MEPAN syndrome (Mitochondrial Enoyl-CoA Reductase Protein-Associated Neurodegeneration), also called MECR-related neurologic disorder, is an ultra-rare autosomal recessive childhood-onset neurodegenerative disorder caused by biallelic pathogenic variants in MECR, the gene encoding the mitochondrial trans-2-enoyl-CoA/ACP reductase that catalyzes the terminal, NADPH-dependent step of mitochondrial fatty acid synthesis (mtFAS). It was the first human disease shown to result from a defect in the mtFAS pathway. Clinically it is defined by a triad of a progressive movement disorder (predominantly dystonia, often with chorea and/or ataxia) beginning between roughly one and 6.5 years of age, optic atrophy developing between ages four and 12 years, and hyperintense T2-weighted signal abnormalities in one or more basal-ganglia structures (caudate, putamen, globus pallidus) on MRI. Cognition is relatively spared, which distinguishes MEPAN from many other pediatric neurodegenerations. The disorder is discussed among the neurodegeneration-with-brain-iron-accumulation (NBIA) "mimics" because of the phenotypic overlap and a demonstrated cellular iron-dysregulation mechanism, even though frank brain iron accumulation is not the core imaging lesion. Mechanistically, deficient MECR activity lowers production of octanoyl-ACP, the precursor of lipoic acid, so protein lipoylation of the lipoate-dependent mitochondrial enzymes (pyruvate dehydrogenase, 2-oxoglutarate dehydrogenase, branched-chain ketoacid dehydrogenase, glycine cleavage system) fails; loss of properly acylated acyl-carrier protein additionally destabilizes iron-sulfur cluster assembly and oxidative-phosphorylation supercomplexes, and in fly and patient-fibroblast models produces iron overload and elevated ceramide. The net result is a mitochondrial bioenergetic deficit with selective vulnerability of basal-ganglia, cerebellar and retinal-ganglion-cell neurons. Management is supportive and symptomatic; there is no approved disease-modifying therapy.
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name: MEPAN Syndrome
creation_date: "2026-09-03T00:00:00Z"
category: Mendelian
disease_term:
preferred_term: MEPAN syndrome
term:
id: MONDO:0015003
label: dystonia, childhood-onset, with optic atrophy and basal ganglia abnormalities
description: >-
MEPAN syndrome (Mitochondrial Enoyl-CoA Reductase Protein-Associated
Neurodegeneration), also called MECR-related neurologic disorder, is an
ultra-rare autosomal recessive childhood-onset neurodegenerative disorder
caused by biallelic pathogenic variants in MECR, the gene encoding the
mitochondrial trans-2-enoyl-CoA/ACP reductase that catalyzes the terminal,
NADPH-dependent step of mitochondrial fatty acid synthesis (mtFAS). It was the
first human disease shown to result from a defect in the mtFAS pathway.
Clinically it is defined by a triad of a progressive movement disorder
(predominantly dystonia, often with chorea and/or ataxia) beginning between
roughly one and 6.5 years of age, optic atrophy developing between ages four
and 12 years, and hyperintense T2-weighted signal abnormalities in one or more
basal-ganglia structures (caudate, putamen, globus pallidus) on MRI.
Cognition is relatively spared, which distinguishes MEPAN from many other
pediatric neurodegenerations. The disorder is discussed among the
neurodegeneration-with-brain-iron-accumulation (NBIA) "mimics" because of the
phenotypic overlap and a demonstrated cellular iron-dysregulation mechanism,
even though frank brain iron accumulation is not the core imaging lesion.
Mechanistically, deficient MECR activity lowers production of octanoyl-ACP,
the precursor of lipoic acid, so protein lipoylation of the lipoate-dependent
mitochondrial enzymes (pyruvate dehydrogenase, 2-oxoglutarate dehydrogenase,
branched-chain ketoacid dehydrogenase, glycine cleavage system) fails; loss of
properly acylated acyl-carrier protein additionally destabilizes iron-sulfur
cluster assembly and oxidative-phosphorylation supercomplexes, and in fly and
patient-fibroblast models produces iron overload and elevated ceramide. The
net result is a mitochondrial bioenergetic deficit with selective vulnerability
of basal-ganglia, cerebellar and retinal-ganglion-cell neurons. Management is
supportive and symptomatic; there is no approved disease-modifying therapy.
synonyms:
- MEPAN syndrome
- MECR-related neurologic disorder
- Mitochondrial Enoyl-CoA Reductase Protein-Associated Neurodegeneration
- childhood-onset dystonia with optic atrophy and basal ganglia abnormalities
- DYTOABG
parents:
- Mitochondrial Disease
references:
- reference: PMID:31070877
title: "MECR-Related Neurologic Disorder."
tags:
- GeneReviews
inheritance:
- name: Autosomal recessive
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
description: >-
MEPAN is inherited in an autosomal recessive manner; affected individuals
carry biallelic (homozygous or compound heterozygous) MECR pathogenic
variants and unaffected parents are obligate heterozygous carriers.
evidence:
- reference: PMID:31070877
reference_title: "MECR-Related Neurologic Disorder."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "MECR-related neurologic disorder is inherited in an autosomal recessive manner."
explanation: GeneReviews states the autosomal recessive inheritance pattern.
- reference: PMID:31070877
reference_title: "MECR-Related Neurologic Disorder."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier."
explanation: GeneReviews gives the 25% sib recurrence risk expected for an autosomal recessive disorder.
pathophysiology:
- name: Biallelic MECR Loss of Function
biological_scale: MOLECULAR
description: >-
Biallelic pathogenic MECR variants (missense, nonsense, or splice-site)
reduce or abolish mitochondrial trans-2-enoyl-CoA/ACP reductase activity,
the enzyme that carries out the terminal NADPH-dependent reduction step of
mitochondrial fatty acid synthesis. Missense alleles typically act as
destabilizing hypomorphs rather than complete nulls.
molecular_functions:
- preferred_term: mitochondrial trans-2-enoyl-CoA/ACP reductase activity
modifier: LOSS_OF_FUNCTION
term:
id: GO:0019166
label: trans-2-enoyl-CoA reductase (NADPH) activity
downstream:
- target: Impaired Mitochondrial Fatty Acid Synthesis
causal_link_type: DIRECT
evidence:
- reference: PMID:27817865
reference_title: "MECR Mutations Cause Childhood-Onset Dystonia and Optic Atrophy, a Mitochondrial Fatty Acid Synthesis Disorder."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "All affected individuals were found to harbor recessive mutations in MECR encoding the mitochondrial trans-2-enoyl-coenzyme A-reductase involved in human mtFAS."
explanation: The founding cohort establishes that recessive MECR variants disable the mtFAS enzyme.
evidence:
- reference: PMID:37734847
reference_title: "Recessive MECR pathogenic variants cause an LHON-like optic neuropathy."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "In yeast, the MECR-R258W mutant showed an impaired oxidative growth, 30% reduction in oxygen consumption rate and 80% decrease in protein levels, pointing to structure destabilisation."
explanation: Demonstrates that a recurrent missense allele destabilizes the MECR protein, reducing its activity.
- name: Impaired Mitochondrial Fatty Acid Synthesis
biological_scale: MOLECULAR
description: >-
Loss of MECR activity impairs the terminal step of mitochondrial fatty acid
synthesis (mtFAS), reducing production of acyl-ACP species including
octanoyl-ACP, the precursor of lipoic acid, and of longer-chain acyl-ACPs
required for mitochondrial complex assembly.
biological_processes:
- preferred_term: mitochondrial fatty acid synthesis (mtFAS)
modifier: DECREASED
term:
id: GO:0006633
label: fatty acid biosynthetic process
downstream:
- target: Deficient Lipoic Acid Synthesis
causal_link_type: DIRECT
- target: Deficient Iron-Sulfur Cluster Assembly
causal_link_type: DIRECT
evidence:
- reference: PMID:27817865
reference_title: "MECR Mutations Cause Childhood-Onset Dystonia and Optic Atrophy, a Mitochondrial Fatty Acid Synthesis Disorder."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Mitochondrial fatty acid synthesis (mtFAS) is an evolutionarily conserved pathway essential for the function of the respiratory chain and several mitochondrial enzyme complexes."
explanation: Establishes mtFAS as the pathway disabled in MEPAN and its role supporting the respiratory chain and enzyme complexes.
- name: Deficient Lipoic Acid Synthesis
biological_scale: MOLECULAR
description: >-
Octanoic acid (octanoyl-ACP) produced by mtFAS is the precursor of lipoic
acid, an essential cofactor for several mitochondrial 2-oxoacid
dehydrogenase complexes; reduced octanoyl-ACP lowers lipoic acid
availability.
biological_processes:
- preferred_term: lipoic acid biosynthesis
modifier: DECREASED
term:
id: GO:0009107
label: lipoate biosynthetic process
downstream:
- target: Impaired Protein Lipoylation
causal_link_type: DIRECT
evidence:
- reference: PMID:37734847
reference_title: "Recessive MECR pathogenic variants cause an LHON-like optic neuropathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Among the fatty acids synthesised by mtFAS, there is octanoic acid, the precursor of lipoic acid (LA), a cofactor involved in the activity of several mitochondrial enzymes, among which the pyruvate dehydrogenase, the α-ketoglutarate dehydrogenase, the branched-chain keto acid dehydrogenase, the 2-oxoadipate dehydrogenase and the glycine cleavage system."
explanation: States that mtFAS-derived octanoic acid is the lipoic acid precursor, linking mtFAS failure to lipoic acid deficiency.
- name: Impaired Protein Lipoylation
biological_scale: MOLECULAR
description: >-
Reduced lipoic acid availability causes failure to lipoylate the
lipoate-dependent mitochondrial enzymes; patient fibroblasts and mouse brain
both show reduced levels of lipoylated proteins.
biological_processes:
- preferred_term: protein lipoylation
modifier: DECREASED
term:
id: GO:0009249
label: protein lipoylation
downstream:
- target: Lipoate-Dependent Enzyme Dysfunction
causal_link_type: DIRECT
evidence:
- reference: PMID:27817865
reference_title: "MECR Mutations Cause Childhood-Onset Dystonia and Optic Atrophy, a Mitochondrial Fatty Acid Synthesis Disorder."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Fibroblast cell lines from affected individuals displayed reduced levels of both MECR and lipoylated proteins as well as defective respiration."
explanation: Patient-derived fibroblasts directly demonstrate reduced protein lipoylation downstream of MECR deficiency.
- name: Lipoate-Dependent Enzyme Dysfunction
biological_scale: MOLECULAR
description: >-
Deficient lipoylation impairs the lipoate-dependent 2-oxoacid dehydrogenase
complexes - pyruvate dehydrogenase and 2-oxoglutarate (alpha-ketoglutarate)
dehydrogenase among them - compromising oxidative decarboxylation flux into
the TCA cycle.
molecular_functions:
- preferred_term: pyruvate dehydrogenase activity
modifier: DECREASED
term:
id: GO:0004739
label: pyruvate dehydrogenase (acetyl-transferring) activity
- preferred_term: 2-oxoglutarate dehydrogenase activity
modifier: DECREASED
term:
id: GO:0004591
label: oxoglutarate dehydrogenase (succinyl-transferring) activity
downstream:
- target: Mitochondrial Bioenergetic Failure
causal_link_type: DIRECT
evidence:
- reference: PMID:37734847
reference_title: "Recessive MECR pathogenic variants cause an LHON-like optic neuropathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Among the fatty acids synthesised by mtFAS, there is octanoic acid, the precursor of lipoic acid (LA), a cofactor involved in the activity of several mitochondrial enzymes, among which the pyruvate dehydrogenase, the α-ketoglutarate dehydrogenase, the branched-chain keto acid dehydrogenase, the 2-oxoadipate dehydrogenase and the glycine cleavage system."
explanation: Names the lipoate-dependent enzymes (PDH, KGDH, BCKDH, glycine cleavage) whose function depends on the lipoic acid supplied by mtFAS.
- name: Deficient Iron-Sulfur Cluster Assembly
biological_scale: MOLECULAR
description: >-
Loss of properly acylated acyl-carrier protein (ACP) destabilizes the
mitochondrial iron-sulfur cluster (ISC) assembly complex and alters
oxidative-phosphorylation complex and supercomplex assembly, an
ACP-acylation-dependent branch demonstrated in Mecr-mutant mouse brain and
in fly models.
biological_processes:
- preferred_term: iron-sulfur cluster assembly
modifier: DECREASED
term:
id: GO:0016226
label: iron-sulfur cluster assembly
downstream:
- target: Mitochondrial Bioenergetic Failure
causal_link_type: DIRECT
- target: Iron and Ceramide Dysregulation
causal_link_type: DIRECT
evidence:
- reference: PMID:41021813
reference_title: "A mouse model of MEPAN demonstrates a role for mitochondrial fatty acid synthesis in iron-sulfur cluster and supercomplex formation."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "LC-MS/MS-based proteomic analysis of Mecr mutant cerebella identified loss of subunits of complex I of oxidative phosphorylation (OXPHOS) and subunits of the iron-sulfur cluster assembly (ISC) complex."
explanation: The MEPAN mouse shows loss of ISC assembly and complex I subunits, supporting the ISC/supercomplex branch.
- name: Iron and Ceramide Dysregulation
biological_scale: CELLULAR
description: >-
Downstream of the Fe-S cluster biogenesis defect, mecr-loss neurons
accumulate free iron and elevated ceramide; lowering either iron or ceramide
suppresses the neurodegenerative phenotype, and MEPAN patient fibroblasts
replicate the elevated-ceramide/impaired-iron signature. This branch is
established primarily in a Drosophila model with patient-fibroblast
corroboration.
downstream:
- target: Basal Ganglia Neurodegeneration
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Retinal Ganglion Cell Degeneration
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:37653044
reference_title: "A defect in mitochondrial fatty acid synthesis impairs iron metabolism and causes elevated ceramide levels."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "We observe a defect in Fe-S cluster biogenesis and increased iron levels in flies lacking mecr, leading to elevated ceramide levels. Reducing the levels of either iron or ceramide suppresses the neurodegenerative phenotypes, indicating an interplay between ceramide and iron metabolism."
explanation: Interventional fly evidence that iron and ceramide dysregulation drives the neurodegeneration.
- reference: PMID:37653044
reference_title: "A defect in mitochondrial fatty acid synthesis impairs iron metabolism and causes elevated ceramide levels."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "we show that human-derived fibroblasts display similar elevated ceramide levels and impaired iron homeostasis."
explanation: Patient-derived fibroblasts corroborate the elevated-ceramide/iron mechanism in human cells.
- name: Mitochondrial Bioenergetic Failure
biological_scale: CELLULAR
description: >-
The combined loss of lipoate-dependent flux, ISC-dependent respiratory
enzymes, and OXPHOS supercomplex integrity produces a mitochondrial
oxidative-phosphorylation deficit, measured as defective respiration in
patient fibroblasts and reduced OXPHOS in Mecr-mutant mouse brain.
cell_types:
- preferred_term: neuron
term:
id: CL:0000540
label: neuron
biological_processes:
- preferred_term: oxidative phosphorylation
modifier: DECREASED
term:
id: GO:0006119
label: oxidative phosphorylation
downstream:
- target: Basal Ganglia Neurodegeneration
causal_link_type: DIRECT
- target: Retinal Ganglion Cell Degeneration
causal_link_type: DIRECT
- target: Cerebellar Purkinje Cell Degeneration
causal_link_type: DIRECT
- target: Ophthalmoplegia
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
External ophthalmoplegia is an oculomotor manifestation of the
mitochondrial bioenergetic deficit seen in mitochondrial disease; reported
in a single detailed MEPAN ophthalmic case, with intermediates unresolved.
evidence:
- reference: PMID:41021813
reference_title: "A mouse model of MEPAN demonstrates a role for mitochondrial fatty acid synthesis in iron-sulfur cluster and supercomplex formation."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "The MEPAN mouse recapitulates the major hallmarks of MEPAN, including a movement disorder, optic neuropathy, defects in protein lipoylation, and reduced mitochondrial oxidative phosphorylation in the brain."
explanation: The mouse model demonstrates reduced brain oxidative phosphorylation as the bioenergetic lesion.
- name: Basal Ganglia Neurodegeneration
biological_scale: TISSUE
description: >-
Selective neurodegeneration of the basal ganglia (caudate, putamen, globus
pallidus), reflected clinically as dystonia and chorea and radiologically as
T2-hyperintense basal-ganglia signal, is the substrate of the extrapyramidal
movement disorder.
cell_types:
- preferred_term: striatal medium spiny neuron
term:
id: CL:1001474
label: medium spiny neuron
downstream:
- target: Dystonia
causal_link_type: DIRECT
- target: Chorea
causal_link_type: DIRECT
- target: Focal T2 hyperintense basal ganglia lesion
causal_link_type: DIRECT
description: >-
The T2-hyperintense basal-ganglia signal is the radiological reflection of
this selective basal-ganglia neurodegeneration.
- target: Dysarthria
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Progressive dysarthria arises as a bulbar/motor-speech consequence of the
extrapyramidal movement disorder; the precise intermediates are unresolved.
evidence:
- reference: PMID:27817865
reference_title: "MECR Mutations Cause Childhood-Onset Dystonia and Optic Atrophy, a Mitochondrial Fatty Acid Synthesis Disorder."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Seven individuals from five unrelated families presented with childhood-onset dystonia, optic atrophy, and basal ganglia signal abnormalities on MRI."
explanation: The founding cohort ties basal-ganglia involvement to the dystonic movement disorder.
- name: Retinal Ganglion Cell Degeneration
biological_scale: TISSUE
description: >-
Degeneration of retinal ganglion cells and their axons in the papillomacular
bundle produces the optic atrophy, with a pattern resembling other
mitochondrial optic neuropathies (LHON, dominant optic atrophy).
cell_types:
- preferred_term: retinal ganglion cell
term:
id: CL:0000740
label: retinal ganglion cell
downstream:
- target: Optic atrophy
causal_link_type: DIRECT
evidence:
- reference: PMID:36262091
reference_title: "Ophthalmic manifestations of MEPAN syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Fundus exam revealed bilateral optic atrophy with pallor most pronounced temporally, corresponding to OCT findings of diffuse retinal nerve fiber layer thinning most prominent in the papillomacular bundle region and severe ganglion cell layer thinning in the maculae."
explanation: Ophthalmic imaging demonstrates retinal ganglion cell layer loss underlying the optic atrophy.
- name: Cerebellar Purkinje Cell Degeneration
biological_scale: TISSUE
conforms_to: "cerebellar_purkinje_degeneration#Purkinje Neuron Degeneration"
description: >-
MECR is highly expressed in cerebellar Purkinje cells, and Purkinje-cell
degeneration - established in a Purkinje-cell-specific Mecr knockout mouse -
is a plausible substrate for the ataxia that accompanies the movement
disorder in a subset of patients. The Purkinje-cell mechanism is
model-derived; the ataxia phenotype itself is documented clinically.
cell_types:
- preferred_term: Purkinje cell
term:
id: CL:0000121
label: Purkinje cell
downstream:
- target: Ataxia
causal_link_type: DIRECT
- target: Nystagmus
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Cerebellar dysfunction is the usual substrate of gaze-evoked nystagmus;
reported in a single MEPAN ophthalmic case, with intermediates unresolved.
evidence:
- reference: PMID:30266742
reference_title: "Impaired Mitochondrial Fatty Acid Synthesis Leads to Neurodegeneration in Mice."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "The mitochondria in KO PCs displayed abnormal morphology, loss of protein lipoylation, and reduced respiratory chain enzymatic activities by the time these mice were 6 months of age, followed by nearly complete loss of PCs by 9 months of age."
explanation: A Purkinje-cell-specific Mecr knockout shows Purkinje-cell degeneration, the model basis for cerebellar involvement.
phenotypes:
- name: Dystonia
category: Clinical
description: >-
Progressive childhood-onset dystonia is the core and usually presenting
feature, beginning between about one and 6.5 years of age; it may be axial
and/or appendicular and can be accompanied by chorea and ataxia.
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Dystonia
term:
id: HP:0001332
label: Dystonia
clinical_course: PROGRESSIVE
evidence:
- reference: PMID:31070877
reference_title: "MECR-Related Neurologic Disorder."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The movement disorder typically presents between ages one and 6.5 years and is mainly dystonia that can be accompanied by chorea and/or ataxia."
explanation: GeneReviews identifies dystonia as the predominant movement disorder with its typical onset window.
- name: Optic atrophy
category: Clinical
description: >-
Optic atrophy typically develops between ages four and 12 years, around the
time of or shortly after the movement disorder, and progresses to reduced
visual acuity and sometimes functional (legal) blindness in adulthood.
frequency: FREQUENT
phenotype_term:
preferred_term: Optic atrophy
term:
id: HP:0000648
label: Optic atrophy
clinical_course: PROGRESSIVE
sequelae:
- target: Reduced visual acuity
causal_link_type: DIRECT
description: >-
GeneReviews states the optic atrophy manifests as reduced visual acuity.
evidence:
- reference: PMID:31070877
reference_title: "MECR-Related Neurologic Disorder."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Optic atrophy typically develops between ages four and 12 years and manifests as reduced visual acuity, which can include functional blindness (also known as legal blindness) in adulthood."
explanation: GeneReviews directly ties the optic atrophy to reduced visual acuity.
evidence:
- reference: PMID:31070877
reference_title: "MECR-Related Neurologic Disorder."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Optic atrophy typically develops between ages four and 12 years and manifests as reduced visual acuity, which can include functional blindness (also known as legal blindness) in adulthood."
explanation: GeneReviews documents optic atrophy, its onset window, and progression to functional blindness.
- name: Chorea
category: Clinical
description: >-
Chorea may accompany the dystonia as part of the mixed hyperkinetic movement
disorder.
frequency: OCCASIONAL
phenotype_term:
preferred_term: Chorea
term:
id: HP:0002072
label: Chorea
evidence:
- reference: PMID:31070877
reference_title: "MECR-Related Neurologic Disorder."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The movement disorder typically presents between ages one and 6.5 years and is mainly dystonia that can be accompanied by chorea and/or ataxia."
explanation: GeneReviews lists chorea as an accompanying movement abnormality.
- name: Ataxia
category: Clinical
description: >-
Ataxia may accompany the movement disorder; cerebellar involvement is
supported mechanistically by Purkinje-cell degeneration in mouse models.
frequency: OCCASIONAL
phenotype_term:
preferred_term: Ataxia
term:
id: HP:0001251
label: Ataxia
evidence:
- reference: PMID:31070877
reference_title: "MECR-Related Neurologic Disorder."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The movement disorder typically presents between ages one and 6.5 years and is mainly dystonia that can be accompanied by chorea and/or ataxia."
explanation: GeneReviews lists ataxia as an accompanying feature of the movement disorder.
- name: Dysarthria
category: Clinical
description: >-
Speech fluency and intelligibility are progressively impaired by dysarthria,
often requiring augmentative communication.
frequency: FREQUENT
phenotype_term:
preferred_term: Dysarthria
term:
id: HP:0001260
label: Dysarthria
clinical_course: PROGRESSIVE
evidence:
- reference: PMID:31070877
reference_title: "MECR-Related Neurologic Disorder."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Speech fluency and intelligibility are progressively impaired due to dysarthria."
explanation: GeneReviews documents progressive dysarthria.
- name: Reduced visual acuity
category: Clinical
description: >-
Optic atrophy manifests functionally as progressively reduced visual acuity,
which can reach functional or legal blindness in adulthood.
frequency: FREQUENT
phenotype_term:
preferred_term: Reduced visual acuity
term:
id: HP:0007663
label: Reduced visual acuity
evidence:
- reference: PMID:31070877
reference_title: "MECR-Related Neurologic Disorder."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Optic atrophy typically develops between ages four and 12 years and manifests as reduced visual acuity, which can include functional blindness (also known as legal blindness) in adulthood."
explanation: GeneReviews ties the optic atrophy to reduced visual acuity.
- name: Focal T2 hyperintense basal ganglia lesion
category: Imaging
description: >-
Brain MRI shows bilateral hyperintense T2-weighted signal in one or several
basal-ganglia structures (caudate, putamen, globus pallidus), a key
diagnostic clue present at or near dystonia onset.
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: T2 hyperintense basal ganglia signal abnormality
term:
id: HP:0007183
label: Focal T2 hyperintense basal ganglia lesion
evidence:
- reference: PMID:38328756
reference_title: "Application of deep brain stimulation for the treatment of childhood-onset dystonia in patients with MEPAN syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "hyperintense T2-weighted abnormalities in one or several structures of the basal ganglia, including the caudate, putamen, and pallidum"
explanation: Describes the characteristic T2-hyperintense basal-ganglia MRI signal.
- name: Nystagmus
category: Clinical
description: >-
Nystagmus (e.g., high-frequency horizontal end-gaze nystagmus) has been
documented on detailed neuro-ophthalmic examination.
phenotype_term:
preferred_term: Nystagmus
term:
id: HP:0000639
label: Nystagmus
evidence:
- reference: PMID:36262091
reference_title: "Ophthalmic manifestations of MEPAN syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "She also displayed a high frequency horizontal end-gaze nystagmus and symmetric bilateral external ophthalmoplegia."
explanation: Documents nystagmus on ophthalmic evaluation of a MEPAN patient.
- name: Ophthalmoplegia
category: Clinical
description: >-
Symmetric bilateral external ophthalmoplegia, a neuro-ophthalmic finding
seen in heritable mitochondrial disease, has been reported.
phenotype_term:
preferred_term: External ophthalmoplegia
term:
id: HP:0000544
label: External ophthalmoplegia
evidence:
- reference: PMID:36262091
reference_title: "Ophthalmic manifestations of MEPAN syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "She also displayed a high frequency horizontal end-gaze nystagmus and symmetric bilateral external ophthalmoplegia."
explanation: Documents external ophthalmoplegia in a detailed ophthalmic case study.
genetic:
- name: MECR
gene_term:
preferred_term: MECR
term:
id: hgnc:19691
label: MECR
relationship_type: CAUSATIVE
variant_origin: GERMLINE
association: >-
Biallelic (homozygous or compound heterozygous) pathogenic MECR variants are
the sole known cause of MEPAN. The founding cohort reported six variants
across five families - nonsense (p.Tyr285*), frameshift (p.Asn83Hisfs*4),
splice-site (c.830+2_830+3insT) and missense in the cofactor-binding domain
(p.Gly232Glu, p.Tyr285Cys, p.Arg258Trp). The recurrent p.Arg258Trp allele
has since been reported in homozygous form causing both classic disease and
atypical adult-onset / LHON-like optic neuropathy, and a homozygous
p.Asp304Tyr allele caused dystonia and basal-ganglia disease without optic
atrophy.
inheritance:
- name: Autosomal recessive
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
evidence:
- reference: PMID:27817865
reference_title: "MECR Mutations Cause Childhood-Onset Dystonia and Optic Atrophy, a Mitochondrial Fatty Acid Synthesis Disorder."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "All six mutations are extremely rare in the general population, segregate with the disease in the families, and are predicted to be deleterious."
explanation: Establishes the recessive MECR variant spectrum segregating with disease in the founding cohort.
- reference: PMID:38296034
reference_title: "Recurrent MECR R258W causes adult-onset optic atrophy: A case report."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Analysis of whole-exome sequencing (WES) revealed a homozygous recurrent variant (NM_016011.5:c.772C > T, p.Arg258Trp) in MECR."
explanation: Documents the recurrent homozygous p.Arg258Trp allele underlying phenotypic heterogeneity.
- reference: PMID:33401012
reference_title: "Whole exome sequencing identifies a novel homozygous MECR mutation in a Chinese patient with childhood-onset dystonia and basal ganglia abnormalities, without optic atrophy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "we identified a novel homozygous MECR mutation (c.910G > T, p.Asp304Tyr) in a Chinese patient with childhood-onset dystonia and basal ganglia abnormalities, without optic atrophy."
explanation: Extends the variant spectrum and shows a genotype associated with dystonia and basal-ganglia disease without optic atrophy.
diagnosis:
- name: Molecular diagnosis by biallelic MECR variants
description: >-
The diagnosis is established in a proband with a childhood-onset movement
disorder in whom molecular genetic testing identifies biallelic (compound
heterozygous or homozygous) pathogenic MECR variants. The characteristic
T2-hyperintense basal-ganglia MRI signal and optic atrophy raise the
clinical suspicion that prompts testing.
diagnosis_term:
preferred_term: molecular genetic testing
term:
id: NCIT:C15709
label: Genetic Testing
results: >-
Two pathogenic MECR variants in trans confirm the diagnosis; a single
heterozygous variant is not diagnostic in this autosomal recessive disorder.
evidence:
- reference: PMID:31070877
reference_title: "MECR-Related Neurologic Disorder."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The diagnosis of MECR-related neurologic disorder is established in a proband with a childhood-onset movement disorder and biallelic (compound heterozygous or homozygous) pathogenic variants in MECR identified by molecular genetic testing."
explanation: GeneReviews states the molecular diagnostic criterion (biallelic MECR variants by molecular genetic testing).
- name: Whole-exome sequencing as the testing approach
description: >-
In practice the biallelic MECR variants are most often ascertained by
whole-exome sequencing in a child with an unexplained childhood-onset
dystonia and basal-ganglia MRI changes.
diagnosis_term:
preferred_term: whole exome sequencing
term:
id: NCIT:C101295
label: Whole Exome Sequencing
evidence:
- reference: PMID:38296034
reference_title: "Recurrent MECR R258W causes adult-onset optic atrophy: A case report."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Analysis of whole-exome sequencing (WES) revealed a homozygous recurrent variant (NM_016011.5:c.772C > T, p.Arg258Trp) in MECR."
explanation: Illustrates whole-exome sequencing as the modality that identifies the causative MECR variant.
prevalence:
- population: Worldwide
measure_type: CASES_IN_LITERATURE
prevalence_class: ULTRA_RARE
notes: >-
Ultra-rare. The founding report described 7 individuals from 5 families
(2016); GeneReviews notes only 13 affected individuals known to its authors;
the MEPAN Foundation reported more than 30 diagnosed individuals worldwide by
early 2023. These are ascertained case counts in a growing cohort, not a true
population prevalence estimate.
evidence:
- reference: PMID:31070877
reference_title: "MECR-Related Neurologic Disorder."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Because only 13 affected individuals are known to the authors, and because nearly half of them were diagnosed retrospectively as adults, the natural history of disease progression and other aspects of the phenotype have not yet been completely defined."
explanation: GeneReviews reports the small number of known affected individuals, supporting the ultra-rare classification.
- reference: PMID:38328756
reference_title: "Application of deep brain stimulation for the treatment of childhood-onset dystonia in patients with MEPAN syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "by early 2023, more than 30 people had been diagnosed with MEPAN syndrome globally since its discovery in 2016"
explanation: Provides an updated global ascertained case count for the growing cohort.
environmental:
- name: Intercurrent febrile illness
description: >-
Febrile illness is listed by GeneReviews among the circumstances to avoid
because it is presumed to exacerbate disease progression, consistent with
the metabolic-decompensation vulnerability of a mitochondrial bioenergetic
disorder in which fever raises energy demand.
effect: Presumed to exacerbate disease progression
notes: >-
No ECTO exposure term binds "febrile illness" as an environmental exposure
(fever is a physiologic state rather than an external agent); exposure_term
is therefore left unbound.
evidence:
- reference: PMID:31070877
reference_title: "MECR-Related Neurologic Disorder."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Stress and febrile illness as much as possible as these are presumed to exacerbate disease progression. Discuss anesthetic risks with a patient's medical team prior to surgical procedures."
explanation: GeneReviews lists febrile illness among circumstances presumed to worsen disease progression.
influences_mechanisms:
- target: Mitochondrial Bioenergetic Failure
environmental_effect: EXACERBATES
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Fever raises systemic and neuronal energy demand, which is presumed to
unmask or worsen the underlying oxidative-phosphorylation deficit; the
mechanistic intermediates are not established.
evidence:
- reference: PMID:31070877
reference_title: "MECR-Related Neurologic Disorder."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Stress and febrile illness as much as possible as these are presumed to exacerbate disease progression. Discuss anesthetic risks with a patient's medical team prior to surgical procedures."
explanation: GeneReviews presumes febrile illness exacerbates progression of this mitochondrial disorder.
- name: Physiologic stress
description: >-
Stress is likewise listed by GeneReviews among circumstances to avoid, on
the presumption that it exacerbates disease progression.
effect: Presumed to exacerbate disease progression
notes: >-
Emotional/physiologic stress has no suitable ECTO exposure term (per the
project's environmental-term guidance on stress); exposure_term left unbound.
evidence:
- reference: PMID:31070877
reference_title: "MECR-Related Neurologic Disorder."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Stress and febrile illness as much as possible as these are presumed to exacerbate disease progression. Discuss anesthetic risks with a patient's medical team prior to surgical procedures."
explanation: GeneReviews lists stress among circumstances presumed to worsen disease progression.
influences_mechanisms:
- target: Mitochondrial Bioenergetic Failure
environmental_effect: EXACERBATES
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Stress is presumed to increase metabolic load on already-compromised
mitochondria; the mechanistic intermediates are not established.
evidence:
- reference: PMID:31070877
reference_title: "MECR-Related Neurologic Disorder."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Stress and febrile illness as much as possible as these are presumed to exacerbate disease progression. Discuss anesthetic risks with a patient's medical team prior to surgical procedures."
explanation: GeneReviews presumes stress exacerbates progression of this mitochondrial disorder.
treatments:
- name: Symptomatic Pharmacotherapy for Dystonia
description: >-
Medications used to relieve dystonia include anticholinergic agents,
baclofen, and benzodiazepines. Responses are variable and the therapy is
symptomatic, not disease-modifying; dopaminergic agents have worsened chorea
in some patients and several agents (benzodiazepines, carbidopa-levodopa,
baclofen, botulinum toxin) were ineffective in a reported refractory sibling
pair.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
evidence:
- reference: PMID:31070877
reference_title: "MECR-Related Neurologic Disorder."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Medications that may relieve dystonia include anticholinergic agents, baclofen, and benzodiazepines."
explanation: GeneReviews lists the standard symptomatic pharmacotherapy for the dystonia.
- name: Deep Brain Stimulation
description: >-
Deep brain stimulation (globus pallidus internus, with pedunculopontine or
ventralis intermedius targets) has been applied to severe
pharmacotherapy-refractory MEPAN dystonia in two pediatric siblings with significant
improvement in dystonia rating scores. It is palliative, not
disease-modifying, and reported in only two patients.
therapeutic_modality: DEVICE
treatment_term:
preferred_term: deep brain stimulation
term:
id: NCIT:C21024
label: Deep Brain Stimulation
evidence:
- reference: PMID:38328756
reference_title: "Application of deep brain stimulation for the treatment of childhood-onset dystonia in patients with MEPAN syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Both patients successfully underwent DBS placement with no perioperative complications and significant improvement in their BFMDRS score."
explanation: First reported use of DBS for MEPAN dystonia with measured improvement in two patients.
- name: Supportive and Rehabilitative Care
description: >-
Multidisciplinary supportive care - visual aids for reduced acuity,
occupational and physical therapy to maintain mobility, speech therapy and
augmentative communication for dysarthria, and feeding support - plus annual
ophthalmologic, neurologic, speech, cognitive and feeding surveillance.
Stress and febrile illness should be minimized as they are presumed to
exacerbate progression.
therapeutic_modality: BEHAVIORAL
treatment_term:
preferred_term: Supportive Care
term:
id: NCIT:C15747
label: Supportive Care
evidence:
- reference: PMID:31070877
reference_title: "MECR-Related Neurologic Disorder."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "occupational therapy and physical therapy to maintain range of movement and special aids (e.g., braces, walkers, wheelchairs) to maintain/improve mobility; speech therapy for dysarthria and augmentative communication if needed."
explanation: GeneReviews specifies the supportive and rehabilitative management.
- reference: PMID:31070877
reference_title: "MECR-Related Neurologic Disorder."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Stress and febrile illness as much as possible as these are presumed to exacerbate disease progression. Discuss anesthetic risks with a patient's medical team prior to surgical procedures."
explanation: >-
GeneReviews lists stress and febrile illness among circumstances to avoid
and advises discussing anesthetic risk before surgery - directly relevant
given the neurosurgical (DBS) option offered elsewhere in this entry.
- name: Lipoic Acid Supplementation
description: >-
Because the mtFAS defect lowers lipoic acid synthesis, lipoic acid (with or
without octanoic acid / medium-chain triglyceride supplementation) has been
tried as a mechanism-targeted therapy. Evidence is limited and mixed: a
single homozygous p.Asp304Tyr patient had controlled progression without
developing optic atrophy on lipoic acid, but medium-chain triglyceride plus
lipoic acid feeding did not prevent neurodegeneration in a Purkinje-cell
Mecr-knockout mouse. It is investigational and should not be presented as
established disease-modifying therapy.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: lipoic acid
term:
id: CHEBI:16494
label: lipoic acid
target_mechanisms:
- target: Deficient Lipoic Acid Synthesis
treatment_effect: RESTORES
description: >-
Exogenous lipoic acid is intended to counter the deficient endogenous
lipoic acid synthesis by supplying the cofactor directly. The strategy is
mechanism-targeted but investigational, with only anecdotal human benefit
and a negative controlled mouse result.
evidence:
- reference: PMID:33401012
reference_title: "Whole exome sequencing identifies a novel homozygous MECR mutation in a Chinese patient with childhood-onset dystonia and basal ganglia abnormalities, without optic atrophy."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "With lipoic acid treatment, the disease progression was under control, and neither visual impairment nor optic atrophy was observed."
explanation: A therapeutic response to lipoic acid is cited as indirect validation that the deficient-lipoic-acid-synthesis node is the actionable target.
evidence:
- reference: PMID:33401012
reference_title: "Whole exome sequencing identifies a novel homozygous MECR mutation in a Chinese patient with childhood-onset dystonia and basal ganglia abnormalities, without optic atrophy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "With lipoic acid treatment, the disease progression was under control, and neither visual impairment nor optic atrophy was observed."
explanation: Anecdotal single-patient report of stabilized progression on lipoic acid.
- reference: PMID:38879137
reference_title: "Exploration of dietary interventions to treat mitochondrial fatty acid disorders in a mouse model."
supports: REFUTE
evidence_source: MODEL_ORGANISM
snippet: "feeding the mice with medium chain triacylglycerols and LA affected fatty acid profiles in the cerebellum and plasma but did not prevent the development of neurodegeneration in these mice."
explanation: A controlled mouse study found medium-chain triglyceride plus lipoic acid supplementation did not prevent neurodegeneration, tempering the anecdotal human benefit.
animal_models:
- name: MEPAN mouse (Mecr Tyr285Cys compound heterozygous)
species: Mouse
genotype: Mecr compound heterozygous (p.Tyr285Cys with truncating alleles)
publication: PMID:41021813
description: >-
CRISPR-engineered mouse carrying the patient-derived p.Tyr285Cys allele in
compound heterozygous combination with truncating alleles.
modeled_mechanisms:
- target: Mitochondrial Bioenergetic Failure
relationship: RECAPITULATES
fidelity: MODERATE
description: >-
The mouse reproduces reduced brain oxidative phosphorylation, protein
lipoylation defects, and loss of OXPHOS/ISC complex subunits.
limitations: >-
Reduced respiration was regional (cerebellum affected, cortex relatively
spared); the p.Tyr285Cys homozygote and mouse basal-ganglia circuitry may
not fully mirror human dystonia phenotyping.
readouts:
- name: Brain mitochondrial oxidative phosphorylation
target: Mitochondrial Bioenergetic Failure
direction: DECREASED
interpretation: Reduced brain OXPHOS is the bioenergetic correlate of the human mechanism.
evidence:
- reference: PMID:41021813
reference_title: "A mouse model of MEPAN demonstrates a role for mitochondrial fatty acid synthesis in iron-sulfur cluster and supercomplex formation."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "reduced mitochondrial oxidative phosphorylation in the brain"
explanation: Reports the reduced brain OXPHOS measurement in the MEPAN mouse.
evidence:
- reference: PMID:41021813
reference_title: "A mouse model of MEPAN demonstrates a role for mitochondrial fatty acid synthesis in iron-sulfur cluster and supercomplex formation."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "The MEPAN mouse recapitulates the major hallmarks of MEPAN, including a movement disorder, optic neuropathy, defects in protein lipoylation, and reduced mitochondrial oxidative phosphorylation in the brain."
explanation: Establishes the mouse as an informative model recapitulating the core MEPAN hallmarks.
- name: Purkinje-cell-specific Mecr knockout mouse
species: Mouse
genotype: Purkinje-cell-specific conditional Mecr knockout
publication: PMID:30266742
description: >-
Conditional knockout inactivating Mecr specifically in cerebellar Purkinje
cells, producing a trackable cerebellar neurodegeneration and ataxia.
modeled_mechanisms:
- target: Cerebellar Purkinje Cell Degeneration
relationship: RECAPITULATES
fidelity: MODERATE
description: >-
Purkinje-cell loss of Mecr causes loss of protein lipoylation, reduced
respiratory chain activity, Purkinje-cell death, and ataxic symptoms.
limitations: >-
Cell-type-restricted knockout models only the cerebellar component, not
the basal-ganglia or optic pathology, and the near-total Purkinje-cell loss
is more severe than the human cerebellar phenotype.
readouts:
- name: Cerebellar Purkinje cell survival
target: Cerebellar Purkinje Cell Degeneration
direction: DECREASED
interpretation: Progressive Purkinje-cell loss is the structural correlate of the cerebellar mechanism node.
evidence:
- reference: PMID:30266742
reference_title: "Impaired Mitochondrial Fatty Acid Synthesis Leads to Neurodegeneration in Mice."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "followed by nearly complete loss of PCs by 9 months of age"
explanation: Documents progressive Purkinje-cell loss in the model.
evidence:
- reference: PMID:30266742
reference_title: "Impaired Mitochondrial Fatty Acid Synthesis Leads to Neurodegeneration in Mice."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "These animals exhibited balancing difficulties ∼7 months of age and ataxic symptoms were evident from 8-9 months of age on."
explanation: The model develops ataxia, supporting cerebellar Purkinje-cell involvement in the movement phenotype.
- name: Drosophila mecr loss-of-function model
species: Drosophila melanogaster
genotype: mecr loss of function (whole-animal and neuron-specific knockdown/mutant)
publication: PMID:37653044
description: >-
Drosophila lacking mecr, the fly ortholog of the terminal mtFAS reductase.
Whole-animal loss is lethal; neuron-restricted loss produces progressive
neurodegeneration. This is the interventional model that established the
iron-Fe-S-ceramide branch: reducing either iron or ceramide suppresses the
neurodegenerative phenotype, and patient fibroblasts reproduce the same
elevated-ceramide/impaired-iron signature.
modeled_mechanisms:
- target: Iron and Ceramide Dysregulation
relationship: RECAPITULATES
fidelity: MODERATE
description: >-
mecr-null neurons show impaired Fe-S cluster biogenesis, increased iron,
and elevated ceramide, and epistatic rescue (lowering iron or ceramide)
suppresses the neurodegeneration - the clearest causal evidence that this
branch drives the phenotype.
limitations: >-
An invertebrate model whose nervous system lacks the basal-ganglia and
retinal-ganglion-cell circuitry that define the human lesion; the iron and
ceramide readouts are cross-corroborated in patient fibroblasts but not in
human brain.
readouts:
- name: Neuronal iron level
target: Iron and Ceramide Dysregulation
direction: INCREASED
interpretation: Elevated iron is one arm of the dysregulation node.
evidence:
- reference: PMID:37653044
reference_title: "A defect in mitochondrial fatty acid synthesis impairs iron metabolism and causes elevated ceramide levels."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "We observe a defect in Fe-S cluster biogenesis and increased iron levels in flies lacking mecr, leading to elevated ceramide levels. Reducing the levels of either iron or ceramide suppresses the neurodegenerative phenotypes, indicating an interplay between ceramide and iron metabolism."
explanation: Reports increased iron in mecr-null flies as measured evidence for this node.
- name: Neuronal ceramide level
target: Iron and Ceramide Dysregulation
direction: INCREASED
interpretation: Elevated ceramide is the second arm of the dysregulation node, and its reduction rescues the phenotype.
evidence:
- reference: PMID:37653044
reference_title: "A defect in mitochondrial fatty acid synthesis impairs iron metabolism and causes elevated ceramide levels."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "We observe a defect in Fe-S cluster biogenesis and increased iron levels in flies lacking mecr, leading to elevated ceramide levels. Reducing the levels of either iron or ceramide suppresses the neurodegenerative phenotypes, indicating an interplay between ceramide and iron metabolism."
explanation: Reports elevated ceramide and its epistatic rescue in the mecr-null fly.
evidence:
- reference: PMID:37653044
reference_title: "A defect in mitochondrial fatty acid synthesis impairs iron metabolism and causes elevated ceramide levels."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "loss of function of Drosophila mitochondrial enoyl coenzyme A reductase (Mecr), which is the enzyme required for the last step of mtFAS, causes lethality, while neuronal loss of Mecr leads to progressive neurodegeneration."
explanation: Establishes the mecr-null fly as an informative model of MECR-loss neurodegeneration.
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: MEPAN Syndrome · 2026-09-03T15:21:14Z · View source
Created de novo MEPAN Syndrome (MECR-related neurologic disorder, MONDO:0015003, gene MECR hgnc:19691). Deep research via just research-disorder claude_code (report lacked reference/term validation sections; sources were independently fetched and snippet-verified). Primary literature: Heimer 2016 founding cohort (PMID:27817865), GeneReviews (PMID:31070877), ophthalmic manifestations (PMID:36262091), adult-onset R258W (PMID:38296034), LHON-like R258W yeast (PMID:37734847), Chinese p.Asp304Tyr + lipoic acid (PMID:33401012), DBS case series (PMID:38328756), MEPAN mouse (PMID:41021813), Purkinje-cell Mecr KO mouse (PMID:30266742), dietary-intervention mouse negative result (PMID:38879137), Drosophila iron/ceramide mechanism (PMID:37653044). Built a branching pathophysiology chain from biallelic MECR LOF through impaired mtFAS to deficient lipoylation/ISC assembly, bioenergetic failure, and selective basal-ganglia/retinal-ganglion/Purkinje-cell degeneration. Model evidence tagged MODEL_ORGANISM/IN_VITRO and kept distinct from human phenotype claims. Lipoic acid treatment carries both a supportive anecdotal human report and a refuting controlled mouse result. Validated: just validate (37/37 snippets), validate-terms, check-causal-targets, check-duplicate-keys, check-entity-refs, check-qualifier-terms, and just validate-disorders all pass.
Overview. MEPAN syndrome (Mitochondrial Enoyl CoA Reductase Protein–Associated Neurodegeneration) is an ultra-rare, autosomal recessive, childhood-onset neurodegenerative disorder caused by biallelic pathogenic variants in MECR. It is defined by two core, largely non-overlapping-in-timing features: a progressive movement disorder (dystonia, often with chorea and/or ataxia) that begins in early childhood, and optic atrophy that develops during the same period or within a few years afterward, with relative sparing of cognition (GeneReviews, NBK540959; Orphanet ORPHA:508093). It was the first human disease shown to result from a defect in the mitochondrial fatty acid synthesis (mtFASII) pathway (Heimer et al., 2016, PMID: 27817865).
Key identifiers: - OMIM: #617282 — "Dystonia, Childhood-Onset, With Optic Atrophy and Basal Ganglia Abnormalities" (DYTOABG); gene locus 608205 (MECR) - Orphanet: ORPHA:508093 - MONDO: MONDO:0015003 - Gene: MECR, HGNC:19691, chromosome 1p35.3, 18 exons - Disease Ontology / other databases: DOID:0081419 (ZFIN "childhood-onset dystonia with optic atrophy and basal ganglia abnormalities") - ICD-10/11 do not have a disease-specific code; it is typically coded under dystonia (G24.-) and hereditary optic atrophy (H47.2) codes, or E-series inborn-error-of-metabolism codes when used in practice.
Synonyms: MEPAN syndrome; MECR-related neurologic disorder; childhood-onset dystonia with optic atrophy and basal ganglia abnormalities (DYTOABG); autosomal recessive childhood-onset dystonia, DYT29 type; childhood-onset generalized dystonia–optic atrophy syndrome (Orphanet; Wikipedia).
Data provenance. Knowledge of MEPAN derives almost entirely from aggregated case-series/cohort data rather than large-scale EHR mining, reflecting its ultra-rarity: the original description (Heimer et al. 2016) reported 7 individuals from 5 families; GeneReviews (last substantively updated ~2019) documented 13 affected individuals from 8 families; by early 2023 more than 30 individuals had been diagnosed globally (per search aggregation of OMIM/patient-advocacy sources). Supplementary mechanistic evidence comes from patient-derived fibroblasts, yeast complementation assays, Drosophila and mouse models, and one small natural-history/longitudinal study (Brain, 2024, discussed below under phenotype).
Disease causal factor: MEPAN is caused exclusively by biallelic (homozygous or compound heterozygous) loss-of-function or hypomorphic pathogenic variants in MECR — there is no known environmental, infectious, or purely mechanistic (non-genetic) etiology. It is a monogenic mitochondrial fatty-acid-synthesis disorder.
Genetic risk factors: - Homozygosity/compound heterozygosity for MECR pathogenic variants (missense, nonsense, splice-site). - Ashkenazi Jewish ancestry is a population-level risk factor due to two recurrent founder variants: - c.695G>A (missense) — carrier frequency ~1:311 in Ashkenazi Jews - c.830+2dupT (splice site) — carrier frequency ~1:136 in Ashkenazi Jews (GeneReviews, PMID: 27817865). Screening of >5,500 Ashkenazi Jewish exomes confirmed these elevated carrier frequencies. Five of the original 8 reported families were of Ashkenazi Jewish origin, though the disease occurs across all ethnicities (e.g., the Chinese proband below, and the Italian LHON-like family). - No modifier genes have been formally established, but intrafamilial phenotypic variability (siblings with the same genotype ranging from minimal symptoms to severe wheelchair dependence) strongly suggests unidentified genetic or environmental modifiers/incomplete penetrance (GeneReviews).
Environmental/triggering risk factors: - Febrile illness/intercurrent infection is repeatedly reported to precipitate acute worsening or stepwise, sometimes irreversible, loss of motor function ("Symptoms may fluctuate temporally with febrile illnesses"; one patient had permanent motor decline after a febrile episode without recovery — GeneReviews). - General anesthesia/propofol exposure has been associated with marked, lasting motor decline in at least one reported patient. - Dopaminergic agents (e.g., levodopa) have worsened chorea in at least one patient, an important negative treatment/exposure signal.
Protective factors: No genetic protective variants are established. The single most consequential "protective" finding to date is pharmacologic: early institution of lipoic acid (LA) ± octanoic acid (C8) supplementation is associated with attenuated or halted disease progression in at least two independently reported cases (see Treatment, §12).
Gene–environment interaction: The mechanistic link is that mtFASII produces the octanoate precursor for lipoic acid, an essential cofactor for pyruvate dehydrogenase, α-ketoglutarate dehydrogenase, and the glycine cleavage system. Febrile/catabolic stress increases metabolic demand on these lipoylation-dependent enzymes at a time when residual MECR activity is already insufficient, plausibly explaining stress-triggered decompensation — this is inferred from the biochemistry rather than directly demonstrated by a controlled gene-environment study.
MEPAN's phenotype spans two organ systems (extrapyramidal motor system and optic nerve) with a third, cognition, notably spared.
No disease-specific EQ-5D/SF-36/PROMIS data were identified in the literature; QoL impact is described qualitatively — progressive loss of independent ambulation, speech intelligibility, and vision drives major functional impairment and caregiver burden, with impact concentrated in physical/mobility and communication domains rather than cognitive/social domains, per GeneReviews' description of variable disability trajectories.
Causal gene: MECR (mitochondrial trans-2-enoyl-CoA reductase), HGNC:19691, OMIM *608205, chromosome 1p35.3, 18 exons, 5 reported protein isoforms via alternative splicing; canonical transcript NM_016011.5 encodes a 373-amino-acid protein.
Pathogenic variant spectrum (as of GeneReviews 2019 update): Six pathogenic variants identified — three missense, two nonsense, one canonical splice-site — across 8 families: - c.695G>A (missense) — Ashkenazi Jewish founder, carrier freq. ~1:311 - c.830+2dupT (splice site) — Ashkenazi Jewish founder, carrier freq. ~1:136 - Additional missense/nonsense variants in non-Ashkenazi families - c.772C>T, p.Arg258Trp — homozygous in an Italian family with an atypical "LHON-like" phenotype (see below); ultra-rare in gnomAD (MAF 6.368×10⁻⁵); reduces MECR protein levels by ~80% in yeast complementation, implying protein instability rather than pure catalytic loss (Bianco et al., 2024, J Med Genet, PMID: 37734847) - c.910G>T, p.Asp304Tyr — homozygous, first reported Chinese patient, dystonia/basal ganglia disease without optic atrophy; disturbed protein stability by modeling (ScienceDirect, 2020)
Population genetic constraint: gnomAD v4.0 reports pLI = 0 and LOEUF = 0.96 for MECR, indicating the gene is not under strong constraint against loss-of-function variants in the heterozygous state (consistent with a fully recessive disease mechanism and viable, asymptomatic carriers).
Variant classification: Per ClinGen (search.clinicalgenome.org/kb/genes/HGNC:19691) and ClinVar, MECR variants associated with disease are classified via standard ACMG/AMP criteria; nonsense variants are interpreted as pathogenic via predicted loss-of-function/nonsense-mediated decay given LOF is an established disease mechanism for this gene.
Functional consequence: Loss-of-function or hypomorphic. Decreased MECR enzymatic activity reduces production of octanoyl-ACP (the terminal mtFASII product and lipoic acid precursor), which in turn: - Impairs protein lipoylation of pyruvate dehydrogenase (PDH), α-ketoglutarate dehydrogenase (KGDH), branched-chain ketoacid dehydrogenase, and the glycine cleavage system H-protein (demonstrated directly in patient fibroblasts). - Impairs mitochondrial RNA processing/translation and respiratory chain complex assembly. - Destabilizes the mitochondrial iron-sulfur cluster (ISC) assembly complex (LYRM4/ISD11, NFS1, ISCU) via loss of acylated acyl-carrier protein (ACP), the form of ACP required for ISC-assembly-complex and OXPHOS-supercomplex stability (Murdock et al., 2025, PNAS, PMID: 41021813).
Modifier genes: None formally established; intrafamilial variability (same genotype, discordant severity) is unexplained.
Epigenetics: No disease-specific epigenetic (DNA methylation/histone) studies were identified for MEPAN.
Chromosomal abnormalities: Not applicable — MEPAN is caused by point/small indel variants in MECR, not by large structural rearrangements or aneuploidy.
Ontology suggestions: Gene — hgnc:19691 (MECR); functional impact category — LOSS_OF_FUNCTION / PARTIAL_LOSS_OF_FUNCTION (per variant; the R258W allele is a destabilizing hypomorph rather than a null).
Suggested CL terms for affected cell types: CL:0000617 (GABAergic neuron, basal ganglia medium spiny neurons implicated), CL:0000740 (retinal ganglion cell — the cell type lost in optic atrophy).
Organ level: - Primary: central nervous system — specifically the basal ganglia (caudate, putamen, globus pallidus), and the optic nerve/retina. - Secondary: none robustly documented as a distinct organ-system complication (e.g., no consistently reported cardiac, hepatic, or renal involvement), consistent with a phenotype relatively restricted to the CNS/optic pathway; mild sensorineural hearing impairment was reported in the Italian LHON-like family (an audiologic/otologic secondary finding). - Body systems: nervous system (extrapyramidal motor system), visual system.
Tissue/cell level: - Basal ganglia neurons (medium spiny neurons of caudate/putamen, and pallidal neurons) — targeted by the dystonia/chorea mechanism. - Retinal ganglion cells and their axons forming the papillomacular bundle — targeted in the optic neuropathy, with OCT showing diffuse retinal nerve fiber layer and ganglion cell layer thinning. - Suggested UBERON terms: UBERON:0002420 (basal ganglion), UBERON:0001884 (globus pallidus), UBERON:0001873 (caudate nucleus), UBERON:0001874 (putamen), UBERON:0000966 (retina), UBERON:0000941 (optic nerve).
Subcellular level: - Mitochondrial matrix (site of mtFASII and MECR enzymatic activity) — GO Cellular Component: GO:0005759 (mitochondrial matrix); MECR also reported at cytoplasm/nucleus at lower levels (GO:0005737, GO:0005634). - Iron-sulfur cluster assembly complex within the mitochondrial matrix.
Localization/laterality: Bilateral, symmetric involvement in both the basal ganglia MRI findings and the optic atrophy — no lateralization reported, consistent with a systemic metabolic (rather than focal/vascular) mechanism.
Epidemiology: - Prevalence: described as affecting fewer than 1 person per 1,000,000 (Orphanet/Wikipedia aggregation); the disease is "ultra-rare." - Case counts: 7 individuals/5 families at first description (2016); 13 individuals/8 families per GeneReviews (2019 update); >30 individuals diagnosed globally by early 2023 (OMIM-derived aggregation), indicating an actively growing ascertained cohort as awareness and testing access increase — not necessarily a true incidence estimate. - Incidence: no formal birth-incidence figure is available; carrier-frequency data in Ashkenazi Jews (see below) allow a rough theoretical incidence estimate for that subpopulation but this was not explicitly published in the sources reviewed.
Inheritance pattern: Autosomal recessive. At each conception for a carrier couple: 25% affected, 50% carrier, 25% unaffected; parents are obligate asymptomatic heterozygous carriers.
Penetrance: Appears to be high/complete for the biallelic genotype causing some phenotype, but expressivity is markedly variable (see below) — some sources describe intrafamilial variability suggestive of possible modifiers, though no formal incomplete-penetrance cases (biallelic carriers who are entirely asymptomatic) have been reported in the literature reviewed.
Expressivity: Highly variable, even between siblings sharing the same genotype — ranging from minimal symptoms to severe disability with total dependence (GeneReviews).
Genetic anticipation: Not applicable/not reported; MEPAN is not a repeat-expansion disorder.
Germline mosaicism: Not specifically reported in the literature reviewed.
Founder effects: Yes — two well-characterized Ashkenazi Jewish founder variants (c.695G>A and c.830+2dupT) account for a disproportionate share of reported cases (5 of the original 8 families).
Consanguinity: Plausibly relevant for homozygous cases outside the Ashkenazi founder-variant context (e.g., the homozygous Chinese p.Asp304Tyr and Italian p.Arg258Trp cases), though explicit consanguinity was not confirmed as stated for these specific families in the sources reviewed.
Carrier frequency: c.695G>A ~1:311 and c.830+2dupT ~1:136 in Ashkenazi Jews (from screening >5,500 Ashkenazi Jewish exomes); population carrier frequency outside this group is not established but is presumably much lower given gnomAD MAFs on the order of 10⁻⁵ for other reported variants.
Population demographics: - Ashkenazi Jewish populations show elevated prevalence due to founder variants; disease is reported worldwide across other ethnicities (Chinese, Italian families documented). - No sex predilection is described — consistent with autosomal (non-X-linked) inheritance. - Age distribution of diagnosed individuals spans childhood through the fifth decade of life in the current cohort, reflecting both the chronic non-lethal course and diagnostic delay/historical underrecognition (disease first described only in 2016).
Clinical/laboratory tests: No specific diagnostic biomarker or enzyme assay is in routine clinical use; standard metabolic screening (lactate, organic acids) is used mainly to exclude mimics rather than to positively diagnose MEPAN.
Neuroimaging: Brain MRI showing bilateral hyperintense T2-weighted signal in basal ganglia structures (caudate, putamen, globus pallidus) at or near dystonia onset is a key suggestive finding; some reports note the pattern can resemble a Leigh-syndrome-like distribution, which is part of why Leigh syndrome sits high on the differential.
Ophthalmic testing: Fundus photography, OCT (showing bilateral optic atrophy with papillomacular bundle predilection and RNFL/ganglion cell thinning), visual evoked potentials, electroretinography, visual field testing (Goldmann), and color vision (pseudoisochromatic plates) — used to characterize and stage the optic neuropathy.
Genetic testing (the definitive diagnostic modality): - Overview: Diagnosis is established by identifying biallelic pathogenic/likely pathogenic MECR variants in a proband with a compatible movement disorder ± optic atrophy phenotype. - Single-gene sequencing of MECR — reasonable first step when clinical suspicion is high (compatible phenotype ± Ashkenazi Jewish ancestry). - Multigene dystonia panels — many panels historically did not include MECR (a real ascertainment gap noted in GeneReviews), so panel selection must be verified. - Exome/genome sequencing (WES/WGS) — appropriate when phenotype is nonspecific or panel testing is uninformative; this is how most reported cases (including the Chinese and several other families) have been diagnosed. - Chromosomal microarray, karyotype, FISH, mitochondrial DNA testing, repeat-expansion testing: not indicated as primary diagnostic tools for MEPAN, since the disease is caused by small-variant defects in a single nuclear gene, not structural or mtDNA lesions.
Omics-based diagnostics: Not part of routine diagnostic workup; research-level fibroblast studies of protein lipoylation status and proteomics have been used to functionally validate variants of uncertain significance in individual cases (e.g., the R258W and D304Y reports).
Clinical diagnostic criteria: No formal consensus diagnostic-criteria document exists (this is too rare a disease for a society guideline); diagnosis rests on the combination of phenotype (childhood dystonia + optic atrophy + basal ganglia MRI signal) plus confirmatory biallelic MECR genotype.
Differential diagnosis (from GeneReviews, NBK540959): - Leigh syndrome (nuclear or mtDNA) — distinguished by seizures, encephalopathy, elevated lactate, brainstem involvement. - Glutaric aciduria type 1 — macrocephaly, widened Sylvian fissures, acute dystonic crises, elevated urinary glutaric acid. - D-2-hydroxyglutaric aciduria — seizures, cardiomyopathy, cognitive regression, elevated urinary D-2-HG. - Biotin-thiamine-responsive basal ganglia disease — good response to biotin/thiamine (an important treatable mimic to exclude). - Huntington disease (juvenile) — caudate atrophy, parkinsonism. - Neurodegeneration with brain iron accumulation (NBIA) spectrum — MRI iron accumulation and parkinsonism; notably, MEPAN is explicitly classified by the NBIA advocacy/clinical community as an "NBIA mimic" because it does not show true brain iron accumulation on imaging despite phenotypic overlap and despite the iron-dysregulation mechanism demonstrated at the cellular level (nbiacure.org). - Wilson disease — liver disease, Kayser-Fleischer rings. - Also relevant per the newly described phenotype: LHON and other mitochondrial optic neuropathies (OPA1-related dominant optic atrophy, MCAT-related disease) should now include MECR in the differential for recessive LHON-like presentations lacking dystonia (Bianco et al. 2024).
Screening: No newborn screening or population carrier-screening program specifically targets MECR; given the Ashkenazi Jewish founder variants, some Ashkenazi Jewish expanded carrier-screening panels may include MECR, though this was not explicitly confirmed as a formal ACMG-recommended addition in the sources reviewed.
There is no approved disease-modifying or curative therapy. Management is currently symptomatic/supportive, with an actively developing precision-medicine research pipeline.
Pharmacotherapy for movement disorder (symptomatic): - Anticholinergic agents (e.g., trihexyphenidyl-class) — NCIT:C15986 (Pharmacotherapy) - Baclofen (GABA-B agonist) — NCIT:C15986 - Benzodiazepines (GABA-A agonists) — NCIT:C15986 - Botulinum toxin injections — reported as used (and having failed) in the DBS case series, implying it is part of the standard symptomatic ladder — NCIT:C15986 / relevant injection procedure term - Caution: dopaminergic agents (e.g., carbidopa-levodopa) have worsened chorea in reported patients and were among the failed therapies in the DBS series — should be used cautiously.
Metabolic/precision supplementation (investigational but in real-world compassionate use): - Lipoic acid (LA) and octanoic acid/C8-rich nutritional supplementation — mechanistically targeted at the mtFASII/lipoylation defect. One patient showed "remarkable improvement" when LA + C8-rich supplement was started within 3 months of symptom onset (GeneReviews). In the Chinese p.Asp304Tyr patient, LA supplementation was associated with controlled disease progression and no development of visual impairment or optic atrophy — the first report explicitly proposing LA as an effective therapeutic strategy for this disease (ScienceDirect, 2020). In the R258W yeast model, LA supplementation partially rescued the growth phenotype, attributed to its antioxidant action rather than direct restoration of lipoylation (Bianco et al. 2024). - "Mito cocktail" (coenzyme Q10, riboflavin, thiamine, alpha-lipoic acid, octanoic acid, vitamin E, vitamin C) — offered empirically by some clinicians; efficacy unproven as a combination (GeneReviews).
Surgical/interventional (advanced dystonia): - Deep brain stimulation (DBS) — first published application in MEPAN reported two pediatric siblings (ages 9–10) who had failed pharmacotherapy (benzodiazepines, carbidopa-levodopa, baclofen, botulinum toxin). GPi+PPN and GPi+VIM targeting respectively produced BFMDRS-M improvements of 34.9% and 49.6%, with zero perioperative complications (though one patient had transient tissue devitalization requiring staged lead placement). Authors concluded DBS provides palliation, not disease modification, and "can be considered for dystonia in patients with rare metabolic disorders" when pharmacotherapy fails (PMID: 38328756). Note this contrasts with an earlier general caution (some sources state DBS "may be unsuitable due to basal ganglia lesions") — the 2024 case series is the more current, direct evidence and should supersede the earlier caution in curation.
Supportive/rehabilitative care: - Visual aids for decreased acuity - Occupational and physical therapy for mobility/activities of daily living - Speech therapy and augmentative/alternative communication for dysarthria - Feeding support as needed for dysphagia - NCIT terms: NCIT:C15302 (Physical Therapy), NCIT:C15747 (Supportive Care), speech/OT via NCIT:C159273 / NCIT:C121351.
Surveillance: Yearly ophthalmologic, neurologic, speech-therapy, cognitive, and feeding evaluations recommended to track progression and trigger timely intervention (GeneReviews).
Advanced/experimental therapeutics in development: - AAV9-mediated gene therapy — preclinical work (University of Florida, supported by the MEPAN Foundation) has shown successful MECR protein expression after AAV9-MECR transfection in HEK293T and Neuro-2a cells, aiming to deliver functional MECR to brain and retina; leverages precedent from FDA-approved AAV gene therapies (e.g., for SMA, LHON) (mepan.org/precision). - Drug repurposing — echinocandin antifungals (anidulafungin, micafungin): Screened on MEPAN patient fibroblasts using Seahorse oxygen-consumption/ATP-production assays; anidulafungin ranked best, followed by micafungin. Echinocandins rescued MECR-deficient yeast growth — notable because their canonical fungal target (glucan synthase) does not exist in human cells, implying a favorable safety profile if repurposed. Rescue was effective only for missense MECR mutants retaining a foldable protein (not for null/truncating alleles), and newer-generation echinocandins (micafungin, anidulafungin) lack the high-dose toxicity seen with first-generation caspofungin (Perlara "Cure Odysseys" drug-repurposing program, described in search aggregation; primary peer-reviewed publication not yet identified in this search — should be treated as an early-stage/preprint-level lead pending verification). - Engineered bacterial lipoate ligase — proposed strategy to bypass the defective endogenous lipoic acid synthesis step (mentioned in Wikipedia's synthesis of primary literature; specific citation not independently verified in this search). - MECR G165Q engineered variant studies (Nature Communications 2023, PMC9899272) demonstrate that long-chain acyl-ACPs are indispensable for mitochondrial respiration distinct from octanoylation for lipoylation — informing structure-function rationale for future targeted therapeutics, though this is a basic-science mechanistic paper rather than a therapeutic trial.
Clinical trials: No MEPAN-specific interventional trial (e.g., an NCT-registered gene-therapy or drug trial) was identified as currently active in this search; the UMDF and MEPAN Foundation direct patients to general rare-disease clinical-trial finders and the mitoSHARE patient registry (umdf.org) rather than to a disease-specific active trial.
Treatment outcomes/adverse events: No systematic response-rate or FAERS-type adverse-event data exist given the small population; adverse treatment signals identified are anecdotal (dopaminergic worsening of chorea; anesthesia/propofol-associated decline).
MEPAN modeling spans yeast, nematode, fly, and mouse — an unusually complete cross-species toolkit for an ultra-rare disease, reflecting the deep evolutionary conservation of mtFASII.
Yeast (Saccharomyces cerevisiae): - Δetr1 (Etr1p-null) mutant yeast fail to synthesize sufficient lipoic acid or assemble cytochrome complexes and cannot respire/grow on non-fermentable carbon sources. - Human MECR (wild-type and patient-variant constructs, e.g., R258W) complements/fails to complement this strain, providing a rapid functional assay for variant pathogenicity, protein stability, and drug-rescue screening (including the echinocandin repurposing work).
Nematode (C. elegans): mecr-1/W09H1.5 encodes the 2-trans-enoyl-thioester reductase; ectopic expression of nematode mecr-1 in yeast Δetr1 restores reductase activity and phenotype rescue, and mecr-1 itself is described as a longevity-associated gene, connecting mtFAS to organismal aging biology (PMC2774161).
Fruit fly (Drosophila melanogaster): - Whole-body loss of Mecr is lethal; neuron-specific knockdown produces progressive neurodegeneration, recapitulating the human neurological phenotype. - Mechanistically, flies lacking mecr show Fe–S cluster biogenesis defects and elevated iron levels, leading to elevated ceramide; genetically or pharmacologically lowering either iron or ceramide suppresses the neurodegenerative phenotype — the clearest causal (interventional) evidence in the entire mechanistic literature (Tesch et al., Nature Metabolism 2023;5:1595–1614, PMID: 37653044). Human MEPAN patient fibroblasts independently show the same elevated-ceramide/impaired-iron-homeostasis signature, supporting translational relevance of the fly findings to human disease. - UAS constructs carrying human wild-type and disease-variant MECR have been introduced into flies for structure-function and rescue studies (FlyBase Human Disease Model Report FBhh0001544).
Mouse (Mus musculus): - A compound-heterozygous Mecr-mutant mouse model (Murdock et al., PNAS 2025;122(40):e2506761122, PMID: 41021813) recapitulates the core triad: movement disorder, optic neuropathy, and defective protein lipoylation, plus reduced brain mitochondrial oxidative phosphorylation. - Proteomic/complexome profiling of mutant mouse brain revealed destabilization of the ISC assembly complex (↓LYRM4, ↓NFS1, ↓ISCU) and altered OXPHOS complex/supercomplex assembly, tied to loss of acylated ACP — this is currently the highest-fidelity mammalian model and the primary source of the ISC/supercomplex mechanistic branch described in Section 6. - Phenotype recapitulation: high fidelity for movement disorder, optic neuropathy, and biochemical lipoylation defect. - Model limitations: Explicit limitations were not detailed in the fetched abstract summary; general caution for any mouse CNS model — potential differences in basal ganglia circuitry/dystonia phenotyping between mouse and human, and uncertain translatability of the iron/ceramide suppressor findings (established in fly, "confirmed" only as elevated markers, not as an interventional rescue, in mouse/human fibroblasts per the sources reviewed) should be flagged as a human-model-fidelity open question.
Cell-based models: Patient-derived dermal fibroblasts (multiple case reports) are the standard human cellular model, used for lipoylation Western blots, Seahorse OCR/ATP assays (echinocandin screening), and ceramide/iron measurement.
Resource note: No mouse strain repository ID (JAX/MGI stock number), zebrafish (ZFIN), or dedicated cell-line repository (ATCC/Cellosaurus) accession for a MEPAN-specific model was identified in this search; the fly model is registered in FlyBase (FBhh0001544).
| Topic | Primary citation | PMID/DOI |
|---|---|---|
| Original disease description, MECR mutations, 7 pts/5 families | Heimer et al., Am J Hum Genet 2016;99:1229–44 | PMID 27817865 |
| GeneReviews clinical/genetic summary | Heimer/Baris et al., MECR-Related Neurologic Disorder, GeneReviews (NCBI Bookshelf) | NBK540959 |
| OMIM entries | Gene *608205; Phenotype #617282 (DYTOABG) | omim.org/entry/608205, /617282 |
| Orphanet | MEPAN syndrome | ORPHA:508093 |
| Mouse model — ISC/supercomplex mechanism | Murdock et al., PNAS 2025;122(40):e2506761122 | PMID 41021813 |
| Drosophila model — iron/ceramide mechanism | Tesch et al., Nat Metab 2023;5:1595–1614 | PMID 37653044 |
| LHON-like phenotype (R258W) | Bianco et al., J Med Genet 2024 | PMID 37734847 |
| Chinese patient, no optic atrophy, LA response | ScienceDirect, Mitochondrion 2020 | PMID (search) 32853756* |
| Ophthalmic manifestations case study | Ophthalmic Genetics 2022;44(5) | DOI 10.1080/13816810.2022.2135112 |
| Deep brain stimulation case series | J Neurosurg Pediatr / PMC10847241 2024 | PMID 38328756 |
| Engineered MECR variant / long-chain acyl-ACP | Nat Commun 2023 | PMC9899272 |
*PMID for the Chinese-patient ScienceDirect paper was not independently confirmed via direct PubMed fetch in this session and should be re-verified before use in a curated evidence item.