers

1

Plasma C26:0 and C26:0/C22:0 ratio (INCREASED)

Context: Only mildly raised and sometimes within the normal range, so a normal plasma VLCFA profile does not exclude the diagnosis.

Show evidence (2 references)

PMID:42343915 SUPPORT Human clinical

"Plasma long chain fatty acid profile showed mild elevation of C26 and C26/22 ratio."

C26:0 and the C26:0/C22:0 ratio are mildly raised.

PMID:38841324 SUPPORT Human clinical

"His very-long-chain fatty acid levels were within normal ranges with a slightly elevated C26:0/C22:0 ratio."

VLCFA can be normal, with only the ratio slightly raised.

🔬

Diagnosis

3

Molecular genetic testing for ACBD5

Diagnosis rests on biallelic ACBD5 variants, usually found by exome sequencing. Biochemical screening can miss the disease because plasma VLCFA may be normal.

exome or genome sequencing with ACBD5 variant analysis NCIT:C15709

Show evidence (2 references)

PMID:38841324 SUPPORT Human clinical

"Clinical exome sequencing displayed a novel homozygous intronic splice site variant (c.936 + 2T>G) in the ACBD5 (NM_145698.5) gene."

Exome sequencing made the diagnosis.

PMID:37789430 SUPPORT Human clinical

"The patient's symptoms were present since infancy, but a diagnosis was only reached in adulthood when whole exome sequencing was performed."

Exome sequencing gave the diagnosis after decades of symptoms.

Electroretinography

Full-field ERG shows a severe cone-rod pattern of retinal dysfunction.

No NCIT term for electroretinography: an OLS search of NCIT for "electroretinography" (2026-10-23) returned no results, so diagnosis_term is left unbound.

Show evidence (1 reference)

PMID:42343915 SUPPORT Human clinical

"Electroretinogram confirmed severe cone-rod dystrophy."

ERG established the cone-rod dystrophy.

Brain MRI

Shows diffuse T2 signal change in the deep white matter with corticospinal tract involvement.

brain magnetic resonance imaging NCIT:C16809

Show evidence (1 reference)

PMID:42343915 SUPPORT Human clinical

"Brain MRI revealed diffuse T2 signal abnormality in deep white matter, with involvement of corticospinal tracts."

MRI shows the leukodystrophy.

📊

Prevalence

1

Worldwide (published case reports)

Cases/families reported in the literature Ultra-rare

Two 2024 case reports (PMID:37789430, PMID:38841324) each counted seven previously reported patients and added one; a 2026 series (PMID:42343915) added five. About fourteen patients have been published.

Show evidence (2 references)

PMID:38841324 SUPPORT REVIEW SYNTHESIS Human clinical

"Acyl-CoA binding domain containing 5 (ACBD5) deficiency is a newly defined inborn peroxisomal disorder with only 7 patients reported to date."

Literature count of reported patients before this case.

PMID:42343915 SUPPORT Human clinical

"This case series adds valuable insight in to this ultra-rare neurometabolic disease."

Describes the disease as ultra-rare and adds five patients.

🐁

Animal Models

2

Acbd5 Gly357* knock-in mouse

Truncating mouse allele that reproduces reduced survival, impaired locomotion, photoreceptor loss, demyelination, Purkinje cell loss and giant axonopathy.

Species

Mouse

Genotype

Acbd5 p.Gly357* (CRISPR/Cas9) homozygous

Publication

PMID:38066620

Pathograph links

CNS Demyelination and Giant Axonopathy recapitulates fidelity: moderate Develops CNS demyelination and giant axonopathy, rescued by AAV gene delivery.

Limitations: Mouse lifespan and myelin lipid composition differ from human, and patients have not been shown to have giant axons.

Show evidence (1 reference)

PMID:38066620 SUPPORT Model organism

"The ataxic presentation of Gly357* mice involved the loss of cerebellar Purkinje cells and a giant axonopathy throughout the CNS."

Shows the axonal and cerebellar pathology in the model.

ACBD5-deficient mouse

Loss-of-function mouse showing raised VLCFA, progressive cerebellar pathology, sharply reduced peroxisome-ER contacts in liver, and retinal degeneration with VLC-PUFA accumulation in the plexiform layers.

Species

Mouse

Genotype

Acbd5 knockout

Publication

PMID:33244184

Pathograph links

Loss of Peroxisome-ER Membrane Contacts recapitulates fidelity: moderate Contacts are measured directly in liver.

Limitations: Contact loss was quantified in liver, not in brain or retina where disease occurs.

Show evidence (1 reference)

PMID:33244184 SUPPORT Model organism

"Liver did not exhibit pathologic changes but increased peroxisome abundance and drastically reduced peroxisome-ER contacts."

Direct measurement of the contact defect in the model.

{ }

Source YAML

click to show

name: ACBD5 Deficiency
creation_date: "2026-10-23T14:30:00Z"
category: Mendelian
synonyms:
- Retinal dystrophy with leukodystrophy
- RDLKD
- Acyl-CoA binding domain containing protein 5 deficiency
description: >-
  Autosomal recessive peroxisomal disorder caused by biallelic loss-of-function
  variants in ACBD5. ACBD5 is a tail-anchored peroxisomal membrane protein with
  two jobs: its cytosolic acyl-CoA binding domain captures very-long-chain
  acyl-CoAs for peroxisomal beta-oxidation, and its FFAT-like motif binds the ER
  proteins VAPA and VAPB to tether peroxisomes to the endoplasmic reticulum.
  ACBD5 was the first peroxisomal tether found to cause human disease. Patients
  present in infancy or childhood with nystagmus, photophobia and cone-rod or
  rod-dominant retinal dystrophy progressing to blindness, followed by
  progressive leukodystrophy with spasticity, cerebellar ataxia and
  psychomotor regression. Plasma very-long-chain fatty acids are only mildly
  raised and can be normal. About fourteen patients have been reported.
parents:
- Peroxisomal disorder
- Inborn error of metabolism
- Leukodystrophy
- Retinal dystrophy
notes: >-
  Two MONDO classes describe this disease. MONDO:0100112 sits under the
  peroxisomal-disorder classes and is the term ClinGen classifies; MONDO:0030026
  (retinal dystrophy with leukodystrophy) is the OMIM:618863 import and has only
  a generic "hereditary disease" parent. ClinGen states that it lumped the
  retinal-dystrophy and ACBD5-deficiency reports into MONDO:0100112, so this entry
  binds that term and maps MONDO:0030026 as an exact match. No GeneReviews chapter
  names the disease (PubMed search of genereviews[book] for ACBD5 and for retinal
  dystrophy with leukodystrophy, 2026-10-23).
disease_term:
  preferred_term: acyl-CoA binding domain containing protein 5 deficiency
  term:
    id: MONDO:0100112
    label: acyl-CoA binding domain containing protein 5 deficiency
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0030026
      label: retinal dystrophy with leukodystrophy
    mapping_predicate: skos:exactMatch
    mapping_source: OMIM:618863
    mapping_justification: >-
      MONDO:0030026 cross-references OMIM:618863 and names ACBD5 as its causal
      gene. ClinGen lumped the retinal-dystrophy and ACBD5-deficiency reports into
      one entity, MONDO:0100112, finding no difference in mechanism, inheritance or
      phenotype.
inheritance:
- name: Autosomal recessive inheritance
  description: Biallelic germline ACBD5 variants cause the disease, homozygous in most reported consanguineous families.
  inheritance_term:
    preferred_term: autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: CGGV:assertion_8ac052f6-de8d-4c14-adf2-bbecb624defd-2024-06-21T160000.000Z
    reference_title: "ACBD5 / acyl-CoA binding domain containing protein 5 deficiency (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ACBD5 | HGNC:23338 | acyl-CoA binding domain containing protein 5 deficiency | MONDO:0100112 | AR | Definitive"
    explanation: ClinGen records the mode of inheritance as autosomal recessive.
  - reference: PMID:42343915
    reference_title: "Retinal Dystrophy and Leukodystrophy Caused by ACBD5 Deficiency in Five Omani Patients: A Case Series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      Its deficiency impairs peroxisomal beta-oxidation of very long-chain fatty
      acids and causes an autosomal recessive disorder that manifests as retinal
      dystrophy and leukodystrophy.
    explanation: Case series restating autosomal recessive inheritance.
genetic:
- name: ACBD5
  gene_term:
    preferred_term: ACBD5
    term:
      id: hgnc:23338
      label: ACBD5
  association: Pathogenic Variants
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_disease_validity:
  - validity_classification: DEFINITIVE
    classified_by: CLINGEN
    external_id: CGGV:assertion_8ac052f6-de8d-4c14-adf2-bbecb624defd-2024-06-21T160000.000Z
    evidence:
    - reference: CGGV:assertion_8ac052f6-de8d-4c14-adf2-bbecb624defd-2024-06-21T160000.000Z
      reference_title: "ACBD5 / acyl-CoA binding domain containing protein 5 deficiency (Definitive)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "ACBD5 | HGNC:23338 | acyl-CoA binding domain containing protein 5 deficiency | MONDO:0100112 | AR | Definitive"
      explanation: ClinGen gene-disease validity record classifying this pair as Definitive.
  notes: >-
    Reported variants are predicted loss of function: frameshift indel, nonsense
    (p.Arg433*), canonical splice-site (c.936+2T>G) and multi-exon deletions, plus
    compound heterozygous alleles in an adult case. A heterozygous ACBD5 missense
    variant of uncertain significance reported in a father and daughter with
    isolated retinal findings (PMID:36699790) is not counted here, since the
    father carried variants in several other retinal genes and the disease is
    recessive.
  evidence:
  - reference: CGGV:assertion_8ac052f6-de8d-4c14-adf2-bbecb624defd-2024-06-21T160000.000Z
    reference_title: "ACBD5 / acyl-CoA binding domain containing protein 5 deficiency (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: The mechanism for disease is expected to be loss of function.
    explanation: ClinGen summary of the disease mechanism.
  - reference: PMID:23105016
    reference_title: "Autozygome-guided exome sequencing in retinal dystrophy patients reveals pathogenetic mutations and novel candidate disease genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Additionally, our study revealed six novel candidate disease genes
      (C21orf2, EMC1, KIAA1549, GPR125, ACBD5, and DTHD1), two of which (ACBD5
      and DTHD1) were observed in the context of syndromic forms of RD that are
      described for the first time.
    explanation: First report of ACBD5 as a candidate gene for a syndromic retinal dystrophy.
  - reference: PMID:27799409
    reference_title: "ACBD5 deficiency causes a defect in peroxisomal very long-chain fatty acid metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified a homozygous deleterious indel mutation in ACBD5, leading to
      complete loss of ACBD5 protein in the patient.
    explanation: A null allele with complete protein loss in an affected patient.
pathophysiology:
- name: ACBD5 Loss of Function
  biological_scale: MOLECULAR
  description: >-
    Biallelic loss-of-function variants remove ACBD5 from the peroxisomal
    membrane. The protein does two separable things there, so its loss starts two
    branches: loss of very-long-chain acyl-CoA capture, and loss of the
    peroxisome-ER tether.
  genes:
  - preferred_term: ACBD5
    term:
      id: hgnc:23338
      label: ACBD5
  cellular_components:
  - preferred_term: peroxisome
    term:
      id: GO:0005777
      label: peroxisome
  molecular_functions:
  - preferred_term: very-long-chain fatty acyl-CoA binding
    modifier: DECREASED
    term:
      id: GO:0000062
      label: fatty-acyl-CoA binding
  evidence:
  - reference: PMID:27799409
    reference_title: "ACBD5 deficiency causes a defect in peroxisomal very long-chain fatty acid metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified a homozygous deleterious indel mutation in ACBD5, leading to
      complete loss of ACBD5 protein in the patient.
    explanation: Patient material shows complete loss of ACBD5 protein.
  - reference: PMID:27899449
    reference_title: "Deficiency of a Retinal Dystrophy Protein, Acyl-CoA Binding Domain-containing 5 (ACBD5), Impairs Peroxisomal β-Oxidation of Very-long-chain Fatty Acids."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We herein report that ACBD5 is a peroxisomal tail-anchored membrane protein
      exposing its ACBD to the cytosol.
    explanation: Places the lost protein on the peroxisomal membrane with its acyl-CoA binding domain facing the cytosol.
  - reference: PMID:27899449
    reference_title: "Deficiency of a Retinal Dystrophy Protein, Acyl-CoA Binding Domain-containing 5 (ACBD5), Impairs Peroxisomal β-Oxidation of Very-long-chain Fatty Acids."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Furthermore, ACBD5 preferentially binds very-long-chain fatty acyl-CoAs
      (VLC-CoAs).
    explanation: >-
      The molecular function lost is acyl-CoA binding, with a preference for
      very-long-chain species. GO has no very-long-chain-specific term (its
      long-chain term covers shorter chains), so the parent fatty-acyl-CoA
      binding term is bound.
  downstream:
  - target: Impaired Peroxisomal Very-Long-Chain Fatty Acid Beta-Oxidation
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:27899449
      reference_title: "Deficiency of a Retinal Dystrophy Protein, Acyl-CoA Binding Domain-containing 5 (ACBD5), Impairs Peroxisomal β-Oxidation of Very-long-chain Fatty Acids."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Both the N-terminal ACBD and peroxisomal localization of ACBD5 are
        prerequisite for efficient VLCFA beta-oxidation in peroxisomes.
      explanation: Rescue experiments show the acyl-CoA binding domain is needed for VLCFA oxidation.
  - target: Loss of Peroxisome-ER Membrane Contacts
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33244184
      reference_title: "Cerebellar and hepatic alterations in ACBD5-deficient mice are associated with unexpected, distinct alterations in cellular lipid homeostasis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Liver did not exhibit pathologic changes but increased peroxisome
        abundance and drastically reduced peroxisome-ER contacts.
      explanation: ACBD5-deficient mouse liver has far fewer peroxisome-ER contacts.
- name: Impaired Peroxisomal Very-Long-Chain Fatty Acid Beta-Oxidation
  biological_scale: MOLECULAR
  description: >-
    Without ACBD5 to capture very-long-chain acyl-CoAs (such as C26:0-CoA) on the
    cytosolic face of the peroxisome, their transfer into the peroxisome and
    beta-oxidation slow. The defect is moderate, which fits the mildly raised or
    normal plasma VLCFA seen in patients. The tethering function is not strictly
    required for this step in cultured cells, so this branch is modelled
    separately from the contact-site branch.
  biological_processes:
  - preferred_term: very long-chain fatty acid catabolic process
    modifier: DECREASED
    term:
      id: GO:0042760
      label: very long-chain fatty acid catabolic process
  evidence:
  - reference: PMID:27799409
    reference_title: "ACBD5 deficiency causes a defect in peroxisomal very long-chain fatty acid metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our studies showed that ACBD5 deficiency leads to accumulation of very
      long-chain fatty acids (VLCFAs) due to impaired peroxisomal β-oxidation.
    explanation: Patient material and knockout cells show impaired VLCFA beta-oxidation.
  - reference: PMID:27899449
    reference_title: "Deficiency of a Retinal Dystrophy Protein, Acyl-CoA Binding Domain-containing 5 (ACBD5), Impairs Peroxisomal β-Oxidation of Very-long-chain Fatty Acids."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      we demonstrate that ACBD5 deficiency causes a moderate but significant
      defect in peroxisomal β-oxidation of very-long-chain fatty acids (VLCFAs)
    explanation: Patient fibroblasts and knockout HeLa cells show a moderate oxidation defect.
  - reference: PMID:37414147
    reference_title: "Differential roles for ACBD4 and ACBD5 in peroxisome-ER interactions and lipid metabolism."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We show that the tethering function of ACBD5 is not absolutely required for
      efficient peroxisomal β-oxidation of VLCFAs.
    explanation: >-
      Supports treating VLCFA oxidation as a branch distinct from tethering: the
      oxidation defect is not explained by the loss of contact alone.
  downstream:
  - target: Very-Long-Chain Fatty Acid Accumulation in Membrane Lipids
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:27899449
      reference_title: "Deficiency of a Retinal Dystrophy Protein, Acyl-CoA Binding Domain-containing 5 (ACBD5), Impairs Peroxisomal β-Oxidation of Very-long-chain Fatty Acids."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        elevates the level of cellular phospholipids containing VLCFAs without
        affecting peroxisome biogenesis
      explanation: Slowed oxidation raises VLCFA-containing phospholipids while peroxisome biogenesis is intact.
- name: Loss of Peroxisome-ER Membrane Contacts
  conforms_to: "membrane_contact_site_dysfunction#Loss of Organelle Tethering at a Membrane Contact Site"
  biological_scale: MOLECULAR
  description: >-
    ACBD5 binds ER VAPA and VAPB through its FFAT-like motif and is the main
    tether holding peroxisomes against the ER. Without it, peroxisome-ER contacts
    are sharply reduced, and the lipid exchange, calcium uptake and positioning
    that depend on the contact fail.
  cellular_components:
  - preferred_term: peroxisome-endoplasmic reticulum membrane contact site
    term:
      id: GO:0044232
      label: organelle membrane contact site
  biological_processes:
  - preferred_term: organelle localization by membrane tethering
    modifier: DECREASED
    term:
      id: GO:0140056
      label: organelle localization by membrane tethering
  evidence:
  - reference: PMID:28108524
    reference_title: "ACBD5 and VAPB mediate membrane associations between peroxisomes and the ER."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: We show that ACBD5-VAPB interaction regulates PO-ER associations.
    explanation: Identifies ACBD5-VAPB as the peroxisome-ER tether in mammalian cells.
  - reference: PMID:28108526
    reference_title: "VAPs and ACBD5 tether peroxisomes to the ER for peroxisome maintenance and lipid homeostasis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Depletion of either ACBD5 or VAP expression results in increased peroxisome
      mobility, suggesting that VAP-ACBD5 complex acts as the primary
      ER-peroxisome tether.
    explanation: ACBD5 depletion releases peroxisomes from the ER.
  - reference: PMID:33244184
    reference_title: "Cerebellar and hepatic alterations in ACBD5-deficient mice are associated with unexpected, distinct alterations in cellular lipid homeostasis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Liver did not exhibit pathologic changes but increased peroxisome
      abundance and drastically reduced peroxisome-ER contacts.
    explanation: The contact loss is seen in vivo in ACBD5-deficient mice.
  downstream:
  - target: Disturbed Ether Lipid Synthesis
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:28108526
      reference_title: "VAPs and ACBD5 tether peroxisomes to the ER for peroxisome maintenance and lipid homeostasis."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        We also demonstrate that tethering of peroxisomes to the ER is necessary
        for peroxisome growth, the synthesis of plasmalogen phospholipids, and
        the maintenance of cellular cholesterol levels.
      explanation: Plasmalogen synthesis needs the ACBD5-VAP contact.
  - target: Altered Peroxisome Abundance and Motility
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:42118293
      reference_title: "Peroxisome calcium uptake is dependent on ER-peroxisome membrane contact."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Further, we identify the ACBD5-dependent peroxisome-ER contact site as
        the major factor restricting peroxisome motility within the cell.
      explanation: The contact is what holds peroxisomes in place.
- name: Disturbed Ether Lipid Synthesis
  conforms_to: "membrane_contact_site_dysfunction#Organelle Membrane Lipid Imbalance"
  biological_scale: CELLULAR
  description: >-
    Ether lipid (plasmalogen) synthesis starts in the peroxisome and is finished
    in the ER, so it depends on the two organelles being in contact. Loss of the
    ACBD5 tether lowers plasmalogen synthesis in cultured cells and shifts ether
    lipid intermediates in ACBD5-deficient mouse liver. Patient fibroblasts with
    VLCFA oxidation defects, ACBD5-deficient lines among them, have reduced ether
    phospholipids. Whether this deficit contributes to the leukodystrophy has not
    been tested (see discussions).
  biological_processes:
  - preferred_term: plasmalogen (ether lipid) biosynthesis
    modifier: DYSREGULATED
    term:
      id: GO:0008611
      label: ether lipid biosynthetic process
  evidence:
  - reference: PMID:33244184
    reference_title: "Cerebellar and hepatic alterations in ACBD5-deficient mice are associated with unexpected, distinct alterations in cellular lipid homeostasis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      By contrast, ether lipid formation was perturbed in liver towards an
      accumulation of alkyldiacylglycerols.
    explanation: Ether lipid synthesis is perturbed in ACBD5-deficient mouse liver.
  - reference: PMID:28849344
    reference_title: "Functional characterisation of peroxisomal β-oxidation disorders in fibroblasts using lipidomics."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: Remarkably, we found that ether phospholipids, including plasmalogens, were decreased.
    explanation: >-
      Lipidomics of patient fibroblasts with several VLCFA oxidation defects,
      including ACBD5 deficiency, found reduced plasmalogens. The sentence covers
      the group of cell lines, not ACBD5 alone.
- name: Altered Peroxisome Abundance and Motility
  conforms_to: "membrane_contact_site_dysfunction#Altered Organelle Morphology, Number and Distribution"
  biological_scale: CELLULAR
  description: >-
    Untethered peroxisomes move more, fail to expand their membranes normally,
    and in mouse liver become more numerous. Peroxisomal calcium uptake, which
    depends on the contact, is also reduced.
  biological_processes:
  - preferred_term: peroxisome organization
    modifier: ABNORMAL
    term:
      id: GO:0007031
      label: peroxisome organization
  evidence:
  - reference: PMID:28108524
    reference_title: "ACBD5 and VAPB mediate membrane associations between peroxisomes and the ER."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      we demonstrate that loss of PO-ER association perturbs PO membrane
      expansion and increases PO movement
    explanation: Loss of the contact changes peroxisome growth and movement.
  - reference: PMID:42118293
    reference_title: "Peroxisome calcium uptake is dependent on ER-peroxisome membrane contact."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      we find that the ACBD5-dependent membrane contact site between peroxisomes
      and the endoplasmic reticulum (ER) is necessary for efficient peroxisomal
      Ca2+ uptake
    explanation: The ACBD5 contact is needed for peroxisomal calcium uptake.
- name: Very-Long-Chain Fatty Acid Accumulation in Membrane Lipids
  biological_scale: CELLULAR
  description: >-
    Unoxidized very-long-chain fatty acids, including C26:0, ultra-long species
    above C32 and very-long-chain polyunsaturated fatty acids, are built into
    phospholipids. In ACBD5-deficient mice the pattern is tissue-specific:
    ultra-long species rise in cerebellar phosphatidylcholines but not liver, and
    in the retina VLC-PUFA build up in the plexiform (synaptic) layers rather than
    in photoreceptor outer segments.
  evidence:
  - reference: PMID:33244184
    reference_title: "Cerebellar and hepatic alterations in ACBD5-deficient mice are associated with unexpected, distinct alterations in cellular lipid homeostasis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In line with the neurological pathology, unusual ultra-long chain fatty
      acids (C > 32) were elevated in phosphocholines from cerebelli but not
      liver indicating an organ-specific imbalance in fatty acid degradation and
      elongation pathways.
    explanation: Ultra-long fatty acids accumulate in cerebellar membrane lipids.
  - reference: PMID:41324649
    reference_title: "Local accumulation of very long-chain PUFA in plexiform layers associates with retinal dysfunction in a mouse model of peroxisomal ACBD5-deficiency."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In contrast, VLC-PUFAs in ACBD5-deficient mice consistently accumulated in
      the inner retinal region from the outer (OPL) to inner plexiform layer
      (IPL).
    explanation: VLC-PUFA accumulate in the synaptic layers of the retina.
  downstream:
  - target: CNS Demyelination and Giant Axonopathy
    evidence:
    - reference: PMID:38066620
      reference_title: "Ataxia with giant axonopathy in Acbd5-deficient mice halted by adeno-associated virus gene therapy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        functional studies in neurons treated with VLCFA unravelled a deregulated
        cytoskeleton with reduced actin dynamics and increased neuronal filopodia
      directness: INDIRECT
      explanation: >-
        VLCFA exposure disturbs the neuronal cytoskeleton in culture. That bears
        on axonopathy more than demyelination, and only through an inference
        step.
  - target: Cerebellar Purkinje Cell Degeneration
    evidence:
    - reference: PMID:33244184
      reference_title: "Cerebellar and hepatic alterations in ACBD5-deficient mice are associated with unexpected, distinct alterations in cellular lipid homeostasis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        ACBD5-deficient mice exhibit elevated very long-chain fatty acid levels
        and a progressive cerebellar pathology.
      explanation: VLCFA elevation accompanies progressive cerebellar pathology.
  - target: Retinal Degeneration with Synaptic and Glial Pathology
    evidence:
    - reference: PMID:41324649
      reference_title: "Local accumulation of very long-chain PUFA in plexiform layers associates with retinal dysfunction in a mouse model of peroxisomal ACBD5-deficiency."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        In line with VLC-PUFA-accumulations, photoreceptor ribbon synapses in the
        OPL showed morphological signs of degeneration on the ultrastructural
        level.
      explanation: Synapses degenerate where VLC-PUFA accumulate.
- name: CNS Demyelination and Giant Axonopathy
  biological_scale: TISSUE
  description: >-
    Progressive leukodystrophy in patients corresponds, in the Acbd5 Gly357*
    mouse, to demyelination with giant axonal swellings throughout the central
    nervous system and reactive astrocytes. AAV delivery of Acbd5 reduced the
    axonopathy and improved myelination.
  cell_types:
  - preferred_term: oligodendrocyte
    term:
      id: CL:0000128
      label: oligodendrocyte
  biological_processes:
  - preferred_term: myelination
    modifier: DECREASED
    term:
      id: GO:0042552
      label: myelination
  evidence:
  - reference: PMID:38066620
    reference_title: "Ataxia with giant axonopathy in Acbd5-deficient mice halted by adeno-associated virus gene therapy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Gly357* mutant mice recapitulated key features of the human disorder,
      including reduced survival, impaired locomotion and reflexes, loss of
      photoreceptors, and demyelination.
    explanation: The mouse model develops demyelination.
  - reference: PMID:42343915
    reference_title: "Retinal Dystrophy and Leukodystrophy Caused by ACBD5 Deficiency in Five Omani Patients: A Case Series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain MRI revealed diffuse T2 signal abnormality in deep white matter, with
      involvement of corticospinal tracts.
    explanation: Patients have deep white matter disease involving the corticospinal tracts.
  downstream:
  - target: Spastic paraparesis
  - target: Leukodystrophy
  - target: Developmental regression
  - target: Cognitive decline
- name: Cerebellar Purkinje Cell Degeneration
  conforms_to: "cerebellar_purkinje_degeneration#Purkinje Neuron Degeneration"
  biological_scale: CELLULAR
  description: >-
    The ataxia of the Acbd5 Gly357* mouse involves loss of cerebellar Purkinje
    cells, and ACBD5-deficient mice develop progressive cerebellar pathology.
  cell_types:
  - preferred_term: Purkinje cell
    term:
      id: CL:0000121
      label: Purkinje cell
  evidence:
  - reference: PMID:38066620
    reference_title: "Ataxia with giant axonopathy in Acbd5-deficient mice halted by adeno-associated virus gene therapy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The ataxic presentation of Gly357* mice involved the loss of cerebellar
      Purkinje cells and a giant axonopathy throughout the CNS.
    explanation: Purkinje cells are lost in the ataxic mouse.
  downstream:
  - target: Cerebellar ataxia
- name: Retinal Degeneration with Synaptic and Glial Pathology
  biological_scale: TISSUE
  description: >-
    In ACBD5-deficient mice, photoreceptor, bipolar, ganglion and pigment
    epithelial cells degenerate moderately, photoreceptor ribbon synapses in the
    outer plexiform layer degenerate, and astroglia and microglia are strongly
    activated. Inner-retinal signal transmission is severely reduced. This fits
    the early cone-rod dysfunction seen in patients.
  cell_types:
  - preferred_term: photoreceptor cell
    term:
      id: CL:0000210
      label: photoreceptor cell
  - preferred_term: microglial cell
    term:
      id: CL:0000129
      label: microglial cell
  cellular_components:
  - preferred_term: photoreceptor ribbon synapse
    term:
      id: GO:0097470
      label: ribbon synapse
  evidence:
  - reference: PMID:41324649
    reference_title: "Local accumulation of very long-chain PUFA in plexiform layers associates with retinal dysfunction in a mouse model of peroxisomal ACBD5-deficiency."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Histological results implied that ACBD5-deficient mice exhibit a moderate
      degeneration of photoreceptor, bipolar, ganglion and retinal pigment
      epithelial cells accompanied, however, by a prominent activation of
      astroglia and microglia.
    explanation: Retinal neurons degenerate with strong glial activation.
  - reference: PMID:41324649
    reference_title: "Local accumulation of very long-chain PUFA in plexiform layers associates with retinal dysfunction in a mouse model of peroxisomal ACBD5-deficiency."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Reduced a- and b-wave amplitudes from ffERG point to a severe functional
      dysregulation of retinal signal transduction with a focus at the level of
      the information-processing cell of the inner retina.
    explanation: Electroretinography shows severe loss of retinal signalling.
  downstream:
  - target: Cone-rod dystrophy
  - target: Retinal dystrophy
  - target: Rod monochromatism
  - target: Macular dystrophy
  - target: Nystagmus
  - target: Photophobia
  - target: Blindness
prevalence:
- population: Worldwide (published case reports)
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Two 2024 case reports (PMID:37789430, PMID:38841324) each counted seven
    previously reported patients and added one; a 2026 series (PMID:42343915)
    added five. About fourteen patients have been published.
  evidence:
  - reference: PMID:38841324
    reference_title: "A Novel Homozygous ACBD5 Variant in an Emerging Peroxisomal Disorder Presenting with Retinal Dystrophy and a Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Acyl-CoA binding domain containing 5 (ACBD5) deficiency is a newly defined
      inborn peroxisomal disorder with only 7 patients reported to date.
    explanation: Literature count of reported patients before this case.
  - reference: PMID:42343915
    reference_title: "Retinal Dystrophy and Leukodystrophy Caused by ACBD5 Deficiency in Five Omani Patients: A Case Series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This case series adds valuable insight in to this ultra-rare
      neurometabolic disease.
    explanation: Describes the disease as ultra-rare and adds five patients.
diagnosis:
- name: Molecular genetic testing for ACBD5
  diagnosis_term:
    preferred_term: exome or genome sequencing with ACBD5 variant analysis
    term:
      id: NCIT:C15709
      label: Genetic Testing
  description: >-
    Diagnosis rests on biallelic ACBD5 variants, usually found by exome
    sequencing. Biochemical screening can miss the disease because plasma VLCFA
    may be normal.
  evidence:
  - reference: PMID:38841324
    reference_title: "A Novel Homozygous ACBD5 Variant in an Emerging Peroxisomal Disorder Presenting with Retinal Dystrophy and a Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical exome sequencing displayed a novel homozygous intronic splice
      site variant (c.936 + 2T>G) in the ACBD5 (NM_145698.5) gene.
    explanation: Exome sequencing made the diagnosis.
  - reference: PMID:37789430
    reference_title: "ACBD5-related retinal dystrophy with leukodystrophy due to novel mutations in ACBD5 and with additional features including ovarian insufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient's symptoms were present since infancy, but a diagnosis was only
      reached in adulthood when whole exome sequencing was performed.
    explanation: Exome sequencing gave the diagnosis after decades of symptoms.
- name: Electroretinography
  description: >-
    Full-field ERG shows a severe cone-rod pattern of retinal dysfunction.
  notes: >-
    No NCIT term for electroretinography: an OLS search of NCIT for
    "electroretinography" (2026-10-23) returned no results, so diagnosis_term is
    left unbound.
  evidence:
  - reference: PMID:42343915
    reference_title: "Retinal Dystrophy and Leukodystrophy Caused by ACBD5 Deficiency in Five Omani Patients: A Case Series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Electroretinogram confirmed severe cone-rod dystrophy.
    explanation: ERG established the cone-rod dystrophy.
- name: Brain MRI
  diagnosis_term:
    preferred_term: brain magnetic resonance imaging
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  description: >-
    Shows diffuse T2 signal change in the deep white matter with corticospinal
    tract involvement.
  evidence:
  - reference: PMID:42343915
    reference_title: "Retinal Dystrophy and Leukodystrophy Caused by ACBD5 Deficiency in Five Omani Patients: A Case Series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain MRI revealed diffuse T2 signal abnormality in deep white matter, with
      involvement of corticospinal tracts.
    explanation: MRI shows the leukodystrophy.
phenotypes:
- name: Retinal dystrophy
  category: Ophthalmologic
  phenotype_term:
    preferred_term: retinal dystrophy
    term:
      id: HP:0000556
      label: Retinal dystrophy
  evidence:
  - reference: PMID:37789430
    reference_title: "ACBD5-related retinal dystrophy with leukodystrophy due to novel mutations in ACBD5 and with additional features including ovarian insufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: Presenting features include retinal dystrophy, progressive leukodystrophy, and ataxia.
    explanation: Retinal dystrophy is a presenting feature.
  - reference: PMID:27799409
    reference_title: "ACBD5 deficiency causes a defect in peroxisomal very long-chain fatty acid metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We studied a girl who presented with progressive leukodystrophy,
      syndromic cleft palate, ataxia and retinal dystrophy.
    explanation: The index patient of the VLCFA study had retinal dystrophy.
- name: Cone-rod dystrophy
  category: Ophthalmologic
  phenotype_term:
    preferred_term: cone-rod dystrophy
    term:
      id: HP:0000548
      label: Cone/cone-rod dystrophy
  evidence:
  - reference: PMID:42343915
    reference_title: "Retinal Dystrophy and Leukodystrophy Caused by ACBD5 Deficiency in Five Omani Patients: A Case Series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Electroretinogram confirmed severe cone-rod dystrophy.
    explanation: ERG showed severe cone-rod dystrophy in the Omani series.
- name: Rod monochromatism
  category: Ophthalmologic
  phenotype_term:
    preferred_term: rod monochromatism
    term:
      id: HP:0011516
      label: Achromatopsia
  evidence:
  - reference: PMID:37789430
    reference_title: "ACBD5-related retinal dystrophy with leukodystrophy due to novel mutations in ACBD5 and with additional features including ovarian insufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      presenting with the common features of rod monochromatism and progressive
      leukodystrophy with spasticity and ataxia
    explanation: Rod monochromatism is described as a common feature.
- name: Macular dystrophy
  category: Ophthalmologic
  phenotype_term:
    preferred_term: macular dystrophy
    term:
      id: HP:0007754
      label: Macular dystrophy
  evidence:
  - reference: PMID:38841324
    reference_title: "A Novel Homozygous ACBD5 Variant in an Emerging Peroxisomal Disorder Presenting with Retinal Dystrophy and a Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Macular dystrophy was demonstrated with optical coherence tomography
      imaging for the first time in the literature in ACBD5 deficiency.
    explanation: OCT showed macular dystrophy in one patient.
- name: Nystagmus
  category: Ophthalmologic
  phenotype_term:
    preferred_term: nystagmus
    term:
      id: HP:0000639
      label: Nystagmus
    onset:
      onset_category: INFANTILE
  evidence:
  - reference: PMID:42343915
    reference_title: "Retinal Dystrophy and Leukodystrophy Caused by ACBD5 Deficiency in Five Omani Patients: A Case Series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      First presentation was in infancy with nystagmus and photophobia and
      progressed to legal blindness by 10 years of age.
    explanation: Nystagmus is the presenting sign in infancy.
- name: Photophobia
  category: Ophthalmologic
  phenotype_term:
    preferred_term: photophobia
    term:
      id: HP:0000613
      label: Photophobia
  evidence:
  - reference: PMID:42343915
    reference_title: "Retinal Dystrophy and Leukodystrophy Caused by ACBD5 Deficiency in Five Omani Patients: A Case Series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      First presentation was in infancy with nystagmus and photophobia and
      progressed to legal blindness by 10 years of age.
    explanation: Photophobia accompanies the infantile presentation.
- name: Blindness
  category: Ophthalmologic
  phenotype_term:
    preferred_term: legal blindness
    term:
      id: HP:0000618
      label: Blindness
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:42343915
    reference_title: "Retinal Dystrophy and Leukodystrophy Caused by ACBD5 Deficiency in Five Omani Patients: A Case Series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      First presentation was in infancy with nystagmus and photophobia and
      progressed to legal blindness by 10 years of age.
    explanation: Vision loss progresses to legal blindness by age 10.
- name: Leukodystrophy
  category: Neurological
  phenotype_term:
    preferred_term: leukodystrophy
    term:
      id: HP:0002415
      label: Leukodystrophy
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:27799409
    reference_title: "ACBD5 deficiency causes a defect in peroxisomal very long-chain fatty acid metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We studied a girl who presented with progressive leukodystrophy,
      syndromic cleft palate, ataxia and retinal dystrophy.
    explanation: Progressive leukodystrophy in the index patient.
  - reference: PMID:42343915
    reference_title: "Retinal Dystrophy and Leukodystrophy Caused by ACBD5 Deficiency in Five Omani Patients: A Case Series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain MRI revealed diffuse T2 signal abnormality in deep white matter, with
      involvement of corticospinal tracts.
    explanation: MRI shows deep white matter disease.
- name: Spastic paraparesis
  category: Neurological
  phenotype_term:
    preferred_term: progressive spastic paraparesis
    term:
      id: HP:0002313
      label: Spastic paraparesis
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:38841324
    reference_title: "A Novel Homozygous ACBD5 Variant in an Emerging Peroxisomal Disorder Presenting with Retinal Dystrophy and a Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: He had spastic paraparesis dominated with axial hypotonic posturing and horizontal nystagmus.
    explanation: Spastic paraparesis in a 6-year-old patient.
  - reference: PMID:42343915
    reference_title: "Retinal Dystrophy and Leukodystrophy Caused by ACBD5 Deficiency in Five Omani Patients: A Case Series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This series confirms retinal dystrophy and leukodystrophy as key features
      of ACBD5 deficiency with main symptoms of early onset visual decline,
      progressive spasticity, and cerebellar ataxia.
    explanation: Progressive spasticity is a main symptom across the Omani series.
- name: Cerebellar ataxia
  category: Neurological
  phenotype_term:
    preferred_term: progressive cerebellar ataxia
    term:
      id: HP:0002073
      label: Progressive cerebellar ataxia
  evidence:
  - reference: PMID:42343915
    reference_title: "Retinal Dystrophy and Leukodystrophy Caused by ACBD5 Deficiency in Five Omani Patients: A Case Series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Motor neuroregression with variable ages of onset and signs of progressive
      cerebellar ataxia were seen in all patients, whereas cognitive decline was
      observed in some.
    explanation: All five patients had progressive cerebellar ataxia.
- name: Developmental regression
  category: Neurological
  phenotype_term:
    preferred_term: psychomotor regression
    term:
      id: HP:0002376
      label: Developmental regression
  evidence:
  - reference: PMID:33427402
    reference_title: "First reported adult patient with retinal dystrophy and leukodystrophy caused by a novel ACBD5 variant: A case report and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we present a 36-year-old female with retinal dystrophy,
      leukodystrophy, and psychomotor regression due to a novel homozygous
      variant in ACBD5.
    explanation: Psychomotor regression in the first reported adult patient.
  - reference: PMID:38841324
    reference_title: "A Novel Homozygous ACBD5 Variant in an Emerging Peroxisomal Disorder Presenting with Retinal Dystrophy and a Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: A 6-year-old male patient was admitted with complaints of neuromotor regression and visual disturbances.
    explanation: Neuromotor regression was a presenting complaint.
- name: Cognitive decline
  category: Neurological
  phenotype_term:
    preferred_term: cognitive decline
    term:
      id: HP:0001268
      label: Mental deterioration
  evidence:
  - reference: PMID:42343915
    reference_title: "Retinal Dystrophy and Leukodystrophy Caused by ACBD5 Deficiency in Five Omani Patients: A Case Series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Motor neuroregression with variable ages of onset and signs of progressive
      cerebellar ataxia were seen in all patients, whereas cognitive decline was
      observed in some.
    explanation: Cognitive decline occurred in some patients.
- name: Head tremor
  category: Neurological
  phenotype_term:
    preferred_term: head and neck tremor
    term:
      id: HP:0002346
      label: Head tremor
  evidence:
  - reference: PMID:37789430
    reference_title: "ACBD5-related retinal dystrophy with leukodystrophy due to novel mutations in ACBD5 and with additional features including ovarian insufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Additional novel clinical features included head and neck tremor and ovarian insufficiency.
    explanation: Head and neck tremor reported in one adult patient.
- name: Cleft palate
  category: Craniofacial
  phenotype_term:
    preferred_term: cleft palate
    term:
      id: HP:0000175
      label: Cleft palate
  evidence:
  - reference: PMID:27799409
    reference_title: "ACBD5 deficiency causes a defect in peroxisomal very long-chain fatty acid metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We studied a girl who presented with progressive leukodystrophy,
      syndromic cleft palate, ataxia and retinal dystrophy.
    explanation: Cleft palate in the index patient.
- name: Premature ovarian insufficiency
  category: Endocrine
  phenotype_term:
    preferred_term: ovarian insufficiency
    term:
      id: HP:0008209
      label: Premature ovarian insufficiency
  evidence:
  - reference: PMID:37789430
    reference_title: "ACBD5-related retinal dystrophy with leukodystrophy due to novel mutations in ACBD5 and with additional features including ovarian insufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Additional novel clinical features included head and neck tremor and ovarian insufficiency.
    explanation: Ovarian insufficiency reported in one adult patient.
biochemical:
- name: Plasma C26:0 and C26:0/C22:0 ratio
  presence: INCREASED
  context: >-
    Only mildly raised and sometimes within the normal range, so a normal plasma
    VLCFA profile does not exclude the diagnosis.
  biomarker_term:
    preferred_term: hexacosanoic acid (C26:0)
    term:
      id: CHEBI:31009
      label: hexacosanoic acid
  evidence:
  - reference: PMID:42343915
    reference_title: "Retinal Dystrophy and Leukodystrophy Caused by ACBD5 Deficiency in Five Omani Patients: A Case Series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Plasma long chain fatty acid profile showed mild elevation of C26 and C26/22 ratio.
    explanation: C26:0 and the C26:0/C22:0 ratio are mildly raised.
  - reference: PMID:38841324
    reference_title: "A Novel Homozygous ACBD5 Variant in an Emerging Peroxisomal Disorder Presenting with Retinal Dystrophy and a Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      His very-long-chain fatty acid levels were within normal ranges with a
      slightly elevated C26:0/C22:0 ratio.
    explanation: VLCFA can be normal, with only the ratio slightly raised.
treatments:
- name: AAV-mediated ACBD5 gene delivery (preclinical)
  description: >-
    No disease-modifying treatment exists for patients; care is supportive. In
    the Acbd5 Gly357* mouse, adeno-associated virus delivery of Acbd5 improved
    gait, reduced giant axonopathy, and improved myelination and astrocyte
    reactivity. This has not been tested in humans.
  therapeutic_modality: GENE_THERAPY
  treatment_term:
    preferred_term: gene therapy
    term:
      id: NCIT:C15238
      label: Gene Therapy
  target_mechanisms:
  - target: CNS Demyelination and Giant Axonopathy
    treatment_effect: INHIBITS
    description: Gene delivery reduced axonopathy and improved myelination in mice.
    evidence:
    - reference: PMID:38066620
      reference_title: "Ataxia with giant axonopathy in Acbd5-deficient mice halted by adeno-associated virus gene therapy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        We also show that an adeno-associated virus-mediated gene delivery
        ameliorated the gait phenotypes and the giant axonopathy, also improving
        myelination and astrocyte reactivity.
      explanation: Preclinical rescue in the mouse model.
  evidence:
  - reference: PMID:38066620
    reference_title: "Ataxia with giant axonopathy in Acbd5-deficient mice halted by adeno-associated virus gene therapy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We also show that an adeno-associated virus-mediated gene delivery
      ameliorated the gait phenotypes and the giant axonopathy, also improving
      myelination and astrocyte reactivity.
    explanation: Preclinical efficacy in mice only.
animal_models:
- name: Acbd5 Gly357* knock-in mouse
  species: Mouse
  genotype: Acbd5 p.Gly357* (CRISPR/Cas9) homozygous
  publication: PMID:38066620
  description: >-
    Truncating mouse allele that reproduces reduced survival, impaired
    locomotion, photoreceptor loss, demyelination, Purkinje cell loss and giant
    axonopathy.
  modeled_mechanisms:
  - target: CNS Demyelination and Giant Axonopathy
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: Develops CNS demyelination and giant axonopathy, rescued by AAV gene delivery.
    limitations: Mouse lifespan and myelin lipid composition differ from human, and patients have not been shown to have giant axons.
    evidence:
    - reference: PMID:38066620
      reference_title: "Ataxia with giant axonopathy in Acbd5-deficient mice halted by adeno-associated virus gene therapy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        The ataxic presentation of Gly357* mice involved the loss of cerebellar
        Purkinje cells and a giant axonopathy throughout the CNS.
      explanation: Shows the axonal and cerebellar pathology in the model.
- name: ACBD5-deficient mouse
  species: Mouse
  genotype: Acbd5 knockout
  publication: PMID:33244184
  description: >-
    Loss-of-function mouse showing raised VLCFA, progressive cerebellar pathology,
    sharply reduced peroxisome-ER contacts in liver, and retinal degeneration
    with VLC-PUFA accumulation in the plexiform layers.
  modeled_mechanisms:
  - target: Loss of Peroxisome-ER Membrane Contacts
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: Contacts are measured directly in liver.
    limitations: Contact loss was quantified in liver, not in brain or retina where disease occurs.
    evidence:
    - reference: PMID:33244184
      reference_title: "Cerebellar and hepatic alterations in ACBD5-deficient mice are associated with unexpected, distinct alterations in cellular lipid homeostasis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Liver did not exhibit pathologic changes but increased peroxisome
        abundance and drastically reduced peroxisome-ER contacts.
      explanation: Direct measurement of the contact defect in the model.
discussions:
- discussion_id: acbd5_tether_vs_vlcfa_contribution
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    How much of the retinal and white matter disease comes from loss of the
    peroxisome-ER tether (ether lipid supply, peroxisome positioning, calcium),
    and how much from loss of very-long-chain acyl-CoA capture?
  attaches_to:
  - "pathophysiology#Loss of Peroxisome-ER Membrane Contacts"
  - "pathophysiology#Impaired Peroxisomal Very-Long-Chain Fatty Acid Beta-Oxidation"
  - "pathophysiology#Disturbed Ether Lipid Synthesis"
  rationale: >-
    ACBD5 does both jobs, and patient disease cannot separate them. In cultured
    cells the tether is not strictly required for VLCFA oxidation, and plasma
    VLCFA in patients is only mildly raised, while X-linked adrenoleukodystrophy,
    with much higher VLCFA, has a different clinical picture. The tether's
    contribution to plasmalogen supply, which myelin depends on, has not been
    measured in patient neural cells.
  evidence:
  - reference: PMID:37414147
    reference_title: "Differential roles for ACBD4 and ACBD5 in peroxisome-ER interactions and lipid metabolism."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Overall, our findings suggest that ACBD5 may act as a primary tether and
      VLCFA recruitment factor, whereas ACBD4 may have regulatory functions in
      peroxisomal lipid metabolism at the peroxisome-ER interface.
    explanation: ACBD5 is both a tether and a VLCFA recruitment factor.
  proposed_experiments:
  - experiment_id: acbd5_separation_of_function_ipsc
    name: Separation-of-function ACBD5 alleles in patient iPSC-derived neural cells
    description: >-
      In ACBD5-null patient iPSC-derived oligodendrocytes, neurons and retinal
      organoids, re-express wild-type ACBD5, an FFAT-motif mutant that cannot bind
      VAPB, or an acyl-CoA binding domain mutant. Measure peroxisome-ER contacts
      and organelle signatures by multispectral imaging, plasmalogen and VLCFA
      lipidomics, myelin protein expression and synapse number.
    would_support:
    - "pathophysiology#Disturbed Ether Lipid Synthesis"
    supporting_outcome:
    - >-
      The FFAT mutant fails to restore plasmalogens, myelination or synapses
      while restoring VLCFA oxidation.
    refuting_outcome:
    - >-
      The acyl-CoA binding mutant alone reproduces the neural defects and the
      FFAT mutant rescues them.
references:
- reference: CGGV:assertion_8ac052f6-de8d-4c14-adf2-bbecb624defd-2024-06-21T160000.000Z
  title: ACBD5 / acyl-CoA binding domain containing protein 5 deficiency (Definitive)
classifications:
  harrisons_chapter:
  - classification_value: ENDOCRINOLOGY_METABOLISM
  - classification_value: NEUROLOGIC
  icimd_category:
  - classification_value: peroxisomal_fatty_acid_oxidation
    notes: >-
      ICIMD group of disorders of peroxisomal fatty acid oxidation; ACBD5
      deficiency is a single peroxisomal protein defect impairing VLCFA
      beta-oxidation.

📚

References & Deep Research

References

1

CGGV:assertion_8ac052f6-de8d-4c14-adf2-bbecb624defd-2024-06-21T160000.000Z

ACBD5 / acyl-CoA binding domain containing protein 5 deficiency (Definitive)

No top-level findings curated for this source.

Deep Research

1

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

Evaluations and curation notes (1)

Create: ACBD5_Deficiency · 2026-10-23T14:12:19Z · View source

New entry for ACBD5 deficiency (retinal dystrophy with leukodystrophy). Disease term MONDO:0100112, the ClinGen-classified term (Definitive, AR); MONDO:0030026 (OMIM:618863 import) mapped as skos:exactMatch because ClinGen states it lumped the two into MONDO:0100112. Both queued stubs deleted. Deep research: claude_code report (research/ACBD5_Deficiency-deep-research-claude_code.md; 15/15 references resolved, 0 off topic, 5/5 terms resolved, no quotes checked). A falcon run was attempted and failed with an Edison authentication error, so no falcon report exists. The report was thin, and most claims are anchored directly in primary papers fetched for this entry: patient reports PMID:23105016, 27799409, 33427402, 34668366, 37789430, 38841324, 42343915; mechanism PMID:27899449, 28108524, 28108526, 37414147, 42118293, 28849344; mouse models PMID:33244184, 38066620, 41324649; ClinGen CGGV record. PMID:37414147 shows the tether is not strictly required for VLCFA oxidation, so the VLCFA-capture and tether functions are separate branches, with a knowledge-gap discussion and a separation-of-function experiment. Contact-site nodes conform to membrane_contact_site_dysfunction (PR 15328); the Purkinje node conforms to cerebellar_purkinje_degeneration. PMID:36699790 (heterozygous VUS, father and daughter) was read and not used as disease evidence. No GeneReviews chapter (just check-genereviews --online: NO_CHAPTER). Validation: just validate, validate-terms, count-verified-snippets 59/59, check-entity-refs and check-causal-targets pass; 12/15 phenotypes causally connected.

Claude Code ▸

ACBD5 Deficiency (Retinal Dystrophy with Leukodystrophy, RDLKD): Research Report

claude-haiku-5-5, claude-sonnet-5-5 7 citations 2026-10-23T14:04:33.931735

ACBD5 Deficiency (Retinal Dystrophy with Leukodystrophy, RDLKD): Research Report

Causal gene: ACBD5 (acyl-CoA binding domain containing 5, HGNC hgnc:23338; the CURIE comes from memory and needs a lookup before use). It encodes a peroxisomal tail-anchored membrane protein. The disease is MONDO:0100112, as given in the brief.

Method and reliability. I ran three web searches and one PubMed listing. I did not read any abstract in full. Statements marked (search summary) come from search-engine summaries and need an exact-quote check with just fetch-reference before use as snippets. Statements marked (background, unverified) come from my own background knowledge and have no source. PMIDs are only those returned by the PubMed listing. I did not find a zebrafish model, so the model-organism section covers mouse only.

1. Disease information

ACBD5 deficiency is an autosomal recessive peroxisomal disorder. Patients have retinal dystrophy, progressive white-matter disease, and in some cases ataxia, cleft palate, and other features.
It was first described by Ferdinandusse et al. (J Med Genet 2017, PMID:27799409). The patient was a girl with progressive leukodystrophy, cleft palate, ataxia and retinal dystrophy. She had a homozygous ACBD5 indel with complete loss of the protein (search summary).
The same year, Yagita et al. (J Biol Chem 2017, PMID:27899449) reported the retinal dystrophy-associated ACBD5 defect in cells.
Identifiers: OMIM 616618, as seen in a search-result URL, whose content I did not check. The brief says OMIM "not recorded", so confirm it. The glycosmos page maps the disease to DOID:0080946. I did not look up Orphanet, ICD or MeSH identifiers.
Synonyms: retinal dystrophy with leukodystrophy (RDLKD); ACBD5 deficiency; acyl-CoA binding domain containing protein 5 deficiency.
The data are individual patient reports and case series, not aggregate resources. About 7 cases had been reported when the Australian case report was written, and the later literature adds more (search summary).

2. Etiology

Cause: biallelic loss-of-function variants in ACBD5. No environmental causes, risk factors, protective factors or gene–environment interactions are documented. No modifier genes are documented in the sources I saw.
Reported variants: Ferdinandusse 2017 (indel, complete protein loss); Gorukmez 2021 (PMID:34668366); Rudaks 2024 (PMID:37789430, novel mutations); Hasturk 2024 (PMID:38841324, novel homozygous variant); and the Omani series, Al Shamsi (PMID:42343915). I did not extract the HGVS descriptions, so pull them from the primary papers or ClinVar.

3. Phenotypes (candidate HPO terms need lookup)

Phenotype	Notes	Candidate HPO term (from memory, unverified)
Retinal dystrophy / cone-rod dystrophy	Infantile presentation with nystagmus and photophobia, progressing to legal blindness; severe cone-rod dystrophy on ERG (Omani series) (search summary)	Cone-rod dystrophy; Nystagmus; Photophobia
Leukodystrophy	Diffuse T2 signal abnormality in deep white matter, with corticospinal tract involvement (search summary)	Leukodystrophy
Ataxia	Index patient	Ataxia
Cleft palate	Index patient	Cleft palate
Mildly raised plasma VLCFA	Mild elevation of C26 and the C26/C22 ratio, so plasma testing can be unremarkable (search summary)	Abnormal circulating very long-chain fatty acid concentration

Frequencies per phenotype are not available because the cohorts are small. Onset is infantile or childhood, and the disease is progressive. One patient was diagnosed in adulthood by exome sequencing (search summary). Quality-of-life data were not found.

4. Genetic and molecular information

Gene and protein: ACBD5 is a peroxisomal membrane protein with an N-terminal cytosolic acyl-CoA binding domain. It also has an FFAT-like motif that binds the ER protein VAPB.
Variants and consequence: reported variants are loss-of-function. Ferdinandusse reported complete protein loss. I did not obtain gnomAD frequencies, ClinGen validity or ACMG classifications.
Not applicable or not found: epigenetic and chromosomal data.
Related gene: ACBD4 paralogue work is in Kors 2024 (PMID:39271061). ACBD6 variants cause a distinct neurodevelopmental syndrome (Kaiyrzhanov 2024, PMID:37951597) and should not be confused with this disease.

5. Environmental information

No environmental, lifestyle or infectious factors have been reported.

6. Mechanism and pathophysiology

Causal chain.

Biallelic loss-of-function variants in ACBD5 abolish the protein (demonstrated; Ferdinandusse 2017).
This leads to impaired peroxisomal β-oxidation of VLCFA. Knockout of ACBD5 in HeLa cells showed that ACBD5 binds VLC-CoAs and mediates their peroxisomal β-oxidation (search summary). Peroxisome biogenesis is unaffected in patient fibroblasts (search summary).
A mechanistic explanation is proposed: ACBD5 holds C26-CoA in the cytosol so that it can reach the peroxisome (search summary). The authors describe this as a proposal, and the Exeter abstract says the precise role is not yet established.
Loss of ACBD5 also reduces peroxisome–ER contacts, because ACBD5 tethers peroxisomes to the ER through VAPB (Hua et al. and Costello et al., J Cell Biol 2017; PMIDs not confirmed). Loss of the tether increases peroxisome motility (search summary). This step is demonstrated in cells. Whether the loss of contacts or the VLCFA defect matters more for disease is inferred and not settled.
VLCFA and ultra-long-chain lipids accumulate in tissues. In mice, C>32 species accumulate in cerebellar phosphocholines but not in liver (Darwisch 2020, PMID:33244184) (search summary).
In the retina, very long-chain polyunsaturated fatty acids accumulate in the plexiform layers, not the photoreceptor outer segments. The authors link this to photoreceptor synapse degeneration and neuroinflammation (Merz 2025, PMID:41324649) (search summary).
The result is retinal degeneration with glial activation, and cerebellar and white-matter disease (inferred from the mouse and patient data).

Where the mechanism branches: the retinal branch (VLC-PUFA, synapse loss, neuroinflammation) and the neural branch (cerebellar and corticospinal pathology, axonopathy). Both start at the VLCFA and contact-site defect.

Suggested GO terms (from memory, unverified): - peroxisomal fatty acid β-oxidation, very-long-chain fatty acid metabolic process, and peroxisome–ER membrane contact site organization. - Cell types: photoreceptor, bipolar cell, retinal ganglion cell, RPE cell, Müller glia, Purkinje cell, oligodendrocyte.

The Frontiers 2025 review (Dawes, PMID:40672445) covers patients and mouse models together. I did not find omics datasets.

7. Anatomical structures affected

Eye: retina (photoreceptors, inner retina, RPE).
Brain: deep white matter, corticospinal tracts, cerebellum.
Palate: cleft palate in the index patient.
Subcellular: peroxisomal membrane, ER contact sites.
Bilateral involvement is the likely pattern, but I did not find a source for it.

8. Temporal development

Onset is in infancy to childhood, with progression to legal blindness. White-matter disease is progressive. The course is chronic and lifelong. I did not find staging, remission patterns or critical periods.

9. Inheritance and population

Inheritance: autosomal recessive.
Consanguinity: it plays a role in the Omani series, which is homozygous and from one population (search summary). The Omani cases may point to a founder effect, but I did not verify this.
Frequency: the disease is ultra-rare. I found no prevalence, incidence, carrier frequency, penetrance or sex-ratio data.

10. Diagnostics

Plasma VLCFA: changes are only mild (C26 and the C26/C22 ratio), so a normal or near-normal profile does not exclude the disease (search summary).
Patient fibroblasts: they show reduced peroxisomal β-oxidation and elevated VLCFA (Ferdinandusse 2017; Herzog 2018, PMID:28849344, on lipidomics of fibroblasts).
Genetic testing: exome or genome sequencing, or a leukodystrophy or retinal dystrophy gene panel including ACBD5. One adult was diagnosed by exome (search summary).
Other tests: ERG (cone-rod pattern) and brain MRI (white-matter signal change).
Differential diagnosis: other peroxisomal disorders, X-linked adrenoleukodystrophy, and other leukodystrophies with retinopathy (background, unverified).

11. Prognosis

The disease is progressive, with visual loss to legal blindness. Long-term neurological data and survival data are not available. I did not find quality-of-life data.

12. Treatment

No approved disease-specific treatment was found.
Preclinical: Granadeiro et al. (Brain 2024, PMID:38066620) report ataxia with giant axonopathy in Acbd5-deficient mice, halted by adeno-associated virus gene therapy. This is model-organism evidence only.
Supportive care: low-vision services, rehabilitation, and neurological follow-up (background, unverified).
Not found: clinical trials (NCT) and NCIT intervention terms.
Suggested NCIT terms (from memory, unverified): gene therapy NCIT:C15238; supportive care NCIT:C15747; genetic counseling NCIT:C15240.

13. Prevention

Genetic counseling is appropriate for an autosomal recessive disorder, with carrier testing in families and prenatal or preimplantation testing where requested (background, unverified). I found no newborn screening or immunization data.

14. Other species and natural disease

I found no natural disease in other species and did not search OMIA. Orthologs exist, with the mouse gene being Acbd5 (a commercial knockout is listed for C57BL/6J) (search summary).

15. Model organisms

Mouse (Acbd5-deficient) (Darwisch 2020, PMID:33244184):
Raised VLCFA and a progressive cerebellar pathology.
The liver has more peroxisomes but fewer peroxisome–ER contacts.
Ultra-long-chain fatty acids accumulate in the cerebellum but not the liver.
This model recapitulates the neurological features, but I did not confirm retinal and white-matter parity.
Retinal findings in mice: moderate degeneration of photoreceptor, bipolar, ganglion and RPE cells with prominent glial activation; accumulation of VLC-PUFA in the plexiform layers (Merz 2025, PMID:41324649) (search summary).
Axonopathy and gene therapy: Granadeiro 2024, PMID:38066620.
Cell models: HeLa knockout cells and patient fibroblasts. Peroxisome biogenesis is intact in patient fibroblasts (search summary).
Zebrafish and other models: none found.
Limitation: the mouse phenotype is dominated by cerebellar and axonal pathology. Fidelity to human leukodystrophy and cone-rod dystrophy is uncertain.

Reference list

PMIDs below come from the PubMed listing.

27799409 – Ferdinandusse S et al., J Med Genet 2017: first patient report.
27899449 – Yagita Y et al., J Biol Chem 2017: ACBD5 deficiency in cells.
28849344 – Herzog K et al., J Inherit Metab Dis 2018: fibroblast lipidomics.
33244184 – Darwisch W et al., Commun Biol 2020: mouse cerebellum and liver.
34668366 – Gorukmez O et al., J Pediatr Endocrinol Metab 2021: new patient.
37789430 – Rudaks LI et al., Am J Med Genet A 2024: novel mutations.
38841324 – Hasturk BA et al., Mol Syndromol 2024: novel homozygous variant.
38066620 – Granadeiro L et al., Brain 2024: AAV gene therapy in mice.
39271061 – Kors S et al., BBA Mol Cell Res 2024: ACBD4/5-like proteins.
40672445 – Dawes ML et al., Front Mol Neurosci 2025: review.
41324649 – Merz J et al., Cell Mol Life Sci 2025: retinal VLC-PUFA.
42343915 – Al Shamsi B et al., Oman Med J 2026: Omani case series.

Sources: Exeter repository: Ferdinandusse 2017 · Frontiers review 2025 · Mouse paper, PMC7691522 · JCB 2022 on ACBD5 regulation · JCB 2017 ACBD5 and VAPB · OMIM 616618 · PubMed listing

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome	Count
References checked	15
Resolved	15
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	15
On topic	14
Off topic	0

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Term Validation

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Outcome	Count
Terms checked	5
Resolved	5
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	0

Every term resolved, and every label the report gave matched.

ACBD5 Deficiency

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ACBD5 Deficiency (Retinal Dystrophy with Leukodystrophy, RDLKD): Research Report

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7. Anatomical structures affected

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