Optic atrophy 15 (OPA15) is an autosomal recessive inherited optic neuropathy caused by biallelic variants in MCAT, which encodes the mitochondrial enzyme malonyl-CoA-acyl carrier protein transacylase. MCAT catalyses the transfer of malonyl groups onto the mitochondrial acyl carrier protein, the second step of the mitochondrial fatty-acid synthesis (mtFAS) pathway, and it is expressed in retinal ganglion cells, which are rich in mitochondria. As with the other nuclear-gene optic neuropathies, the disease is understood as a mitochondrial endophenotype in which the retinal ganglion cell and its long, energy-demanding axon fail selectively. The gene-disease relationship rests on three reports and a handful of families, and the presentations they describe span a wide spectrum. The original report identified two brothers from a consanguineous Chinese family carrying homozygous missense variants (p.Leu81Arg and p.Arg212Trp); they had insidious, gradual childhood vision loss with nystagmus and acuity reduced to finger counting by age 8. The second report identified a sporadic French woman compound heterozygous for a splice-donor variant (c.424-2A>G) and a missense variant (p.Glu347Lys); she presented at age 20 with acute, bilateral but asymmetric central visual loss resembling Leber hereditary optic neuropathy. A third report identified a boy homozygous for p.Thr271Ile with a severe infantile multisystem presentation - hypotonia, failure to thrive, nystagmus, and symmetric T2/FLAIR signal change in the dorsal medulla, periaqueductal gray, substantia nigra, medial hypothalamus and habenular nuclei on brain MRI. All three are part of one gene-defined entity, and MCAT is now recognised as one of the nuclear genes causing an autosomal recessive LHON-like optic neuropathy (arLHON), alongside DNAJC30 and NDUFS2. The mechanism downstream of the gene is partly established. The disease variants destabilise the MCAT protein and reduce its intracellular expression; retinal-ganglion-cell-specific knockdown of Mcat in mice reproduces an attenuated retinal nerve fibre layer. In the multisystem patient, the mitochondrial consequence was measured directly in the patient's own fibroblasts and lymphoblasts: a combined oxidative phosphorylation deficiency with reduced complex I, II and IV subunits and respiratory-chain enzyme activities, rescued by re-expressing wild-type MCAT. That patient's protein lipoylation was normal, and in a mutant myoblast line the p.Thr271Ile allele restored lipoylation but only partially restored respiration - dissociating the two branches of mtFAS output and implicating impaired respiratory-chain assembly, rather than lipoylation, as the disease-relevant consequence. What remains inferential is the final step: whether that respiratory-chain deficit is what selectively kills retinal ganglion cells, since the one patient with measured OXPHOS deficiency had multisystem disease and the isolated-optic-atrophy patients had no such measurement. The entry records that last step as a gap.
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name: Optic Atrophy 15
creation_date: "2026-10-25T00:00:00Z"
category: Mendelian
disease_term:
preferred_term: Optic atrophy 15
term:
id: MONDO:0957935
label: optic atrophy 15
description: >-
Optic atrophy 15 (OPA15) is an autosomal recessive inherited optic neuropathy
caused by biallelic variants in MCAT, which encodes the mitochondrial enzyme
malonyl-CoA-acyl carrier protein transacylase. MCAT catalyses the transfer of
malonyl groups onto the mitochondrial acyl carrier protein, the second step of
the mitochondrial fatty-acid synthesis (mtFAS) pathway, and it is expressed in
retinal ganglion cells, which are rich in mitochondria. As with the other
nuclear-gene optic neuropathies, the disease is understood as a mitochondrial
endophenotype in which the retinal ganglion cell and its long, energy-demanding
axon fail selectively.
The gene-disease relationship rests on three reports and a handful of
families, and the presentations they describe span a wide spectrum. The
original report identified two brothers from a consanguineous Chinese family
carrying homozygous missense variants (p.Leu81Arg and p.Arg212Trp); they had
insidious, gradual childhood vision loss with nystagmus and acuity reduced to
finger counting by age 8. The second report identified a sporadic French woman
compound heterozygous for a splice-donor variant (c.424-2A>G) and a missense
variant (p.Glu347Lys); she presented at age 20 with acute, bilateral but
asymmetric central visual loss resembling Leber hereditary optic neuropathy. A
third report identified a boy homozygous for p.Thr271Ile with a severe
infantile multisystem presentation - hypotonia, failure to thrive, nystagmus,
and symmetric T2/FLAIR signal change in the dorsal medulla, periaqueductal
gray, substantia nigra, medial hypothalamus and habenular nuclei on brain MRI.
All three are part of one gene-defined entity, and MCAT is now recognised as
one of the nuclear genes causing an autosomal recessive LHON-like optic
neuropathy (arLHON), alongside DNAJC30 and NDUFS2.
The mechanism downstream of the gene is partly established. The disease
variants destabilise the MCAT protein and reduce its intracellular expression;
retinal-ganglion-cell-specific knockdown of Mcat in mice reproduces an
attenuated retinal nerve fibre layer. In the multisystem patient, the
mitochondrial consequence was measured directly in the patient's own
fibroblasts and lymphoblasts: a combined oxidative phosphorylation deficiency
with reduced complex I, II and IV subunits and respiratory-chain enzyme
activities, rescued by re-expressing wild-type MCAT. That patient's protein
lipoylation was normal, and in a mutant myoblast line the p.Thr271Ile allele
restored lipoylation but only partially restored respiration - dissociating the
two branches of mtFAS output and implicating impaired respiratory-chain
assembly, rather than lipoylation, as the disease-relevant consequence. What
remains inferential is the final step: whether that respiratory-chain deficit
is what selectively kills retinal ganglion cells, since the one patient with
measured OXPHOS deficiency had multisystem disease and the
isolated-optic-atrophy patients had no such measurement. The entry records that
last step as a gap.
parents:
- hereditary disease
- Mitochondrial Disease
synonyms:
- OPA15
- MCAT-related optic neuropathy
- MCAT-related nuclear LHON-like optic neuropathy
- autosomal recessive optic neuropathy, MCAT-related
notes: >-
No GeneReviews chapter exists for optic atrophy 15 or MCAT-related optic
neuropathy, confirmed on 2026-10-25 against the committed Bookshelf index and
a live PubMed [book] title search over the name and all four synonyms.
classifications:
harrisons_chapter:
- classification_value: NEUROLOGIC
notes: >-
An inherited optic neuropathy - a neurodegenerative disease of the retinal
ganglion cell and its axon.
- classification_value: GENETICS_ENVIRONMENT_DISEASE
notes: >-
A Mendelian disorder identified by exome/targeted sequencing.
mechanistic_category:
- classification_value: mitochondrial disease
notes: >-
Assigned on the mitochondrial mechanism - MCAT is a mitochondrial
fatty-acid-synthesis enzyme and the retinal ganglion cell phenotype is read
as a mitochondrial endophenotype. A combined oxidative phosphorylation
deficiency was measured directly in the multisystem patient's own
fibroblasts and lymphoblasts; what is missing is any bioenergetic
measurement in the patients with isolated optic atrophy.
references:
- reference: PMID:31915829
title: "Novel mutations in malonyl-CoA-acyl carrier protein transacylase provoke autosomal recessive optic neuropathy."
- reference: PMID:33918393
title: "MCAT Mutations Cause Nuclear LHON-like Optic Neuropathy."
- reference: PMID:36881526
title: "Recessive pathogenic variants in MCAT cause combined oxidative phosphorylation deficiency."
inheritance:
- name: Autosomal recessive inheritance
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
description: >-
All reported pedigrees are biallelic: homozygous missense variants in a
consanguineous family, compound heterozygous variants in a sporadic case, and
a homozygous missense variant in a third family.
evidence:
- reference: PMID:31915829
reference_title: "Novel mutations in malonyl-CoA-acyl carrier protein transacylase provoke autosomal recessive optic neuropathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
a novel double homozygous mutation p.L81R and pR212W in malonyl CoA-acyl
carrier protein transacylase (MCAT), a mitochondrial protein involved in
fatty acid biosynthesis, has now been identified as responsible for an
autosomal recessive optic neuropathy from a Chinese consanguineous family
explanation: >-
States the autosomal recessive inheritance and the homozygous biallelic
genotype in the index family.
genetic:
- name: MCAT
gene_term:
preferred_term: MCAT
term:
id: hgnc:29622
label: MCAT
relationship_type: CAUSATIVE
variant_origin: GERMLINE
notes: >-
Biallelic MCAT variants cause the disease. Reported genotypes are homozygous
p.Leu81Arg plus p.Arg212Trp (consanguineous Chinese brothers), compound
heterozygous c.424-2A>G (splice donor) plus p.Glu347Lys (sporadic French
case), and homozygous p.Thr271Ile (boy with multisystem disease). The
variants are hypomorphic rather than null - they destabilise the protein and
reduce its expression - and no fully inactivating human genotype has been
reported. The gene-disease assertion rests on three families, and MCAT is a
recognised nuclear arLHON gene.
evidence:
- reference: PMID:33918393
reference_title: "MCAT Mutations Cause Nuclear LHON-like Optic Neuropathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
we identified two novel MCAT mutations in a female patient who presented
with acute, sudden, bilateral, yet asymmetric, central visual loss at the
age of 20
explanation: >-
The second independent family establishing MCAT as causative, with a
compound heterozygous genotype distinct from the index family.
- reference: PMID:36881526
reference_title: "Recessive pathogenic variants in MCAT cause combined oxidative phosphorylation deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
By whole exome sequencing, we identified a homozygous variant in MCAT
c.812T>C; p.T271I (rs760294168; NM_173467.4) in the proband, which was
heterozygous in both parents consistent with autosomal recessive
inheritance
explanation: >-
The third independent family, a homozygous missense genotype segregating
as autosomal recessive.
- reference: PMID:31915829
reference_title: "Novel mutations in malonyl-CoA-acyl carrier protein transacylase provoke autosomal recessive optic neuropathy."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
The disease variants lead to structurally unstable MCAT protein with
significantly reduced intracellular expression.
explanation: >-
Functional support that the pathogenic variants reduce MCAT protein
stability and abundance (hypomorphic, partial loss of function).
- reference: PMID:33918393
reference_title: "MCAT Mutations Cause Nuclear LHON-like Optic Neuropathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
snippet: >-
This presentation is consistent with a Leber hereditary optic neuropathy
(LHON)-like phenotype, whose existence and association with NDUFS2 and
DNAJC30 has only recently been described
explanation: >-
Places MCAT disease in the recently described autosomal recessive LHON-like
group alongside NDUFS2 and DNAJC30.
pathophysiology:
- name: Biallelic MCAT Loss of Function
biological_scale: MOLECULAR
description: >-
Biallelic germline MCAT variants reduce the stability and intracellular
abundance of malonyl-CoA-acyl carrier protein transacylase; the
protein-instability data come from cultured cells. The enzyme is expressed in
the mitochondria-rich retinal ganglion cells that degenerate in this disease.
molecular_functions:
- preferred_term: malonyl-CoA-acyl carrier protein transacylase activity
modifier: DECREASED
term:
id: GO:0004314
label: "[acyl-carrier-protein] S-malonyltransferase activity"
genes:
- preferred_term: MCAT
term:
id: hgnc:29622
label: MCAT
genetic_context:
variant_origin: GERMLINE
functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
downstream:
- target: Impaired Mitochondrial Fatty-Acid Synthesis
causal_link_type: DIRECT
description: >-
Reduced functional MCAT lowers its malonyl-transfer contribution to
mitochondrial fatty-acid synthesis.
evidence:
- reference: PMID:31915829
reference_title: "Novel mutations in malonyl-CoA-acyl carrier protein transacylase provoke autosomal recessive optic neuropathy."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
The disease variants lead to structurally unstable MCAT protein with
significantly reduced intracellular expression.
explanation: >-
Loss of stable MCAT protein is the molecular lesion that reduces its
enzymatic contribution to the pathway.
evidence:
- reference: PMID:31915829
reference_title: "Novel mutations in malonyl-CoA-acyl carrier protein transacylase provoke autosomal recessive optic neuropathy."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "MCAT is expressed in RGC that are rich in mitochondria."
explanation: >-
Establishes that the affected enzyme is expressed in the cell type that
degenerates in this disease; the retinal ganglion cell expression data in
this report are from the mouse.
- name: Impaired Mitochondrial Fatty-Acid Synthesis
biological_scale: MOLECULAR
description: >-
MCAT catalyses the S-malonyl transfer onto the mitochondrial acyl carrier
protein, the second step of mitochondrial fatty-acid synthesis. Reduced MCAT
activity impairs this pathway.
biological_processes:
- preferred_term: mitochondrial fatty-acid biosynthesis
term:
id: GO:0006633
label: fatty acid biosynthetic process
modifier: DECREASED
downstream:
- target: Impaired Respiratory-Chain Assembly and Combined OXPHOS Deficiency
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: >-
mtFAS supplies acyl-ACP needed for respiratory-chain complex assembly;
loss of mtFAS output reduces assembly of complexes I, II and IV. The
intermediate steps (acyl-ACP supply to the NDUFAB1/Fe-S machinery) are
known from general biology.
evidence:
- reference: PMID:36881526
reference_title: "Recessive pathogenic variants in MCAT cause combined oxidative phosphorylation deficiency."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
quote_role: BACKGROUND
snippet: >-
loss-of-function of mtFAS genes, including Mcat, is associated with
severe loss of electron transport chain (ETC) complexes in mouse
immortalized skeletal myoblasts
explanation: >-
Prior myoblast work (restated here) linking loss of mtFAS output to loss
of assembled electron-transport-chain complexes.
evidence:
- reference: PMID:33918393
reference_title: "MCAT Mutations Cause Nuclear LHON-like Optic Neuropathy."
supports: SUPPORT
evidence_source: OTHER
quote_role: BACKGROUND
snippet: >-
which encodes a mitochondrial protein involved in fatty-acid biogenesis
explanation: >-
Identifies MCAT's function as a mitochondrial fatty-acid-synthesis enzyme.
- name: Impaired Respiratory-Chain Assembly and Combined OXPHOS Deficiency
biological_scale: CELLULAR
description: >-
In the multisystem patient's fibroblasts and lymphoblasts, reduced MCAT
produced a combined oxidative phosphorylation deficiency - reduced complex I
(NDUFB8), II (SDHB) and IV (COXII) subunits with correspondingly decreased
respiratory-chain enzyme activities - rescued by re-expressing wild-type
MCAT. In that patient protein lipoylation was normal, and in a mutant myoblast
line the p.Thr271Ile allele restored lipoylation but only partially restored
respiration, implicating impaired respiratory-chain assembly rather than
lipoylation as the relevant consequence. mtFAS's role here is the supply of
acyl-ACP for complex assembly (via mitochondrial ACP/NDUFAB1), not fatty-acid
synthesis as an end in itself.
cell_types:
- preferred_term: fibroblast
term:
id: CL:0000057
label: fibroblast
- preferred_term: lymphoblast
term:
id: CL:0017005
label: lymphoblast
biological_processes:
- preferred_term: mitochondrial respiratory chain complex assembly
term:
id: GO:0033108
label: mitochondrial respiratory chain complex assembly
modifier: DECREASED
- preferred_term: cellular respiration
term:
id: GO:0045333
label: cellular respiration
modifier: DECREASED
downstream:
- target: Retinal Ganglion Cell and Optic Nerve Axon Degeneration
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Impaired oxidative phosphorylation is proposed to drive degeneration of
the mitochondria-rich retinal ganglion cell; the selective vulnerability of
retinal ganglion cells to OXPHOS deficits is the inferred final step.
evidence:
- reference: PMID:36881526
reference_title: "Recessive pathogenic variants in MCAT cause combined oxidative phosphorylation deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Protein levels for NDUFB8 and COXII, subunits of complex I and IV
respectively, were markedly reduced in lymphoblasts and fibroblasts, as
well as SDHB for complex II in fibroblasts. ETC enzyme activities were
decreased in parallel.
explanation: >-
Direct patient-cell evidence of a combined oxidative phosphorylation
deficiency resulting from biallelic MCAT variants.
- reference: PMID:36881526
reference_title: "Recessive pathogenic variants in MCAT cause combined oxidative phosphorylation deficiency."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
expression of wild-type human MCAT fully rescued both basal and maximal
respiration rates. In contrast, expression of the p.T271I mutant only
partially rescued respiration
explanation: >-
The disease allele restores lipoylation but not respiration, dissociating
the two mtFAS output branches and implicating respiratory-chain function.
- reference: PMID:36881526
reference_title: "Recessive pathogenic variants in MCAT cause combined oxidative phosphorylation deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
reveals normal lipoylation of the PDH and OGDH E2 components (DLAT and
DLST, respectively) in the patient sample
explanation: >-
Lipoylation was intact in the patient, so the lipoic-acid branch of mtFAS
is not the operative lesion here.
- name: Retinal Ganglion Cell and Optic Nerve Axon Degeneration
biological_scale: TISSUE
description: >-
Progressive loss of retinal ganglion cells and their optic nerve axons, seen
as a reduced retinal nerve fibre layer and reproduced by
retinal-ganglion-cell-specific Mcat knockdown in mice.
cell_types:
- preferred_term: retinal ganglion cell
term:
id: CL:0000740
label: retinal ganglion cell
downstream:
- target: Optic atrophy
causal_link_type: DIRECT
- target: Reduced visual acuity
causal_link_type: DIRECT
- target: Abnormal retinal nerve fiber layer morphology
causal_link_type: DIRECT
evidence:
- reference: PMID:31915829
reference_title: "Novel mutations in malonyl-CoA-acyl carrier protein transacylase provoke autosomal recessive optic neuropathy."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
RGC-specific knockdown of Mcat in mice, lead to an attenuated retinal
neurofiber layer, that resembles the phenotype of optic neuropathy.
explanation: >-
Model-organism support that loss of Mcat in retinal ganglion cells
produces the retinal nerve fibre layer loss of optic neuropathy.
- reference: PMID:31915829
reference_title: "Novel mutations in malonyl-CoA-acyl carrier protein transacylase provoke autosomal recessive optic neuropathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
progressive degeneration of optic nerve and retinal ganglion cells (RGC)
explanation: >-
Describes the tissue-level lesion - progressive degeneration of the optic
nerve and retinal ganglion cells.
phenotypes:
- name: Optic atrophy
category: Eye
phenotype_term:
preferred_term: Optic atrophy
term:
id: HP:0000648
label: Optic atrophy
evidence:
- reference: PMID:31915829
reference_title: "Novel mutations in malonyl-CoA-acyl carrier protein transacylase provoke autosomal recessive optic neuropathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
has now been identified as responsible for an autosomal recessive optic
neuropathy from a Chinese consanguineous family
explanation: >-
The defining feature of the disease is optic neuropathy / optic atrophy.
- name: Reduced visual acuity
category: Eye
phenotype_term:
preferred_term: Reduced visual acuity
term:
id: HP:0007663
label: Reduced visual acuity
evidence:
- reference: PMID:33918393
reference_title: "MCAT Mutations Cause Nuclear LHON-like Optic Neuropathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
snippet: >-
The two siblings were described as suffering from gradual, insidious
vision loss leading to severe visual dysfunction, nystagmus, and visual
acuity reduced to finger counting by the age of 8
explanation: >-
Documents severe reduction of visual acuity in the index family, retold
here from the original report.
- name: Nystagmus
category: Eye
phenotype_term:
preferred_term: Nystagmus
term:
id: HP:0000639
label: Nystagmus
evidence:
- reference: PMID:33918393
reference_title: "MCAT Mutations Cause Nuclear LHON-like Optic Neuropathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
snippet: >-
The two siblings were described as suffering from gradual, insidious
vision loss leading to severe visual dysfunction, nystagmus, and visual
acuity reduced to finger counting by the age of 8
explanation: >-
Records nystagmus in the early-onset presentation, retold here from the
original report.
- reference: PMID:36881526
reference_title: "Recessive pathogenic variants in MCAT cause combined oxidative phosphorylation deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
we report a proband presenting with hypotonia, failure to thrive,
nystagmus, and abnormal brain MRI findings
explanation: >-
Nystagmus in the independently reported multisystem proband.
- name: Blindness
category: Eye
phenotype_term:
preferred_term: Blindness
term:
id: HP:0000618
label: Blindness
evidence:
- reference: PMID:33918393
reference_title: "MCAT Mutations Cause Nuclear LHON-like Optic Neuropathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
snippet: >-
two siblings from China affected by insidious optic nerve degeneration in
childhood, leading to blindness in the first decade of life
explanation: >-
Documents blindness in the first decade in the early-onset presentation,
retold here from the original report.
- name: Central scotoma
category: Eye
phenotype_term:
preferred_term: Central scotoma
term:
id: HP:0000603
label: Central scotoma
evidence:
- reference: PMID:33918393
reference_title: "MCAT Mutations Cause Nuclear LHON-like Optic Neuropathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
she exhibited a central scotoma (Figure 1B)—but normal peripheral
vision—as well as photophobia and dyschromatopsia (blue–yellow axis)
explanation: >-
Central scotoma in the LHON-like adult-onset presentation.
- name: Dyschromatopsia
category: Eye
phenotype_term:
preferred_term: Dyschromatopsia
term:
id: HP:0007641
label: Dyschromatopsia
evidence:
- reference: PMID:33918393
reference_title: "MCAT Mutations Cause Nuclear LHON-like Optic Neuropathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
she exhibited a central scotoma (Figure 1B)—but normal peripheral
vision—as well as photophobia and dyschromatopsia (blue–yellow axis)
explanation: >-
Blue-yellow dyschromatopsia in the adult-onset case.
- name: Photophobia
category: Eye
phenotype_term:
preferred_term: Photophobia
term:
id: HP:0000613
label: Photophobia
evidence:
- reference: PMID:33918393
reference_title: "MCAT Mutations Cause Nuclear LHON-like Optic Neuropathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
she exhibited a central scotoma (Figure 1B)—but normal peripheral
vision—as well as photophobia and dyschromatopsia (blue–yellow axis)
explanation: >-
Photophobia in the adult-onset case.
- name: Abnormal retinal nerve fiber layer morphology
category: Eye
phenotype_term:
preferred_term: Reduced retinal nerve fibre layer on OCT
term:
id: HP:0020119
label: Abnormal retinal nerve fiber layer morphology
evidence:
- reference: PMID:33918393
reference_title: "MCAT Mutations Cause Nuclear LHON-like Optic Neuropathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Retinal nerve fibre layer optical coherence tomography revealed a dramatic
generalized reduction in optic nerve fibres
explanation: >-
OCT reduction of the retinal nerve fibre layer, the structural readout of
ganglion-cell axon loss.
- name: Abnormal brainstem MRI signal intensity
category: Neurologic
description: >-
Feature of the severe infantile multisystem presentation (single proband):
bilaterally symmetric T2/FLAIR hyperintensity in the dorsal medulla,
periaqueductal gray, substantia nigra, medial hypothalamus and habenular
nuclei.
phenotype_term:
preferred_term: Symmetric brainstem T2/FLAIR signal change
term:
id: HP:0012747
label: Abnormal brainstem MRI signal intensity
evidence:
- reference: PMID:36881526
reference_title: "Recessive pathogenic variants in MCAT cause combined oxidative phosphorylation deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "A brain MRI completed at 21 months was notable for bilaterally symmetrical increase in signal intensity on T2- and T2 FLAIR (fluid attenuated inversion recovery)-weighted sequences in the dorsal medulla, periaqueductal gray matter, substantia nigra, medial hypothalamus, and habenular nuclei."
explanation: >-
Symmetric brainstem and deep-gray signal change on MRI in the multisystem
proband.
- name: Generalized hypotonia
category: Neurologic
description: >-
Feature of the severe infantile multisystem presentation (a single reported
proband with combined OXPHOS deficiency), not of the isolated optic-atrophy
presentations.
phenotype_term:
preferred_term: Hypotonia
term:
id: HP:0001290
label: Generalized hypotonia
evidence:
- reference: PMID:36881526
reference_title: "Recessive pathogenic variants in MCAT cause combined oxidative phosphorylation deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
we report a proband presenting with hypotonia, failure to thrive,
nystagmus, and abnormal brain MRI findings
explanation: >-
Hypotonia in the multisystem presentation of MCAT disease.
- name: Failure to thrive
category: Growth
description: >-
Feature of the severe infantile multisystem presentation (single proband).
phenotype_term:
preferred_term: Failure to thrive
term:
id: HP:0001508
label: Failure to thrive
evidence:
- reference: PMID:36881526
reference_title: "Recessive pathogenic variants in MCAT cause combined oxidative phosphorylation deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
we report a proband presenting with hypotonia, failure to thrive,
nystagmus, and abnormal brain MRI findings
explanation: >-
Failure to thrive in the multisystem presentation of MCAT disease.
- name: Global developmental delay
category: Neurologic
description: >-
Feature of the severe infantile multisystem presentation (single proband).
phenotype_term:
preferred_term: Global developmental delay
term:
id: HP:0001263
label: Global developmental delay
evidence:
- reference: PMID:36881526
reference_title: "Recessive pathogenic variants in MCAT cause combined oxidative phosphorylation deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
A 2-year-old boy, born prematurely, with a past medical history notable
for failure to thrive and global developmental delay
explanation: >-
Global developmental delay in the multisystem presentation.
- name: Microcephaly
category: Head and neck
description: >-
Feature of the severe infantile multisystem presentation (single proband).
phenotype_term:
preferred_term: Microcephaly
term:
id: HP:0000252
label: Microcephaly
evidence:
- reference: PMID:36881526
reference_title: "Recessive pathogenic variants in MCAT cause combined oxidative phosphorylation deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "his head circumference was at the 0.4 percentile (Z=−2.59)"
explanation: >-
Head circumference well below the normal range in the multisystem proband.
- name: Short stature
category: Growth
description: >-
Feature of the severe infantile multisystem presentation (single proband).
phenotype_term:
preferred_term: Short stature
term:
id: HP:0004322
label: Short stature
evidence:
- reference: PMID:36881526
reference_title: "Recessive pathogenic variants in MCAT cause combined oxidative phosphorylation deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "height was at the 0.46 percentile (Z=−2.61)"
explanation: >-
Height well below the normal range in the multisystem proband.
- name: Esotropia
category: Eye
description: >-
Feature of the severe infantile multisystem presentation (single proband).
phenotype_term:
preferred_term: Esotropia
term:
id: HP:0000565
label: Esotropia
evidence:
- reference: PMID:36881526
reference_title: "Recessive pathogenic variants in MCAT cause combined oxidative phosphorylation deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
at 8 months of age was noted to have esotropia and horizontal jerk
nystagmus
explanation: >-
Esotropia in the multisystem proband.
- name: Hyperreflexia
category: Neurologic
description: >-
Feature of the severe infantile multisystem presentation (single proband);
brisk reflexes alongside truncal and peripheral hypotonia.
phenotype_term:
preferred_term: Brisk reflexes
term:
id: HP:0001347
label: Hyperreflexia
evidence:
- reference: PMID:36881526
reference_title: "Recessive pathogenic variants in MCAT cause combined oxidative phosphorylation deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
truncal and peripheral hypotonia, decreased muscle mass, and brisk
reflexes
explanation: >-
Brisk (hyperactive) reflexes on neurological exam in the multisystem
proband.
diagnosis:
- name: Molecular genetic testing
diagnosis_term:
preferred_term: Genetic Testing
term:
id: NCIT:C15709
label: Genetic Testing
description: >-
Diagnosis is molecular: biallelic MCAT variants are identified by exome or
targeted sequencing, after exclusion of primary mtDNA LHON and OPA1.
evidence:
- reference: PMID:36881526
reference_title: "Recessive pathogenic variants in MCAT cause combined oxidative phosphorylation deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
By whole exome sequencing, we identified a homozygous variant in MCAT
c.812T>C; p.T271I (rs760294168; NM_173467.4) in the proband, which was
heterozygous in both parents consistent with autosomal recessive
inheritance
explanation: >-
Exome sequencing established the molecular diagnosis in the proband.
treatments:
- name: High-dose methylprednisolone (ineffective)
therapeutic_modality: SMALL_MOLECULE
description: >-
The adult LHON-like patient received intravenous methylprednisolone boluses
on the assumption of an inflammatory optic neuropathy; vision did not
improve, consistent with the mitochondrial rather than inflammatory mechanism
of the disease. No disease-specific therapy is established.
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: methylprednisolone
term:
id: CHEBI:6888
label: 6alpha-methylprednisolone
evidence:
- reference: PMID:33918393
reference_title: "MCAT Mutations Cause Nuclear LHON-like Optic Neuropathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Ten days later, she received three more boluses of methylprednisolone,
which did not improve her visual acuity.
explanation: >-
Documents that corticosteroid treatment did not improve vision in the
LHON-like presentation.
discussions:
- discussion_id: oxphos_to_rgc_death_unproven
kind: KNOWLEDGE_GAP
prompt: >-
Is the combined OXPHOS deficiency seen in MCAT disease what selectively kills
retinal ganglion cells, or is the retinal-ganglion-cell death driven by
something else?
rationale: >-
The upstream chain is now supported: biallelic MCAT variants destabilise the
protein, impair mtFAS, and produce a measured combined oxidative
phosphorylation deficiency, with the respiratory-chain branch rather than
lipoylation implicated. What is not demonstrated is the final step. The one
patient with measured OXPHOS deficiency had severe multisystem disease rather
than isolated optic atrophy, and that deficiency was measured in fibroblasts
and lymphoblasts rather than retinal ganglion cells; the patients with
isolated optic atrophy had no bioenergetic measurement. So the link between
the respiratory-chain deficit and the selective retinal ganglion cell loss
remains inferred from the general vulnerability of these cells to
mitochondrial dysfunction.
attaches_to:
- pathophysiology#Impaired Respiratory-Chain Assembly and Combined OXPHOS Deficiency
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.
Create: optic atrophy 15 (MCAT) · 2026-10-25T02:46:20Z · View source
New de-novo entry for optic atrophy 15 (OPA15, MONDO:0957935), the autosomal recessive optic neuropathy caused by biallelic MCAT (hgnc:29622, verified by OAK lookup) variants. entry_type DISEASE: a single gene-defined Mendelian entity with a phenotypic spectrum (insidious childhood optic atrophy, adult LHON-like acute loss, severe infantile multisystem disease), not a grouping or subtype. Deep research: falcon was requested but failed authentication (403); the run fell back to openscientist, which produced research/Optic_Atrophy_15-deep-research-openscientist.md (6 references, all resolved, 0 off-topic, confabulation 0.0; term validation 21/25, 1 label variant that matched the canonical GO label I used). The report was verified to be about the correct disease by inspecting its citations (the two correct primary MCAT papers) and its gene naming (MCAT throughout). Evidence: every KB snippet was quoted directly from primary sources I fetched and read, not transcribed from the DR report. Three primary reports cited: Li 2020 (PMID:31915829, index consanguineous family, protein-instability and mouse RGC-knockdown data), Gerber 2021 (PMID:33918393, adult LHON-like compound-het case), and Webb 2023 (PMID:36881526, infantile multisystem case with directly measured combined OXPHOS deficiency and a C2C12 rescue that dissociates lipoylation from respiration). Pathograph is a four-node causal chain (MCAT LoF -> impaired mtFAS -> impaired respiratory-chain assembly / combined OXPHOS deficiency -> RGC/optic-nerve degeneration -> phenotypes), bare-name downstream targets, with a KNOWLEDGE_GAP recording that the final step (OXPHOS deficit -> selective RGC death) remains inferential. Named Entity Confusion preflight (just preflight-dr) could NOT be run: it requires the 1.3 GB local MONDO sqlite build, which was not downloaded under a disk-space constraint on this runner (the oaklib sqlite builds had filled the volume and were cleared). Entity match was instead confirmed manually as above. The arLHON review PMID:37071596 was read but deliberately NOT cited, because citing it would have required committing a churned full-text re-fetch of a cache file four other entries depend on; the arLHON-grouping claim is carried in description prose supported by the primary papers. No GeneReviews chapter exists (confirmed online with synonyms; recorded in notes). Validated: just validate, validate-terms, count-verified-snippets (23/23), validate-disorders (batched gate), check-entity-refs, check-causal-targets, check-duplicate-keys, check-enum-values, check-coarse-phenotypes, check-qualifier-terms, check-block-scalar-comments, check-reference-titles, check-title-snippets, check-snippet-grading, normalize-cache, check-term-cache-integrity -- all green.
Disease: Optic Atrophy 15 (OPA15) Causal gene: MCAT (malonyl-CoA–acyl carrier protein transacylase, mitochondrial) MONDO ID: MONDO:0957935 · OMIM: #620583 · Orphanet: ORPHA:98676 (autosomal recessive isolated optic atrophy) Synonyms: OPA15; MCAT-related optic neuropathy; MCAT-related nuclear LHON-like optic neuropathy; autosomal recessive optic neuropathy, MCAT-related Category: Mendelian (autosomal recessive)
Optic Atrophy 15 (OPA15) is an ultra-rare autosomal recessive mitochondrial optic neuropathy caused by biallelic loss-of-function variants in the nuclear gene MCAT (malonyl-CoA–acyl carrier protein transacylase), the enzyme that performs the second (malonyl-transfer) step of mitochondrial fatty-acid synthesis (mtFAS / type II FAS; EC 2.3.1.39). It is one of a small group of nuclear genes — alongside DNAJC30, NDUFS2, NDUFA12, and MECR — that cause an autosomal recessive Leber-hereditary-optic-neuropathy-like (arLHON, OMIM 619382) phenotype that clinically mimics classic mtDNA-driven LHON. The gene is named explicitly here because the serial disease name "Optic Atrophy 15" does not by itself indicate the causal gene; the subject of this report is strictly the MCAT-driven disorder defined by MONDO:0957935 / OMIM #620583, not the distinct gene-specific optic atrophies (e.g., OPA1, MECR/MEPAN).
Mechanistically, reduced MCAT enzyme lowers mtFAS flux, which starves two downstream branches: (1) octanoyl-ACP → lipoic acid synthesis / protein lipoylation of key mitochondrial enzymes (PDH, OGDH, BCKDH, glycine cleavage system), and (2) long-chain acyl-ACP supply to the NFS1–ISD11(LYRM4)–ACP complex required for iron–sulfur (Fe-S) cluster biogenesis and for assembly/stability of the electron-transport-chain (ETC) complexes and supercomplexes. The net result is combined OXPHOS deficiency. Because retinal ganglion cells (RGCs) — especially the small-caliber fibers of the papillomacular bundle — are exquisitely dependent on efficient oxidative phosphorylation, they selectively degenerate, producing optic nerve atrophy and vision loss. Functional-rescue data point to the respiratory-chain assembly branch, not lipoylation, as the actionable driver of the optic phenotype.
Clinically, OPA15 spans a spectrum: an insidious childhood optic atrophy (nystagmus, progressive bilateral vision loss, blindness within the first decade), an adult acute/subacute LHON-like central vision loss, and, in its most severe form, an infantile multisystem mitochondrial disease with hypotonia, failure to thrive, and abnormal brain MRI. Diagnosis is molecular (whole-exome/whole-genome sequencing or broad optic-atrophy nuclear gene panels after exclusion of primary mtDNA LHON and OPA1). There is no approved disease-specific therapy; management relies on empirical idebenone (by analogy to LHON), low-vision rehabilitation, avoidance of mitochondrial toxins, and genetic counseling. This report consolidates 9 confirmed findings drawn from the three primary case reports (Li 2020, Gerber 2021, Webb 2023) and two mechanistic/review papers on arLHON and mtFAS.
OPA15 (OMIM #620583; MONDO:0957935) is an autosomal recessive optic neuropathy caused by homozygous or compound-heterozygous pathogenic variants in MCAT (malonyl-CoA–acyl carrier protein transacylase; OMIM 614479; HGNC:29622; NCBI Gene 27349; Ensembl ENSG00000100294; UniProt Q8IVS2; chromosome 22q13.2). The condition was first described by Li et al. 2020 (Hum Mol Genet 29:444–458) in two Chinese siblings from a consanguineous family who carried double homozygous missense variants p.Leu81Arg (c.242T>G) and p.Arg212Trp (c.634C>T). HEK293 expression studies showed that these variants produce structurally unstable MCAT with markedly reduced intracellular protein, establishing a loss-of-function mechanism. Gerber et al. 2021 (Genes 12:521) subsequently reported a compound-heterozygous genotype — c.424-2A>G (a canonical splice-acceptor variant causing exon-2 skipping) plus c.824G>A (p.Glu275Lys). MCAT catalyzes the second step of mitochondrial fatty-acid synthesis (mtFAS/FASII), transferring the malonyl moiety from malonyl-CoA onto the mitochondrial acyl-carrier protein (NDUFAB1).
Supporting quote — PMID: 37071596: "biallelic mutations in the NDUFS2, DNAJC30, MCAT and NDUFA12 nuclear genes have been identified in unresolved LHON cases, identifying an autosomal recessive LHON (arLHON, OMIM:619382)." This confirms MCAT as one of the nuclear genes causing autosomal recessive LHON-like optic neuropathy.
Two principal presentations are documented, plus a severe syndromic form:
Supporting quote — PMID: 37071596: "The clinical presentation of arLHON copies that of typical LHON due to mtDNA mutations (mtLHON), with an acute phase of sudden and severe vision loss, telangiectatic and tortuous vessels around the optic nerve and swelling of the retinal nerve fibre layer."
Suggested HPO terms: HP:0000648 Optic atrophy; HP:0000543 Optic disc pallor; HP:0000639 Nystagmus; HP:0030532 Central scotoma; HP:0000551 Abnormality of color vision; HP:0000496 Abnormal eye movement; HP:0001290 Hypotonia (syndromic); HP:0001508 Failure to thrive (syndromic); HP:0000007 Autosomal recessive inheritance.
The causal chain runs: biallelic MCAT LoF variants → unstable, reduced MCAT protein (Li 2020) → reduced malonyl transfer from malonyl-CoA to mitochondrial ACP → decreased mtFAS flux (GO:0006633 fatty-acid biosynthesis; EC 2.3.1.39). Lower acyl-ACP then starves two branches: (a) reduced octanoyl-ACP → impaired lipoic-acid synthesis and protein lipoylation of PDH, OGDH, BCKDH, and the glycine cleavage system; and (b) reduced long-chain acyl-ACP binding to the LYRM/ISD11 (LYRM4) factor → impaired Fe-S cluster biogenesis (NFS1–ISD11–ACP complex) and defective ETC complex/supercomplex assembly. Webb 2023 demonstrated combined OXPHOS deficiency with reduced NDUFB8 (CI), COXII (CIV), and SDHB (CII) and decreased ETC enzyme activities in patient fibroblasts and lymphoblasts. Mitochondria-rich RGCs, which depend on efficient OXPHOS, degenerate, producing optic nerve atrophy and vision loss. Mouse evidence: RGC-specific Mcat knockdown attenuated the retinal nerve fiber layer, phenocopying the human optic neuropathy (Li 2020). Importantly, some MCAT patients lacked systemic lipoylation defects or lactic acidosis, implicating the Fe-S/supercomplex branch rather than lipoate deficiency as the RGC driver.
Supporting quote — PMID: 37734847: "reinforcing the impairment of mtFAS as novel pathogenic mechanism in LHON."
Suggested terms: GO:0006633 (fatty-acid biosynthesis), GO:0009249 (protein lipoylation), GO:0016226 (iron-sulfur cluster assembly), GO:0010257 (NADH dehydrogenase complex assembly); CL:0000740 retinal ganglion cell; UBERON:0000941 optic nerve; GO:0005759 mitochondrial matrix.
OPA15 is ultra-rare, with only a handful of families reported worldwide: two Chinese consanguineous siblings (Li 2020), one French woman plus separate cases (Gerber 2021), and one proband with multisystem disease (Webb 2023). No prevalence or incidence estimates exist. Orphanet classifies MCAT under autosomal recessive isolated optic atrophy (ORPHA:98676). Inheritance is autosomal recessive (HP:0000007); consanguinity contributed to the index family (homozygous L81R + R212W). As a recessive disease gene, MCAT is expected to have a low pLI (not haploinsufficient). As part of the broader arLHON group (DNAJC30, NDUFS2, NDUFA12, MCAT, MECR), the LHON-like presentations share classic LHON features — strong male predominance (~8.5:1 male:female across arLHON) and incomplete, sex-biased penetrance — although MCAT-specific sex and penetrance figures are not established given the few cases. No founder variant is described for MCAT, unlike DNAJC30 p.Tyr51Cys in Eastern Europeans.
Supporting quote — PMID: 37071596: "As for mtLHON, arLHON predominantly affected male compared with female carriers."
No disease-specific or approved therapy exists for OPA15. Management is extrapolated from LHON/arLHON. Idebenone (a short-chain benzoquinone antioxidant; approved as Raxone in the EU for LHON) bypasses complex I to restore ATP synthesis in RGCs. In the arLHON cohort, DNAJC30 patients showed high idebenone-responsive visual recovery (up to ~81%), whereas the reported MCAT patient did not recover with corticosteroid boluses; MCAT-specific idebenone efficacy is not established. AAV gene-replacement therapies in clinical use (lenadogene nolparvovec, rAAV2/2-ND4; REFLECT trial) target the mitochondrial MT-ND4 m.11778G>A form and are NOT applicable to nuclear MCAT disease. Prognosis: the childhood-onset form (Li 2020) is severe and progressive, reaching blindness within the first decade; the adult LHON-like form (Gerber 2021) shows subacute severe central vision loss with persistent central scotoma. A key mechanistic insight for therapy comes from Webb 2023: the T271I MCAT variant rescued protein lipoylation but not respiration in MCAT-deficient C2C12 cells, indicating that the OXPHOS/respiration branch, not lipoylation, is the actionable disease driver.
Supporting quote — PMID: 37071596: "Idebenone treatment significantly improved vision recovery in DNAJC30-associated patients."
Suggested NCIT term: idebenone (therapeutic antioxidant / neuroprotective agent).
Gene/protein: MCAT (malonyl-CoA–ACP transacylase, mitochondrial); HGNC:29622; NCBI Gene 27349; Ensembl ENSG00000100294; UniProt Q8IVS2; EC 2.3.1.39; chr22q13.2. It catalyzes malonyl transfer from malonyl-CoA to mitochondrial ACP (NDUFAB1) — step 2 of mtFAS (type II FAS). Subcellular localization: mitochondrial matrix (GO:0005759). CHEBI entities: malonyl-CoA (CHEBI:15531), acyl carrier protein, octanoate/lipoic acid (CHEBI:30314). Pathogenic variants (all germline, recessive): missense p.Leu81Arg (c.242T>G) and p.Arg212Trp (c.634C>T) (Li 2020); splice c.424-2A>G + missense p.Glu275Lys (c.824G>A) (Gerber 2021); missense p.Thr271Ile plus a second allele (Webb 2023). The functional consequence is loss of function via protein destabilization / reduced expression, confirmed in HEK293 and C2C12 systems.
Model organisms: (1) Mouse Mcat (NCBI Gene 223722; MGI:2388651; UniProt Q8R3F5) — RGC-specific knockdown attenuated the RNFL, recapitulating optic neuropathy (Li 2020, in vivo). (2) Cellular models — MCAT-deficient mouse C2C12 myoblasts rescued with WT vs mutant human MCAT to assay lipoylation and respiration (Webb 2023, in vitro), and HEK293 overexpression stability assays (Li 2020). (3) Broader mtFAS loss-of-function models (Mcat/Mecr) in mouse myoblasts show severe loss of ETC complexes. mtFAS/FASII is highly conserved from bacteria to humans, enabling yeast complementation studies.
Supporting quote — PMID: 37734847: "We modelled the candidate variant in yeast and studied mitochondrial dysfunction in yeast and fibroblasts." This illustrates the yeast/fibroblast modeling approach used for mtFAS genes (here MECR, paralleling MCAT).
OPA15 has no specific biochemical biomarker; diagnosis is molecular. The recommended workup for inherited optic neuropathy includes: history, best-corrected visual acuity, color-vision testing (dyschromatopsia, often blue-yellow in MCAT), fundus exam (optic disc pallor, attenuated disc capillaries), automated perimetry (central/cecocentral scotoma), OCT (peripapillary RNFL and macular ganglion-cell-layer thinning, global and temporal-predominant), and electrophysiology (abnormal VEP; reduced PERG N95 reflecting RGC dysfunction). Brain/orbit MRI shows optic nerve thinning/signal change and helps exclude compressive, demyelinating, toxic, nutritional, and metabolic mimics. Genetic strategy: first exclude primary mtDNA LHON variants (m.11778G>A, m.14484T>C, m.3460G>A) and OPA1, then perform whole-exome/whole-genome sequencing or a broad optic-atrophy nuclear gene panel (MCAT is included among ~50 nuclear HON genes). Diagnostic yield of exome sequencing for nuclear hereditary optic neuropathy is ~31.5% (149/473) in a large 2024/2025 cohort (PMID: 39423307); MCAT is a very rare cause — the "LHON-like optic atrophy" fundus category accounted for only ~3.64% of nuclear HON. Variant interpretation follows ACMG/AMP; reported MCAT alleles (missense and canonical splice) are classified pathogenic/likely pathogenic.
Differential diagnosis: mitochondrial LHON (MT-ND1/4/6), dominant optic atrophy (OPA1), WFS1/Wolfram, FDXR, ACO2, AFG3L2, NR2F1 (BBSOAS), MECR/MEPAN, toxic/nutritional optic neuropathy, optic neuritis, and compressive lesions.
Supporting quote — PMID: 37071596: "NDUFS2, DNAJC30, MCAT and NDUFA12 should be investigated in these individuals, knowing that other arLHON genes might exist."
Primary affected structures: retina and optic nerve of the central visual system. Cell type: retinal ganglion cells (CL:0000740), with preferential loss of the papillomacular bundle (small-caliber fibers), as in other mitochondrial optic neuropathies. Tissue: retinal nerve fiber layer (UBERON:0001789 retina; UBERON:0000941 optic nerve; UBERON:0004327 retinal nerve fiber layer). Subcellular compartment: mitochondrion/mitochondrial matrix (GO:0005759). Secondary/syndromic involvement in the severe multisystem presentation (Webb 2023): CNS (abnormal brain MRI), skeletal muscle (hypotonia), and growth (failure to thrive), reflecting systemic combined OXPHOS deficiency. Lateralization: bilateral, may be asymmetric (Gerber 2021 patient worse in the left eye). Temporal profile: onset ranges from early childhood (Li 2020, diagnosed age 8, insidious/chronic progressive to blindness in the first decade) to young adulthood (Gerber 2021, acute/subacute at age 20, LHON-like); the multisystem form presents in infancy. The course is chronic and progressive with variable, usually poor, visual recovery; the LHON-like form shows an acute phase followed by a chronic atrophic phase. No remission/relapsing pattern is established.
Supporting quote — PMID: 37071596: "This is followed by a chronic phase of retinal nerve fibre layer loss, but eventually affected individuals recover partial or full visual acuity" — describing the acute-then-chronic course of the LHON-like presentation.
OPA15 is a monogenic (Mendelian, autosomal recessive) disorder caused solely by biallelic MCAT loss-of-function variants; there is no infectious, autoimmune, or primary environmental cause. No susceptibility loci, GWAS associations, modifier genes, or epigenetic mechanisms have been reported for MCAT disease (data not available). No environmental or lifestyle factors are proven. By analogy to LHON — where tobacco smoking and heavy alcohol are recognized precipitants/aggravators of RGC bioenergetic failure — avoidance of mitochondrial toxins and of drugs impairing oxidative phosphorylation is prudent, though unproven for MCAT (inferred, not demonstrated). The variable penetrance/expressivity of the broader arLHON group suggests gene–environment or gene–sex interactions as in LHON, but this is not established for MCAT specifically. Prevention: no primary prevention or vaccine applies; secondary/tertiary prevention equals early molecular diagnosis, ophthalmologic monitoring (OCT, perimetry), low-vision rehabilitation, and empirical neuroprotection (idebenone) in LHON-like cases. Genetic counseling: autosomal recessive 25% sibling recurrence risk; carrier testing of relatives/partners, cascade testing, and prenatal diagnosis or preimplantation genetic testing are appropriate for families with known biallelic MCAT variants — particularly relevant in consanguineous unions. No newborn or population carrier screening programs exist for this ultra-rare gene.
MCAT biallelic LoF
│ (reduced/unstable protein)
▼
↓ malonyl transfer → ↓ mtFAS flux (acyl-ACP)
│
├────────────── Branch A ──────────────┐
│ ↓ octanoyl-ACP → ↓ lipoic acid │ (lipoylation defect —
│ → ↓ protein lipoylation (PDH/OGDH) │ NOT primary optic driver)
│ │
└────────────── Branch B ──────────────┘
↓ long-chain acyl-ACP → LYRM4/ISD11
→ ↓ Fe-S cluster biogenesis
→ ↓ ETC complex/supercomplex assembly ◄── ACTIONABLE DRIVER
│
▼
Combined OXPHOS deficiency
│
▼
RGC bioenergetic failure (papillomacular bundle)
│
▼
RNFL thinning / optic nerve atrophy → vision loss
| Study | PMID | Genotype (MCAT) | Variant type | Phenotype | Onset |
|---|---|---|---|---|---|
| Li et al. 2020 | 31915829 | p.Leu81Arg (c.242T>G) + p.Arg212Trp (c.634C>T), homozygous (consanguineous) | Missense (destabilizing) | Insidious optic atrophy, nystagmus, blindness in 1st decade | Childhood (~age 8) |
| Gerber et al. 2021 | 33918393 | c.424-2A>G (splice) + p.Glu275Lys (c.824G>A) | Splice + missense | Acute/subacute LHON-like central vision loss, scotoma, dyschromatopsia | Young adult (age 20) |
| Webb et al. 2023 | 36881526 | p.Thr271Ile + second allele | Missense | Multisystem: hypotonia, failure to thrive, nystagmus, abnormal MRI; combined OXPHOS deficiency | Infancy |
| Gene | Pathway role | Idebenone response | Notes |
|---|---|---|---|
| MCAT | mtFAS step 2 (malonyl transfer) | Not established (one patient no recovery) | OXPHOS-assembly branch is driver |
| MECR | mtFAS (enoyl reductase) | Not established | Paralogous mtFAS mechanism |
| DNAJC30 | Complex V assembly/turnover | High (~81% recovery) | Founder p.Tyr51Cys in Eastern Europe |
| NDUFS2 | Complex I subunit | Variable | Core CI gene |
| NDUFA12 | Complex I assembly | Variable | CI accessory factor |
| PMID | Title / focus | Role in this report |
|---|---|---|
| 31915829 | Li et al. 2020, Hum Mol Genet — first OPA15/MCAT description | Primary source: index consanguineous family, variants, protein-stability assay, mouse RGC knockdown |
| 33918393 | Gerber et al. 2021, Genes — adult LHON-like MCAT case | Primary source: compound-het splice+missense genotype, acute phenotype, 10-year follow-up |
| 36881526 | Webb et al. 2023 — combined OXPHOS deficiency / MCAT | Primary source: multisystem phenotype, combined OXPHOS deficiency, C2C12 rescue (lipoylation vs respiration) |
| 37071596 | Autosomal recessive LHON, a new neuro-ophthalmo-genetic paradigm | Framework for arLHON: MCAT as an arLHON gene, clinical course, male predominance, idebenone, diagnostic approach |
| 37734847 | Recessive mtFAS (MECR) optic neuropathy | Supports mtFAS impairment as a shared pathogenic mechanism; yeast/fibroblast modeling approach |
| 39423307 | Nuclear HON exome cohort (Brain 2024/2025) | Diagnostic yield context (~31.5%); MCAT rarity within nuclear HON |
How the evidence converges: The three primary case reports independently establish MCAT causality across distinct genotypes and ancestries, supporting genuine disease causation rather than chance association. The arLHON review (PMID: 37071596) situates MCAT within a coherent clinical and therapeutic framework, and the MECR mtFAS paper (PMID: 37734847) provides convergent mechanistic validation that disrupting mtFAS causes LHON-like optic neuropathy. The Webb 2023 C2C12 rescue experiment is the pivotal mechanistic result distinguishing the two downstream branches, redirecting therapeutic attention from lipoylation toward respiratory-chain assembly.
Evidence source types distinguished throughout: human clinical (Li 2020, Gerber 2021, Webb 2023; exome cohort PMID 39423307), review/synthesis (PMID 37071596), model organism / in vitro (mouse RGC knockdown, C2C12 and HEK293 assays, yeast complementation for the paralogous mtFAS gene MECR, PMID 37734847).
Checked with linkml-reference-validator 0.4.0.
| Outcome | Count |
|---|---|
| References checked | 6 |
| Resolved | 6 |
| Unresolved (possible confabulation) | 0 |
| Unverifiable | 0 |
| References weighed for topical relevance | 6 |
| On topic | 6 |
| Off topic | 0 |
All extracted references resolved successfully.
Checked with linkml-term-validator 0.4.5, through the ols: adapter.
| Outcome | Count |
|---|---|
| Terms checked | 25 |
| Resolved | 21 |
| Unresolved (possible confabulation) | 0 |
| Obsolete | 0 |
| Unverifiable | 4 |
| Terms whose name was checked | 4 |
| Terms named correctly | 3 |
| Terms named as a different term | 0 |
| Terms whose name is worth a second look | 1 |
The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:
GO:0006633 (2 mentions) - the report calls it "fatty-acid biosynthesis"; GO calls it fatty acid biosynthetic process, and lists "fatty acid biosynthesis" among its other namesTerms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA, OMIM, MGI.
21 of 25 terms resolved to a current term; the rest could not be looked up either way.