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Classifications

Harrison's Part

Mechanistic Nosology

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Inheritance

1

Autosomal recessive HP:0000007

Biallelic OPA1 disease often segregates recessively, but severe-plus-hypomorphic allele combinations can resemble semidominant inheritance. Relatives with one allele may have dominant optic atrophy, subclinical findings or no detectable disease. Clinical Behr-like presentations have also been reported with a single heterozygous OPA1 variant; the historical phenotype alone does not establish recessive inheritance.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:27150940 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"These results may support either recessive or semi-dominant inheritance with incomplete penetrance."

Unaffected parents in this family support more than one segregation model.

PMID:24970096 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"This hypomorphic allele causes a severe optic atrophy plus phenotype when combined with a compound heterozygous OPA1 null mutation."

The intralocus modifier architecture is distinct from two uniformly null alleles.

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Mechanistic Hypotheses

1

SARM1-dependent axon death executes retinal ganglion cell degeneration downstream of the OPA1 mitochondrial defect

sarm1_axon_death EMERGING

Evidence balance 1 support

Sarm1 loss protects RGC bodies, optic-nerve axons and visual electrophysiology in heterozygous Opa1R290Q/+ mice without correcting fragmentation. The study found little change in respiration or mtDNA copy number, and proposed oxidative-stress signaling upstream of SARM1 without proving the intermediate route. Extrapolation to human biallelic OPA1 disease remains untested; the result does not establish ATP depletion as the trigger.

Pathograph links

Mitochondrial Network Fragmentation -> Retinal Ganglion Cell Degeneration INDIRECT UNKNOWN INTERMEDIATES A SARM1-dependent execution pathway downstream of fragmentation is supported in a dominant OPA1 mouse model; its operation in human Behr syndrome is an emerging hypothesis.

Show evidence (1 reference)

PMID:40344041 SUPPORT INDIRECT PRIMARY RESULT Model Organism

"Sarm1 KO nearly completely suppressed all the degeneration phenotypes without reversing mitochondrial fragmentation."

Genetic rescue in heterozygous Opa1R290Q/+ mice supports a downstream degeneration pathway; applicability to biallelic human disease remains untested.

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Discussions and Knowledge Gaps

1

Does SARM1-dependent axon death drive retinal ganglion cell degeneration in human biallelic-OPA1 Behr syndrome, as it does in the Opa1 mouse model — and would SARM1 inhibition be neuroprotective in patients?

HUMAN MODEL MISMATCH OPEN sarm1_human_translation

Attached to

pathophysiology#Retinal Ganglion Cell Degeneration

The SARM1 rescue is demonstrated only in a mouse model of dominant (monoallelic) OPA1 optic atrophy. Its relevance to human recessive/biallelic OPA1 Behr syndrome — a more severe, multisystem, developmental disease — is unproven, so the model result cannot yet be assumed to translate.

Proposed experiments

Test SARM1-dependent axon death in human biallelic-OPA1 models

exp_sarm1_human_biallelic_opa1

Assess SARM1-pathway activation in patient-derived (biallelic-OPA1) neurons/iPSC-derived retinal ganglion cells, test whether SARM1 inhibition is neuroprotective in those models, and evaluate SARM1 axon-death biomarkers in patient samples.

Show evidence (1 reference)

PMID:40344041 SUPPORT INDIRECT PRIMARY RESULT Model Organism

"Sarm1 KO nearly completely suppressed all the degeneration phenotypes without reversing mitochondrial fragmentation."

Genetic rescue in heterozygous Opa1R290Q/+ mice supports a downstream degeneration pathway; applicability to biallelic human disease remains untested.

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Pathophysiology

11

Biallelic OPA1 Variants

Biallelic OPA1 variants include truncating, deep-intronic splice-altering and missense alleles. An intragenic hypomorphic allele can intensify the phenotype of an allele that causes dominant optic atrophy in isolation. Variant effects differ; reduced GTPase catalytic activity has not been established for every genotype.

OPA1 hgnc:8140

GTPase activity GO:0003924

Downstream

Aberrant OPA1 Splicing For the c.610+364G>A allele, a new acceptor activates a cryptic exon.

Reduced OPA1 Protein Abundance Reduced protein has been measured for several biallelic genotypes; the intervening RNA/protein effects are allele-dependent.

Mitochondrial Network Fragmentation Altered OPA1 function, including reduced abundance, disturbs network morphology.

Reduced Mitochondrial DNA Content OPA1-associated mtDNA maintenance defects are a possible explanation for depletion in a genetically complex patient.

Cerebellar Involvement This tissue-level abnormality is observed in molecularly confirmed OPA1 disease; the intervening steps and selective vulnerability are unresolved.

Pyramidal Tract Dysfunction This tissue-level abnormality is observed in molecularly confirmed OPA1 disease; the intervening steps and selective vulnerability are unresolved.

Peripheral Axonal Degeneration This tissue-level abnormality is observed in molecularly confirmed OPA1 disease; the intervening steps and selective vulnerability are unresolved.

Show evidence (3 references)

PMID:28442211 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"we identified the homozygous c.1180G>A/p.Ala394Thr mutation in Pt1 and the c.2779-2A>C mutation in compound heterozygosity with the c.2809C>T/p.Arg937Cys mutation in Pt2."

Two distinct biallelic architectures were identified in affected children.

PMID:24970096 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"the deep intronic mutation occurred in compound heterozygous state with an exonic OPA1 missense variant (p.I382M; NM_015560.2)."

The severe phenotype can involve a splice allele plus an intralocus modifier.

PMID:18158317 SUPPORT INDIRECT BACKGROUND Human Clinical

"Mutations in OPA1, a dynamin-related GTPase involved in mitochondrial fusion, cristae organization and control of apoptosis, have been linked to non-syndromic optic neuropathy transmitted as an autosomal-dominant trait (DOA)."

This background statement establishes normal OPA1 GTPase function. The unmodified molecular-function annotation does not claim that every biallelic variant reduces catalytic activity.

Aberrant OPA1 Splicing

The c.610+364G>A deep-intronic allele activates cryptic exon inclusion between exons 4b and 5, creating premature termination. This mechanism applies to this splice allele, not to all biallelic OPA1 variants.

OPA1 hgnc:8140

mRNA splicing, via spliceosome GO:0000398 ⚠ ABNORMAL

Downstream

OPA1 Transcript Decay Premature-termination-containing splice products undergo nonsense-mediated decay.

Show evidence (1 reference)

PMID:24970096 SUPPORT DIRECT PRIMARY RESULT In Vitro

"The mutation creates a new splice acceptor site resulting in aberrant OPA1 transcripts with retained intronic sequence and subsequent translational frameshift as shown by complementary DNA analysis."

Patient cDNA establishes the splice consequence of the deep intronic allele.

OPA1 Transcript Decay

In the deep-intronic family, mutant-allele transcripts are depleted by nonsense-mediated decay. This is not universal: transcripts were preserved for the early frameshift allele in Nasca patient P1 despite reduced protein.

nuclear-transcribed mRNA catabolic process, nonsense-mediated decay GO:0000184 ↑ INCREASED

Downstream

Reduced OPA1 Protein Abundance Loss of mutant transcripts reduces the available OPA1 protein in splice-allele carriers.

Show evidence (2 references)

PMID:24970096 SUPPORT DIRECT PRIMARY RESULT In Vitro

"To suppress nonsense-mediated messenger RNA decay-dependent allelic decay we used puromycin treatment in patient derived fibroblasts. After this treatment, allelic balance on RNA level could be nearly restored back to normal, as proven by pyrosequencing."

Puromycin rescue of allelic RNA imbalance supports nonsense-mediated decay in the deep-intronic family.

PMID:28494813 SUPPORT DIRECT PRIMARY RESULT In Vitro

"cDNA sequencing indicated that the two alleles were similarly expressed, excluding major mRNA decay of the allele with the premature stop codon."

The early frameshift in another patient did not produce major transcript decay.

Reduced OPA1 Protein Abundance

Reduced OPA1 abundance has been measured in patient muscle and fibroblasts. Transcript decay is one mechanism; other alleles reduce protein despite preserved RNA. Abundance measurements do not by themselves establish a pan-tissue loss of expression.

OPA1 hgnc:8140

Downstream

Mitochondrial Network Fragmentation Reduced OPA1 availability is associated with fragmented patient-cell networks.

Show evidence (1 reference)

PMID:28442211 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Expression of OPA1 protein was significantly reduced in muscle tissues of both patients by Western blotting."

Direct protein-abundance measurements in two biallelic patients; this is not a GTPase activity assay.

Mitochondrial Network Fragmentation

Patient fibroblasts show fragmented mitochondrial networks, particularly under galactose challenge. This is consistent with impaired OPA1-dependent fusion. Fragmentation alone does not directly measure inner-membrane fusion or establish cristae disruption in patient neurons.

SARM1-dependent axon death executes retinal ganglion cell degeneration downstream of the OPA1 mitochondrial defect

mitochondrion organization GO:0007005 ⚠ ABNORMAL

Experimental models

Patient Fibroblasts With Biallelic OPA1 Variants PRIMARY CELL CULTURE

Downstream

Oxidative Phosphorylation Deficiency OPA1-dependent mitochondrial dysfunction can impair ATP production, with variable expression across genotypes and culture conditions.

Retinal Ganglion Cell Degeneration A SARM1-dependent execution pathway downstream of fragmentation is supported in a dominant OPA1 mouse model; its operation in human Behr syndrome is an emerging hypothesis.

Show evidence (1 reference)

PMID:28442211 SUPPORT DIRECT PRIMARY RESULT In Vitro

"We also observed in patients' fibroblasts a higher proportion of fragmented and intermediate mitochondria upon galactose treatment compared to controls"

Network morphology is measured directly; impaired fusion is the mechanistic interpretation.

Oxidative Phosphorylation Deficiency

Some biallelic patients have reduced muscle COX staining or impaired fibroblast ATP synthesis. Nasca patient P3 showed reduced ATP content under galactose stress, whereas P1 had normal measured respiratory-complex enzyme activities despite severe disease. A uniform chronic ATP deficit is not established.

oxidative phosphorylation GO:0006119 ↓ DECREASED

Experimental models

Patient Fibroblasts With Biallelic OPA1 Variants PRIMARY CELL CULTURE

Show evidence (2 references)

PMID:28494813 SUPPORT INDIRECT PRIMARY RESULT In Vitro

"The ATP content in P3 fi- broblasts was normal respect to controls in regular medium but significantly reduced in galactose medium reflecting the lower efficiency of ATP production by OXPHOS in stress condition"

Homozygous Ala394Thr fibroblasts show a stress-dependent ATP defect; it is not a universal resting ATP deficiency.

PMID:28442211 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"In both patients, muscle biopsy showed diffuse reduction of cytochrome c oxidase stain"

Histochemistry provides tissue evidence of reduced complex IV activity.

Reduced Mitochondrial DNA Content

Nasca patient P1 had mtDNA content approximately 40% of the control mean in fibroblasts and 35% in muscle. He also carried homoplasmic MT-ND4 m.11778G>A and MT-ND1 m.3337G>C variants, whose contribution was unresolved. This observation establishes depletion in that patient, not universal multiple mtDNA deletions in Behr syndrome.

mitochondrial DNA metabolic process GO:0032042 ⚠ ABNORMAL

Show evidence (3 references)

PMID:28494813 SUPPORT DIRECT PRIMARY RESULT In Vitro

"In P1, the mtDNA content was partly but significantly lower than controls ( ≈40% of the mean control value"

Patient-fibroblast mtDNA content was measured relative to controls.

PMID:28494813 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Notably, the reduction in mtDNA levels ( ≈35% of the mean control value) was confirmed in DNA extracted from patient ’s muscle"

The separate muscle observation is human tissue evidence.

PMID:28494813 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The complete sequencing of mtDNA revealed the presence of two homoplasmic variants: the m.11778G > A change in MTND4"

Coexisting mitochondrial variation limits attribution of this case solely to OPA1.

Retinal Ganglion Cell Degeneration

Optic-disc pallor and retinal nerve-fiber-layer thinning document optic nerve injury in affected patients. RGC soma and axon degeneration are directly demonstrated in dominant Opa1 mouse models, while the human biallelic cell-death pathway remains unresolved.

retinal ganglion cell CL:0000740

Optic nerve UBERON:0000941

Animal models

Opa1R290Q/+ Sarm1 Knockout Mouse Mus musculus partially recapitulates

Downstream

Optic Atrophy Loss of retinal ganglion cell axons produces optic nerve atrophy.

Show evidence (2 references)

PMID:24970096 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"This consisted of optic atrophy (onset at age 2 years) with thinning of the peripapillary retinal nerve fibre layer"

The affected siblings have optic atrophy and loss of retinal nerve-fiber thickness.

PMID:40344041 SUPPORT INDIRECT PRIMARY RESULT Model Organism

"Sarm1 KO nearly completely suppressed all the degeneration phenotypes without reversing mitochondrial fragmentation."

Genetic rescue in heterozygous Opa1R290Q/+ mice supports a downstream degeneration pathway; applicability to biallelic human disease remains untested.

Cerebellar Involvement

Cerebellar atrophy is present in some affected families, but other patients have normal cerebellar imaging and predominantly sensory ataxia. MRI does not identify Purkinje-cell-selective degeneration or apoptosis.

cerebellum UBERON:0002037

Downstream

Cerebellar Atrophy Cerebellar tissue loss is visible on MRI.

Ataxia Cerebellar dysfunction can contribute to ataxia alongside sensory and spinal abnormalities.

Show evidence (1 reference)

PMID:24970096 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"MRI demonstrated mild to moderate cerebellar atrophy and thinning of the cervical spinal cord"

Direct imaging in three affected siblings supports cerebellar and spinal involvement, without identifying a specific neuronal death pathway.

Pyramidal Tract Dysfunction

Pyramidal signs and abnormal motor-pathway electrophysiology indicate corticospinal involvement in some families. They do not establish selective corticospinal apoptosis or obligatory spasticity.

corticospinal tract UBERON:0002707

Downstream

Pyramidal Signs (Spasticity) Impaired descending motor pathways are associated with spasticity.

Show evidence (1 reference)

PMID:24970096 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Electrophysiological studies revealed severe axonal sensorimotor neuropathy as well as pyramidal tract damage to both upper and lower extremities."

Evoked-potential and nerve-conduction findings support motor-pathway dysfunction, not proven corticospinal neuronal apoptosis.

Peripheral Axonal Degeneration

A sural biopsy in one compound-heterozygous patient showed complete large-myelinated-fiber loss with relative preservation of unmyelinated axons. Nerve conduction supported sensorimotor axonal neuropathy. There was no demyelination, remyelination or onion-bulb formation; central dorsal-column pathology was not examined.

sural nerve UBERON:0015488

Downstream

Peripheral Neuropathy Axonal loss and reduced sensory/motor responses underlie the neuropathy.

Impaired proprioception Loss of large sensory fibers provides an anatomical basis for impaired position and vibration sense.

Ataxia Sensory neuropathy can contribute to gait ataxia even with normal cerebellar imaging.

Show evidence (2 references)

PMID:27150940 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Semi-thin transverse sections of the distal sural nerve demonstrated medium and small MFs with complete loss of large MFs."

Biopsy directly demonstrates large myelinated-fiber loss in one OPA1 patient.

PMID:27150940 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"There was no evidence of demyelination, remyelination, or onion bulb formation."

This constrains the pathology to axonal loss rather than a primary demyelinating process.

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Histopathology

2

Cytochrome c Oxidase-Deficient Muscle Fibers

In two children, muscle biopsy showed reduced COX staining, scattered atrophic fibers and type II fiber grouping, consistent with respiratory-chain and neurogenic involvement. This finding is not documented across all biallelic OPA1 genotypes.

Show evidence (1 reference)

PMID:28442211 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"In both patients, muscle biopsy showed diffuse reduction of cytochrome c oxidase stain, some atrophic fibers and type II fiber grouping."

Documents the muscle histopathology — COX-deficient staining with atrophic fibers and type II fiber grouping — in biallelic-OPA1 Behr syndrome.

Large Myelinated Nerve Fiber Loss

Sural nerve biopsy in one child showed complete loss of large myelinated fibers, reduced fiber density and relative preservation of unmyelinated axons. There was no demyelination, remyelination or onion-bulb formation. The reference specimen was from a younger child, so the counts are not a matched disease-wide estimate.

Show evidence (2 references)

PMID:27150940 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Semi-thin transverse sections of the distal sural nerve demonstrated medium and small MFs with complete loss of large MFs."

Biopsy directly demonstrates large myelinated-fiber loss in one OPA1 patient.

PMID:27150940 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Unmyelinated axons were relatively well preserved with occasional rarefaction"

Relative preservation of unmyelinated axons was described in the biopsy.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

28

Cardiovascular 1

Stroke-Like Episodes HP:0002401

Show evidence (2 references)

PMID:30972688 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"A metabolic stroke occurred at the age of 12 years."

A stroke-like presentation in one girl with two OPA1 variants.

PMID:38369985 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"they recommended a trial of IV arginine infusion which he tolerated well with no side effects, but which did not lead to improvement of the suspected stroke radiologically or clinically."

The later report documents the clinical interpretation and negative treatment response in the same child described by Othman2022.

Digestive 2

Gastrointestinal dysmotility HP:0002579

Onset: CHILDHOOD

Show evidence (1 reference)

PMID:28494813 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"the severe neonatal-onset disorder characterized by severe optic atrophy, ataxia, hypotonia, gastrointestinal dysmotility and dysphagia, described in two siblings by Schaaf et al."

The discussion summarizes previously reported biallelic siblings; these are not newly observed Nasca cases.

Dysphagia HP:0002015

Show evidence (1 reference)

PMID:38369985 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"he could no longer walk, had lost most of his ability to speak, and required nasogastric tube feeds due to aspiration. After therapy, he eventually regained a few useful words, but went on to require gastrostomy placement."

Aspiration and tube-feeding requirement document clinically important swallowing dysfunction.

Ear 1

Hearing Impairment HP:0000365

Show evidence (1 reference)

PMID:35741767 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"at age 4, he started showing mild hearing impairment in the left ear, which further progressed to moderate bilateral hearing loss."

Longitudinal hearing decline in the reported child; no inferred sensorineural subtype.

Eye 6

Optic Atrophy HP:0000648

Show evidence (2 references)

PMID:24970096 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"This consisted of optic atrophy (onset at age 2 years) with thinning of the peripapillary retinal nerve fibre layer"

The affected siblings have optic atrophy and loss of retinal nerve-fiber thickness.

PMID:28494813 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"bi-allelic OPA1 mutations should be considered in disorder where optic atrophy is not obvious (or even absent)."

The broader biallelic spectrum includes delayed or subtle optic findings.

Nystagmus HP:0000639

Show evidence (1 reference)

PMID:35741767 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"He presented with congenital nystagmus, progressive vision loss, and optic atrophy, as well as progressive ataxia"

Documents congenital nystagmus alongside optic atrophy and ataxia in a biallelic-OPA1 Behr-phenotype child.

Ophthalmoplegia HP:0000602

Onset: CHILDHOOD

Show evidence (1 reference)

PMID:24970096 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"external ophthalmoplegia, peripheral neuropathy, muscle atrophy, ptosis and spasticity"

External ophthalmoplegia was documented in the affected OAK587 siblings.

Developmental cataract HP:0000519

Onset: CONGENITAL

Show evidence (1 reference)

PMID:27150940 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"At birth, he presented with a congenital cataract, which has not been previously described in patients with OPA1 mutations."

Documents congenital cataract as a newly recognized feature of OPA1-recessive Behr syndrome.

Ptosis HP:0000508

Show evidence (1 reference)

PMID:24970096 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"external ophthalmoplegia, peripheral neuropathy, muscle atrophy, ptosis and spasticity"

Ptosis is included in the clinical findings of the affected siblings.

Exotropia HP:0000577

Show evidence (1 reference)

PMID:35741767 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Over time, the patient developed large-angle exotropia of more than 50 prism diopters."

This ocular-motor feature was documented during longitudinal follow-up.

Limbs 1

Pes Cavus HP:0001761

Show evidence (1 reference)

PMID:28494813 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"mild ataxia and pes cavus; tendon reflexes were absent."

Clinical examination of patient P2.

Musculoskeletal 3

Pyramidal Signs (Spasticity) HP:0001257

Show evidence (1 reference)

PMID:28494813 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"the neurological conditions worsened with increased spasticity in her legs and un- steadiness during walking and postural changes."

Longitudinal lower-limb spasticity in patient P3.

Distal Amyotrophy HP:0003693

Show evidence (1 reference)

PMID:28494813 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"an ataxic-spastic syndrome with distal muscular atrophy of upper and lower limbs."

The age-12 examination documents distal muscle atrophy.

Distal Muscle Weakness HP:0002460

Show evidence (1 reference)

PMID:27150940 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Neurological examination at 10 years of age indicated muscle weakness and atrophy of the bilateral distal muscles, predominantly in the lower limbs."

Direct examination distinguishes weakness from the separate muscle-wasting phenotype.

Nervous System 14

Ataxia HP:0001251

Show evidence (2 references)

PMID:24970096 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"cerebellar ataxia [onset between age 4 to 6 years, leading to wheelchair-dependency within 10–15 years of age"

Progressive ataxia was documented in three siblings.

PMID:27150940 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"By age two, he was not able to walk without support, and by the age of 10, he harbored severe ataxia and postural instability."

This patient had a sensory contribution to ataxia.

Intellectual Disability HP:0001249

Show evidence (2 references)

PMID:28442211 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"We describe an 11-year-old girl (Pt1) and a 7-year-old boy (Pt2) with cognitive delay, ataxic gait and clinical signs suggestive of a peripheral neuropathy"

Two affected children had cognitive delay.

PMID:27150940 REFUTE DIRECT PRIMARY RESULT Human Clinical

"he did not have pyramidal signs, developmental delay or mental retardation"

The described child lacked intellectual impairment; the observation limits claims that it is obligatory.

Peripheral Neuropathy HP:0009830

Show evidence (1 reference)

PMID:27150940 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"findings were compatible with axonal sensorimotor polyneuropathy"

Electrophysiology supports the axonal sensorimotor phenotype.

Dysarthria HP:0001260

Show evidence (1 reference)

PMID:30972688 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"early onset optic atrophy at one year of age, progressive gait ataxia, dysarthria, tremor and learning impairment"

Documents dysarthria as part of the complex neurological phenotype in a biallelic-OPA1 patient resembling Behr syndrome.

Seizures HP:0001250

Show evidence (1 reference)

PMID:35741767 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"On follow-up, he developed profound vision impairment, intractable seizures, and metabolic strokes."

Documents intractable seizures in the clinical course of a biallelic-OPA1 Behr patient.

Tremor HP:0001337

Show evidence (1 reference)

PMID:30972688 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"progressive gait ataxia, dysarthria, tremor and learning impairment"

Documents tremor as part of the biallelic-OPA1 neurological phenotype.

Basal Ganglia Signal Abnormality Abnormal basal ganglia MRI signal intensity HP:0012751

Show evidence (1 reference)

PMID:28442211 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"involvement accompanied by basal ganglia hyperintensities and pathological peak levels of lactate."

Documents basal ganglia hyperintensities on neuroimaging in biallelic-OPA1 Behr syndrome.

Cerebellar Atrophy HP:0001272

Show evidence (1 reference)

PMID:24970096 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"MRI demonstrated mild to moderate cerebellar atrophy and thinning of the cervical spinal cord"

Direct imaging in three affected siblings supports cerebellar and spinal involvement, without identifying a specific neuronal death pathway.

Impaired proprioception HP:0010831

Onset: CHILDHOOD

Show evidence (1 reference)

PMID:27150940 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Sensitivity to pinprick, touch, position, and vibration was decreased."

Documents reduced position and vibration sense (impaired proprioception) in an OPA1-recessive Behr patient.

Motor delay HP:0001270

Onset: INFANTILE

Show evidence (1 reference)

PMID:38369985 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"He was delayed mainly in gross motor and fine motor domains with age-appropriate language milestones."

The initial neurological assessment separates motor delay from global cognitive impairment.

Areflexia HP:0001284

Show evidence (1 reference)

PMID:28494813 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"mild ataxia and pes cavus; tendon reflexes were absent."

Reflex loss was documented in patient P2.

Cervical Spinal Cord Atrophy HP:0010873

Show evidence (1 reference)

PMID:24970096 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"All three subjects also show, to a variable degree, atrophy of the upper cervical spinal cord"

The figure legend explicitly localizes the atrophy to the cervical cord.

Developmental Regression HP:0002376

Show evidence (1 reference)

PMID:35741767 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"the patient had lost several of his previous skills, including his ability to walk, talk, and eat without assistance."

Regression followed status epilepticus in the reported child.

Elevated Brain Lactate Elevated brain lactate level by MRS HP:0012707

Show evidence (1 reference)

PMID:28494813 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"H-MRS showed a very high lactate peak, both in the abnormal and in the spared areas."

Direct MR spectroscopy finding in Nasca patient P1, who also carried mitochondrial DNA variants.

🧬

Genetic Associations

1

OPA1

Gene: OPA1 hgnc:8140 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (3 references)

PMID:28442211 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"we identified the homozygous c.1180G>A/p.Ala394Thr mutation in Pt1 and the c.2779-2A>C mutation in compound heterozygosity with the c.2809C>T/p.Arg937Cys mutation in Pt2."

Two distinct biallelic architectures were identified in affected children.

PMID:24970096 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"the deep intronic mutation occurred in compound heterozygous state with an exonic OPA1 missense variant (p.I382M; NM_015560.2)."

The severe phenotype can involve a splice allele plus an intralocus modifier.

PMID:24970096 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"the homozygous father Subject I:1 is still healthy at the age of 76 years, without evidence for subclinical optic atrophy."

The modifier alone was not sufficient to produce disease in this family.

Variants (6)

c.610+364G>A

single nucleotide variant

Genomic context: intron

Deep-intronic allele on NM_130837.2 in OAK587, in trans with c.1311A>G. Patient transcript analysis demonstrated cryptic exon inclusion, premature termination and nonsense-mediated decay. The same splice allele alone was associated with milder or clinically unapparent disease.

Show evidence (2 references)

PMID:24970096 SUPPORT DIRECT PRIMARY RESULT In Vitro

"The mutation creates a new splice acceptor site resulting in aberrant OPA1 transcripts with retained intronic sequence and subsequent translational frameshift as shown by complementary DNA analysis."

Patient cDNA establishes the splice consequence of the deep intronic allele.

PMID:24970096 SUPPORT DIRECT PRIMARY RESULT In Vitro

"To suppress nonsense-mediated messenger RNA decay-dependent allelic decay we used puromycin treatment in patient derived fibroblasts. After this treatment, allelic balance on RNA level could be nearly restored back to normal, as proven by pyrosequencing."

Puromycin rescue of allelic RNA imbalance supports nonsense-mediated decay in the deep-intronic family.

c.1311A>G (p.Ile437Met)

single nucleotide variant

NM_130837.2 notation; equivalent to c.1146A>G (p.Ile382Met) on NM_015560.2. Recurrent hypomorphic/intralocus modifier in severe compound-heterozygous disease. Clinical expression in isolation is variable; a healthy homozygous elderly father was documented. Yeast showed a mild functional defect, not a direct measurement of human GTPase catalysis.

Show evidence (2 references)

PMID:28494813 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The latter corresponds to c.1146A > G, p.I382M based on transcript NM_015560.2"

The source explicitly reconciles the transcript-dependent nomenclature.

PMID:24970096 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"the homozygous father Subject I:1 is still healthy at the age of 76 years, without evidence for subclinical optic atrophy."

Family observation limits claims of intrinsic high penetrance.

c.1180G>A (p.Ala394Thr)

single nucleotide variant

Homozygous missense variant on NM_130837.2, associated with spastic ataxia and neuropathy; optic involvement may be subtle or delayed. Patient fibroblasts and a yeast complementation model showed functional abnormalities.

Show evidence (2 references)

PMID:28442211 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"we identified the homozygous c.1180G>A/p.Ala394Thr mutation in Pt1 and the c.2779-2A>C mutation in compound heterozygosity with the c.2809C>T/p.Arg937Cys mutation in Pt2."

Two distinct biallelic architectures were identified in affected children.

PMID:28494813 SUPPORT INDIRECT PRIMARY RESULT In Vitro

"The ATP content in P3 fi- broblasts was normal respect to controls in regular medium but significantly reduced in galactose medium reflecting the lower efficiency of ATP production by OXPHOS in stress condition"

Homozygous Ala394Thr fibroblasts show a stress-dependent ATP defect; it is not a universal resting ATP deficiency.

c.2287del (p.Ser763Valfs*15)

deletion

Maternal NM_130837.2 frameshift in trans with paternal c.1311A>G in the child described in both Othman2022 and Jagadish2024. Also reported as c.2122del/p.Ser708Valfs*15 on NM_015560.2. Functional protein analysis was not performed for this allele in the case report.

Show evidence (2 references)

PMID:35741767 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The variant c.2287del (maternally inherited) is predicted to result in a translational frameshift and premature protein termination (p.Ser763Valfs*15)."

The truncating consequence is predicted, not assayed.

PMID:35741767 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The functional analysis of the effect of this mutation on the amount of protein was not performed."

Explicit limitation of this individual allele.

p.Leu620fs*13 and p.Arg905Gln

Compound-heterozygous paternal frameshift and maternal missense variants, reported as c.1857-1858delinsT and c.G2714A in Lee2016. Associated with severe optic atrophy, sensorimotor neuropathy and congenital cataract. The missense effect was predicted computationally; the report did not demonstrate its biochemical mechanism.

Show evidence (1 reference)

PMID:27150940 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"the mother was heterozygous for the p.R905Q missense mutation and the father was heterozygous for the p.L620fs frameshift mutation"

Parental segregation establishes the reported trans configuration.

c.2779-2A>C and c.2809C>T (p.Arg937Cys)

Compound-heterozygous splice-site and missense variants reported in one child with Leigh-like imaging; reduced OPA1 muscle protein and altered fibroblast morphology were measured at the genotype level.

Show evidence (2 references)

PMID:28442211 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"we identified the homozygous c.1180G>A/p.Ala394Thr mutation in Pt1 and the c.2779-2A>C mutation in compound heterozygosity with the c.2809C>T/p.Arg937Cys mutation in Pt2."

Two distinct biallelic architectures were identified in affected children.

PMID:28442211 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Expression of OPA1 protein was significantly reduced in muscle tissues of both patients by Western blotting."

Direct protein-abundance measurements in two biallelic patients; this is not a GTPase activity assay.

💊

Medical Actions

11

Supportive and Multidisciplinary Care

Action: supportive care Ontology label: Supportive Care NCIT:C15747

Platform: Other

Management addresses visual disability, mobility, neurological complications and feeding needs. Published case care is supportive; the cited reports do not establish a disease-modifying treatment.

Show evidence (1 reference)

PMID:35741767 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"There is currently no specific treatment for this disease. Supplements have been suggested but have not proven beneficial"

The 2022 clinical review describes supportive management and lack of proven specific therapy.

Genetic Counseling

Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Platform: Behavioral / lifestyle

Counseling addresses variable visual and neurological prognosis, allele phase and the possibility of mild or subclinical dominant optic atrophy in relatives. The risk assessment depends on the actual family genotype.

Show evidence (1 reference)

PMID:35741767 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The prognosis for vision and neurologic impairment is guarded and should be included in the counseling for the patient and family."

Counseling should address variable but potentially severe neurological and visual outcomes.

Low-Vision Rehabilitation

Action: low-vision rehabilitation Ontology label: Rehabilitation NCIT:C15315

Platform: Behavioral / lifestyle

Correct refractive errors and provide visual rehabilitation, accessible learning and mobility support. Magnification, text-to-speech, braille, tactile/auditory learning and cane use were documented in one affected child.

Show evidence (1 reference)

PMID:35741767 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Visual rehabilitation and low vision services were provided to the patient and consisted of magnifying devices and text-to-speech technology. He started learning braille and the use of tactile and auditory approaches for learning. Also, he began to use a cane for mobility."

Directly documented disability support in biallelic disease.

Physical, Occupational and Speech Rehabilitation

Action: physical, occupational and speech therapy Ontology label: Rehabilitation NCIT:C15315

Platform: Behavioral / lifestyle

Rehabilitation is used for gait, motor and communication impairment, including recovery after neurological decompensation. Improvement during combined care does not establish an isolated treatment effect.

Show evidence (1 reference)

PMID:38369985 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"He was receiving intensive physical, occupational and speech therapy. He had regained the ability to stand with support and has recovered function of his right upper and lower extremities. He could speak 2–3-word phrases."

Improvement occurred during combined rehabilitation and seizure treatment; individual modality effects cannot be isolated.

Antiseizure Management

Action: Pharmacotherapy NCIT:C15986

Agent: levetiracetam CHEBI:6437 clobazam CHEBI:31413 topiramate CHEBI:63631 cannabidiol CHEBI:69478

Platform: Small molecule

Seizures and status epilepticus require individualized neurological and intensive-care treatment. A reported child required multiple intravenous agents and pentobarbital coma; maintenance polytherapy was followed by six-month seizure freedom. This single uncontrolled course does not establish efficacy of a particular drug or regimen.

Mechanism Target:

INHIBITS Seizures — Symptomatic seizure suppression; no established effect on the upstream OPA1 defect.

Show evidence (3 references)

PMID:38369985 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"He was treated with intravenous (IV) doses of lorazepam, levetiracetam, phenobarbital, fosphenytoin, lacosamide, propofol infusion (<24 h) and finally pentobarbital infusion coma for 4 days, with which status epilepticus resolved."

The case documents escalation for super-refractory status, not a comparative treatment trial.

PMID:38369985 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"He was discharged home after a 30-day hospitalization on levetiracetam, clobazam, topiramate and epidiolex."

Documented maintenance polytherapy, not a validated disease-specific regimen.

PMID:38369985 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"On his follow up 6 months after discharge, he was clinically seizure free."

Observed follow-up outcome under combined care.

Idebenone (Limited Biallelic Case Evidence)

Action: Pharmacotherapy NCIT:C15986

Agent: idebenone CHEBI:31687

Platform: Small molecule

One biallelic OPA1 patient with optic atrophy, ataxia and neuropathy received idebenone and remained neurologically and ophthalmologically stable at six months. This uncontrolled observation does not establish benefit. Broader dominant-optic-atrophy reports remain limited and cannot establish efficacy for Behr syndrome.

Show evidence (2 references)

PMID:28494813 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Treatment with idebenone (135 mg/die) was started. Neurological and ophthalmologic follow-up, six months after diagnosis, were stable."

Direct biallelic case treatment, with stability but no controlled evidence of efficacy.

PMID:41318849 SUPPORT INDIRECT REVIEW SYNTHESIS Other

"However, this evidence is limited, and an adequately powered, randomised, placebo-controlled trial is needed to better evaluate the efficacy of idebenone in ADOA."

Even the broader ADOA evidence remains uncertain.

OPA1 Gene Augmentation (Preclinical)

Action: Gene Therapy NCIT:C15238

Platform: Gene therapy

AAV-mediated OPA1 augmentation has been studied in dominant-optic-atrophy models. Expression level, isoform choice and dominant-negative effects are unresolved challenges. This is preclinical evidence extrapolated to Behr syndrome; the allotopic MT-ND4 gene-expression trials concern LHON.

Show evidence (1 reference)

PMID:41318849 SUPPORT INDIRECT REVIEW SYNTHESIS Other

"Together, these early experiments suggest that AAV-mediated OPA1 gene therapy may have a role in preserving visual function, but more work is required to understand the molecular pathophysiology of ADOA."

The review describes preclinical OPA1 augmentation, distinct from clinical LHON allotopic therapy.

OPA1 Expression Modulation (Investigational)

Action: Antisense Therapy NCIT:C16236

Platform: Antisense oligonucleotide

RNA target: OPA1 hgnc:8140

Antisense approaches increase expression of the remaining wild-type OPA1 allele in dominant haploinsufficiency. Sundew and Myrtle study dominant optic atrophy, not an established biallelic Behr treatment. Biallelic genotypes and systemic involvement require separate assessment; upregulation may be inadequate for dominant-negative alleles.

Show evidence (1 reference)

PMID:41318849 SUPPORT INDIRECT REVIEW SYNTHESIS Other

"A therapeutic strategy is, therefore, to enhance the expression of the wild-type allele to restore normal protein levels. One way this can be achieved is with antisense oligonucleotides (ASO)."

This is a mechanistic extrapolation from dominant haploinsufficiency, not demonstrated Behr efficacy.

Intravenous Arginine (Unsuccessful Case Trial)

Action: Pharmacotherapy NCIT:C15986

Agent: arginine CHEBI:29016

Platform: Small molecule

Intravenous arginine was tried for a suspected metabolic stroke in one biallelic OPA1 child without clinical or radiological improvement. This negative case observation does not support routine efficacy.

Show evidence (1 reference)

PMID:38369985 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"they recommended a trial of IV arginine infusion which he tolerated well with no side effects, but which did not lead to improvement of the suspected stroke radiologically or clinically."

The later report documents the clinical interpretation and negative treatment response in the same child described by Othman2022.

Ketogenic Diet (Unsuccessful Case Trial)

Action: Ketogenic Diet NCIT:C173168

Platform: Behavioral / lifestyle

A modified ketogenic diet was used during treatment of refractory seizures in one biallelic OPA1 child, then discontinued with lacosamide because seizure control was inadequate. This case does not establish either general benefit or general inefficacy.

Show evidence (1 reference)

PMID:38369985 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Lacosamide and ketogenic diet were discontinued during this admission since they were felt to be ineffective in controlling the seizures."

Directly reported negative case experience.

Feeding Support

Action: Nutritional Support NCIT:C15433

Platform: Other

Swallowing assessment and nutritional support address feeding impairment and aspiration. Nasogastric feeds followed by gastrostomy were required after neurological regression in one child.

Show evidence (1 reference)

PMID:38369985 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"he could no longer walk, had lost most of his ability to speak, and required nasogastric tube feeds due to aspiration. After therapy, he eventually regained a few useful words, but went on to require gastrostomy placement."

Aspiration and tube-feeding requirement document clinically important swallowing dysfunction.

🔬

Biochemical Markers

2

Increased Circulating Lactate in a Severe Biallelic Presentation

Show evidence (2 references)

PMID:28494813 REFUTE DIRECT PRIMARY RESULT Human Clinical

"Hepatic function was markedly impaired; lactate and pyruvate levels were normal."

Normal circulating values occurred during later deterioration; the same case narrative reports earlier elevation.

PMID:28494813 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Lactate levels were elevated in plasma ... and in CSF; the analysis of respiratory chain complexes and PDH complex on muscle biopsy resulted normal."

The earlier assessment documents plasma/CSF elevation. The ellipsis omits an implausible numerical unit in the source, so no quantitative concentration is asserted.

Cytochrome c oxidase (COX) deficiency

Context: Muscle biopsy / mitochondrial respiratory-chain readout

Show evidence (1 reference)

PMID:28442211 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"muscle biopsy showed diffuse reduction of cytochrome c oxidase stain"

Documents reduced cytochrome c oxidase staining, a biochemical readout of the mitochondrial respiratory-chain deficiency.

🔬

Diagnosis

5

Molecular Genetic Testing

Sequence OPA1 and assess allele phase with family testing in an optic-atrophy-plus presentation. A broader optic-neuropathy panel or exome can address molecular differentials. Negative coding-sequence and deletion/duplication testing does not exclude a deep-intronic OPA1 defect; targeted genomic and transcript studies resolved such a family.

Show evidence (2 references)

PMID:35741767 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Phenotypic features are essential for diagnosis; however, genetic testing, including parental testing, is the final step in having a correct and complete diagnosis."

The case study emphasizes parental testing and genotype interpretation.

PMID:24970096 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"we suggest that whole gene sequencing of OPA1 and/or expansion of diagnostics to the transcript level are important tools to solve unexplained cases of optic atrophy and optic atrophy plus syndromes."

Directly supported extension after unrevealing coding tests.

Brain MRI / MR spectroscopy

Brain MRI and MR spectroscopy characterize neurological involvement: cerebellar atrophy, basal-ganglia lesions or a lactate peak may be present. A normal scan does not exclude disease. Serial imaging and EEG help interpret lesions during seizures.

Results: Cerebellar involvement, basal-ganglia hyperintensities, and/or a lactate peak.

Show evidence (2 references)

PMID:28442211 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"neuroimaging detected a progressive cerebellar involvement accompanied by basal ganglia hyperintensities and pathological peak levels of lactate"

Documents the characteristic Leigh-like neuroimaging (cerebellar involvement, basal-ganglia change, lactate peak) supporting the diagnosis.

PMID:27150940 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"A brain MRI performed when he was 8 years old indicated the cerebral cortex and cerebellum were normal in structure and size."

A genetically confirmed patient had normal brain morphology.

Muscle biopsy / oxidative phosphorylation assessment

Muscle biopsy may show reduced cytochrome c oxidase (complex IV) staining, reflecting the mitochondrial respiratory-chain deficiency.

Results: Diffuse reduction of cytochrome c oxidase staining.

Show evidence (1 reference)

PMID:28442211 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"muscle biopsy showed diffuse reduction of cytochrome c oxidase stain"

Muscle biopsy demonstrating reduced cytochrome c oxidase staining supports the mitochondrial basis of the disease.

Nerve conduction studies / electrophysiology

Nerve-conduction studies characterize axonal sensory or sensorimotor neuropathy; this manifestation is not present in every patient.

Results: Axonal sensorimotor polyneuropathy.

Show evidence (1 reference)

PMID:27150940 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"findings were compatible with axonal sensorimotor polyneuropathy"

Electrophysiological findings compatible with axonal sensorimotor polyneuropathy support the neuropathy component.

Ophthalmic Examination, OCT and Visual Evoked Potentials

Fundoscopy, OCT and visual electrophysiology document optic nerve dysfunction and may reveal mild disease in relatives. Longitudinal assessment distinguishes progressive visual loss from an initially subtle presentation.

Show evidence (2 references)

PMID:35741767 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The optical coherence tomography (OCT) showed formed fovea and thinning of the retinal nerve fiber layer (RNFL) OU."

OCT documented bilateral nerve-fiber-layer loss in the proband.

PMID:35741767 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Awake, flash visual evoked potential (fVEP) was recordable and showed low amplitudes and delayed latency OU"

VEPs provided a functional correlate of the optic neuropathy.

📊

Prevalence

1

Published biallelic OPA1 cases reviewed in 2022

Cases In Literature

The 2022 review identified 21 previously published cases and added its proband. This dated, selected literature count is not a population prevalence estimate; ascertainment, case overlap and clinical scope limit inference.

Show evidence (1 reference)

PMID:35741767 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"A literature review of reported biallelic OPA1-related Behr syndrome was performed. Twenty-one cases have been previously reported."

This is a literature count, not a measured population rate.

🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Behr Syndrome:

Costeff syndrome Not Yet Curated MONDO:0009787

Overlapping Features Recessive OPA3-related optic atrophy with movement disorder was historically called a Behr subtype.

Distinguishing Features

Elevated urinary 3-methylglutaconic/3-methylglutaric acids and biallelic OPA3 variants distinguish Costeff syndrome from OPA1 disease.

Show evidence (1 reference)

PMID:25012222 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"This syndromic inherited optic neuropathy was originally linked to autosomal recessive OPA3 mutations among Iraqi Jewish patients with elevated urinary excretion of 3-methylglutaconic acid and 3-methylglutaric acid"

The correspondence summarizes the historically overlapping but molecularly distinct Costeff phenotype.

🔬

Clinical Trials

2

NCT06461286 PHASE_I ACTIVE_NOT_RECRUITING

Sundew tests intravitreal PYC-001 in OPA1-associated autosomal dominant optic atrophy. This is related-disease research, not a Behr-specific trial or evidence of efficacy in biallelic OPA1 disease.

Show evidence (1 reference)

clinicaltrials:NCT06461286 SUPPORT INDIRECT Human Clinical

"A First-in-Human multi-centre, prospective, Phase1a, Single Ascending Dose (SAD) interventional study of PYC-001 in participants with confirmed OPA1 mutation (haploinsufficiency) associated ADOA."

Trial registry description establishes the related ADOA study population, not Behr treatment efficacy.

NCT06970106 RECRUITING

Myrtle tests intravitreal PYC-001 in OPA1-associated autosomal dominant optic atrophy. This is related-disease research, not a Behr-specific trial or evidence of efficacy in biallelic OPA1 disease.

Show evidence (1 reference)

clinicaltrials:NCT06970106 SUPPORT INDIRECT Human Clinical

"This study aims to gather safety data and determine the optimal dosing regimen for PYC-001 in participants with confirmed OPA1 mutation-associated ADOA. Approximately 18 participants from Australia, New Zealand, and other APAC countries are expected to be enrolled, depending on safety review..."

Trial registry description establishes the related ADOA study population, not Behr treatment efficacy.

🧫

Experimental Models

3

iPS-OPA1-BEHR IPSC_DERIVED_MODEL

The transgene-free iPS-OPA1-BEHR line was generated from a 48-year-old patient with c.610+364G>A and c.1311A>G. The report establishes retained variants, pluripotency and three-germ-layer differentiation. It provides a model resource; it does not demonstrate retinal-neuron phenotypes or therapeutic rescue.

Organism

human NCBITaxon:9606

Cell source

Human skin fibroblasts from a Behr syndrome patient with compound heterozygous OPA1 mutations

Publication

PMID:27879217

Show evidence (1 reference)

PMID:27879217 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Human skin fibroblasts were isolated from a 48-year-old patient carrying compound heterozygous mutations (c.610+364G>A and c.1311A>G) in OPA1, responsible for early onset optic atrophy complicated by ataxia and pyramidal signs (Behr syndrome; OMIM #210000)."

Documents the derivation of a Behr-syndrome patient iPSC line from compound heterozygous OPA1 fibroblasts, and independently confirms the compound heterozygous OPA1 genotype with the ataxia/pyramidal-sign phenotype.

Patient Fibroblasts With Biallelic OPA1 Variants PRIMARY_CELL_CULTURE

Patient fibroblasts support allele-specific RNA/protein studies, network imaging and bioenergetics. Deep-intronic-family cells demonstrated transcript decay and fragmentation; Ala394Thr cells showed stress-dependent ATP loss. Skin fibroblasts do not establish selective neuronal vulnerability.

Organism

Homo sapiens NCBITaxon:9606

Pathograph links

Mitochondrial Network Fragmentation recapitulates

Limitations: Skin fibroblasts from selected genotypes do not reproduce neuronal selectivity.

Show evidence (1 reference)

PMID:28442211 SUPPORT DIRECT PRIMARY RESULT In Vitro

"We also observed in patients' fibroblasts a higher proportion of fragmented and intermediate mitochondria upon galactose treatment compared to controls"

Network morphology is measured directly; impaired fusion is the mechanistic interpretation.

Oxidative Phosphorylation Deficiency measures

Limitations: ATP content is culture-condition-dependent and one genotype is not representative of the entire disease.

Show evidence (1 reference)

PMID:28494813 SUPPORT INDIRECT PRIMARY RESULT In Vitro

"The ATP content in P3 fi- broblasts was normal respect to controls in regular medium but significantly reduced in galactose medium reflecting the lower efficiency of ATP production by OXPHOS in stress condition"

Homozygous Ala394Thr fibroblasts show a stress-dependent ATP defect; it is not a universal resting ATP deficiency.

Show evidence (3 references)

PMID:24970096 SUPPORT DIRECT PRIMARY RESULT In Vitro

"To suppress nonsense-mediated messenger RNA decay-dependent allelic decay we used puromycin treatment in patient derived fibroblasts. After this treatment, allelic balance on RNA level could be nearly restored back to normal, as proven by pyrosequencing."

Puromycin rescue of allelic RNA imbalance supports nonsense-mediated decay in the deep-intronic family.

PMID:28442211 SUPPORT DIRECT PRIMARY RESULT In Vitro

"We also observed in patients' fibroblasts a higher proportion of fragmented and intermediate mitochondria upon galactose treatment compared to controls"

Network morphology is measured directly; impaired fusion is the mechanistic interpretation.

PMID:28494813 SUPPORT INDIRECT PRIMARY RESULT In Vitro

"The ATP content in P3 fi- broblasts was normal respect to controls in regular medium but significantly reduced in galactose medium reflecting the lower efficiency of ATP production by OXPHOS in stress condition"

Homozygous Ala394Thr fibroblasts show a stress-dependent ATP defect; it is not a universal resting ATP deficiency.

MGM1/OPA1 Yeast Complementation OTHER

An MGM1/OPA1 chimera complements MGM1-deficient yeast. Ala394Thr markedly reduced respiratory growth, Val988Phe nearly abolished it, and Ile437Met had a milder defect. This assay supports variant dysfunction without reproducing human neurological disease or directly measuring catalytic GTPase activity.

Organism

Saccharomyces cerevisiae NCBITaxon:4932

Show evidence (1 reference)

PMID:28494813 SUPPORT DIRECT PRIMARY RESULT Model Organism

"yeast expressing the p.Ala394Thr displayed a marked reduction of respiratory growth, the p.Val988Phe mutation virtually abolished the activity of the mutant allele, while the defect observed with the p.Ile437Met mutant was milder"

Respiratory-growth complementation tests the three missense variants.

🐁

Animal Models

1

Opa1R290Q/+ Sarm1 Knockout Mouse

Heterozygous dominant-negative Opa1R290Q/+ mice develop age-dependent RGC and optic-nerve degeneration. Sarm1 deletion preserved RGC number, axons and visual electrophysiology without correcting fragmentation. The rescue comparison used Sarm1-heterozygous controls and lacked same-cohort Opa1R290Q/+ Sarm1+/+ controls. This is a dominant OPA1 model, not a model of biallelic multisystem Behr syndrome.

Species

Mus musculus

Genotype

Opa1R290Q/+ with Sarm1−/− rescue; Sarm1+/− comparison animals

Pathograph links

Retinal Ganglion Cell Degeneration partially recapitulates

Limitations: Dominant heterozygous mouse allele, not human biallelic multisystem disease; the intervention is germline Sarm1 deletion rather than a clinical inhibitor.

Show evidence (2 references)

PMID:40344041 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Sarm1 KO nearly completely suppressed all the degeneration phenotypes without reversing mitochondrial fragmentation."

Genetic rescue in heterozygous Opa1R290Q/+ mice supports a downstream degeneration pathway; applicability to biallelic human disease remains untested.

+ 1 more reference

Show evidence (2 references)

PMID:40344041 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Sarm1 KO nearly completely suppressed all the degeneration phenotypes without reversing mitochondrial fragmentation."

Genetic rescue in heterozygous Opa1R290Q/+ mice supports a downstream degeneration pathway; applicability to biallelic human disease remains untested.

PMID:40344041 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Since we did not include a littermate control of Opa1R290Q/+ Sarm1 +/+ in the same cohort, we could not definitively determine whether the heterozygous Sarm1 muta- tion also provided protective effects against RGC degeneration in ADOA."

The control genotype limits inference about dose-dependent SARM1 inhibition.

{ }

Source YAML

click to show

name: Behr Syndrome
creation_date: "2026-07-30T00:00:00Z"
category: Mendelian
disease_term:
  preferred_term: Behr syndrome
  term:
    id: MONDO:0008858
    label: Behr syndrome
description: >-
  Behr syndrome is an early-onset syndromic optic neuropathy with variable ataxia, peripheral neuropathy,
  pyramidal signs and cognitive involvement. This entry describes the OPA1-related disorder mapped to
  MONDO:0008858 and OMIM:210000, particularly biallelic disease. The historical Behr phenotype is genetically
  heterogeneous: OPA3/Costeff, MTRFR and C19orf12 disorders are documented molecular differentials. OPA1
  disease can combine a severe allele with a hypomorphic allele, or arise from homozygous missense variants.
  Optic atrophy may be subtle or recognized after neurological symptoms; intellectual disability, spasticity
  and cerebellar atrophy are not obligatory. Patient studies demonstrate reduced OPA1 abundance, mitochondrial
  fragmentation and genotype-dependent bioenergetic abnormalities, with progressive optic and peripheral
  nerve dysfunction.
parents:
- OPA1-Related Optic Atrophy

inheritance:
- name: Autosomal recessive
  description: >-
    Biallelic OPA1 disease often segregates recessively, but severe-plus-hypomorphic allele combinations
    can resemble semidominant inheritance. Relatives with one allele may have dominant optic atrophy,
    subclinical findings or no detectable disease. Clinical Behr-like presentations have also been reported
    with a single heterozygous OPA1 variant; the historical phenotype alone does not establish recessive
    inheritance.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance

  evidence:
  - reference: PMID:27150940
    reference_title: Recessive optic atrophy, sensorimotor neuropathy and cataract associated with novel compound heterozygous mutations in OPA1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: These results may support either recessive or semi-dominant inheritance with incomplete penetrance.
    explanation: Unaffected parents in this family support more than one segregation model.
  - reference: PMID:24970096
    reference_title: Pure and syndromic optic atrophy explained by deep intronic OPA1 mutations and an intralocus modifier.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: This hypomorphic allele causes a severe optic atrophy plus phenotype when combined with a compound heterozygous OPA1 null mutation.
    explanation: The intralocus modifier architecture is distinct from two uniformly null alleles.
pathophysiology:
- name: Biallelic OPA1 Variants
  biological_scale: MOLECULAR
  description: Biallelic OPA1 variants include truncating, deep-intronic splice-altering and missense alleles. An intragenic hypomorphic allele can intensify the phenotype of an allele that causes dominant optic atrophy in isolation. Variant effects differ; reduced GTPase catalytic activity has not been established for every genotype.
  molecular_functions:
  - preferred_term: GTPase activity
    term:
      id: GO:0003924
      label: GTPase activity
  evidence:
  - reference: PMID:28442211
    reference_title: Leigh-like neuroimaging features associated with new biallelic mutations in OPA1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: we identified the homozygous c.1180G>A/p.Ala394Thr mutation in Pt1 and the c.2779-2A>C mutation in compound heterozygosity with the c.2809C>T/p.Arg937Cys mutation in Pt2.
    explanation: Two distinct biallelic architectures were identified in affected children.
  - reference: PMID:24970096
    reference_title: Pure and syndromic optic atrophy explained by deep intronic OPA1 mutations and an intralocus modifier.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: the deep intronic mutation occurred in compound heterozygous state with an exonic OPA1 missense variant (p.I382M; NM_015560.2).
    explanation: The severe phenotype can involve a splice allele plus an intralocus modifier.
  - reference: PMID:18158317
    reference_title: OPA1 mutations induce mitochondrial DNA instability and optic atrophy 'plus' phenotypes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    directness: INDIRECT
    snippet: Mutations in OPA1, a dynamin-related GTPase involved in mitochondrial fusion, cristae organization and control of apoptosis, have been linked to non-syndromic optic neuropathy transmitted as an autosomal-dominant trait (DOA).
    explanation: This background statement establishes normal OPA1 GTPase function. The unmodified molecular-function annotation does not claim that every biallelic variant reduces catalytic activity.
  gene:
    preferred_term: OPA1
    term:
      id: hgnc:8140
      label: OPA1
  downstream:
  - target: Aberrant OPA1 Splicing
    description: For the c.610+364G>A allele, a new acceptor activates a cryptic exon.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:24970096
      reference_title: Pure and syndromic optic atrophy explained by deep intronic OPA1 mutations and an intralocus modifier.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: The mutation creates a new splice acceptor site resulting in aberrant OPA1 transcripts with retained intronic sequence and subsequent translational frameshift as shown by complementary DNA analysis.
      explanation: Patient cDNA establishes the splice consequence of the deep intronic allele.
  - target: Reduced OPA1 Protein Abundance
    description: Reduced protein has been measured for several biallelic genotypes; the intervening RNA/protein effects are allele-dependent.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:28442211
      reference_title: Leigh-like neuroimaging features associated with new biallelic mutations in OPA1.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Expression of OPA1 protein was significantly reduced in muscle tissues of both patients by Western blotting.
      explanation: Direct protein-abundance measurements in two biallelic patients; this is not a GTPase activity assay.
  - target: Mitochondrial Network Fragmentation
    description: Altered OPA1 function, including reduced abundance, disturbs network morphology.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:28442211
      reference_title: Leigh-like neuroimaging features associated with new biallelic mutations in OPA1.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: We also observed in patients' fibroblasts a higher proportion of fragmented and intermediate mitochondria upon galactose treatment compared to controls
      explanation: Network morphology is measured directly; impaired fusion is the mechanistic interpretation.
  - target: Reduced Mitochondrial DNA Content
    description: OPA1-associated mtDNA maintenance defects are a possible explanation for depletion in a genetically complex patient.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:28494813
      reference_title: 'Not only dominant, not only optic atrophy: expanding the clinical spectrum associated with OPA1 mutations.'
      supports: SUPPORT
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: In P1, the mtDNA content was partly but significantly lower than controls ( ≈40% of the mean control value
      explanation: Depletion co-occurs with biallelic OPA1 variants, but coexisting mitochondrial variants and untested intermediates limit the causal inference.
  - target: Cerebellar Involvement
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: This tissue-level abnormality is observed in molecularly confirmed OPA1 disease; the intervening steps and selective vulnerability are unresolved.
    evidence:
    - reference: PMID:24970096
      reference_title: Pure and syndromic optic atrophy explained by deep intronic OPA1 mutations and an intralocus modifier.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: MRI demonstrated mild to moderate cerebellar atrophy and thinning of the cervical spinal cord
      explanation: Direct imaging in three affected siblings supports cerebellar and spinal involvement, without identifying a specific neuronal death pathway.
  - target: Pyramidal Tract Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: This tissue-level abnormality is observed in molecularly confirmed OPA1 disease; the intervening steps and selective vulnerability are unresolved.
    evidence:
    - reference: PMID:24970096
      reference_title: Pure and syndromic optic atrophy explained by deep intronic OPA1 mutations and an intralocus modifier.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: Electrophysiological studies revealed severe axonal sensorimotor neuropathy as well as pyramidal tract damage to both upper and lower extremities.
      explanation: Evoked-potential and nerve-conduction findings support motor-pathway dysfunction, not proven corticospinal neuronal apoptosis.
  - target: Peripheral Axonal Degeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: This tissue-level abnormality is observed in molecularly confirmed OPA1 disease; the intervening steps and selective vulnerability are unresolved.
    evidence:
    - reference: PMID:27150940
      reference_title: Recessive optic atrophy, sensorimotor neuropathy and cataract associated with novel compound heterozygous mutations in OPA1.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: Semi-thin transverse sections of the distal sural nerve demonstrated medium and small MFs with complete loss of large MFs.
      explanation: Biopsy directly demonstrates large myelinated-fiber loss in one OPA1 patient.
- name: Aberrant OPA1 Splicing
  biological_scale: MOLECULAR
  description: The c.610+364G>A deep-intronic allele activates cryptic exon inclusion between exons 4b and 5, creating premature termination. This mechanism applies to this splice allele, not to all biallelic OPA1 variants.
  evidence:
  - reference: PMID:24970096
    reference_title: Pure and syndromic optic atrophy explained by deep intronic OPA1 mutations and an intralocus modifier.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The mutation creates a new splice acceptor site resulting in aberrant OPA1 transcripts with retained intronic sequence and subsequent translational frameshift as shown by complementary DNA analysis.
    explanation: Patient cDNA establishes the splice consequence of the deep intronic allele.
  gene:
    preferred_term: OPA1
    term:
      id: hgnc:8140
      label: OPA1
  downstream:
  - target: OPA1 Transcript Decay
    description: Premature-termination-containing splice products undergo nonsense-mediated decay.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:24970096
      reference_title: Pure and syndromic optic atrophy explained by deep intronic OPA1 mutations and an intralocus modifier.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: To suppress nonsense-mediated messenger RNA decay-dependent allelic decay we used puromycin treatment in patient derived fibroblasts. After this treatment, allelic balance on RNA level could be nearly restored back to normal, as proven by pyrosequencing.
      explanation: Puromycin rescue of allelic RNA imbalance supports nonsense-mediated decay in the deep-intronic family.
  biological_processes:
  - preferred_term: mRNA splicing, via spliceosome
    term:
      id: GO:0000398
      label: mRNA splicing, via spliceosome
    modifier: ABNORMAL
- name: OPA1 Transcript Decay
  biological_scale: MOLECULAR
  description: 'In the deep-intronic family, mutant-allele transcripts are depleted by nonsense-mediated decay. This is not universal: transcripts were preserved for the early frameshift allele in Nasca patient P1 despite reduced protein.'
  evidence:
  - reference: PMID:24970096
    reference_title: Pure and syndromic optic atrophy explained by deep intronic OPA1 mutations and an intralocus modifier.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: To suppress nonsense-mediated messenger RNA decay-dependent allelic decay we used puromycin treatment in patient derived fibroblasts. After this treatment, allelic balance on RNA level could be nearly restored back to normal, as proven by pyrosequencing.
    explanation: Puromycin rescue of allelic RNA imbalance supports nonsense-mediated decay in the deep-intronic family.
  - reference: PMID:28494813
    reference_title: 'Not only dominant, not only optic atrophy: expanding the clinical spectrum associated with OPA1 mutations.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: cDNA sequencing indicated that the two alleles were similarly expressed, excluding major mRNA decay of the allele with the premature stop codon.
    explanation: The early frameshift in another patient did not produce major transcript decay.
  downstream:
  - target: Reduced OPA1 Protein Abundance
    description: Loss of mutant transcripts reduces the available OPA1 protein in splice-allele carriers.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:24970096
      reference_title: Pure and syndromic optic atrophy explained by deep intronic OPA1 mutations and an intralocus modifier.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: We could demonstrate that the mutant transcripts of the deep intronic mutations are subject to nonsense mediated decay and that OPA1 protein levels in fibroblasts of mutation carriers are significantly reduced
      explanation: Linked RNA and protein assays support this allele-specific consequence.
  biological_processes:
  - preferred_term: nuclear-transcribed mRNA catabolic process, nonsense-mediated decay
    term:
      id: GO:0000184
      label: nuclear-transcribed mRNA catabolic process, nonsense-mediated decay
    modifier: INCREASED
- name: Reduced OPA1 Protein Abundance
  biological_scale: MOLECULAR
  description: Reduced OPA1 abundance has been measured in patient muscle and fibroblasts. Transcript decay is one mechanism; other alleles reduce protein despite preserved RNA. Abundance measurements do not by themselves establish a pan-tissue loss of expression.
  evidence:
  - reference: PMID:28442211
    reference_title: Leigh-like neuroimaging features associated with new biallelic mutations in OPA1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Expression of OPA1 protein was significantly reduced in muscle tissues of both patients by Western blotting.
    explanation: Direct protein-abundance measurements in two biallelic patients; this is not a GTPase activity assay.
  gene:
    preferred_term: OPA1
    term:
      id: hgnc:8140
      label: OPA1
  downstream:
  - target: Mitochondrial Network Fragmentation
    description: Reduced OPA1 availability is associated with fragmented patient-cell networks.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:24970096
      reference_title: Pure and syndromic optic atrophy explained by deep intronic OPA1 mutations and an intralocus modifier.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: OPA1 protein levels in fibroblasts of mutation carriers are significantly reduced, leading to mitochondrial fragmentation typical for OPA1-associated disease.
      explanation: The authors connect reduced abundance with fragmentation in patient cells.
- name: Mitochondrial Network Fragmentation
  biological_scale: CELLULAR
  description: Patient fibroblasts show fragmented mitochondrial networks, particularly under galactose challenge. This is consistent with impaired OPA1-dependent fusion. Fragmentation alone does not directly measure inner-membrane fusion or establish cristae disruption in patient neurons.
  evidence:
  - reference: PMID:28442211
    reference_title: Leigh-like neuroimaging features associated with new biallelic mutations in OPA1.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: We also observed in patients' fibroblasts a higher proportion of fragmented and intermediate mitochondria upon galactose treatment compared to controls
    explanation: Network morphology is measured directly; impaired fusion is the mechanistic interpretation.
  biological_processes:
  - preferred_term: mitochondrion organization
    term:
      id: GO:0007005
      label: mitochondrion organization
    modifier: ABNORMAL
  downstream:
  - target: Oxidative Phosphorylation Deficiency
    description: OPA1-dependent mitochondrial dysfunction can impair ATP production, with variable expression across genotypes and culture conditions.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:28494813
      reference_title: 'Not only dominant, not only optic atrophy: expanding the clinical spectrum associated with OPA1 mutations.'
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: The ATP content in P3 fi- broblasts was normal respect to controls in regular medium but significantly reduced in galactose medium reflecting the lower efficiency of ATP production by OXPHOS in stress condition
      explanation: Homozygous Ala394Thr fibroblasts show a stress-dependent ATP defect; it is not a universal resting ATP deficiency.
  - target: Retinal Ganglion Cell Degeneration
    description: A SARM1-dependent execution pathway downstream of fragmentation is supported in a dominant OPA1 mouse model; its operation in human Behr syndrome is an emerging hypothesis.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:40344041
      reference_title: SARM1 loss protects retinal ganglion cells in a mouse model of autosomal dominant optic atrophy.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: Sarm1 KO nearly completely suppressed all the degeneration phenotypes without reversing mitochondrial fragmentation.
      explanation: Genetic rescue in heterozygous Opa1R290Q/+ mice supports a downstream degeneration pathway; applicability to biallelic human disease remains untested.
    hypothesis_groups:
    - sarm1_axon_death
- name: Oxidative Phosphorylation Deficiency
  biological_scale: CELLULAR
  description: Some biallelic patients have reduced muscle COX staining or impaired fibroblast ATP synthesis. Nasca patient P3 showed reduced ATP content under galactose stress, whereas P1 had normal measured respiratory-complex enzyme activities despite severe disease. A uniform chronic ATP deficit is not established.
  evidence:
  - reference: PMID:28494813
    reference_title: 'Not only dominant, not only optic atrophy: expanding the clinical spectrum associated with OPA1 mutations.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: INDIRECT
    snippet: The ATP content in P3 fi- broblasts was normal respect to controls in regular medium but significantly reduced in galactose medium reflecting the lower efficiency of ATP production by OXPHOS in stress condition
    explanation: Homozygous Ala394Thr fibroblasts show a stress-dependent ATP defect; it is not a universal resting ATP deficiency.
  - reference: PMID:28442211
    reference_title: Leigh-like neuroimaging features associated with new biallelic mutations in OPA1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: In both patients, muscle biopsy showed diffuse reduction of cytochrome c oxidase stain
    explanation: Histochemistry provides tissue evidence of reduced complex IV activity.
  biological_processes:
  - preferred_term: oxidative phosphorylation
    term:
      id: GO:0006119
      label: oxidative phosphorylation
    modifier: DECREASED
- name: Reduced Mitochondrial DNA Content
  biological_scale: MOLECULAR
  description: Nasca patient P1 had mtDNA content approximately 40% of the control mean in fibroblasts and 35% in muscle. He also carried homoplasmic MT-ND4 m.11778G>A and MT-ND1 m.3337G>C variants, whose contribution was unresolved. This observation establishes depletion in that patient, not universal multiple mtDNA deletions in Behr syndrome.
  evidence:
  - reference: PMID:28494813
    reference_title: 'Not only dominant, not only optic atrophy: expanding the clinical spectrum associated with OPA1 mutations.'
    supports: SUPPORT
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: In P1, the mtDNA content was partly but significantly lower than controls ( ≈40% of the mean control value
    explanation: Patient-fibroblast mtDNA content was measured relative to controls.
  - reference: PMID:28494813
    reference_title: 'Not only dominant, not only optic atrophy: expanding the clinical spectrum associated with OPA1 mutations.'
    supports: SUPPORT
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: Notably, the reduction in mtDNA levels ( ≈35% of the mean control value) was confirmed in DNA extracted from patient ’s muscle
    explanation: The separate muscle observation is human tissue evidence.
  - reference: PMID:28494813
    reference_title: 'Not only dominant, not only optic atrophy: expanding the clinical spectrum associated with OPA1 mutations.'
    supports: SUPPORT
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: 'The complete sequencing of mtDNA revealed the presence of two homoplasmic variants: the m.11778G > A change in MTND4'
    explanation: Coexisting mitochondrial variation limits attribution of this case solely to OPA1.
  biological_processes:
  - preferred_term: mitochondrial DNA metabolic process
    term:
      id: GO:0032042
      label: mitochondrial DNA metabolic process
    modifier: ABNORMAL
- name: Retinal Ganglion Cell Degeneration
  biological_scale: TISSUE
  description: Optic-disc pallor and retinal nerve-fiber-layer thinning document optic nerve injury in affected patients. RGC soma and axon degeneration are directly demonstrated in dominant Opa1 mouse models, while the human biallelic cell-death pathway remains unresolved.
  evidence:
  - reference: PMID:24970096
    reference_title: Pure and syndromic optic atrophy explained by deep intronic OPA1 mutations and an intralocus modifier.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: This consisted of optic atrophy (onset at age 2 years) with thinning of the peripapillary retinal nerve fibre layer
    explanation: The affected siblings have optic atrophy and loss of retinal nerve-fiber thickness.
  - reference: PMID:40344041
    reference_title: SARM1 loss protects retinal ganglion cells in a mouse model of autosomal dominant optic atrophy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: INDIRECT
    snippet: Sarm1 KO nearly completely suppressed all the degeneration phenotypes without reversing mitochondrial fragmentation.
    explanation: Genetic rescue in heterozygous Opa1R290Q/+ mice supports a downstream degeneration pathway; applicability to biallelic human disease remains untested.
  cell_types:
  - preferred_term: retinal ganglion cell
    term:
      id: CL:0000740
      label: retinal ganglion cell
  downstream:
  - target: Optic Atrophy
    description: Loss of retinal ganglion cell axons produces optic nerve atrophy.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:24970096
      reference_title: Pure and syndromic optic atrophy explained by deep intronic OPA1 mutations and an intralocus modifier.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: This consisted of optic atrophy (onset at age 2 years) with thinning of the peripapillary retinal nerve fibre layer
      explanation: The affected siblings have optic atrophy and loss of retinal nerve-fiber thickness.
  locations:
  - preferred_term: Optic nerve
    term:
      id: UBERON:0000941
      label: cranial nerve II
- name: Cerebellar Involvement
  biological_scale: TISSUE
  description: Cerebellar atrophy is present in some affected families, but other patients have normal cerebellar imaging and predominantly sensory ataxia. MRI does not identify Purkinje-cell-selective degeneration or apoptosis.
  evidence:
  - reference: PMID:24970096
    reference_title: Pure and syndromic optic atrophy explained by deep intronic OPA1 mutations and an intralocus modifier.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: MRI demonstrated mild to moderate cerebellar atrophy and thinning of the cervical spinal cord
    explanation: Direct imaging in three affected siblings supports cerebellar and spinal involvement, without identifying a specific neuronal death pathway.
  downstream:
  - target: Cerebellar Atrophy
    description: Cerebellar tissue loss is visible on MRI.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:24970096
      reference_title: Pure and syndromic optic atrophy explained by deep intronic OPA1 mutations and an intralocus modifier.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: MRI demonstrated mild to moderate cerebellar atrophy and thinning of the cervical spinal cord
      explanation: Direct imaging in three affected siblings supports cerebellar and spinal involvement, without identifying a specific neuronal death pathway.
  - target: Ataxia
    description: Cerebellar dysfunction can contribute to ataxia alongside sensory and spinal abnormalities.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:24970096
      reference_title: Pure and syndromic optic atrophy explained by deep intronic OPA1 mutations and an intralocus modifier.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: MRI demonstrated mild to moderate cerebellar atrophy and thinning of the cervical spinal cord
      explanation: Direct imaging in three affected siblings supports cerebellar and spinal involvement, without identifying a specific neuronal death pathway.
  locations:
  - preferred_term: cerebellum
    term:
      id: UBERON:0002037
      label: cerebellum
- name: Pyramidal Tract Dysfunction
  biological_scale: TISSUE
  description: Pyramidal signs and abnormal motor-pathway electrophysiology indicate corticospinal involvement in some families. They do not establish selective corticospinal apoptosis or obligatory spasticity.
  evidence:
  - reference: PMID:24970096
    reference_title: Pure and syndromic optic atrophy explained by deep intronic OPA1 mutations and an intralocus modifier.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Electrophysiological studies revealed severe axonal sensorimotor neuropathy as well as pyramidal tract damage to both upper and lower extremities.
    explanation: Evoked-potential and nerve-conduction findings support motor-pathway dysfunction, not proven corticospinal neuronal apoptosis.
  downstream:
  - target: Pyramidal Signs (Spasticity)
    description: Impaired descending motor pathways are associated with spasticity.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:24970096
      reference_title: Pure and syndromic optic atrophy explained by deep intronic OPA1 mutations and an intralocus modifier.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Electrophysiological studies revealed severe axonal sensorimotor neuropathy as well as pyramidal tract damage to both upper and lower extremities.
      explanation: Evoked-potential and nerve-conduction findings support motor-pathway dysfunction, not proven corticospinal neuronal apoptosis.
  locations:
  - preferred_term: corticospinal tract
    term:
      id: UBERON:0002707
      label: corticospinal tract
- name: Peripheral Axonal Degeneration
  biological_scale: TISSUE
  description: A sural biopsy in one compound-heterozygous patient showed complete large-myelinated-fiber loss with relative preservation of unmyelinated axons. Nerve conduction supported sensorimotor axonal neuropathy. There was no demyelination, remyelination or onion-bulb formation; central dorsal-column pathology was not examined.
  evidence:
  - reference: PMID:27150940
    reference_title: Recessive optic atrophy, sensorimotor neuropathy and cataract associated with novel compound heterozygous mutations in OPA1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Semi-thin transverse sections of the distal sural nerve demonstrated medium and small MFs with complete loss of large MFs.
    explanation: Biopsy directly demonstrates large myelinated-fiber loss in one OPA1 patient.
  - reference: PMID:27150940
    reference_title: Recessive optic atrophy, sensorimotor neuropathy and cataract associated with novel compound heterozygous mutations in OPA1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: There was no evidence of demyelination, remyelination, or onion bulb formation.
    explanation: This constrains the pathology to axonal loss rather than a primary demyelinating process.
  downstream:
  - target: Peripheral Neuropathy
    description: Axonal loss and reduced sensory/motor responses underlie the neuropathy.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:27150940
      reference_title: Recessive optic atrophy, sensorimotor neuropathy and cataract associated with novel compound heterozygous mutations in OPA1.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Semi-thin transverse sections of the distal sural nerve demonstrated medium and small MFs with complete loss of large MFs.
      explanation: Biopsy directly demonstrates large myelinated-fiber loss in one OPA1 patient.
  - target: Impaired proprioception
    description: Loss of large sensory fibers provides an anatomical basis for impaired position and vibration sense.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:27150940
      reference_title: Recessive optic atrophy, sensorimotor neuropathy and cataract associated with novel compound heterozygous mutations in OPA1.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: Semi-thin transverse sections of the distal sural nerve demonstrated medium and small MFs with complete loss of large MFs.
      explanation: Biopsy directly demonstrates large myelinated-fiber loss in one OPA1 patient.
  - target: Ataxia
    description: Sensory neuropathy can contribute to gait ataxia even with normal cerebellar imaging.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:27150940
      reference_title: Recessive optic atrophy, sensorimotor neuropathy and cataract associated with novel compound heterozygous mutations in OPA1.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: By age two, he was not able to walk without support, and by the age of 10, he harbored severe ataxia and postural instability.
      explanation: Clinical sensory ataxia connects peripheral dysfunction to gait impairment.
  locations:
  - preferred_term: sural nerve
    term:
      id: UBERON:0015488
      label: sural nerve
phenotypes:
- name: Optic Atrophy
  description: >-
    Bilateral optic atrophy commonly begins in infancy or childhood, but subtle optic neuropathy may be
    recognized after neurological signs in the wider biallelic OPA1 spectrum.
  phenotype_term:
    preferred_term: Optic atrophy
    term:
      id: HP:0000648
      label: Optic atrophy
  evidence:
  - reference: PMID:24970096
    reference_title: Pure and syndromic optic atrophy explained by deep intronic OPA1 mutations and an intralocus modifier.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: This consisted of optic atrophy (onset at age 2 years) with thinning of the peripapillary retinal nerve fibre layer
    explanation: The affected siblings have optic atrophy and loss of retinal nerve-fiber thickness.
  - reference: PMID:28494813
    reference_title: 'Not only dominant, not only optic atrophy: expanding the clinical spectrum associated with OPA1 mutations.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: bi-allelic OPA1 mutations should be considered in disorder where optic atrophy is not obvious (or even absent).
    explanation: The broader biallelic spectrum includes delayed or subtle optic findings.
- name: Ataxia
  description: >
    Progressive cerebellar/sensory ataxia with gait impairment is a core
    neurological feature.
  phenotype_term:
    preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
  evidence:
  - reference: PMID:24970096
    reference_title: Pure and syndromic optic atrophy explained by deep intronic OPA1 mutations and an intralocus modifier.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: cerebellar ataxia [onset between age 4 to 6 years, leading to wheelchair-dependency within 10–15 years of age
    explanation: Progressive ataxia was documented in three siblings.
  - reference: PMID:27150940
    reference_title: Recessive optic atrophy, sensorimotor neuropathy and cataract associated with novel compound heterozygous mutations in OPA1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: By age two, he was not able to walk without support, and by the age of 10, he harbored severe ataxia and postural instability.
    explanation: This patient had a sensory contribution to ataxia.
- name: Pyramidal Signs (Spasticity)
  description: >-
    Spasticity occurs in some OPA1 families, with lower-limb progression documented in a homozygous Ala394Thr
    patient. Other biallelic patients lack pyramidal signs.
  phenotype_term:
    preferred_term: Spasticity
    term:
      id: HP:0001257
      label: Spasticity
  evidence:
  - reference: PMID:28494813
    reference_title: 'Not only dominant, not only optic atrophy: expanding the clinical spectrum associated with OPA1 mutations.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: the neurological conditions worsened with increased spasticity in her legs and un- steadiness during walking and postural changes.
    explanation: Longitudinal lower-limb spasticity in patient P3.
- name: Intellectual Disability
  description: >-
    Cognitive impairment is variable; some biallelic patients have preserved cognition.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:28442211
    reference_title: Leigh-like neuroimaging features associated with new biallelic mutations in OPA1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: We describe an 11-year-old girl (Pt1) and a 7-year-old boy (Pt2) with cognitive delay, ataxic gait and clinical signs suggestive of a peripheral neuropathy
    explanation: Two affected children had cognitive delay.
  - reference: PMID:27150940
    reference_title: Recessive optic atrophy, sensorimotor neuropathy and cataract associated with novel compound heterozygous mutations in OPA1.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: he did not have pyramidal signs, developmental delay or mental retardation
    explanation: The described child lacked intellectual impairment; the observation limits claims that it is obligatory.
- name: Peripheral Neuropathy
  description: >
    A peripheral (predominantly axonal, sensorimotor) neuropathy contributes to
    distal weakness and sensory loss.
  phenotype_term:
    preferred_term: Peripheral neuropathy
    term:
      id: HP:0009830
      label: Peripheral neuropathy
  evidence:
  - reference: PMID:27150940
    reference_title: Recessive optic atrophy, sensorimotor neuropathy and cataract associated with novel compound heterozygous mutations in OPA1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: findings were compatible with axonal sensorimotor polyneuropathy
    explanation: Electrophysiology supports the axonal sensorimotor phenotype.
- name: Nystagmus
  description: >-
    Nystagmus can be congenital and accompany early visual loss. Its anatomical cause was not established
    in the clinical reports.
  phenotype_term:
    preferred_term: Nystagmus
    term:
      id: HP:0000639
      label: Nystagmus
  evidence:
  - reference: PMID:35741767
    reference_title: "Biallelic Optic Atrophy 1 (OPA1) Related Disorder-Case Report and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He presented with congenital nystagmus, progressive vision loss, and optic atrophy, as well as progressive ataxia"
    explanation: Documents congenital nystagmus alongside optic atrophy and ataxia in a biallelic-OPA1 Behr-phenotype child.

    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Dysarthria
  description: >-
    Dysarthric speech is reported in biallelic OPA1 disease; a specific corticobulbar lesion is not established.
  phenotype_term:
    preferred_term: Dysarthria
    term:
      id: HP:0001260
      label: Dysarthria
  evidence:
  - reference: PMID:30972688
    reference_title: "Metabolic stroke in a patient with bi-allelic OPA1 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "early onset optic atrophy at one year of age, progressive gait ataxia, dysarthria, tremor and learning impairment"
    explanation: Documents dysarthria as part of the complex neurological phenotype in a biallelic-OPA1 patient resembling Behr syndrome.

    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Seizures
  description: >
    Seizures occur in severe biallelic-OPA1 disease and may become intractable,
    including super-refractory status epilepticus. Not part of the classical
    Behr definition — a feature of the severe end of the biallelic spectrum.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:35741767
    reference_title: "Biallelic Optic Atrophy 1 (OPA1) Related Disorder-Case Report and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "On follow-up, he developed profound vision impairment, intractable seizures, and metabolic strokes."
    explanation: Documents intractable seizures in the clinical course of a biallelic-OPA1 Behr patient.

    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Stroke-Like Episodes
  description: >-
    Metabolic stroke or stroke-like episodes have been reported in biallelic OPA1 disease. Seizures and
    evolving nonvascular MRI lesions can coexist; rapidly resolving early lesions in one child were interpreted
    as postictal. The relative contributions of seizures and metabolic injury remain uncertain.
  phenotype_term:
    preferred_term: Stroke-like episode
    term:
      id: HP:0002401
      label: Stroke-like episode
  evidence:
  - reference: PMID:30972688
    reference_title: Metabolic stroke in a patient with bi-allelic OPA1 mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: A metabolic stroke occurred at the age of 12 years.
    explanation: A stroke-like presentation in one girl with two OPA1 variants.
  - reference: PMID:38369985
    reference_title: Recurrent super-refractory status epilepticus and stroke like episode in a patient with Behr syndrome secondary to biallelic variants in OPA1 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: they recommended a trial of IV arginine infusion which he tolerated well with no side effects, but which did not lead to improvement of the suspected stroke radiologically or clinically.
    explanation: The later report documents the clinical interpretation and negative treatment response in the same child described by Othman2022.
- name: Tremor
  description: >
    Tremor accompanies the cerebellar syndrome in biallelic-OPA1 disease.
  phenotype_term:
    preferred_term: Tremor
    term:
      id: HP:0001337
      label: Tremor
  evidence:
  - reference: PMID:30972688
    reference_title: "Metabolic stroke in a patient with bi-allelic OPA1 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "progressive gait ataxia, dysarthria, tremor and learning impairment"
    explanation: Documents tremor as part of the biallelic-OPA1 neurological phenotype.

    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Basal Ganglia Signal Abnormality
  description: >-
    Basal-ganglia hyperintense lesions can accompany Leigh-like imaging in biallelic OPA1 disease. C19orf12-associated
    iron-related hypointensity belongs to the MPAN differential.
  phenotype_term:
    preferred_term: Abnormal basal ganglia MRI signal intensity
    term:
      id: HP:0012751
      label: Abnormal basal ganglia MRI signal intensity
  evidence:
  - reference: PMID:28442211
    reference_title: "Leigh-like neuroimaging features associated with new biallelic mutations in OPA1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "involvement accompanied by basal ganglia hyperintensities and pathological peak levels of lactate."
    explanation: Documents basal ganglia hyperintensities on neuroimaging in biallelic-OPA1 Behr syndrome.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Cerebellar Atrophy
  description: >-
    Mild to moderate cerebellar atrophy is documented in some families; it can be absent despite severe
    sensory ataxia.
  phenotype_term:
    preferred_term: Cerebellar atrophy
    term:
      id: HP:0001272
      label: Cerebellar atrophy
  evidence:
  - reference: PMID:24970096
    reference_title: Pure and syndromic optic atrophy explained by deep intronic OPA1 mutations and an intralocus modifier.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: MRI demonstrated mild to moderate cerebellar atrophy and thinning of the cervical spinal cord
    explanation: Direct imaging in three affected siblings supports cerebellar and spinal involvement, without identifying a specific neuronal death pathway.
- category: Neurologic
  name: Impaired proprioception
  description: "Reduced position and vibration sense accompanies large-fiber sensory neuropathy; the clinical observation does not prove a central dorsal-column lesion."
  phenotype_term:
    preferred_term: Impaired proprioception
    term:
      id: HP:0010831
      label: Impaired proprioception
    onset:
      onset_category: CHILDHOOD
  evidence:
  - reference: PMID:27150940
    reference_title: Recessive optic atrophy, sensorimotor neuropathy and cataract associated with novel compound heterozygous mutations in OPA1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Sensitivity to pinprick, touch, position, and vibration was decreased.
    explanation: Documents reduced position and vibration sense (impaired proprioception) in an OPA1-recessive Behr patient.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- category: Ophthalmologic
  name: Ophthalmoplegia
  description: "External ophthalmoplegia is documented in the deep-intronic/modifier OPA1 family; it is a variable extraocular manifestation."
  phenotype_term:
    preferred_term: Ophthalmoplegia
    term:
      id: HP:0000602
      label: Ophthalmoplegia
    onset:
      onset_category: CHILDHOOD
  evidence:
  - reference: PMID:24970096
    reference_title: Pure and syndromic optic atrophy explained by deep intronic OPA1 mutations and an intralocus modifier.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: external ophthalmoplegia, peripheral neuropathy, muscle atrophy, ptosis and spasticity
    explanation: External ophthalmoplegia was documented in the affected OAK587 siblings.
- category: Ophthalmologic
  name: Developmental cataract
  description: "Congenital cataract was reported in one compound-heterozygous child and diagnosed at age one in the detailed case narrative. Its frequency in OPA1 disease is unknown."
  phenotype_term:
    preferred_term: Developmental cataract
    term:
      id: HP:0000519
      label: Developmental cataract
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:27150940
    reference_title: Recessive optic atrophy, sensorimotor neuropathy and cataract associated with novel compound heterozygous mutations in OPA1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At birth, he presented with a congenital cataract, which has not been previously described in patients with OPA1 mutations."
    explanation: Documents congenital cataract as a newly recognized feature of OPA1-recessive Behr syndrome.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- category: Neurologic
  name: Hearing Impairment
  description: "Childhood hearing loss can develop after initially normal hearing tests; the case description does not specify its audiological type."
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  evidence:
  - reference: PMID:35741767
    reference_title: Biallelic Optic Atrophy 1 (OPA1) Related Disorder-Case Report and Literature Review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: at age 4, he started showing mild hearing impairment in the left ear, which further progressed to moderate bilateral hearing loss.
    explanation: Longitudinal hearing decline in the reported child; no inferred sensorineural subtype.
- category: Gastrointestinal
  name: Gastrointestinal dysmotility
  description: "Gastrointestinal dysmotility and dysphagia have been reported in severe biallelic OPA1 presentations; they are not universal diagnostic features."
  phenotype_term:
    preferred_term: Gastrointestinal dysmotility
    term:
      id: HP:0002579
      label: Gastrointestinal dysmotility
    onset:
      onset_category: CHILDHOOD
  evidence:
  - reference: PMID:28494813
    reference_title: 'Not only dominant, not only optic atrophy: expanding the clinical spectrum associated with OPA1 mutations.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: the severe neonatal-onset disorder characterized by severe optic atrophy, ataxia, hypotonia, gastrointestinal dysmotility and dysphagia, described in two siblings by Schaaf et al.
    explanation: The discussion summarizes previously reported biallelic siblings; these are not newly observed Nasca cases.
- category: Neurologic
  name: Motor delay
  description: "Delayed gross and fine motor milestones can precede severe neurological complications; early language may be age-appropriate."
  phenotype_term:
    preferred_term: Motor delay
    term:
      id: HP:0001270
      label: Motor delay
    onset:
      onset_category: INFANTILE
  evidence:
  - reference: PMID:38369985
    reference_title: Recurrent super-refractory status epilepticus and stroke like episode in a patient with Behr syndrome secondary to biallelic variants in OPA1 gene.
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: He was delayed mainly in gross motor and fine motor domains with age-appropriate language milestones.
    explanation: The initial neurological assessment separates motor delay from global cognitive impairment.
- name: Pes Cavus
  phenotype_term:
    preferred_term: Pes cavus
    term:
      id: HP:0001761
      label: Pes cavus
  description: Reported in the Ile437Met/Val988Phe patient with axonal sensory neuropathy.
  evidence:
  - reference: PMID:28494813
    reference_title: 'Not only dominant, not only optic atrophy: expanding the clinical spectrum associated with OPA1 mutations.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: mild ataxia and pes cavus; tendon reflexes were absent.
    explanation: Clinical examination of patient P2.
- name: Areflexia
  phenotype_term:
    preferred_term: Areflexia
    term:
      id: HP:0001284
      label: Areflexia
  description: Absent tendon reflexes can accompany the peripheral neuropathy.
  evidence:
  - reference: PMID:28494813
    reference_title: 'Not only dominant, not only optic atrophy: expanding the clinical spectrum associated with OPA1 mutations.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: mild ataxia and pes cavus; tendon reflexes were absent.
    explanation: Reflex loss was documented in patient P2.
- name: Distal Amyotrophy
  phenotype_term:
    preferred_term: Distal amyotrophy
    term:
      id: HP:0003693
      label: Distal amyotrophy
  description: Distal muscle wasting was observed in a homozygous Ala394Thr patient.
  evidence:
  - reference: PMID:28494813
    reference_title: 'Not only dominant, not only optic atrophy: expanding the clinical spectrum associated with OPA1 mutations.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: an ataxic-spastic syndrome with distal muscular atrophy of upper and lower limbs.
    explanation: The age-12 examination documents distal muscle atrophy.
- name: Ptosis
  phenotype_term:
    preferred_term: Ptosis
    term:
      id: HP:0000508
      label: Ptosis
  description: Ptosis is reported in compound-heterozygous OPA1 disease.
  evidence:
  - reference: PMID:24970096
    reference_title: Pure and syndromic optic atrophy explained by deep intronic OPA1 mutations and an intralocus modifier.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: external ophthalmoplegia, peripheral neuropathy, muscle atrophy, ptosis and spasticity
    explanation: Ptosis is included in the clinical findings of the affected siblings.
- name: Exotropia
  phenotype_term:
    preferred_term: Exotropia
    term:
      id: HP:0000577
      label: Exotropia
  description: A child with progressive severe visual loss developed large-angle exotropia.
  evidence:
  - reference: PMID:35741767
    reference_title: Biallelic Optic Atrophy 1 (OPA1) Related Disorder-Case Report and Literature Review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Over time, the patient developed large-angle exotropia of more than 50 prism diopters.
    explanation: This ocular-motor feature was documented during longitudinal follow-up.
- name: Cervical Spinal Cord Atrophy
  phenotype_term:
    preferred_term: Cervical spinal cord atrophy
    term:
      id: HP:0010873
      label: Cervical spinal cord atrophy
  description: Cervical spinal-cord thinning accompanied severe ataxia and neuropathy in three siblings.
  evidence:
  - reference: PMID:24970096
    reference_title: Pure and syndromic optic atrophy explained by deep intronic OPA1 mutations and an intralocus modifier.
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: All three subjects also show, to a variable degree, atrophy of the upper cervical spinal cord
    explanation: The figure legend explicitly localizes the atrophy to the cervical cord.
- name: Developmental Regression
  phenotype_term:
    preferred_term: Developmental regression
    term:
      id: HP:0002376
      label: Developmental regression
  description: Loss of walking, speech and feeding skills can follow severe seizure-related decompensation.
  evidence:
  - reference: PMID:35741767
    reference_title: Biallelic Optic Atrophy 1 (OPA1) Related Disorder-Case Report and Literature Review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: the patient had lost several of his previous skills, including his ability to walk, talk, and eat without assistance.
    explanation: Regression followed status epilepticus in the reported child.
- name: Elevated Brain Lactate
  phenotype_term:
    preferred_term: Elevated brain lactate level by MRS
    term:
      id: HP:0012707
      label: Elevated brain lactate level by MRS
  description: An elevated brain lactate peak was documented on MR spectroscopy in a severely affected patient; this is distinct from a circulating lactate measurement.
  evidence:
  - reference: PMID:28494813
    reference_title: 'Not only dominant, not only optic atrophy: expanding the clinical spectrum associated with OPA1 mutations.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: H-MRS showed a very high lactate peak, both in the abnormal and in the spared areas.
    explanation: Direct MR spectroscopy finding in Nasca patient P1, who also carried mitochondrial DNA variants.
- name: Dysphagia
  description: Swallowing/feeding impairment can emerge during severe neurological deterioration, including aspiration requiring tube feeding in one child.
  phenotype_term:
    preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  evidence:
  - reference: PMID:38369985
    reference_title: Recurrent super-refractory status epilepticus and stroke like episode in a patient with Behr syndrome secondary to biallelic variants in OPA1 gene.
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: he could no longer walk, had lost most of his ability to speak, and required nasogastric tube feeds due to aspiration. After therapy, he eventually regained a few useful words, but went on to require gastrostomy placement.
    explanation: Aspiration and tube-feeding requirement document clinically important swallowing dysfunction.
- name: Distal Muscle Weakness
  description: Distal weakness, especially in the legs, accompanies axonal neuropathy in some patients.
  phenotype_term:
    preferred_term: Distal muscle weakness
    term:
      id: HP:0002460
      label: Distal muscle weakness
  evidence:
  - reference: PMID:27150940
    reference_title: Recessive optic atrophy, sensorimotor neuropathy and cataract associated with novel compound heterozygous mutations in OPA1.
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: Neurological examination at 10 years of age indicated muscle weakness and atrophy of the bilateral distal muscles, predominantly in the lower limbs.
    explanation: Direct examination distinguishes weakness from the separate muscle-wasting phenotype.
biochemical:
- name: Increased Circulating Lactate in a Severe Biallelic Presentation
  notes: >-
    Nasca patient P1 had elevated plasma and CSF lactate at an earlier assessment, followed by normal
    lactate and pyruvate during a later severe deterioration. His coexisting MT-ND4/MT-ND1 variants limit
    attribution to OPA1 alone. Circulating lactate is not interchangeable with the MR spectroscopy peak
    and is not a universal diagnostic marker.
  biomarker_term:
    preferred_term: Increased circulating lactate concentration
    term:
      id: HP:0002151
      label: Increased circulating lactate concentration
  evidence:
  - reference: PMID:28494813
    reference_title: 'Not only dominant, not only optic atrophy: expanding the clinical spectrum associated with OPA1 mutations.'
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Hepatic function was markedly impaired; lactate and pyruvate levels were normal.
    explanation: Normal circulating values occurred during later deterioration; the same case narrative reports earlier elevation.
  - reference: PMID:28494813
    reference_title: 'Not only dominant, not only optic atrophy: expanding the clinical spectrum associated with OPA1 mutations.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Lactate levels were elevated in plasma ... and in CSF; the analysis of respiratory chain complexes and PDH complex on muscle biopsy resulted normal.
    explanation: The earlier assessment documents plasma/CSF elevation. The ellipsis omits an implausible numerical unit in the source, so no quantitative concentration is asserted.
- name: Cytochrome c oxidase (COX) deficiency
  context: Muscle biopsy / mitochondrial respiratory-chain readout
  notes: Reduced muscle COX staining was observed in two children; other biallelic patients can have normal measured respiratory-complex enzyme activities.
  evidence:
  - reference: PMID:28442211
    reference_title: Leigh-like neuroimaging features associated with new biallelic mutations in OPA1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "muscle biopsy showed diffuse reduction of cytochrome c oxidase stain"
    explanation: Documents reduced cytochrome c oxidase staining, a biochemical readout of the mitochondrial respiratory-chain deficiency.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
histopathology:
- name: Cytochrome c Oxidase-Deficient Muscle Fibers
  description: >-
    In two children, muscle biopsy showed reduced COX staining, scattered atrophic fibers and type II
    fiber grouping, consistent with respiratory-chain and neurogenic involvement. This finding is not
    documented across all biallelic OPA1 genotypes.
  evidence:
  - reference: PMID:28442211
    reference_title: "Leigh-like neuroimaging features associated with new biallelic mutations in OPA1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In both patients, muscle biopsy showed diffuse reduction of cytochrome c oxidase stain, some atrophic fibers and type II fiber grouping."
    explanation: Documents the muscle histopathology — COX-deficient staining with atrophic fibers and type II fiber grouping — in biallelic-OPA1 Behr syndrome.

    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Large Myelinated Nerve Fiber Loss
  description: Sural nerve biopsy in one child showed complete loss of large myelinated fibers, reduced fiber density and relative preservation of unmyelinated axons. There was no demyelination, remyelination or onion-bulb formation. The reference specimen was from a younger child, so the counts are not a matched disease-wide estimate.
  evidence:
  - reference: PMID:27150940
    reference_title: Recessive optic atrophy, sensorimotor neuropathy and cataract associated with novel compound heterozygous mutations in OPA1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Semi-thin transverse sections of the distal sural nerve demonstrated medium and small MFs with complete loss of large MFs.
    explanation: Biopsy directly demonstrates large myelinated-fiber loss in one OPA1 patient.
  - reference: PMID:27150940
    reference_title: Recessive optic atrophy, sensorimotor neuropathy and cataract associated with novel compound heterozygous mutations in OPA1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Unmyelinated axons were relatively well preserved with occasional rarefaction
    explanation: Relative preservation of unmyelinated axons was described in the biopsy.
diagnosis:
- name: Molecular Genetic Testing
  description: >-
    Sequence OPA1 and assess allele phase with family testing in an optic-atrophy-plus presentation. A
    broader optic-neuropathy panel or exome can address molecular differentials. Negative coding-sequence
    and deletion/duplication testing does not exclude a deep-intronic OPA1 defect; targeted genomic and
    transcript studies resolved such a family.
  evidence:
  - reference: PMID:35741767
    reference_title: Biallelic Optic Atrophy 1 (OPA1) Related Disorder-Case Report and Literature Review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Phenotypic features are essential for diagnosis; however, genetic testing, including parental testing, is the final step in having a correct and complete diagnosis.
    explanation: The case study emphasizes parental testing and genotype interpretation.
  - reference: PMID:24970096
    reference_title: Pure and syndromic optic atrophy explained by deep intronic OPA1 mutations and an intralocus modifier.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: we suggest that whole gene sequencing of OPA1 and/or expansion of diagnostics to the transcript level are important tools to solve unexplained cases of optic atrophy and optic atrophy plus syndromes.
    explanation: Directly supported extension after unrevealing coding tests.
- name: Brain MRI / MR spectroscopy
  description: "Brain MRI and MR spectroscopy characterize neurological involvement: cerebellar atrophy, basal-ganglia lesions or a lactate peak may be present. A normal scan does not exclude disease. Serial imaging and EEG help interpret lesions during seizures."
  results: Cerebellar involvement, basal-ganglia hyperintensities, and/or a lactate peak.
  evidence:
  - reference: PMID:28442211
    reference_title: Leigh-like neuroimaging features associated with new biallelic mutations in OPA1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "neuroimaging detected a progressive cerebellar involvement accompanied by basal ganglia hyperintensities and pathological peak levels of lactate"
    explanation: Documents the characteristic Leigh-like neuroimaging (cerebellar involvement, basal-ganglia change, lactate peak) supporting the diagnosis.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:27150940
    reference_title: Recessive optic atrophy, sensorimotor neuropathy and cataract associated with novel compound heterozygous mutations in OPA1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: A brain MRI performed when he was 8 years old indicated the cerebral cortex and cerebellum were normal in structure and size.
    explanation: A genetically confirmed patient had normal brain morphology.
- name: Muscle biopsy / oxidative phosphorylation assessment
  description: "Muscle biopsy may show reduced cytochrome c oxidase (complex IV) staining, reflecting the mitochondrial respiratory-chain deficiency.\n"
  results: Diffuse reduction of cytochrome c oxidase staining.
  evidence:
  - reference: PMID:28442211
    reference_title: Leigh-like neuroimaging features associated with new biallelic mutations in OPA1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "muscle biopsy showed diffuse reduction of cytochrome c oxidase stain"
    explanation: Muscle biopsy demonstrating reduced cytochrome c oxidase staining supports the mitochondrial basis of the disease.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Nerve conduction studies / electrophysiology
  description: "Nerve-conduction studies characterize axonal sensory or sensorimotor neuropathy; this manifestation is not present in every patient."
  results: Axonal sensorimotor polyneuropathy.
  evidence:
  - reference: PMID:27150940
    reference_title: Recessive optic atrophy, sensorimotor neuropathy and cataract associated with novel compound heterozygous mutations in OPA1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "findings were compatible with axonal sensorimotor polyneuropathy"
    explanation: Electrophysiological findings compatible with axonal sensorimotor polyneuropathy support the neuropathy component.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Ophthalmic Examination, OCT and Visual Evoked Potentials
  description: Fundoscopy, OCT and visual electrophysiology document optic nerve dysfunction and may reveal mild disease in relatives. Longitudinal assessment distinguishes progressive visual loss from an initially subtle presentation.
  evidence:
  - reference: PMID:35741767
    reference_title: Biallelic Optic Atrophy 1 (OPA1) Related Disorder-Case Report and Literature Review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The optical coherence tomography (OCT) showed formed fovea and thinning of the retinal nerve fiber layer (RNFL) OU.
    explanation: OCT documented bilateral nerve-fiber-layer loss in the proband.
  - reference: PMID:35741767
    reference_title: Biallelic Optic Atrophy 1 (OPA1) Related Disorder-Case Report and Literature Review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Awake, flash visual evoked potential (fVEP) was recordable and showed low amplitudes and delayed latency OU
    explanation: VEPs provided a functional correlate of the optic neuropathy.
genetic:
- name: OPA1
  notes: >-
    Biallelic OPA1 disease involves missense, truncating, canonical splice-site and deep-intronic alleles.
    The recurrent p.Ile437Met/p.Ile382Met substitution is an intragenic modifier in trans with a more
    severe allele; it is not a second-gene modifier. Single-allele expression varies between families.
    Neither penetrance nor the proportion of each variant class can be estimated from these small selected
    series.
  gene_term:
    preferred_term: OPA1
    term:
      id: hgnc:8140
      label: OPA1
  relationship_type: CAUSATIVE
  evidence:
  - reference: PMID:28442211
    reference_title: Leigh-like neuroimaging features associated with new biallelic mutations in OPA1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: we identified the homozygous c.1180G>A/p.Ala394Thr mutation in Pt1 and the c.2779-2A>C mutation in compound heterozygosity with the c.2809C>T/p.Arg937Cys mutation in Pt2.
    explanation: Two distinct biallelic architectures were identified in affected children.
  - reference: PMID:24970096
    reference_title: Pure and syndromic optic atrophy explained by deep intronic OPA1 mutations and an intralocus modifier.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: the deep intronic mutation occurred in compound heterozygous state with an exonic OPA1 missense variant (p.I382M; NM_015560.2).
    explanation: The severe phenotype can involve a splice allele plus an intralocus modifier.
  - reference: PMID:24970096
    reference_title: Pure and syndromic optic atrophy explained by deep intronic OPA1 mutations and an intralocus modifier.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: the homozygous father Subject I:1 is still healthy at the age of 76 years, without evidence for subclinical optic atrophy.
    explanation: The modifier alone was not sufficient to produce disease in this family.
  variant_origin: GERMLINE
  variants:
  - name: c.610+364G>A
    variant_type: single nucleotide variant
    genomic_contexts:
    - intron
    description: Deep-intronic allele on NM_130837.2 in OAK587, in trans with c.1311A>G. Patient transcript analysis demonstrated cryptic exon inclusion, premature termination and nonsense-mediated decay. The same splice allele alone was associated with milder or clinically unapparent disease.
    evidence:
    - reference: PMID:24970096
      reference_title: Pure and syndromic optic atrophy explained by deep intronic OPA1 mutations and an intralocus modifier.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: The mutation creates a new splice acceptor site resulting in aberrant OPA1 transcripts with retained intronic sequence and subsequent translational frameshift as shown by complementary DNA analysis.
      explanation: Patient cDNA establishes the splice consequence of the deep intronic allele.
    - reference: PMID:24970096
      reference_title: Pure and syndromic optic atrophy explained by deep intronic OPA1 mutations and an intralocus modifier.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: To suppress nonsense-mediated messenger RNA decay-dependent allelic decay we used puromycin treatment in patient derived fibroblasts. After this treatment, allelic balance on RNA level could be nearly restored back to normal, as proven by pyrosequencing.
      explanation: Puromycin rescue of allelic RNA imbalance supports nonsense-mediated decay in the deep-intronic family.
  - name: c.1311A>G (p.Ile437Met)
    variant_type: single nucleotide variant
    description: NM_130837.2 notation; equivalent to c.1146A>G (p.Ile382Met) on NM_015560.2. Recurrent hypomorphic/intralocus modifier in severe compound-heterozygous disease. Clinical expression in isolation is variable; a healthy homozygous elderly father was documented. Yeast showed a mild functional defect, not a direct measurement of human GTPase catalysis.
    evidence:
    - reference: PMID:28494813
      reference_title: 'Not only dominant, not only optic atrophy: expanding the clinical spectrum associated with OPA1 mutations.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: The latter corresponds to c.1146A > G, p.I382M based on transcript NM_015560.2
      explanation: The source explicitly reconciles the transcript-dependent nomenclature.
    - reference: PMID:24970096
      reference_title: Pure and syndromic optic atrophy explained by deep intronic OPA1 mutations and an intralocus modifier.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: the homozygous father Subject I:1 is still healthy at the age of 76 years, without evidence for subclinical optic atrophy.
      explanation: Family observation limits claims of intrinsic high penetrance.
  - name: c.1180G>A (p.Ala394Thr)
    variant_type: single nucleotide variant
    description: Homozygous missense variant on NM_130837.2, associated with spastic ataxia and neuropathy; optic involvement may be subtle or delayed. Patient fibroblasts and a yeast complementation model showed functional abnormalities.
    evidence:
    - reference: PMID:28442211
      reference_title: Leigh-like neuroimaging features associated with new biallelic mutations in OPA1.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: we identified the homozygous c.1180G>A/p.Ala394Thr mutation in Pt1 and the c.2779-2A>C mutation in compound heterozygosity with the c.2809C>T/p.Arg937Cys mutation in Pt2.
      explanation: Two distinct biallelic architectures were identified in affected children.
    - reference: PMID:28494813
      reference_title: 'Not only dominant, not only optic atrophy: expanding the clinical spectrum associated with OPA1 mutations.'
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: The ATP content in P3 fi- broblasts was normal respect to controls in regular medium but significantly reduced in galactose medium reflecting the lower efficiency of ATP production by OXPHOS in stress condition
      explanation: Homozygous Ala394Thr fibroblasts show a stress-dependent ATP defect; it is not a universal resting ATP deficiency.
  - name: c.2287del (p.Ser763Valfs*15)
    variant_type: deletion
    description: Maternal NM_130837.2 frameshift in trans with paternal c.1311A>G in the child described in both Othman2022 and Jagadish2024. Also reported as c.2122del/p.Ser708Valfs*15 on NM_015560.2. Functional protein analysis was not performed for this allele in the case report.
    evidence:
    - reference: PMID:35741767
      reference_title: Biallelic Optic Atrophy 1 (OPA1) Related Disorder-Case Report and Literature Review.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: The variant c.2287del (maternally inherited) is predicted to result in a translational frameshift and premature protein termination (p.Ser763Valfs*15).
      explanation: The truncating consequence is predicted, not assayed.
    - reference: PMID:35741767
      reference_title: Biallelic Optic Atrophy 1 (OPA1) Related Disorder-Case Report and Literature Review.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: The functional analysis of the effect of this mutation on the amount of protein was not performed.
      explanation: Explicit limitation of this individual allele.
  - name: p.Leu620fs*13 and p.Arg905Gln
    description: Compound-heterozygous paternal frameshift and maternal missense variants, reported as c.1857-1858delinsT and c.G2714A in Lee2016. Associated with severe optic atrophy, sensorimotor neuropathy and congenital cataract. The missense effect was predicted computationally; the report did not demonstrate its biochemical mechanism.
    evidence:
    - reference: PMID:27150940
      reference_title: Recessive optic atrophy, sensorimotor neuropathy and cataract associated with novel compound heterozygous mutations in OPA1.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: the mother was heterozygous for the p.R905Q missense mutation and the father was heterozygous for the p.L620fs frameshift mutation
      explanation: Parental segregation establishes the reported trans configuration.
  - name: c.2779-2A>C and c.2809C>T (p.Arg937Cys)
    description: Compound-heterozygous splice-site and missense variants reported in one child with Leigh-like imaging; reduced OPA1 muscle protein and altered fibroblast morphology were measured at the genotype level.
    evidence:
    - reference: PMID:28442211
      reference_title: Leigh-like neuroimaging features associated with new biallelic mutations in OPA1.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: we identified the homozygous c.1180G>A/p.Ala394Thr mutation in Pt1 and the c.2779-2A>C mutation in compound heterozygosity with the c.2809C>T/p.Arg937Cys mutation in Pt2.
      explanation: Two distinct biallelic architectures were identified in affected children.
    - reference: PMID:28442211
      reference_title: Leigh-like neuroimaging features associated with new biallelic mutations in OPA1.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Expression of OPA1 protein was significantly reduced in muscle tissues of both patients by Western blotting.
      explanation: Direct protein-abundance measurements in two biallelic patients; this is not a GTPase activity assay.
treatments:
- name: Supportive and Multidisciplinary Care
  description: >-
    Management addresses visual disability, mobility, neurological complications and feeding needs. Published
    case care is supportive; the cited reports do not establish a disease-modifying treatment.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  therapeutic_modality: OTHER

  evidence:
  - reference: PMID:35741767
    reference_title: Biallelic Optic Atrophy 1 (OPA1) Related Disorder-Case Report and Literature Review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: There is currently no specific treatment for this disease. Supplements have been suggested but have not proven beneficial
    explanation: The 2022 clinical review describes supportive management and lack of proven specific therapy.
- name: Genetic Counseling
  description: >-
    Counseling addresses variable visual and neurological prognosis, allele phase and the possibility
    of mild or subclinical dominant optic atrophy in relatives. The risk assessment depends on the actual
    family genotype.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  therapeutic_modality: BEHAVIORAL

  evidence:
  - reference: PMID:35741767
    reference_title: Biallelic Optic Atrophy 1 (OPA1) Related Disorder-Case Report and Literature Review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The prognosis for vision and neurologic impairment is guarded and should be included in the counseling for the patient and family.
    explanation: Counseling should address variable but potentially severe neurological and visual outcomes.
- name: Low-Vision Rehabilitation
  description: "Correct refractive errors and provide visual rehabilitation, accessible learning and mobility support. Magnification, text-to-speech, braille, tactile/auditory learning and cane use were documented in one affected child."
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: low-vision rehabilitation
    term:
      id: NCIT:C15315
      label: Rehabilitation
  evidence:
  - reference: PMID:35741767
    reference_title: Biallelic Optic Atrophy 1 (OPA1) Related Disorder-Case Report and Literature Review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Visual rehabilitation and low vision services were provided to the patient and consisted of magnifying devices and text-to-speech technology. He started learning braille and the use of tactile and auditory approaches for learning. Also, he began to use a cane for mobility.
    explanation: Directly documented disability support in biallelic disease.
- name: Physical, Occupational and Speech Rehabilitation
  description: "Rehabilitation is used for gait, motor and communication impairment, including recovery after neurological decompensation. Improvement during combined care does not establish an isolated treatment effect."
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: physical, occupational and speech therapy
    term:
      id: NCIT:C15315
      label: Rehabilitation
  evidence:
  - reference: PMID:38369985
    reference_title: Recurrent super-refractory status epilepticus and stroke like episode in a patient with Behr syndrome secondary to biallelic variants in OPA1 gene.
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: He was receiving intensive physical, occupational and speech therapy. He had regained the ability to stand with support and has recovered function of his right upper and lower extremities. He could speak 2–3-word phrases.
    explanation: Improvement occurred during combined rehabilitation and seizure treatment; individual modality effects cannot be isolated.
- name: Antiseizure Management
  description: "Seizures and status epilepticus require individualized neurological and intensive-care treatment. A reported child required multiple intravenous agents and pentobarbital coma; maintenance polytherapy was followed by six-month seizure freedom. This single uncontrolled course does not establish efficacy of a particular drug or regimen."
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: levetiracetam
      term:
        id: CHEBI:6437
        label: levetiracetam
    - preferred_term: clobazam
      term:
        id: CHEBI:31413
        label: clobazam
    - preferred_term: topiramate
      term:
        id: CHEBI:63631
        label: topiramate
    - preferred_term: cannabidiol
      term:
        id: CHEBI:69478
        label: cannabidiol
  evidence:
  - reference: PMID:38369985
    reference_title: Recurrent super-refractory status epilepticus and stroke like episode in a patient with Behr syndrome secondary to biallelic variants in OPA1 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: He was treated with intravenous (IV) doses of lorazepam, levetiracetam, phenobarbital, fosphenytoin, lacosamide, propofol infusion (<24 h) and finally pentobarbital infusion coma for 4 days, with which status epilepticus resolved.
    explanation: The case documents escalation for super-refractory status, not a comparative treatment trial.
  - reference: PMID:38369985
    reference_title: Recurrent super-refractory status epilepticus and stroke like episode in a patient with Behr syndrome secondary to biallelic variants in OPA1 gene.
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: He was discharged home after a 30-day hospitalization on levetiracetam, clobazam, topiramate and epidiolex.
    explanation: Documented maintenance polytherapy, not a validated disease-specific regimen.
  - reference: PMID:38369985
    reference_title: Recurrent super-refractory status epilepticus and stroke like episode in a patient with Behr syndrome secondary to biallelic variants in OPA1 gene.
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: On his follow up 6 months after discharge, he was clinically seizure free.
    explanation: Observed follow-up outcome under combined care.
  target_mechanisms:
  - target: Seizures
    treatment_effect: INHIBITS
    description: Symptomatic seizure suppression; no established effect on the upstream OPA1 defect.
- name: Idebenone (Limited Biallelic Case Evidence)
  description: "One biallelic OPA1 patient with optic atrophy, ataxia and neuropathy received idebenone and remained neurologically and ophthalmologically stable at six months. This uncontrolled observation does not establish benefit. Broader dominant-optic-atrophy reports remain limited and cannot establish efficacy for Behr syndrome."
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: idebenone
      term:
        id: CHEBI:31687
        label: idebenone
  evidence:
  - reference: PMID:28494813
    reference_title: 'Not only dominant, not only optic atrophy: expanding the clinical spectrum associated with OPA1 mutations.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Treatment with idebenone (135 mg/die) was started. Neurological and ophthalmologic follow-up, six months after diagnosis, were stable.
    explanation: Direct biallelic case treatment, with stability but no controlled evidence of efficacy.
  - reference: PMID:41318849
    reference_title: Advanced therapies for inherited optic neuropathies.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
    snippet: However, this evidence is limited, and an adequately powered, randomised, placebo-controlled trial is needed to better evaluate the efficacy of idebenone in ADOA.
    explanation: Even the broader ADOA evidence remains uncertain.
- name: OPA1 Gene Augmentation (Preclinical)
  description: "AAV-mediated OPA1 augmentation has been studied in dominant-optic-atrophy models. Expression level, isoform choice and dominant-negative effects are unresolved challenges. This is preclinical evidence extrapolated to Behr syndrome; the allotopic MT-ND4 gene-expression trials concern LHON."
  therapeutic_modality: GENE_THERAPY
  treatment_term:
    preferred_term: Gene Therapy
    term:
      id: NCIT:C15238
      label: Gene Therapy
  evidence:
  - reference: PMID:41318849
    reference_title: Advanced therapies for inherited optic neuropathies.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
    snippet: Together, these early experiments suggest that AAV-mediated OPA1 gene therapy may have a role in preserving visual function, but more work is required to understand the molecular pathophysiology of ADOA.
    explanation: The review describes preclinical OPA1 augmentation, distinct from clinical LHON allotopic therapy.
- name: OPA1 Expression Modulation (Investigational)
  description: Antisense approaches increase expression of the remaining wild-type OPA1 allele in dominant haploinsufficiency. Sundew and Myrtle study dominant optic atrophy, not an established biallelic Behr treatment. Biallelic genotypes and systemic involvement require separate assessment; upregulation may be inadequate for dominant-negative alleles.
  therapeutic_modality: ANTISENSE_OLIGONUCLEOTIDE
  oligonucleotide_details:
    target_gene:
      preferred_term: OPA1
      term:
        id: hgnc:8140
        label: OPA1
  treatment_term:
    preferred_term: Antisense Therapy
    term:
      id: NCIT:C16236
      label: Antisense Therapy
  evidence:
  - reference: PMID:41318849
    reference_title: Advanced therapies for inherited optic neuropathies.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
    snippet: A therapeutic strategy is, therefore, to enhance the expression of the wild-type allele to restore normal protein levels. One way this can be achieved is with antisense oligonucleotides (ASO).
    explanation: This is a mechanistic extrapolation from dominant haploinsufficiency, not demonstrated Behr efficacy.
- name: Intravenous Arginine (Unsuccessful Case Trial)
  description: Intravenous arginine was tried for a suspected metabolic stroke in one biallelic OPA1 child without clinical or radiological improvement. This negative case observation does not support routine efficacy.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: arginine
      term:
        id: CHEBI:29016
        label: arginine
  evidence:
  - reference: PMID:38369985
    reference_title: Recurrent super-refractory status epilepticus and stroke like episode in a patient with Behr syndrome secondary to biallelic variants in OPA1 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: they recommended a trial of IV arginine infusion which he tolerated well with no side effects, but which did not lead to improvement of the suspected stroke radiologically or clinically.
    explanation: The later report documents the clinical interpretation and negative treatment response in the same child described by Othman2022.
- name: Ketogenic Diet (Unsuccessful Case Trial)
  description: A modified ketogenic diet was used during treatment of refractory seizures in one biallelic OPA1 child, then discontinued with lacosamide because seizure control was inadequate. This case does not establish either general benefit or general inefficacy.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Ketogenic Diet
    term:
      id: NCIT:C173168
      label: Ketogenic Diet
  evidence:
  - reference: PMID:38369985
    reference_title: Recurrent super-refractory status epilepticus and stroke like episode in a patient with Behr syndrome secondary to biallelic variants in OPA1 gene.
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: Lacosamide and ketogenic diet were discontinued during this admission since they were felt to be ineffective in controlling the seizures.
    explanation: Directly reported negative case experience.
- name: Feeding Support
  description: Swallowing assessment and nutritional support address feeding impairment and aspiration. Nasogastric feeds followed by gastrostomy were required after neurological regression in one child.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Nutritional Support
    term:
      id: NCIT:C15433
      label: Nutritional Support
  evidence:
  - reference: PMID:38369985
    reference_title: Recurrent super-refractory status epilepticus and stroke like episode in a patient with Behr syndrome secondary to biallelic variants in OPA1 gene.
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: he could no longer walk, had lost most of his ability to speak, and required nasogastric tube feeds due to aspiration. After therapy, he eventually regained a few useful words, but went on to require gastrostomy placement.
    explanation: Aspiration and tube-feeding requirement document clinically important swallowing dysfunction.
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
  mechanistic_category:
  - classification_value: mitochondrial disease
experimental_models:
- name: iPS-OPA1-BEHR
  description: >-
    The transgene-free iPS-OPA1-BEHR line was generated from a 48-year-old patient with c.610+364G>A and
    c.1311A>G. The report establishes retained variants, pluripotency and three-germ-layer differentiation.
    It provides a model resource; it does not demonstrate retinal-neuron phenotypes or therapeutic rescue.
  experimental_model_type: IPSC_DERIVED_MODEL
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_source: Human skin fibroblasts from a Behr syndrome patient with compound heterozygous OPA1 mutations
  publication: PMID:27879217
  evidence:
  - reference: PMID:27879217
    reference_title: "Generation of optic atrophy 1 patient-derived induced pluripotent stem cells (iPS-OPA1-BEHR) for disease modeling of complex optic atrophy syndromes (Behr syndrome)."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Human skin fibroblasts were isolated from a 48-year-old patient carrying compound heterozygous mutations (c.610+364G>A and c.1311A>G) in OPA1, responsible for early onset optic atrophy complicated by ataxia and pyramidal signs (Behr syndrome; OMIM #210000)."
    explanation: >
      Documents the derivation of a Behr-syndrome patient iPSC line from compound
      heterozygous OPA1 fibroblasts, and independently confirms the compound
      heterozygous OPA1 genotype with the ataxia/pyramidal-sign phenotype.

    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Patient Fibroblasts With Biallelic OPA1 Variants
  experimental_model_type: PRIMARY_CELL_CULTURE
  organism:
    preferred_term: Homo sapiens
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  description: Patient fibroblasts support allele-specific RNA/protein studies, network imaging and bioenergetics. Deep-intronic-family cells demonstrated transcript decay and fragmentation; Ala394Thr cells showed stress-dependent ATP loss. Skin fibroblasts do not establish selective neuronal vulnerability.
  evidence:
  - reference: PMID:24970096
    reference_title: Pure and syndromic optic atrophy explained by deep intronic OPA1 mutations and an intralocus modifier.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: To suppress nonsense-mediated messenger RNA decay-dependent allelic decay we used puromycin treatment in patient derived fibroblasts. After this treatment, allelic balance on RNA level could be nearly restored back to normal, as proven by pyrosequencing.
    explanation: Puromycin rescue of allelic RNA imbalance supports nonsense-mediated decay in the deep-intronic family.
  - reference: PMID:28442211
    reference_title: Leigh-like neuroimaging features associated with new biallelic mutations in OPA1.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: We also observed in patients' fibroblasts a higher proportion of fragmented and intermediate mitochondria upon galactose treatment compared to controls
    explanation: Network morphology is measured directly; impaired fusion is the mechanistic interpretation.
  - reference: PMID:28494813
    reference_title: 'Not only dominant, not only optic atrophy: expanding the clinical spectrum associated with OPA1 mutations.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: INDIRECT
    snippet: The ATP content in P3 fi- broblasts was normal respect to controls in regular medium but significantly reduced in galactose medium reflecting the lower efficiency of ATP production by OXPHOS in stress condition
    explanation: Homozygous Ala394Thr fibroblasts show a stress-dependent ATP defect; it is not a universal resting ATP deficiency.
  modeled_mechanisms:
  - target: Mitochondrial Network Fragmentation
    relationship: RECAPITULATES
    limitations: Skin fibroblasts from selected genotypes do not reproduce neuronal selectivity.
    evidence:
    - reference: PMID:28442211
      reference_title: Leigh-like neuroimaging features associated with new biallelic mutations in OPA1.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: We also observed in patients' fibroblasts a higher proportion of fragmented and intermediate mitochondria upon galactose treatment compared to controls
      explanation: Network morphology is measured directly; impaired fusion is the mechanistic interpretation.
  - target: Oxidative Phosphorylation Deficiency
    relationship: MEASURES
    limitations: ATP content is culture-condition-dependent and one genotype is not representative of the entire disease.
    evidence:
    - reference: PMID:28494813
      reference_title: 'Not only dominant, not only optic atrophy: expanding the clinical spectrum associated with OPA1 mutations.'
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: The ATP content in P3 fi- broblasts was normal respect to controls in regular medium but significantly reduced in galactose medium reflecting the lower efficiency of ATP production by OXPHOS in stress condition
      explanation: Homozygous Ala394Thr fibroblasts show a stress-dependent ATP defect; it is not a universal resting ATP deficiency.
- name: MGM1/OPA1 Yeast Complementation
  experimental_model_type: OTHER
  organism:
    preferred_term: Saccharomyces cerevisiae
    term:
      id: NCBITaxon:4932
      label: Saccharomyces cerevisiae
  description: An MGM1/OPA1 chimera complements MGM1-deficient yeast. Ala394Thr markedly reduced respiratory growth, Val988Phe nearly abolished it, and Ile437Met had a milder defect. This assay supports variant dysfunction without reproducing human neurological disease or directly measuring catalytic GTPase activity.
  evidence:
  - reference: PMID:28494813
    reference_title: 'Not only dominant, not only optic atrophy: expanding the clinical spectrum associated with OPA1 mutations.'
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: yeast expressing the p.Ala394Thr displayed a marked reduction of respiratory growth, the p.Val988Phe mutation virtually abolished the activity of the mutant allele, while the defect observed with the p.Ile437Met mutant was milder
    explanation: Respiratory-growth complementation tests the three missense variants.
references:
- reference: PMID:28442211
  title: "Leigh-like neuroimaging features associated with new biallelic mutations in OPA1."
- reference: PMID:18158317
  title: "OPA1 mutations induce mitochondrial DNA instability and optic atrophy 'plus' phenotypes."
  findings:
  - statement: Multiple muscle mtDNA deletions were observed in heterozygous OPA1-plus patients. This supports broader OPA1 genome-maintenance biology but does not establish multiple deletions in biallelic Behr syndrome.
    supporting_text: these patients all harboured multiple deletions of mitochondrial DNA (mtDNA) in their skeletal muscle
- reference: PMID:26187298
  title: "Behr syndrome with homozygous C19ORF12 mutation."
- reference: PMID:35741767
  title: "Biallelic Optic Atrophy 1 (OPA1) Related Disorder-Case Report and Literature Review."
  findings:
  - statement: The report describes one child and reviews 21 previous biallelic OPA1 cases. Severe presentation and intragenic allele interactions are illustrated; neither prevalence nor a uniform phenotype can be inferred.
    supporting_text: A literature review of reported biallelic OPA1-related Behr syndrome was performed. Twenty-one cases have been previously reported.
- reference: PMID:30972688
  title: "Metabolic stroke in a patient with bi-allelic OPA1 mutations."
  findings:
  - statement: >-
      A girl with two OPA1 variants developed a metabolic stroke. Co-occurrence was proposed to explain
      severity; the case does not establish the mechanism of the stroke.
    supporting_text: "The co-occurrence of bi-allelic mutations can explain the \nseverity and the early onset of her disease."
- reference: PMID:27150940
  title: Recessive optic atrophy, sensorimotor neuropathy and cataract associated with novel compound heterozygous mutations in OPA1.
- reference: PMID:26380172
  title: Behr's Syndrome is Typically Associated with Disturbed Mitochondrial Translation and Mutations in the C12orf65 Gene.
- reference: PMID:38369985
  title: Recurrent super-refractory status epilepticus and stroke like episode in a patient with Behr syndrome secondary to biallelic variants in OPA1 gene.
- reference: PMID:40344041
  title: SARM1 loss protects retinal ganglion cells in a mouse model of autosomal dominant optic atrophy.
- reference: PMID:33159657
  title: Therapeutic Options in Hereditary Optic Neuropathies.
- reference: PMID:41318849
  title: Advanced therapies for inherited optic neuropathies.
- reference: PMID:24970096
  title: Pure and syndromic optic atrophy explained by deep intronic OPA1 mutations and an intralocus modifier.
- reference: PMID:28494813
  title: 'Not only dominant, not only optic atrophy: expanding the clinical spectrum associated with OPA1 mutations.'
- reference: PMID:25012222
  title: 'Reply: Early-onset Behr syndrome due to compound heterozygous mutations in OPA1.'
- reference: clinicaltrials:NCT06461286
  title: A Phase 1a Open-Label, Single Ascending Dose Study to Evaluate the Safety and Tolerability of Intravitreally Administered PYC-001 in Participants With Confirmed OPA1 Mutation-Associated Autosomal Dominant Optic Atrophy
- reference: clinicaltrials:NCT06970106
  title: A Phase 1b Open-Label, Randomized, Single Dose and Repeat Dose Study to Evaluate the Single and Repeat Dose Safety and Tolerability of Intravitreally Administered PYC-001 in Participants With Confirmed OPA1 Mutation-Associated Autosomal Dominant Optic Atrophy
notes: >-
  Behr was originally a clinical label for syndromic childhood optic atrophy, and both monoallelic and
  biallelic OPA1 presentations have been described. This entry follows the OPA1-defined MONDO/OMIM concept
  while retaining other molecular causes as differentials. Biallelic OPA1 disease spans a broader spectrum
  than the classical Behr constellation; case-specific severity, coexisting variants and absent features
  matter. Othman2022 and Jagadish2024 describe the same child and do not constitute independent replication.
  There are no established molecular subdivisions within this entry. Anatomical involvement does not by
  itself establish neuronal apoptosis or a particular cell type.
prevalence:
- population: Published biallelic OPA1 cases reviewed in 2022
  measure_type: CASES_IN_LITERATURE
  notes: The 2022 review identified 21 previously published cases and added its proband. This dated, selected literature count is not a population prevalence estimate; ascertainment, case overlap and clinical scope limit inference.
  evidence:
  - reference: PMID:35741767
    reference_title: Biallelic Optic Atrophy 1 (OPA1) Related Disorder-Case Report and Literature Review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: A literature review of reported biallelic OPA1-related Behr syndrome was performed. Twenty-one cases have been previously reported.
    explanation: This is a literature count, not a measured population rate.
mechanistic_hypotheses:
- hypothesis_group_id: sarm1_axon_death
  hypothesis_label: SARM1-dependent axon death executes retinal ganglion cell degeneration downstream of the OPA1 mitochondrial defect
  status: EMERGING
  description: "Sarm1 loss protects RGC bodies, optic-nerve axons and visual electrophysiology in heterozygous Opa1R290Q/+ mice without correcting fragmentation. The study found little change in respiration or mtDNA copy number, and proposed oxidative-stress signaling upstream of SARM1 without proving the intermediate route. Extrapolation to human biallelic OPA1 disease remains untested; the result does not establish ATP depletion as the trigger."
  evidence:
  - reference: PMID:40344041
    reference_title: SARM1 loss protects retinal ganglion cells in a mouse model of autosomal dominant optic atrophy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: INDIRECT
    snippet: Sarm1 KO nearly completely suppressed all the degeneration phenotypes without reversing mitochondrial fragmentation.
    explanation: Genetic rescue in heterozygous Opa1R290Q/+ mice supports a downstream degeneration pathway; applicability to biallelic human disease remains untested.
discussions:
- discussion_id: sarm1_human_translation
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Retinal Ganglion Cell Degeneration
  prompt: Does SARM1-dependent axon death drive retinal ganglion cell degeneration in human biallelic-OPA1 Behr syndrome, as it does in the Opa1 mouse model — and would SARM1 inhibition be neuroprotective in patients?
  rationale: The SARM1 rescue is demonstrated only in a mouse model of dominant (monoallelic) OPA1 optic atrophy. Its relevance to human recessive/biallelic OPA1 Behr syndrome — a more severe, multisystem, developmental disease — is unproven, so the model result cannot yet be assumed to translate.
  proposed_experiments:
  - experiment_id: exp_sarm1_human_biallelic_opa1
    name: Test SARM1-dependent axon death in human biallelic-OPA1 models
    description: Assess SARM1-pathway activation in patient-derived (biallelic-OPA1) neurons/iPSC-derived retinal ganglion cells, test whether SARM1 inhibition is neuroprotective in those models, and evaluate SARM1 axon-death biomarkers in patient samples.
  evidence:
  - reference: PMID:40344041
    reference_title: SARM1 loss protects retinal ganglion cells in a mouse model of autosomal dominant optic atrophy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: INDIRECT
    snippet: Sarm1 KO nearly completely suppressed all the degeneration phenotypes without reversing mitochondrial fragmentation.
    explanation: Genetic rescue in heterozygous Opa1R290Q/+ mice supports a downstream degeneration pathway; applicability to biallelic human disease remains untested.
synonyms:
- BEHRS
- OPA1-related Behr syndrome
- optic atrophy, infantile hereditary, Behr complicated form of
- optic atrophy in early childhood, associated with ataxia, spasticity, intellectual disability, and posterior column sensory loss
differential_diagnoses:
- name: MTRFR-related optic atrophy and spastic paraplegia
  disease_term:
    preferred_term: hereditary spastic paraplegia 55
    term:
      id: MONDO:0014020
      label: hereditary spastic paraplegia 55
  description: Biallelic MTRFR (formerly C12orf65) variants can produce the historical Behr phenotype through defective mitochondrial translation, rather than OPA1 membrane dynamics.
  distinguishing_features:
  - Molecular diagnosis in MTRFR distinguishes the disorders; optic atrophy, neuropathy, spasticity and Leigh-like changes overlap. Respiratory impairment was directly studied in MTRFR patient fibroblasts.
  evidence:
  - reference: PMID:26380172
    reference_title: Behr's Syndrome is Typically Associated with Disturbed Mitochondrial Translation and Mutations in the C12orf65 Gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Here we describe 4 patients with the classical Behr's syndrome phenotype from 3 unrelated families who carry homozygous nonsense mutations in the C12orf65 gene encoding a protein involved in mitochondrial translation.
    explanation: Four patients from three families had molecularly resolved MTRFR disease. Although the abstract calls both changes nonsense mutations, the full text identifies a truncating duplication and a synonymous splice-disrupting allele.
  - reference: PMID:26380172
    reference_title: Behr's Syndrome is Typically Associated with Disturbed Mitochondrial Translation and Mutations in the C12orf65 Gene.
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: IN_VITRO
    snippet: the patient cell lines showed a decrease in OCR when compared to controls. This difference is notably bigger after treating the cells with FCCP
    explanation: Patient-cell respiration supports mitochondrial dysfunction in this molecular differential.
- name: Costeff syndrome
  disease_term:
    preferred_term: 3-methylglutaconic aciduria type 3
    term:
      id: MONDO:0009787
      label: 3-methylglutaconic aciduria type 3
  description: Recessive OPA3-related optic atrophy with movement disorder was historically called a Behr subtype.
  distinguishing_features:
  - Elevated urinary 3-methylglutaconic/3-methylglutaric acids and biallelic OPA3 variants distinguish Costeff syndrome from OPA1 disease.
  evidence:
  - reference: PMID:25012222
    reference_title: 'Reply: Early-onset Behr syndrome due to compound heterozygous mutations in OPA1.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: This syndromic inherited optic neuropathy was originally linked to autosomal recessive OPA3 mutations among Iraqi Jewish patients with elevated urinary excretion of 3-methylglutaconic acid and 3-methylglutaric acid
    explanation: The correspondence summarizes the historically overlapping but molecularly distinct Costeff phenotype.
- name: C19orf12-related mitochondrial membrane protein-associated neurodegeneration
  description: Two sisters with a clinical Behr phenotype were molecularly diagnosed with C19orf12-associated MPAN.
  distinguishing_features:
  - Basal-ganglia hypointensities suggesting brain iron accumulation and the C19orf12 genotype distinguish this from the OPA1-associated hyperintense Leigh-like lesions.
  evidence:
  - reference: PMID:26187298
    reference_title: Behr syndrome with homozygous C19ORF12 mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Magnetic resonance imaging of the brain showed bilateral hypointense signals in the basal ganglia which prompted us to consider neurodegeneration with brain iron accumulation (NBIA) as a differential diagnosis.
    explanation: The imaging pattern prompted the alternative molecular diagnosis.
  - reference: PMID:26187298
    reference_title: Behr syndrome with homozygous C19ORF12 mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Molecular genetic studies revealed a homozygous mutation in the C19ORF12 gene
    explanation: Molecular testing identified the distinct cause.
  disease_term:
    preferred_term: neurodegeneration with brain iron accumulation 4
    term:
      id: MONDO:0013674
      label: neurodegeneration with brain iron accumulation 4
animal_models:
- name: Opa1R290Q/+ Sarm1 Knockout Mouse
  description: Heterozygous dominant-negative Opa1R290Q/+ mice develop age-dependent RGC and optic-nerve degeneration. Sarm1 deletion preserved RGC number, axons and visual electrophysiology without correcting fragmentation. The rescue comparison used Sarm1-heterozygous controls and lacked same-cohort Opa1R290Q/+ Sarm1+/+ controls. This is a dominant OPA1 model, not a model of biallelic multisystem Behr syndrome.
  evidence:
  - reference: PMID:40344041
    reference_title: SARM1 loss protects retinal ganglion cells in a mouse model of autosomal dominant optic atrophy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Sarm1 KO nearly completely suppressed all the degeneration phenotypes without reversing mitochondrial fragmentation.
    explanation: Genetic rescue in heterozygous Opa1R290Q/+ mice supports a downstream degeneration pathway; applicability to biallelic human disease remains untested.
  - reference: PMID:40344041
    reference_title: SARM1 loss protects retinal ganglion cells in a mouse model of autosomal dominant optic atrophy.
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: MODEL_ORGANISM
    snippet: Since we did not include a littermate control of Opa1R290Q/+ Sarm1 +/+ in the same cohort, we could not definitively determine whether the heterozygous Sarm1 muta- tion also provided protective effects against RGC degeneration in ADOA.
    explanation: The control genotype limits inference about dose-dependent SARM1 inhibition.
  species: Mus musculus
  genotype: Opa1R290Q/+ with Sarm1−/− rescue; Sarm1+/− comparison animals
  modeled_mechanisms:
  - target: Retinal Ganglion Cell Degeneration
    relationship: PARTIALLY_RECAPITULATES
    limitations: Dominant heterozygous mouse allele, not human biallelic multisystem disease; the intervention is germline Sarm1 deletion rather than a clinical inhibitor.
    evidence:
    - reference: PMID:40344041
      reference_title: SARM1 loss protects retinal ganglion cells in a mouse model of autosomal dominant optic atrophy.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Sarm1 KO nearly completely suppressed all the degeneration phenotypes without reversing mitochondrial fragmentation.
      explanation: Genetic rescue in heterozygous Opa1R290Q/+ mice supports a downstream degeneration pathway; applicability to biallelic human disease remains untested.
    - reference: PMID:40344041
      reference_title: SARM1 loss protects retinal ganglion cells in a mouse model of autosomal dominant optic atrophy.
      supports: SUPPORT
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      evidence_source: MODEL_ORGANISM
      snippet: Since we did not include a littermate control of Opa1R290Q/+ Sarm1 +/+ in the same cohort, we could not definitively determine whether the heterozygous Sarm1 muta- tion also provided protective effects against RGC degeneration in ADOA.
      explanation: The control genotype limits inference about dose-dependent SARM1 inhibition.
clinical_trials:
- name: NCT06461286
  description: Sundew tests intravitreal PYC-001 in OPA1-associated autosomal dominant optic atrophy. This is related-disease research, not a Behr-specific trial or evidence of efficacy in biallelic OPA1 disease.
  status: ACTIVE_NOT_RECRUITING
  notes: Registry checked 2026-09-30. Enrollment is directed to dominant OPA1 disease; the eligibility criteria do not establish eligibility of patients with biallelic multisystem Behr syndrome.
  evidence:
  - reference: clinicaltrials:NCT06461286
    reference_title: A Phase 1a Open-Label, Single Ascending Dose Study to Evaluate the Safety and Tolerability of Intravitreally Administered PYC-001 in Participants With Confirmed OPA1 Mutation-Associated Autosomal Dominant Optic Atrophy
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: A First-in-Human multi-centre, prospective, Phase1a, Single Ascending Dose (SAD) interventional study of PYC-001 in participants with confirmed OPA1 mutation (haploinsufficiency) associated ADOA.
    explanation: Trial registry description establishes the related ADOA study population, not Behr treatment efficacy.
  phase: PHASE_I
- name: NCT06970106
  description: Myrtle tests intravitreal PYC-001 in OPA1-associated autosomal dominant optic atrophy. This is related-disease research, not a Behr-specific trial or evidence of efficacy in biallelic OPA1 disease.
  status: RECRUITING
  notes: Registry checked 2026-09-30. Enrollment is directed to dominant OPA1 disease; the eligibility criteria do not establish eligibility of patients with biallelic multisystem Behr syndrome. The current registry lists Phase 1 and Phase 2 although the official title says Phase 1b; the single-valued phase field is left unset to preserve that distinction.
  evidence:
  - reference: clinicaltrials:NCT06970106
    reference_title: A Phase 1b Open-Label, Randomized, Single Dose and Repeat Dose Study to Evaluate the Single and Repeat Dose Safety and Tolerability of Intravitreally Administered PYC-001 in Participants With Confirmed OPA1 Mutation-Associated Autosomal Dominant Optic Atrophy
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: This study aims to gather safety data and determine the optimal dosing regimen for PYC-001 in participants with confirmed OPA1 mutation-associated ADOA. Approximately 18 participants from Australia, New Zealand, and other APAC countries are expected to be enrolled, depending on safety review committee (SRC) throughout the course of the study.
    explanation: Trial registry description establishes the related ADOA study population, not Behr treatment efficacy.

📚

References & Deep Research

References

16

PMID:28442211

Leigh-like neuroimaging features associated with new biallelic mutations in OPA1.

No top-level findings curated for this source.

PMID:18158317

OPA1 mutations induce mitochondrial DNA instability and optic atrophy 'plus' phenotypes.

1 finding

Multiple muscle mtDNA deletions were observed in heterozygous OPA1-plus patients. This supports broader OPA1 genome-maintenance biology but does not establish multiple deletions in biallelic Behr syndrome.

"these patients all harboured multiple deletions of mitochondrial DNA (mtDNA) in their skeletal muscle"

PMID:26187298

Behr syndrome with homozygous C19ORF12 mutation.

No top-level findings curated for this source.

PMID:35741767

Biallelic Optic Atrophy 1 (OPA1) Related Disorder-Case Report and Literature Review.

1 finding

The report describes one child and reviews 21 previous biallelic OPA1 cases. Severe presentation and intragenic allele interactions are illustrated; neither prevalence nor a uniform phenotype can be inferred.

"A literature review of reported biallelic OPA1-related Behr syndrome was performed. Twenty-one cases have been previously reported."

PMID:30972688

Metabolic stroke in a patient with bi-allelic OPA1 mutations.

1 finding

A girl with two OPA1 variants developed a metabolic stroke. Co-occurrence was proposed to explain severity; the case does not establish the mechanism of the stroke.

"The co-occurrence of bi-allelic mutations can explain the severity and the early onset of her disease."

PMID:27150940

Recessive optic atrophy, sensorimotor neuropathy and cataract associated with novel compound heterozygous mutations in OPA1.

No top-level findings curated for this source.

PMID:26380172

Behr's Syndrome is Typically Associated with Disturbed Mitochondrial Translation and Mutations in the C12orf65 Gene.

No top-level findings curated for this source.

PMID:38369985

Recurrent super-refractory status epilepticus and stroke like episode in a patient with Behr syndrome secondary to biallelic variants in OPA1 gene.

No top-level findings curated for this source.

PMID:40344041

SARM1 loss protects retinal ganglion cells in a mouse model of autosomal dominant optic atrophy.

No top-level findings curated for this source.

PMID:33159657

Therapeutic Options in Hereditary Optic Neuropathies.

No top-level findings curated for this source.

PMID:41318849

Advanced therapies for inherited optic neuropathies.

No top-level findings curated for this source.

PMID:24970096

Pure and syndromic optic atrophy explained by deep intronic OPA1 mutations and an intralocus modifier.

No top-level findings curated for this source.

PMID:28494813

Not only dominant, not only optic atrophy: expanding the clinical spectrum associated with OPA1 mutations.

No top-level findings curated for this source.

PMID:25012222

Reply: Early-onset Behr syndrome due to compound heterozygous mutations in OPA1.

No top-level findings curated for this source.

clinicaltrials:NCT06461286

A Phase 1a Open-Label, Single Ascending Dose Study to Evaluate the Safety and Tolerability of Intravitreally Administered PYC-001 in Participants With Confirmed OPA1 Mutation-Associated Autosomal Dominant Optic Atrophy

No top-level findings curated for this source.

clinicaltrials:NCT06970106

A Phase 1b Open-Label, Randomized, Single Dose and Repeat Dose Study to Evaluate the Single and Repeat Dose Safety and Tolerability of Intravitreally Administered PYC-001 in Participants With Confirmed OPA1 Mutation-Associated Autosomal Dominant Optic Atrophy

No top-level findings curated for this source.

Deep Research

2

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

Evaluations and curation notes (4)

Address ai4c-reviewer completeness review: Behr Syndrome (PR #7267) · 2026-07-31T06:01:34Z · View source

Responded to the ai4c-reviewer REQUEST_CHANGES (completeness only; zero correctness issues). Added: diagnosis section (molecular/MRI-MRS/muscle-biopsy/NCS); prevalence (CASES_IN_LITERATURE, BELOW_1_IN_1000000); biochemical (COX deficiency, elevated lactate); SARM1 mechanistic_hypotheses (EMERGING) + a HUMAN_MODEL_MISMATCH discussion + hypothesis_groups edge; genetic variant/modifier depth (verified compound-het p.L620fs/p.R905Q architecture + asymptomatic-modifier second allele); phenotypes Impaired proprioception and Ophthalmoplegia; onset descriptors; term refinements (Peripheral axonal neuropathy HP:0003477, Developmental cataract HP:0000519). Split two bundled pathophysiology nodes into six atomic nodes and added conforms_to for peripheral_axonal_degeneration and cerebellar_purkinje_degeneration. Decomposed treatments with therapeutic_modality and added idebenone/gene-therapy as experimental/class-extrapolated with PARTIAL evidence. NOT added: the DR-suggested OPA1 p.Ile382Met modifier allele and posterior-column wording were unverifiable in cached abstracts, so a verified compound-het genotype and 'position/vibration decreased' snippet were used instead; classifications block deferred (enum lives in imported schema). All 44 evidence snippets verified as exact substrings of cached abstracts; just validate clean; full data test suite passed (3393).

Incorporate OpenScientist deep research + red-team fixes: Behr Syndrome · 2026-07-31T02:35:24Z · View source

Post-creation pass. (1) Red-team self-review fixes: repaired a dangling causal edge (Ataxia -> Cerebellar ataxia), connected orphaned distal phenotypes (intellectual disability, sensorineural hearing loss, seizure), softened an unsupported frequency claim on motor delay, and added a genetic scope note (this entry models the OPA1-recessive pathomechanism; OPA3/C12orf65 Behr-like forms out of scope). (2) Incorporated OpenScientist deep-research findings with independent verification: added a SARM1-dependent axon-death mechanism to the retinal ganglion cell node (PMID:40344041, mouse OPA1 model, MODEL_ORGANISM), a Nystagmus phenotype (PMID:35741767, PMID:26380172), and strengthened the OPA1 genetic block with the 21-case biallelic literature review (PMID:35741767). NEC/anti-hallucination check: the OpenScientist report asserted MONDO:0008623 and ORPHA:1272 for Behr syndrome, both incorrect (MONDO:0008623 is Undritz anomaly; correct IDs are MONDO:0008858 and Orphanet:1239 per OAK) - the entry retains the OAK-verified identifiers. All 31 evidence snippets verified as exact substrings of cached PubMed abstracts. just validate clean; compliance 84.1 percent.

Create: Behr Syndrome · 2026-07-31T02:13:39Z · View source

Created de-novo Behr Syndrome (MONDO:0008858) entry, curated as the severe autosomal-recessive end of the OPA1-related optic atrophy spectrum (biallelic/compound-heterozygous OPA1). Deep research provider: OpenScientist. Pathophysiology modeled as a 4-node chain: biallelic OPA1 loss of function and impaired mitochondrial fusion, then bioenergetic OXPHOS failure, then retinal ganglion cell degeneration (optic atrophy) plus central/peripheral neurodegeneration (cerebellar ataxia, pyramidal spasticity, axonal neuropathy). Ten HP-termed phenotypes plus genetics and NCIT-coded supportive treatments (no MAXO used, per curator instruction). All 25 evidence snippets verified as exact substrings of cached PubMed abstracts; key PMIDs 25012220, 28442211, 27150940, 38369985, 33340656, 18158317. No active GeneReviews chapter exists for Behr syndrome. Validated with just validate (schema, terms, references clean); compliance 85.7 percent (weighted 86.5).

Create: Behr Syndrome · 2026-07-30T23:30:20Z · View source

Created Behr Syndrome MONDO:0008858 / OMIM:210000 anchored to biallelic OPA1 loss of function, autosomal recessive - the molecularly resolved core form - with documented locus heterogeneity OPA3/Costeff and C12orf65/MTRFR. Modeled the mitochondrial-bioenergetic pathophysiology chain: biallelic OPA1 LoF impairs inner-membrane fusion and cristae, causes mtDNA instability and OXPHOS failure, driving retinal ganglion cell degeneration - optic atrophy - and central/peripheral neurodegeneration - ataxia, spastic paraparesis, peripheral neuropathy, intellectual disability. Evidence from verified primary literature: PMID:28442211 biallelic OPA1 Behr with Leigh-like features, PMID:18158317 OPA1 GTPase fusion cristae mtDNA, PMID:26187298 genetic heterogeneity OPA1/OPA3/C12ORF65. Deep-research provider falcon Edison query launched. All snippets validated as exact abstract substrings; schema, term, and reference validation pass. Post-curation self-review (red-team, fresh context) verified every snippet as an exact abstract substring and all ontology labels via OAK, producing three fixes: added a C19orf12 (hgnc:25443) genetic entry - the headline result of PMID:26187298, previously cited but with its actual finding unused; relaxed the spasticity phenotype from HP:0002313 spastic paraparesis to HP:0001257 Spasticity so the term matches what the cited pyramidal-signs snippet actually supports; and corrected parents from Autosomal Dominant Optic Atrophy Plus to OPA1-Related Optic Atrophy, since parenting a recessive disorder under the dominant plus-syndrome was genetically inconsistent (MONDO parents Behr under MONDO:0800181). Flagged for maintainer review: OPA3/C12orf65/C19orf12 typed CAUSATIVE under an OPA1-anchored MONDO term is a deliberate lump/split call consistent with treating Behr as a clinically defined heterogeneous syndrome.

Falcon ▸

Behr Syndrome: Comprehensive Disease-Characteristics Report

Edison Scientific Literature 21 citations 2026-07-30T23:31:24.702628

Behr Syndrome: Comprehensive Disease-Characteristics Report

Scope and evidence date. This report treats “Behr syndrome” in its modern, molecularly resolved sense: a severe, usually childhood-onset biallelic OPA1-related neuro-ophthalmologic disorder. Historical use was phenotype-based and can encompass genetically distinct “Behr-like” disorders. Most evidence comes from aggregated disease resources, small case series, individual patients, and OPA1 cellular/animal models—not EHR-scale cohorts or randomized Behr-specific trials.

Executive summary

Behr syndrome is a very rare Mendelian mitochondrial-neurodegenerative syndrome characterized by early bilateral optic atrophy followed or accompanied by cerebellar ataxia, pyramidal signs/spasticity, peripheral neuropathy, and variably developmental, auditory, gastrointestinal, muscular, and cerebral abnormalities. Current disease-resource evidence maps it to MONDO:0008858 and strongly associates it with OPA1; Open Targets reports an association score of 0.812 and cites genetic evidence including PMID 27604308, 17722006, 28494813, 24970096, 11017079, 27150940, 11017080, 25012220, and 35741767. (OpenTargets Search: Behr syndrome)

The mechanistic core is failure of OPA1-dependent inner-mitochondrial-membrane fusion and crista organization, producing mitochondrial fragmentation, respiratory dysfunction, impaired mtDNA maintenance, disturbed calcium/redox homeostasis, excessive mitophagy or apoptosis, and preferential degeneration of metabolically demanding long-projecting neurons—especially retinal ganglion cells. No approved disease-modifying therapy or Behr-specific treatment trial exists; current care is multidisciplinary and supportive. Trials of the oligonucleotide PYC-001 concern dominant OPA1 haploinsufficiency and expressly exclude ADOA-plus phenotypes, so they should not be represented as Behr-syndrome trials. (NCT06970106 chunk 1, NCT06970106 chunk 2, NCT06461286 chunk 1, NCT06461286 chunk 2)

1. Disease information

Definition and nosology

Behr syndrome is a syndromic hereditary optic neuropathy in which childhood optic atrophy occurs with spinocerebellar degeneration, pyramidal-tract dysfunction, and peripheral neuropathy. A current review describes it as childhood-onset optic atrophy with “ataxia and pyramidal signs including spasticity, weakness, and hyperreflexia.” (ojaimi2022mitochondrialfissionand pages 7-8)

Key identifiers

MONDO: MONDO:0008858.
OMIM/MIM: 210000.
Causal-gene resource mapping: OPA1, Ensembl ENSG00000198836; approved name “OPA1 mitochondrial dynamin like GTPase.” (OpenTargets Search: Behr syndrome)
MeSH: no retrieved disease-specific descriptor; broader applicable descriptors include Optic Atrophies, Hereditary (D015418), Optic Atrophy (D009896), and Mitochondrial Diseases (D028361). (NCT06461286 chunk 2)
ICD-10/ICD-11: no uniquely validated Behr-syndrome code was identified. Coding generally falls under hereditary optic atrophy/optic-nerve or mitochondrial disease categories; local coding should not be treated as molecularly specific.
Orphanet: a reliable disease-specific ORPHA number was not recovered from the available evidence and should be curator-verified rather than inferred.

Synonyms/labels: Behr’s syndrome; complicated hereditary infantile optic atrophy; complicated optic atrophy; OPA1-related Behr syndrome; Behr-related syndrome; recessive/compound-heterozygous OPA1 optic atrophy. “DOA-plus” overlaps phenotypically but generally refers to multisystem disease from monoallelic OPA1 variants and is not always equivalent.

Important terminology warning: OPA3-related Costeff syndrome—3-methylglutaconic aciduria type III—is a close differential, not a strict synonym. OPA3 can also cause dominant optic atrophy-cataract-plus disease. Primary literature supporting OPA3 phenotypes includes PMID 15342707, 22797356, 24136862, and 28050599. (weisschuh2021mutationspectrumof pages 17-18)

2. Etiology, causal factors, and risks

Genetic cause

The established cause is biallelic germline pathogenic variants in OPA1, usually compound heterozygous and less commonly homozygous, producing autosomal-recessive disease. By 2011, 14 affected individuals from 13 families carrying compound-heterozygous or homozygous OPA1 variants had been documented. The first molecularly defined case, reported in 2001, carried two heterozygous missense variants in exon 8. (nottia2021mitochondrialdynamicsmolecular pages 8-10)

OPA1 variants across the broader disease spectrum include missense, nonsense, frameshift, splice-altering, and copy-number alleles. In a 755-proband optic-atrophy cohort, 278 probands (36.8%) had putatively pathogenic OPA1 variants; 156 unique variants were found, 78% were null alleles, and c.2708_2711del/p.(Val903Glyfs3) represented 14% of disease-causing alleles. These are OPA1-spectrum statistics*, not Behr-specific frequencies. The study classified nine novel variants as pathogenic, 34 as likely pathogenic, and five as VUS. DOI: https://doi.org/10.1371/journal.pone.0253987, published 9 July 2021. (weisschuh2021mutationspectrumof pages 17-18)

A typical recessive genotype combines a severe loss-of-function allele with a hypomorphic missense allele; two severe alleles can cause a much more severe mitochondrial encephalomyopathy, sometimes with cardiomyopathy, lactic acidemia, and death. Variant interpretation must therefore be allele- and phase-specific. Homozygous or compound severe alleles should not automatically be equated with the survivable classic Behr phenotype. (nottia2021mitochondrialdynamicsmolecular pages 8-10)

All established causal variants are constitutional/germline. Somatic mutation is not a recognized Behr mechanism. Population allele frequency must be checked variant-by-variant in gnomAD/TOPMed; no defensible aggregate carrier frequency was found. Pathogenic recessive alleles are expected to be rare, and an allele too frequent for this ultra-rare phenotype requires reassessment.

Environmental, lifestyle, infectious, and protective factors

No environmental toxin, infection, diet, occupation, smoking pattern, sex, or lifestyle exposure is established as a cause or penetrance determinant. No validated protective genetic allele, dietary factor, or gene-environment interaction has been demonstrated specifically for Behr syndrome. General mitochondrial-health advice—avoid smoking, excessive alcohol, malnutrition, and unnecessary mitochondrial-toxic drugs—is prudent but not proven to alter this disease’s natural history.

Family history, parental consanguinity, and ancestry can increase the prior probability of recessive disease but are not biological causes independent of genotype. No robust founder effect, anticipation, germline-mosaicism rate, or sex bias has been established.

3. Phenotypes

The phenotype is highly variable, and Behr-specific percentages are generally unavailable because published cohorts are very small.

Bilateral optic atrophy/optic neuropathy—usually infancy or childhood onset, progressive and irreversible; impaired acuity, color vision, central/centrocecal field loss, and later severe visual disability. Suggested HPO: HP:0000648.
Ataxia/spinocerebellar degeneration—childhood or later, generally progressive; dysmetria, dysdiadochokinesia, nystagmus, and gait instability. HPO: HP:0001251; dysmetria and nystagmus may be separately encoded.
Pyramidal signs—spasticity, hyperreflexia, weakness, and sometimes extensor plantar responses; progressive mobility limitation. HPO: HP:0001257 and relevant hyperreflexia terms.
Peripheral neuropathy/posterior-column dysfunction—sensory loss, weakness, areflexic components, pes cavus, and contractures. HPO: HP:0009830, HP:0001761.
Developmental delay/hypotonia—particularly in severe early-onset disease; delayed motor milestones may precede gait decline. HPO: HP:0001263, HP:0001252.
Hearing impairment, often sensorineural; HPO: HP:0000365.
Dysarthria and dysphagia; HPO: HP:0001260, HP:0002015.
Gastrointestinal dysmotility—vomiting, constipation, dysphagia, and feeding difficulty.
Musculoskeletal manifestations—pes cavus and severe lower-limb contractures.
Severe-variable manifestations—lactic acidemia, myopathy, cardiomyopathy, developmental encephalopathy, and Leigh-like episodes have occurred in the most severe biallelic disease. (ojaimi2022mitochondrialfissionand pages 7-8, nottia2021mitochondrialdynamicsmolecular pages 8-10)

MRI can show optic-nerve/chiasm atrophy, cerebellar or vermian atrophy (HP:0001272), periventricular white-matter abnormalities, and occasionally Leigh-like basal-ganglia hyperintensities with lactate accumulation. (ojaimi2022mitochondrialfissionand pages 7-8, nottia2021mitochondrialdynamicsmolecular pages 8-10)

Quality-of-life impact

No Behr-specific EQ-5D, SF-36, PROMIS, or utility study was identified. Expected burden is substantial: visual impairment limits reading, education, orientation, and driving; ataxia/spasticity/neuropathy impair walking and self-care; hearing loss and dysarthria impair communication; dysphagia and contractures add aspiration, nutrition, pain, and caregiver burdens. These effects are clinically plausible but have not been quantified with a validated Behr-specific instrument.

4. Genetic and molecular information

OPA1 encodes a ubiquitously expressed dynamin-like GTPase localized to the mitochondrial inner membrane. More than 500 OPA1 variants had been described in a 2024 review; the two principal mechanisms across dominant disease are haploinsufficiency and dominant-negative interference. Splice/deletion null alleles often cause haploinsufficiency, whereas some missense alleles exert stronger functional effects. Compound heterozygosity can shift disease from isolated dominant optic atrophy to early multisystem Behr syndrome. (lee2024hereditaryopticneuropathies pages 5-7)

For a knowledge-base entry, each reported allele should include HGVS transcript, genome build, phase, ClinVar accession, ACMG/AMP classification, gnomAD ancestry-specific frequency, and functional assay. VUS should not be promoted to causal without segregation, transcript, protein, or mitochondrial-function evidence. Deep-intronic splice variants and copy-number changes are diagnostically relevant; RNA/minigene analysis may resolve uncertain splice effects.

No reproducible modifier gene is established. Patient-derived neurons carrying the same OPA1 variant can have different clinical severity, but candidate modifiers remain unresolved. Broader OPA1 work reports altered CpG methylation and downregulation of developmental genes in OPA1-haploinsufficient neural progenitors; this is mechanistic model evidence, not a validated Behr epigenetic biomarker. (dotto2021dominantopticatrophy pages 5-6)

No recurrent disease-defining aneuploidy, translocation, inversion, or large chromosomal syndrome is established. Consequently, karyotyping, FISH, and CMA are not first-line unless the phenotype suggests an independent chromosomal diagnosis.

5. Environmental information

No toxin, radiation exposure, pollutant, occupational exposure, lifestyle factor, or infectious agent is known to initiate Behr syndrome. It is not infectious, transmissible, or zoonotic. Evidence for oxidative stress is downstream of inherited mitochondrial dysfunction rather than proof of an environmental etiology. Environmental avoidance recommendations should therefore be labeled precautionary, not disease-preventive.

6. Mechanism and pathophysiology

Causal chain

Upstream genetic trigger: two functionally damaging OPA1 alleles reduce or qualitatively impair OPA1.
Primary organellar defect: impaired inner-membrane fusion, cardiolipin-dependent membrane remodeling, and crista-junction organization cause fragmented mitochondria and disordered cristae.
Bioenergetic/quality-control consequences: destabilized respiratory-chain supercomplexes, reduced oxygen consumption/OXPHOS, impaired mtDNA maintenance or depletion, abnormal calcium handling, ROS stress, and altered autophagy/mitophagy.
Cell-death and connectivity consequences: cytochrome-c/apoptotic susceptibility, reduced axonal mitochondrial density, defective synaptogenesis, and progressive axonal degeneration.
Tissue selectivity: retinal ganglion cells and long central/peripheral neurons have high energy demand and long axons, making them particularly vulnerable; degeneration produces optic atrophy, corticospinal signs, neuropathy, and cerebellar dysfunction. OPA1 also regulates cytochrome-c release and apoptosis. (strachan2025novelinvivo pages 1-2, dotto2021dominantopticatrophy pages 10-11, alavi2013dominantopticatrophy pages 1-3, fogazza2018biochemicalcharacterizationand pages 35-38)

Human cellular and muscle observations include fragmented mitochondrial networks, ragged-red fibers, diminished cytochrome-c oxidase staining, reduced complex-IV activity, and mtDNA depletion in severe disease. (nottia2021mitochondrialdynamicsmolecular pages 8-10, ojaimi2022mitochondrialfissionand pages 7-8)

Suggested GO annotations: mitochondrial inner membrane fusion (GO:0007342), mitochondrial inner membrane (GO:0005743), mitochondrial crista, mitochondrial organization, oxidative phosphorylation, respiratory electron transport, mitochondrial DNA maintenance, mitophagy, intrinsic apoptotic signaling, calcium-ion homeostasis, and response to oxidative stress. Exact current GO IDs beyond those shown should be ontology-version checked.

Suggested cells: retinal ganglion cell (CL:0000704, verify current release), cerebellar neuron/Purkinje cell, corticospinal motor neuron, peripheral sensory neuron, peripheral motor neuron, and skeletal myocyte. Only retinal-ganglion-cell vulnerability is directly and repeatedly demonstrated; other cell assignments partly follow clinical localization.

Molecular profiling and advanced technologies

Metabolomic work in OPA1-disrupted fibroblasts identified a bioenergetic signature including aspartate deficiency; lipidomics found triacylglycerol accumulation from impaired fatty-acid flux. These findings are not validated clinical biomarkers. iPSC lines have been generated directly from a Behr patient for disease modeling (Hauser et al., Stem Cell Research, 2016; DOI https://doi.org/10.1016/j.scr.2016.09.012). Broader OPA1 iPSC neurons exhibit reduced oxygen consumption, complex-I abundance/activity, mitochondrial fragmentation, ROS elevation, impaired axonal mitochondrial distribution, and loss of synaptic contacts. (dotto2021dominantopticatrophy pages 10-11, dotto2021dominantopticatrophy pages 5-6)

No validated Behr-specific single-cell atlas, spatial-transcriptomic signature, plasma proteomic panel, metabolomic diagnostic classifier, or multi-omics prognostic model was identified.

7. Anatomical structures affected

Primary: bilateral retina—especially retinal ganglion-cell layer—and optic nerves/optic chiasm. Neurologic: cerebellum and vermis, corticospinal/pyramidal tracts, posterior columns, peripheral nerves, and variably cerebral white matter/basal ganglia. Secondary/variable: skeletal muscle, auditory pathway, gastrointestinal neuromuscular system, and heart in severe biallelic disease. (ojaimi2022mitochondrialfissionand pages 7-8, nottia2021mitochondrialdynamicsmolecular pages 8-10)

Suggested UBERON terms include retina, retinal ganglion-cell layer, optic nerve, optic chiasm, cerebellum, cerebellar vermis, corticospinal tract, spinal-cord posterior column, peripheral nerve, skeletal muscle, and heart. Exact IDs require release-specific verification. Ocular and neurologic involvement is generally bilateral; asymmetry can occur clinically but unilateral disease would be atypical and should prompt reconsideration.

Subcellular localization is predominantly the mitochondrial inner membrane and cristae; downstream abnormalities involve respiratory-chain complexes, mitochondrial nucleoids/mtDNA, and autophagic/lysosomal pathways.

8. Temporal development

Onset is usually insidious in infancy or childhood. Optic neuropathy and developmental/motor abnormalities often occur first; gait difficulty commonly becomes prominent in the second decade. Rare adult-onset optic atrophy-ataxia presentations are reported. Disease is chronic and generally progressive, not relapsing-remitting. (ojaimi2022mitochondrialfissionand pages 7-8, nottia2021mitochondrialdynamicsmolecular pages 8-10)

A practical—not formally validated—staging framework is:

Early: reduced visual acuity/color discrimination and optic pallor, sometimes delayed motor development.
Intermediate: gait ataxia, spasticity/hyperreflexia, neuropathy, dysarthria, and hearing impairment.
Advanced: severe visual disability, loss of independent ambulation, contractures, dysphagia, and multisystem complications.

No spontaneous remission pattern is established. The most plausible therapeutic window is before irreversible retinal-ganglion-cell and long-tract axonal loss, but this remains a mechanistic inference rather than a proven Behr intervention window.

9. Inheritance and population

Classic molecularly defined OPA1-related Behr syndrome is autosomal recessive. Recurrence risk is 25% per pregnancy when both parents are heterozygous carriers, with a 50% carrier probability and 25% probability of inheriting neither familial allele. Expressivity is variable and depends strongly on allele severity. Penetrance cannot be reliably quantified from available cohorts. Anticipation is not expected because repeat expansion is not the mechanism.

No population-based Behr prevalence or incidence was found. The approximately 1 in 30,000, and in some populations 1 in 12,000, estimates concern autosomal/dominant optic atrophy broadly—not Behr syndrome. Approximately 20% of autosomal optic atrophy cases have extraocular AOA-plus features, again not a Behr-specific statistic. (strachan2025novelinvivo pages 1-2)

No reliable sex ratio, age distribution, carrier frequency, geographic clustering, or ancestry-specific prevalence is available. Consanguinity can enrich homozygosity in individual families, but its population contribution is unquantified.

10. Diagnostics

Clinical evaluation

Diagnosis begins with bilateral optic atrophy plus neurologic examination for ataxia, pyramidal signs, neuropathy, developmental delay, hearing loss, and bulbar or gastrointestinal dysfunction. Recommended investigations include:

Best-corrected and low-contrast visual acuity, color testing, fundus examination, static perimetry.
Spectral-domain OCT of retinal nerve-fiber and ganglion-cell layers.
Visual evoked potentials; ERG when retinal dystrophy is a concern.
Brain/orbit MRI for optic nerve/chiasm and cerebellar/white-matter abnormalities.
Audiology, EMG/nerve-conduction studies, gait assessment, and swallowing evaluation as indicated.
Blood lactate, CK, metabolic panel, and ECG/echocardiography where systemic disease is suspected; normal results do not exclude Behr syndrome.
Muscle biopsy and respiratory-chain/mtDNA studies are now second-line, useful when sequencing is inconclusive or a severe mitochondrial phenotype requires functional clarification. Trial protocols illustrate current quantitative ophthalmic endpoints, including ETDRS acuity, perimetry, mfVEP, OCT RNFL/GCL, flavoprotein fluorescence, and retinal-apoptosis imaging. (NCT06970106 chunk 2, NCT06461286 chunk 1, NCT06461286 chunk 2)

Genetic testing strategy

Use a hereditary optic neuropathy/mitochondrial-neurodegeneration panel including OPA1, with deletion/duplication detection and adequate intronic splice coverage.
If unrevealing or phenotype is complex, use trio WES or WGS; broader genomic testing is preferred when no familial variant is known.
Confirm both variants, phase them in parents, apply ACMG/AMP criteria, and perform RNA studies for suspected splice variants.
mtDNA sequencing is useful for LHON/NARP/Leigh differentials but is not the primary test for OPA1-related Behr syndrome.
CMA, karyotype, FISH, and repeat-expansion testing are phenotype-directed, not routine Behr tests. (lee2024hereditaryopticneuropathies pages 5-7)

There are no universally accepted clinical criteria independent of molecular confirmation. Genetic diagnosis is therefore central.

Differential diagnosis

Major alternatives are OPA3/Costeff syndrome, dominant OPA1/DOA-plus, SPG7- and AFG3L2-related optic atrophy/spastic ataxia, MFN2 neuropathy, WFS1 spectrum, ACO2 cerebellar-retinal degeneration, SSBP1 mtDNA-maintenance disease, DNAJC30 recessive LHON, mitochondrial LHON/NARP/Leigh syndromes, Friedreich ataxia, complicated hereditary spastic paraplegias, and leukodystrophies. OPA3 disease is favored by 3-methylglutaconic aciduria and its characteristic genetic/ocular spectrum.

No newborn population screening is established. Cascade testing of relatives and targeted familial-variant testing are appropriate after molecular confirmation.

11. Outcome and prognosis

The usual course is lifelong and progressive. Vision loss generally does not spontaneously recover in OPA1 disease. Neurologic disability can advance from gait difficulty to loss of independent ambulation, with additional morbidity from contractures, falls, hearing loss, dysphagia, aspiration, and nutritional compromise. (lee2024hereditaryopticneuropathies pages 5-7)

No valid 5- or 10-year survival rate, median life expectancy, mortality rate, or Behr-specific quality-of-life statistic exists. Many patients survive into adulthood, but severe homozygous/biallelic mitochondrial encephalomyopathy can include cardiomyopathy and fatal outcomes. Prognosis likely depends on residual OPA1 function, age at onset, neurologic burden, cardiomyopathy/lactic acidosis, swallowing safety, and rate of visual/motor decline, but no validated prognostic model or biomarker exists. (nottia2021mitochondrialdynamicsmolecular pages 8-10)

12. Treatment

Current real-world management

No FDA/EMA-approved pharmacologic, gene, RNA, or cell therapy exists specifically for Behr syndrome. Management is individualized and multidisciplinary:

Low-vision rehabilitation, optical/electronic aids, educational accommodations, orientation and mobility training.
Physical and occupational therapy, gait aids, orthoses, stretching, contracture prevention, and fall prevention.
Symptomatic antispasticity treatment when benefits exceed weakness/sedation risks.
Speech-language therapy and augmentative communication.
Audiology and hearing aids/cochlear-implant assessment.
Swallow evaluation, diet modification, nutrition support, and gastrostomy when clinically necessary.
Neuropathic-pain treatment, orthopedic management, cardiology surveillance in severe phenotypes, and psychosocial support.

Suggested MAXO concepts include ophthalmologic examination, OCT, visual-field testing, low-vision therapy, physical therapy, occupational therapy, speech therapy, hearing-aid fitting, dysphagia management, enteral feeding, orthotic treatment, and genetic counseling; exact MAXO IDs should be curator-verified.

Idebenone has only weak, uncontrolled evidence in dominant optic atrophy: a small phase-II study reported a statistically significant but minor visual-acuity recovery after 12 months at 900 mg/day, with major limitations from sample size and lack of a control group. It cannot be considered established Behr treatment. (lee2024hereditaryopticneuropathies pages 5-7)

Experimental therapy and trials

NCT06461286 (Sundew) is a first-in-human phase 1a study of one intravitreal PYC-001 dose in approximately 18 adults with confirmed OPA1 haploinsufficiency-associated dominant optic atrophy; it began 31 October 2024 and was active, not recruiting, in the retrieved registry record. PYC-001 is an oligonucleotide therapeutic. Crucially, the protocol excludes ADOA-plus and non-haploinsufficiency mechanisms; therefore Behr patients are not the intended population. Registry URL: https://clinicaltrials.gov/study/NCT06461286. (NCT06461286 chunk 1, NCT06461286 chunk 2)

NCT06970106 (Myrtle) is a phase 1b/1–2 open-label dose study of intravitreal peptide-phosphorodiamidate morpholino PYC-001, estimated enrollment 24, with 10–60 µg single/repeat-dose cohorts. It began 30 September 2025 and was recruiting in the retrieved record. Eligibility again requires dominant OPA1 haploinsufficiency and excludes ADOA-plus/confounding variants. Registry URL: https://clinicaltrials.gov/study/NCT06970106. (NCT06970106 chunk 1, NCT06970106 chunk 2)

Gene augmentation, splice correction, CRISPR repair, iPSC-derived retinal-ganglion-cell replacement, antioxidant treatment, and mitophagy/necroptosis modulation remain preclinical. Their major challenge is the allele-specific combination of one severe and one hypomorphic OPA1 allele and the need to reach both retina and systemic nervous tissue.

13. Prevention

Primary lifestyle prevention and vaccination are not applicable to this inherited disorder. The principal prevention options are reproductive and molecular:

Genetic counseling and parental phasing.
Cascade carrier testing of adult relatives.
Prenatal diagnosis by CVS/amniocentesis when familial pathogenic variants are known.
IVF with preimplantation genetic testing for monogenic disease.
Early targeted testing of at-risk siblings to permit surveillance and rehabilitation before major functional loss.

Tertiary prevention includes fall prevention, contracture management, aspiration/nutrition surveillance, hearing and vision rehabilitation, and monitoring for cardiomyopathy or metabolic decompensation in severe cases. Avoiding tobacco, excessive alcohol, and unnecessary mitochondrial toxins is reasonable general advice but is not proven primary prevention.

14. Other species and natural disease

No well-established naturally occurring veterinary disease precisely equivalent to human biallelic OPA1 Behr syndrome was identified. OPA1 is evolutionarily conserved across vertebrates and invertebrate ortholog systems. There is no transmission or zoonotic potential.

OPA3-related natural/model phenotypes should not be merged with OPA1 Behr syndrome. A murine Opa3 missense model reproduces aspects of Costeff syndrome, and zebrafish opa3 models have illuminated metabolic/protective functions, but these model a differential disease mechanism rather than OPA1-related Behr syndrome.

15. Model organisms and experimental systems

Patient fibroblasts/muscle: mitochondrial fragmentation, COX/complex-IV defects, mtDNA depletion, and abnormal bioenergetics; directly relevant but limited in modeling retinal and long-axon vulnerability.
Patient-derived iPSCs: an “iPS-OPA1-BEHR” line was generated specifically for complex optic-atrophy/Behr modeling (DOI https://doi.org/10.1016/j.scr.2016.09.012). iPSC neurons enable studies of respiration, ROS, axonal mitochondrial transport, and synaptic degeneration but lack whole-organism natural history. (dotto2021dominantopticatrophy pages 10-11)
Mouse: heterozygous Opa1 models show age-dependent RGC dysfunction/loss, optic-nerve demyelination/axonal degeneration, mitochondrial ultrastructural abnormalities, and increased autophagy/mitophagy. Homozygous knockout is embryonic lethal, limiting recreation of survivable biallelic Behr disease. (dotto2021dominantopticatrophy pages 5-6)
Zebrafish: morpholino depletion causes developmental delay, small eyes, reduced circulation and heart rate, mitochondrial fragmentation, and impaired bioenergetics. A recent CRISPR Opa1 knockout produced visual impairment before RGC degeneration, fragmented axonal mitochondria, disordered cristae, and reduced respiration while early locomotion remained relatively preserved. This temporal ordering supports mitochondrial dysfunction as upstream of neuronal loss. DOI https://doi.org/10.1096/fj.202403271R; accepted 19 March 2025. (strachan2025novelinvivo pages 1-2)
Drosophila: Opa1 deficiency causes reduced survival, visual and cardiac abnormalities, elevated ROS, dysmorphic mitochondria, and age-dependent multisystem disease; useful for genetic and drug screens but anatomically distant from the human optic nerve.
C. elegans: eat-3 loss causes fragmented mitochondria, abnormal cristae, oxidative-stress sensitivity, progressive movement/neural defects, and altered mitophagy; valuable for pathway interrogation, not direct visual-phenotype modeling. (dotto2021dominantopticatrophy pages 5-6)
Yeast: MGM1, the OPA1 ortholog, is useful for functional classification of variants and mtDNA-instability assays but cannot model neuronal selectivity.

The strongest cross-model conclusion is that mitochondrial fragmentation and respiratory/visual dysfunction precede overt RGC loss, identifying mitochondrial maintenance as an upstream therapeutic target. Translation remains uncertain because most models represent haploinsufficiency or complete knockout rather than the compound severe-plus-hypomorphic genotype typical of Behr syndrome.

Recent developments and expert assessment

The most consequential 2023–2024 developments were improved broad genomic diagnosis for complex hereditary optic neuropathies, increasing use of RNA/functional assays for splice variants, maturation of patient-specific iPSC systems, and entry of an OPA1-directed oligonucleotide into a 2024 first-in-human dominant-optic-atrophy trial. A 2024 expert review nevertheless concluded that treatment studies remain nascent and that present management is largely supportive. The same review emphasizes that compound-heterozygous OPA1 variants cause the early optic-neuropathy, spinocerebellar, peripheral-neuropathy, pyramidal, and developmental phenotype recognized as Behr-related syndrome. DOI https://doi.org/10.3390/jcto2030006, published June 2024. (lee2024hereditaryopticneuropathies pages 5-7)

A useful exact abstract statement from the 2025 model study is: “mitochondrial disruption and visual impairment precede degeneration of RGCs.” This supports intervention before irreversible ganglion-cell loss but does not establish clinical efficacy. (strachan2025novelinvivo pages 1-2)

A second key exact summary from the modern clinical literature is that Behr syndrome is characterized by “childhood-onset optic atrophy combined with ataxia and pyramidal signs including spasticity, weakness, and hyperreflexia.” (ojaimi2022mitochondrialfissionand pages 7-8)

Ontology-ready summary

The following artifact provides compact annotations and curation caveats.

Domain	Evidence-backed finding	Suggested ontology terms/IDs	Evidence caveat
Disease identity	Behr syndrome is a rare Mendelian syndromic optic neuropathy; Open Targets maps it to MONDO:0008858 and associates it primarily with OPA1 (OpenTargets Search: Behr syndrome)	MONDO:0008858; OMIM:210000; MeSH/Orphanet/ICD IDs curator verification needed	MONDO/OPA1 support is strong, but external identifier crosswalks beyond MONDO/OMIM should be curator-checked
Nosology / synonymy	Current literature supports OPA1-related Behr syndrome / Behr-related syndrome for biallelic OPA1 disease; this should be distinguished from OPA3-related Costeff syndrome, which is a differential diagnosis rather than a true synonym (weisschuh2021mutationspectrumof pages 17-18, lee2024hereditaryopticneuropathies pages 5-7)	Synonym candidate: “OPA1-related Behr syndrome”; Differential diagnosis: OPA3-related Costeff syndrome (ontology ID curator verification needed)	Historical literature used “Behr syndrome” broadly; modern molecular classification separates OPA1- from OPA3-related disease
Etiology / gene	The principal evidence-backed causal gene is OPA1 (OPA1 mitochondrial dynamin like GTPase) (OpenTargets Search: Behr syndrome, ojaimi2022mitochondrialfissionand pages 7-8)	HGNC:8156 curator verification needed; OPA1	Evidence in retrieved contexts centers on OPA1; other historical “Behr-like” phenocopies are not excluded globally
Inheritance	Reported disease mechanism is biallelic germline OPA1 pathogenic variants, consistent with autosomal recessive inheritance in classic OPA1-related Behr syndrome (ojaimi2022mitochondrialfissionand pages 7-8, nottia2021mitochondrialdynamicsmolecular pages 8-10, lee2024hereditaryopticneuropathies pages 5-7)	Inheritance: autosomal recessive; Variant origin: germline	Some OPA1 disorders are dominant DOA/DOA+; inheritance must be tied specifically to the Behr syndrome subset
Core phenotype	Childhood/early-onset optic atrophy is the core presentation (ojaimi2022mitochondrialfissionand pages 7-8, nottia2021mitochondrialdynamicsmolecular pages 8-10)	HPO: HP:0000648 optic atrophy	Frequency not well quantified in retrieved contexts
Core phenotype	Spasticity / pyramidal signs / hyperreflexia are characteristic neurologic features (ojaimi2022mitochondrialfissionand pages 7-8)	HPO: HP:0001257 spasticity; pyramidal signs curator verification for exact HPO term	Literature often groups pyramidal signs broadly; exact HPO mapping may need refinement
Core phenotype	Ataxia / spinocerebellar degeneration is a recurring major feature (ojaimi2022mitochondrialfissionand pages 7-8, nottia2021mitochondrialdynamicsmolecular pages 8-10, lee2024hereditaryopticneuropathies pages 5-7)	HPO: HP:0001251 ataxia	Cerebellar signs may include dysmetria/dysdiadochokinesis/nystagmus not fully decomposed here
Core phenotype	Peripheral neuropathy is repeatedly described (nottia2021mitochondrialdynamicsmolecular pages 8-10, lee2024hereditaryopticneuropathies pages 5-7)	HPO: HP:0009830 peripheral neuropathy	Subtype (axonal/sensory-motor) may vary and is not consistently specified in the retrieved contexts
Core phenotype	Developmental delay / delayed motor development can occur, especially in severe early-onset cases (ojaimi2022mitochondrialfissionand pages 7-8, nottia2021mitochondrialdynamicsmolecular pages 8-10, lee2024hereditaryopticneuropathies pages 5-7)	HPO: HP:0001263 developmental delay	Severity and domain specificity are variably reported
Associated phenotype	Hearing impairment / sensorineural deafness may occur (ojaimi2022mitochondrialfissionand pages 7-8, nottia2021mitochondrialdynamicsmolecular pages 8-10, lee2024hereditaryopticneuropathies pages 5-7)	HPO: HP:0000365 hearing impairment	Common in broader OPA1 syndromic disease, not necessarily present in all Behr syndrome cases
Associated phenotype	Dysarthria is reported among neurologic manifestations (ojaimi2022mitochondrialfissionand pages 7-8)	HPO: HP:0001260 dysarthria	Limited frequency data in retrieved contexts
Associated phenotype	Dysphagia and other gastrointestinal dysmotility features are described (ojaimi2022mitochondrialfissionand pages 7-8, nottia2021mitochondrialdynamicsmolecular pages 8-10)	HPO: HP:0002015 dysphagia	GI findings may be underreported and are not universal
Associated phenotype	Pes cavus and contractures can occur (ojaimi2022mitochondrialfissionand pages 7-8)	HPO: HP:0001761 pes cavus	Musculoskeletal findings may overlap with neuropathy-related foot deformity
Imaging phenotype	Brain MRI may show cerebellar atrophy, including vermian atrophy (ojaimi2022mitochondrialfissionand pages 7-8, nottia2021mitochondrialdynamicsmolecular pages 8-10)	HPO: HP:0001272 cerebellar atrophy	Exact HPO for vermian atrophy may be more specific; curator refinement may help
Anatomy / tissue	Major affected ocular cell type is the retinal ganglion cell; degeneration of RGCs underlies optic neuropathy (strachan2025novelinvivo pages 1-2, alavi2013dominantopticatrophy pages 1-3, fogazza2018biochemicalcharacterizationand pages 35-38)	CL:0000704 retinal ganglion cell curator verification needed; UBERON retina/retinal ganglion cell layer curator verification needed	Cell ontology ID should be verified before ingestion
Anatomy / organ	The optic nerve is a primary affected structure; optic nerve/chiasm atrophy is reported (ojaimi2022mitochondrialfissionand pages 7-8, alavi2013dominantopticatrophy pages 1-3)	UBERON optic nerve curator verification needed	Chiasmal involvement may merit separate anatomical annotation
Anatomy / organ	The cerebellum is a major CNS site involved clinically and on MRI (ojaimi2022mitochondrialfissionand pages 7-8)	UBERON cerebellum curator verification needed	Vermis-specific annotation may be preferable when supported
Anatomy / system	Corticospinal/pyramidal system involvement is inferred from spasticity and hyperreflexia (ojaimi2022mitochondrialfissionand pages 7-8)	UBERON corticospinal tract / pyramidal tract curator verification needed	Structure-level assignment is phenotype-inferred rather than directly demonstrated in retrieved contexts
Anatomy / system	Peripheral nerve involvement is supported by neuropathy and contractures (nottia2021mitochondrialdynamicsmolecular pages 8-10, ojaimi2022mitochondrialfissionand pages 7-8)	UBERON peripheral nerve curator verification needed	Specific nerves/cell subclasses were not defined in retrieved contexts
Molecular location	OPA1 is localized to the mitochondrial inner membrane (strachan2025novelinvivo pages 1-2, dotto2021dominantopticatrophy pages 10-11, alavi2013dominantopticatrophy pages 1-3)	GO:0005743 mitochondrial inner membrane	Strongly supported for OPA1 biology, but not unique to Behr syndrome
Biological process	A central upstream defect is impaired mitochondrial inner membrane fusion due to OPA1 dysfunction (strachan2025novelinvivo pages 1-2, alavi2013dominantopticatrophy pages 1-3)	GO:0007342 mitochondrial inner membrane fusion	GO label/ID should be curator-verified in pipeline if strict ontology versioning is required
Cellular component	Abnormal mitochondrial cristae organization is repeatedly implicated (strachan2025novelinvivo pages 1-2, dotto2021dominantopticatrophy pages 10-11, fogazza2018biochemicalcharacterizationand pages 35-38)	GO: mitochondrial crista ID curator verification needed	Exact GO ID not supplied in retrieved contexts
Biological process	Downstream consequences include impaired oxidative phosphorylation / respiratory function (strachan2025novelinvivo pages 1-2, dotto2021dominantopticatrophy pages 5-6)	GO: oxidative phosphorylation ID curator verification needed	Evidence is strong mechanistically but often derived from broader OPA1/AOA models rather than Behr-only cohorts
Biological process	OPA1 dysfunction is linked to defective mtDNA maintenance / depletion in severe disease (nottia2021mitochondrialdynamicsmolecular pages 8-10, alavi2013dominantopticatrophy pages 1-3)	GO: mitochondrial DNA maintenance ID curator verification needed	mtDNA depletion may be more prominent in severe or specific molecular contexts
Biological process	OPA1 participates in regulation of apoptosis, including cytochrome c release/cristae remodeling pathways (dotto2021dominantopticatrophy pages 10-11, alavi2013dominantopticatrophy pages 1-3, fogazza2018biochemicalcharacterizationand pages 35-38)	GO: apoptosis ID curator verification needed	Much mechanistic evidence comes from OPA1 biology and model systems, not exclusively human Behr tissue
Biological process	Increased mitophagy / autophagy is a recurrent downstream mechanism in OPA1-deficient models (dotto2021dominantopticatrophy pages 5-6, fogazza2018biochemicalcharacterizationand pages 35-38)	GO: mitophagy ID curator verification needed	Model-system evidence stronger than direct human Behr syndrome tissue evidence
Diagnostics	Recommended workup in suspected hereditary optic neuropathy includes next-generation sequencing, with broader exome/genome testing for complex phenotypes; OPA1 diagnosis is established by identifying pathogenic variants (lee2024hereditaryopticneuropathies pages 5-7, ojaimi2022mitochondrialfissionand pages 7-8)	MAXO: genetic testing curator verification needed; assay types: targeted panel / WES / WGS	Diagnostic strategy derives from hereditary optic neuropathy practice, not a Behr-specific guideline
Diagnostics	Ophthalmic and functional measures used in OPA1 trials include BCVA/ETDRS, visual fields/perimetry, color vision, contrast sensitivity, mfVEP, RNFL and GCL thickness by OCT (NCT06970106 chunk 2, NCT06461286 chunk 1, NCT06461286 chunk 2)	MAXO: ophthalmologic examination; optical coherence tomography; visual field testing; visual evoked potentials all curator verification needed	Trial measures are from dominant OPA1 studies but remain relevant for phenotyping syndromic OPA1 disease
Management	No approved curative therapy is established; management is largely supportive (lee2024hereditaryopticneuropathies pages 5-7)	MAXO: supportive care; rehabilitation; low-vision services curator verification needed	Statement reflects broader OPA1/DOA literature, not a dedicated Behr syndrome management guideline
Management	Practical supportive interventions may include multidisciplinary rehabilitation for gait/spasticity/neuropathy, speech therapy for dysarthria, swallowing support for dysphagia, audiology/hearing aids, and genetic counseling (ojaimi2022mitochondrialfissionand pages 7-8, lee2024hereditaryopticneuropathies pages 5-7)	MAXO: physical therapy; occupational therapy; speech therapy; dysphagia management; hearing aid provision; genetic counseling all curator verification needed	These are evidence-informed generic interventions rather than trial-proven Behr-specific therapies
Recent development	2024–2025 OPA1 interventional trials test PYC-001, an intravitreal peptide-phosphorodiamidate morpholino oligonucleotide, in OPA1 haploinsufficiency-associated autosomal dominant optic atrophy, not specifically Behr syndrome (NCT06970106 chunk 1, NCT06970106 chunk 2, NCT06461286 chunk 1, NCT06461286 chunk 2)	Clinical trials: NCT06461286; NCT06970106	Important to avoid overgeneralizing these dominant OPA1 trial data to recessive OPA1 Behr syndrome
Differential diagnosis	Differential genetic diagnoses for optic atrophy-plus phenotypes include OPA3, WFS1, MFN2, SPG7, AFG3L2, ACO2, and others (weisschuh2021mutationspectrumof pages 17-18, lee2024hereditaryopticneuropathies pages 5-7)	Disease/gene ontology entries curator verification needed	Differential list is not exhaustive and depends on presenting phenotype
Evidence source	Most information here is aggregated disease-level literature/review evidence, supplemented by Open Targets disease-gene association and OPA1 trial registry records, rather than EHR-derived patient aggregation (OpenTargets Search: Behr syndrome, lee2024hereditaryopticneuropathies pages 5-7)	Evidence categories: review, genetic association, clinical trial registry	Primary case-level extraction would still be needed for precise variant-phenotype curation

Table: This compact table summarizes ontology-ready facts for OPA1-related Behr syndrome, including identifiers, inheritance, phenotypes, anatomy, mechanisms, diagnostics, and supportive management. It also flags areas needing curator verification and clearly separates Behr syndrome from OPA3/Costeff syndrome.

Evidence limitations

Behr syndrome has no large registry-quality natural-history cohort, prevalence study, controlled treatment trial, validated quality-of-life instrument, or standardized diagnostic/management guideline. Numerical data from dominant optic atrophy must not be imported as Behr-specific statistics. Likewise, evidence from OPA1 haploinsufficiency models and trials is mechanistically relevant but not automatically applicable to biallelic systemic disease. Variant-level curation should return to primary case reports and ClinVar/gnomAD records before database ingestion.

References

(OpenTargets Search: Behr syndrome): Open Targets Query (Behr syndrome, 1 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(NCT06970106 chunk 1): Safety of Single and Repeat Dose of PYC-001 Eye Injections in People With Autosomal Dominant Optic Atrophy (Myrtle). PYC Therapeutics. 2025. ClinicalTrials.gov Identifier: NCT06970106
(NCT06970106 chunk 2): Safety of Single and Repeat Dose of PYC-001 Eye Injections in People With Autosomal Dominant Optic Atrophy (Myrtle). PYC Therapeutics. 2025. ClinicalTrials.gov Identifier: NCT06970106
(NCT06461286 chunk 1): SAD of IVT PYC-001 in OPA1 Mutation-Associated Autosomal Dominant Optic Atrophy (Sundew). PYC Therapeutics. 2024. ClinicalTrials.gov Identifier: NCT06461286
(NCT06461286 chunk 2): SAD of IVT PYC-001 in OPA1 Mutation-Associated Autosomal Dominant Optic Atrophy (Sundew). PYC Therapeutics. 2024. ClinicalTrials.gov Identifier: NCT06461286
(ojaimi2022mitochondrialfissionand pages 7-8): Mode Al Ojaimi, Azza Salah, and Ayman El-Hattab. Mitochondrial fission and fusion: molecular mechanisms, biological functions, and related disorders. Membranes, 12:893, Sep 2022. URL: https://doi.org/10.3390/membranes12090893, doi:10.3390/membranes12090893. This article has 167 citations.
(weisschuh2021mutationspectrumof pages 17-18): Nicole Weisschuh, Simone Schimpf-Linzenbold, Pascale Mazzola, Sinja Kieninger, Ting Xiao, Ulrich Kellner, Teresa Neuhann, Carina Kelbsch, Felix Tonagel, Helmut Wilhelm, Susanne Kohl, and Bernd Wissinger. Mutation spectrum of the opa1 gene in a large cohort of patients with suspected dominant optic atrophy: identification and classification of 48 novel variants. PLoS ONE, 16:e0253987, Jul 2021. URL: https://doi.org/10.1371/journal.pone.0253987, doi:10.1371/journal.pone.0253987. This article has 37 citations and is from a peer-reviewed journal.
(nottia2021mitochondrialdynamicsmolecular pages 8-10): Michela Di Nottia, Daniela Verrigni, Alessandra Torraco, Teresa Rizza, Enrico Bertini, and Rosalba Carrozzo. Mitochondrial dynamics: molecular mechanisms, related primary mitochondrial disorders and therapeutic approaches. Genes, 12:247, Feb 2021. URL: https://doi.org/10.3390/genes12020247, doi:10.3390/genes12020247. This article has 57 citations.
(lee2024hereditaryopticneuropathies pages 5-7): Samuel K. Lee, Caroline Mura, Nicolas J. Abreu, Janet C. Rucker, Steven L. Galetta, Laura J. Balcer, and Scott N. Grossman. Hereditary optic neuropathies: an updated review. Journal of Clinical & Translational Ophthalmology, 2:64-78, Jun 2024. URL: https://doi.org/10.3390/jcto2030006, doi:10.3390/jcto2030006. This article has 5 citations.
(dotto2021dominantopticatrophy pages 5-6): Valentina Del Dotto and Valerio Carelli. Dominant optic atrophy (doa): modeling the kaleidoscopic roles of opa1 in mitochondrial homeostasis. Frontiers in Neurology, Jun 2021. URL: https://doi.org/10.3389/fneur.2021.681326, doi:10.3389/fneur.2021.681326. This article has 23 citations and is from a peer-reviewed journal.
(strachan2025novelinvivo pages 1-2): Elin L. Strachan, Eugene T. Dillon, Mairéad Sullivan, Jeffrey C. Glennon, Amandine Peyrel, Jérôme Sarniguet, Kevin Dubois, Benjamin Delprat, Breandán N. Kennedy, and Niamh C. O'Sullivan. Novel in vivo models of autosomal optic atrophy reveal conserved pathological changes in neuronal mitochondrial structure and function. The FASEB Journal, Apr 2025. URL: https://doi.org/10.1096/fj.202403271r, doi:10.1096/fj.202403271r. This article has 1 citations.
(dotto2021dominantopticatrophy pages 10-11): Valentina Del Dotto and Valerio Carelli. Dominant optic atrophy (doa): modeling the kaleidoscopic roles of opa1 in mitochondrial homeostasis. Frontiers in Neurology, Jun 2021. URL: https://doi.org/10.3389/fneur.2021.681326, doi:10.3389/fneur.2021.681326. This article has 23 citations and is from a peer-reviewed journal.
(alavi2013dominantopticatrophy pages 1-3): Marcel V Alavi and Nico Fuhrmann. Dominant optic atrophy, opa1, and mitochondrial quality control: understanding mitochondrial network dynamics. Molecular Neurodegeneration, 8:32, Sep 2013. URL: https://doi.org/10.1186/1750-1326-8-32, doi:10.1186/1750-1326-8-32. This article has 178 citations and is from a highest quality peer-reviewed journal.
(fogazza2018biochemicalcharacterizationand pages 35-38): Mario Fogazza. Biochemical characterization and validation of a novel cellmodel for dominant optic atrophy. ArXiv, Apr 2018. URL: https://doi.org/10.6092/unibo/amsdottorato/8630, doi:10.6092/unibo/amsdottorato/8630. This article has 0 citations.

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Behr Syndrome: Comprehensive Disease Characteristics Report

openscientist-autonomous 24 citations 2026-07-31T02:29:33.340718

Behr Syndrome: Comprehensive Disease Characteristics Report

Summary

Behr syndrome (OMIM #210000; MONDO:0008623; Orphanet ORPHA:1272) is a rare, childhood-onset, genetically heterogeneous neurodegenerative "optic-atrophy-plus" disorder. First described in 1909 by the ophthalmologist Carl Behr, it is defined by a clinical tetrad of early childhood-onset bilateral optic atrophy, cerebellar ataxia, pyramidal/spastic signs (spastic paraparesis), and peripheral (sensorimotor axonal) neuropathy, frequently accompanied by intellectual disability/learning difficulties, nystagmus, and ophthalmoparesis. Rather than a single-gene disease, Behr syndrome is best understood as a convergent clinical phenotype produced by biallelic/recessive loss-of-function variants in a set of mitochondrial or mitochondria-associated genes.

The molecular etiology is entirely genetic. Reported causal genes include biallelic OPA1 (mitochondrial fusion GTPase), C12orf65/MTRFR (mitochondrial translation release factor), OPA3 (Costeff syndrome / 3-methylglutaconic aciduria type III), C19orf12 (MPAN/NBIA), and UCHL1. Nearly all encode mitochondrial or mitochondria-associated proteins, and patient cells consistently show impaired oxidative phosphorylation (OXPHOS), fragmented mitochondria, and reduced oxygen consumption. The unifying pathomechanism is mitochondrial dysfunction and energy failure in high-demand neurons, with retinal ganglion cells (RGCs) being selectively vulnerable due to their high energy requirement and long, partly unmyelinated axons. Downstream axon degeneration proceeds through SARM1-dependent axon death, positioning SARM1 as a promising therapeutic node.

There is no disease-specific cure. Management is supportive and symptomatic (low-vision aids, physiotherapy for spasticity/ataxia, seizure and neuropathy management, genotype-guided surveillance such as cardiac follow-up in UCHL1-related disease). Emerging therapies from the broader mitochondrial optic neuropathy field—the antioxidant idebenone (a short-chain CoQ10 analogue that bypasses complex I) and gene-based therapies (allotopic expression, variant-agnostic gene-expression modulation)—are being explored for OPA1 disease. Prognosis is gene- and severity-dependent, ranging from near-normal lifespan with preserved ambulation beyond the fifth decade (OPA3/Costeff) to early death from intractable seizures, metabolic strokes, or hypertrophic cardiomyopathy (severe biallelic OPA1; UCHL1).

Key Findings

1. Disease Definition and Core Clinical Tetrad (F001)

Behr syndrome is a childhood-onset neurodegenerative disorder defined by optic atrophy accompanied by additional neurological signs. Across case series it is consistently described as a clinical tetrad: early childhood-onset bilateral optic atrophy, cerebellar ataxia, pyramidal/spastic signs (spastic paraparesis), and peripheral sensorimotor axonal neuropathy, often with intellectual disability/learning difficulties, nystagmus, and ophthalmoparesis.

"Behr syndrome, first described in 1909 by the ophthalmologist Carl Behr, is a clinical entity characterised by a progressive optic atrophy, ataxia, pyramidal signs and mental retardation." — PMID: 26187298

"Behr's syndrome is a classical phenotypic description of childhood-onset optic atrophy combined with various neurological symptoms, including ophthalmoparesis, nystagmus, spastic paraparesis, ataxia, peripheral neuropathy and learning difficulties." — PMID: 26380172

2. Genetic Heterogeneity with a Shared Mitochondrial Pathomechanism (F002)

Behr syndrome is genetically heterogeneous, but its causal genes converge mechanistically. Reported genes include biallelic OPA1, C12orf65/MTRFR, OPA3, C19orf12, and UCHL1. Nearly all encode mitochondrial or mitochondria-associated proteins. Patient cell lines demonstrate impaired oxidative phosphorylation, reduced OPA1 protein, fragmented mitochondria, and reduced oxygen consumption—a shared cellular signature of mitochondrial energetic failure.

"Some reported cases have been found to carry mutations in the OPA1, OPA3 or C12ORF65 genes which are known causes of pure optic atrophy or optic atrophy complicated by movement disorder." — PMID: 26187298

"C12orf65 (chromosome 12 open reading frame 65) gene encodes a mitochondrial matrix protein essential for the release of newly synthesized proteins from mitochondrial ribosomes. Biallelic pathogenic variants result in loss of function in the protein complex necessary for oxidative phosphorylation." — PMID: 40993840

The C12orf65/MTRFR form additionally implicates disturbed mitochondrial translation as a route to the same OXPHOS deficit (PMID: 26380172).

3. Biallelic OPA1 Causes Severe Early-Onset Behr Syndrome with Metabolic Strokes (F003)

While monoallelic OPA1 variants cause classic autosomal dominant optic atrophy (DOA, MIM 605290), biallelic (compound heterozygous/homozygous) OPA1 variants cause the severe syndromic Behr phenotype. By 2022, roughly 21 biallelic OPA1-Behr cases had been reviewed, all sharing an early-onset, severe ocular phenotype plus systemic features. Additional manifestations include congenital cataract, sensorimotor axonal polyneuropathy, intractable seizures / super-refractory status epilepticus, and stroke-like/metabolic stroke episodes with elevated lactate. A recurrent second allele, p.Ile382Met, is asymptomatic alone and acts as a phenotypic modifier.

"A biallelic mode of inheritance causes syndromic DOA or Behr phenotype, MIM # 605290." — PMID: 35741767

"Twenty-one cases have been previously reported. All share an early-onset, severe ocular phenotype and systemic features, which seem to be the hallmark of the disease." — PMID: 35741767

"The co-occurrence of bi-allelic mutations can explain the severity and the early onset of her disease." — PMID: 30972688

4. OPA3-Related Costeff Syndrome: A Behr-Overlapping Founder Disorder (F004)

Costeff syndrome (OPA3-related 3-methylglutaconic aciduria type III) is an autosomal-recessive neurodegenerative disorder that overlaps clinically with Behr syndrome: early-onset bilateral optic atrophy with choreoathetosis, later ataxia and spastic paraparesis, plus elevated urinary 3-methylglutaconic and 3-methylglutaric acid. It is prevalent among Iraqi Jews via a founder splice mutation c.143-1G>C. Natural-history data (n=28) show first signs in infancy/early childhood; ataxia and chorea dominate in childhood and are relatively stable, whereas pyramidal dysfunction appears later and progresses with age (r=0.71, p<0.001). The majority remain ambulatory beyond the fifth decade, and cognition is generally intact/low-average.

"Costeff syndrome (CS) is a rare autosomal-recessive neurological disorder, which is known almost exclusively in patients of Iraqi Jewish descent, manifesting in childhood with optic atrophy, ataxia, chorea and spastic paraparesis." — PMID: 25201222

"Pyramidal dysfunction appeared later and progressed with age (r = 0.71, p < 0.001) leading to spastic paraparesis and marked gait impairment." — PMID: 25201222

"Costeff syndrome or OPA3-related 3-methylglutaconic aciduria is an autosomal recessive neurodegenerative disorder characterized by early onset optic atrophy and choreoathetosis with later onset of ataxia and spasticity." — PMID: 26190011

5. RGC Degeneration Proceeds via Mitochondrial Dysfunction and SARM1-Dependent Axon Death (F005)

OPA1 encodes a dynamin-related inner-membrane GTPase controlling mitochondrial fusion, cristae structure, OXPHOS, mtDNA maintenance, calcium homeostasis, and apoptosis. Retinal ganglion cells are selectively vulnerable owing to their high energy demand and long, unmyelinated intraretinal axons. Critically, mouse Opa1 models (e.g., Opa1^R290Q/+) recapitulate mitochondrial defects, age-related RGC loss, and optic nerve degeneration, and SARM1 knockout nearly completely suppresses degeneration without reversing mitochondrial fragmentation—placing SARM1 downstream of the mitochondrial defect as the executioner of axon death. ADOA mutant neurons additionally show impaired fusion, loss of membrane potential, cytochrome c release, sustained intracellular Ca²⁺ rise, and mitophagy.

"Sarm1 KO nearly completely suppressed all the degeneration phenotypes without reversing mitochondrial fragmentation." — PMID: 40344041

"OPA1 encodes a dynamin-related GTPase imported into mitochondria and located to the inner membrane and intermembrane space." — PMID: 33340656

"LHON and DOA are both characterized by selective neurodegeneration of retinal ganglion cells (RGCs) triggered by mitochondrial dysfunction." — PMID: 36813316

6. No Cure Exists; Management Is Supportive with Emerging Therapies (F006)

Treatment of Behr syndrome and related mitochondrial optic neuropathies is largely supportive/symptomatic (low-vision aids, physiotherapy/rehabilitation for spasticity and ataxia, seizure and neuropathy management). For the broader disease class, idebenone—a short-chain CoQ10 analogue/antioxidant that bypasses complex I—is approved in Europe for LHON and has been tried in OPA1-DOA. Gene therapy (allotopic expression) reached Phase III for LHON, and variant-agnostic gene-expression-modulation trials are underway for OPA1-DOA. Other agents (antioxidants, anti-apoptotic drugs, mitobiogenesis activators) remain at Phase II/preclinical stages. Avoidance of mitochondrial toxins (certain drugs, tobacco/alcohol) is advised.

"Clinical trials for LHON have demonstrated the efficacy of idebenone, an oral neuroprotective agent, and gene replacement therapy using allotopic gene expression. Early phase clinical trials are underway for ADOA caused by variants in the nuclear gene OPA1 using innovative techniques to modulate gene expression in a variant-agnostic manner." — PMID: 41318849

"The successful launch of the antioxidant idebenone for Leber's Hereditary Optic Neuropathy (LHON), followed by its introduction into clinical practice across Europe, was an important step forward." — PMID: 33159657

7. Ultra-Rare Recessive Disorder with Founder Effects and Consanguinity Contribution (F007)

Behr syndrome has no precise prevalence estimate (Orphanet lists it as a rare disease; fewer than ~25 biallelic OPA1 cases reported by 2022). It sits within the mitochondrial optic neuropathy spectrum: autosomal dominant optic atrophy, the parent disorder for OPA1, has prevalence ~1/10,000 in Denmark (founder effect) and ~1/30,000–1/50,000 elsewhere, with ~20% showing syndromic "plus" features. Behr syndrome forms are inherited autosomal recessively (biallelic OPA1, C12orf65, C19orf12, UCHL1) or AR (OPA3/Costeff, an Iraqi-Jewish founder disorder). Consanguinity increases the risk of homozygous recessive forms.

"The prevalence of the disease varies from 1/10000 in Denmark due to a founder effect, to 1/30000 in the rest of the world." — PMID: 22776096

"About 20% of DOA patients harbour extraocular multi-systemic features" — PMID: 22776096

8. Animal and Cellular Models Recapitulate Behr-Spectrum Pathology (F008)

Multiple models reproduce the disease's mitochondrial pathology. The Opa1^R290Q/+ mouse recapitulates ADOA (mitochondrial defects, age-related RGC loss, optic nerve degeneration, reduced RGC function). The Opa3^L122P mouse (Costeff model) shows disrupted mitochondrial function impairing skeletal integrity. Patient-derived iPSCs (iPS-OPA1-BEHR) were generated from compound-heterozygous OPA1 fibroblasts for disease modeling, and patient fibroblasts show increased fragmented/intermediate mitochondria under galactose stress and reduced OPA1 protein. C. elegans and zebrafish (Danio rerio) are used for OPA1/mitophagy studies and idebenone/QS10 rescue experiments. Orthologous genes are conserved across vertebrates (mouse Opa1, Opa3).

"We generated a mouse model carrying the pathogenic Opa1R290Q/+ allele that recapitulated key features of human ADOA, including mitochondrial defects, age-related RGC loss, optic nerve degeneration, and reduced RGC functions." — PMID: 40344041

"The generated iPS-OPA1-BEHR line might be a useful platform to study the pathomechanism of early onset complicated optic atrophy syndromes." — PMID: 27879217

9. Phenotype Spectrum with HPO Terms and Variable Expressivity (F009)

Core, near-obligate features and their HPO terms include: bilateral optic atrophy (HP:0000648) with childhood-onset progressive visual loss/reduced visual acuity (HP:0000505, HP:0007766), cerebellar/gait ataxia (HP:0001251, HP:0002066), spasticity/spastic paraparesis (HP:0001257, HP:0002061), pyramidal signs (hyperreflexia, HP:0001347), peripheral sensorimotor axonal neuropathy (HP:0007141/HP:0003477), and intellectual disability/learning difficulties (HP:0001249). Frequent/variable features: nystagmus (HP:0000639), ophthalmoparesis/strabismus (HP:0000602/HP:0000486), dysarthria (HP:0001260), dystonia/choreoathetosis (HP:0001332/HP:0001266, esp. OPA3), congenital cataract (HP:0000519), scoliosis (HP:0002650), seizures (HP:0001250), tremor (HP:0001337). Rare/severe features: metabolic stroke-like episodes with elevated lactate (HP:0001943/HP:0002151), hypertrophic cardiomyopathy (HP:0001639, UCHL1), multiorgan failure and early death (severe biallelic OPA1). OPA3/Costeff adds 3-methylglutaconic aciduria (HP:0003535). Expressivity is highly variable even within families.

"childhood-onset optic atrophy combined with various neurological symptoms, including ophthalmoparesis, nystagmus, spastic paraparesis, ataxia, peripheral neuropathy and learning difficulties" — PMID: 26380172

"two unrelated sporadic girls manifesting a spastic ataxic syndrome associated with peripheral neuropathy and, only in one, optic atrophy" — PMID: 28494813

"In their late 30's, both siblings developed a hypertrophic cardiomyopathy and died of sudden cardiac death" — PMID: 32656641

10. Diagnosis: Clinical Recognition Plus NGS, with Supportive Testing (F010)

Molecular diagnosis is established by gene panel testing or whole-exome/whole-genome sequencing (targeted mitochondrial-disorder panels of ~132 genes and trio-WES have identified causal OPA1, C12orf65, OPA3, C19orf12, UCHL1 variants). Supportive tests include: ophthalmology (fundoscopy showing optic disc pallor, OCT showing RNFL/ganglion-cell-layer thinning, visual fields, VEP); brain MRI (cerebellar atrophy, basal ganglia signal changes, Leigh-like lesions, elevated lactate peak on MRS); nerve conduction studies/EMG confirming axonal sensorimotor polyneuropathy; muscle biopsy (reduced cytochrome c oxidase staining, ragged-red-type changes) and biochemical OXPHOS assays; and urine organic acids (elevated 3-methylglutaconic and 3-methylglutaric acid in OPA3/Costeff). Chromosomal microarray may reveal contributory copy-number changes (e.g., a 3q deletion co-occurring with OPA1).

"The molecular diagnosis is based on gene panel testing or whole-exome/genome sequencing." — PMID: 32656641

"muscle biopsy showed diffuse reduction of cytochrome c oxidase stain" — PMID: 28442211

"Magnetic resonance imaging of the brain showed bilateral hypointense signals in the basal ganglia which prompted us to consider neurodegeneration with brain iron accumulation (NBIA) as a differential diagnosis." — PMID: 26187298

11. Chronic Progressive Course; Prognosis Varies by Gene and Severity (F011)

Onset is typically infancy to early childhood with an insidious, chronic-progressive course. Anatomical involvement spans the eye/optic nerve (retinal ganglion cells CL:0000740; optic nerve UBERON:0000941; retina UBERON:0000966), cerebellum (UBERON:0002037), corticospinal/pyramidal tracts and spinal cord (UBERON:0002240), basal ganglia (UBERON:0002420), peripheral nerves (UBERON:0001021), and skeletal muscle (UBERON:0001134) in severe forms; the subcellular target is the mitochondrion (GO:0005739; inner membrane GO:0005743). Prognosis is gene- and severity-dependent: OPA3/Costeff patients often remain ambulatory beyond the fifth decade with intact cognition and near-normal lifespan, whereas severe biallelic OPA1 cases show early-onset severe visual loss, intractable seizures, metabolic strokes, and possible early death/multiorgan failure. A UCHL1 family died of hypertrophic cardiomyopathy/sudden cardiac death at ages 40–43. Visual impairment is generally permanent (often legally blind); motor disability accrues over decades.

"The course of neurological deterioration was slow and the majority of patients could still walk beyond the fifth decade." — PMID: 25201222

"died of sudden cardiac death at age 43 and 40, respectively" — PMID: 32656641

12. Identifiers, Synonyms, and Purely Genetic Etiology (F012)

Identifiers: OMIM #210000 (Behr syndrome / optic atrophy plus); related OMIM entries — OPA1 605290, OPA3/Costeff (3-MGA type III) 258501, COXPD7/C12orf65 613559, MPAN/C19orf12 614298; Orphanet ORPHA:1272; MeSH "Optic Atrophy, Hereditary, Behr"/"Behr syndrome"; MONDO:0008623; ICD-10 H47.2 (optic atrophy)/G31.8; ICD-11 9C40.

Synonyms: "optic atrophy, infantile, with ataxia and spasticity," "optic atrophy-ataxia syndrome," "Behr complicated optic atrophy," "early-onset optic atrophy plus."

Etiology is entirely genetic (biallelic/recessive OPA1, C12orf65/MTRFR, OPA3, C19orf12, UCHL1; occasionally digenic/modifier contributions such as OPA1 p.Ile382Met/p.Ile437Met and co-occurring mtDNA variants). No infectious, toxic, or environmental cause is known; no established environmental or genetic protective factors exist. Information is derived from a mix of aggregated disease-level resources (OMIM/Orphanet) and individual case reports/small case series.

"Behr syndrome; OMIM #210000" — PMID: 27879217

"The mother, aunt, and grandmother are heterozygous for the Ile382Met mutation and are asymptomatic." — PMID: 30972688

13. Prevention Is Genetic (F013)

Because Behr syndrome is autosomal recessive with no environmental cause, primary prevention relies on genetic counseling for at-risk/consanguineous families and founder populations (e.g., Iraqi-Jewish OPA3 carrier testing for c.143-1G>C), carrier screening, cascade testing of relatives, and reproductive options including prenatal testing and preimplantation genetic diagnosis (PGD) once familial variants are known. Secondary prevention: early ophthalmologic and neurologic evaluation of affected sibs. Tertiary prevention: cardiac surveillance/echocardiography in UCHL1-related disease (hypertrophic cardiomyopathy risk), seizure management, physiotherapy/orthopedic management of spasticity and scoliosis, low-vision support, and avoidance of mitochondrial toxins. No newborn screening or vaccine is applicable.

"highlights the importance of cardiac follow-up and treatment in neurodegenerative disease associated with UCHL1 mutations" — PMID: 32656641

"Genetic testing of patients presenting with Behr syndrome should include C19ORF12 mutation screening." — PMID: 26187298

Detailed Section-by-Section Report

1. Disease Information

Behr syndrome is a childhood-onset, progressive neurodegenerative disorder characterized by the combination of bilateral optic atrophy with additional neurological deficits (ataxia, pyramidal/spastic signs, peripheral neuropathy, and cognitive impairment). It is not a single-gene entity but a convergent phenotype ("optic-atrophy-plus") arising from several mitochondrial-related genes.

Key identifiers: OMIM #210000; MONDO:0008623; Orphanet ORPHA:1272; MeSH "Behr syndrome"/"Optic Atrophy, Hereditary, Behr"; ICD-10 H47.2/G31.8; ICD-11 9C40.
Synonyms: optic atrophy–ataxia syndrome; infantile optic atrophy with ataxia and spasticity; Behr complicated optic atrophy; early-onset optic atrophy plus.
Data source type: A mixture of aggregated disease-level resources (OMIM, Orphanet) and individual patient-level case reports/small case series—not EHR-derived population data.

2. Etiology

Causal factors: Entirely genetic. Behr syndrome results from biallelic (recessive) loss-of-function variants, most commonly in OPA1, along with C12orf65/MTRFR, OPA3, C19orf12, and UCHL1. Some cases involve modifier/digenic contributions (e.g., the hypomorphic OPA1 p.Ile382Met allele; co-occurring mtDNA variants; a concurrent 3q chromosomal deletion in one OPA1 case).

Genetic risk factors: Consanguinity and membership in founder populations (Iraqi Jews for OPA3 c.143-1G>C) raise recessive-disease risk. Carrier parents are typically asymptomatic.

Environmental risk factors / protective factors / gene–environment interactions: None established. No toxin, infection, lifestyle, or dietary factor is known to cause, prevent, or modify Behr syndrome, though avoidance of mitochondrial toxins (tobacco, alcohol, certain drugs) is advised on mechanistic grounds.

3. Phenotypes

See Finding 9 for the full HPO-annotated spectrum. In brief, the phenotype is dominated by early-childhood, progressive, bilateral, symmetric visual loss from optic atrophy (near-obligate), plus cerebellar ataxia, spastic paraparesis with pyramidal signs, sensorimotor axonal neuropathy, and intellectual disability. Onset is neonatal-to-early-childhood; severity ranges from mild (some OPA3/Costeff) to severe/lethal (biallelic OPA1, UCHL1). Progression is generally slow but relentless, with permanent visual impairment and accruing motor disability substantially reducing quality of life (mobility, independent living, education/employment, and—via blindness—daily functioning).

4. Genetic/Molecular Information

Gene	HGNC / locus	Protein role	Behr-relevant OMIM	Inheritance in Behr	Notable variants
OPA1	HGNC:8140 (3q29)	Inner-membrane dynamin GTPase; fusion, cristae, mtDNA, apoptosis	605290	Biallelic (recessive/semi-dominant)	p.Ile382Met (modifier), p.Leu730Ser, p.R905Q, p.L620fs*13
C12orf65/MTRFR	HGNC:26784 (12q24)	Mitochondrial translation release factor	613559 (COXPD7)	Biallelic	LoF variants
OPA3	HGNC:8141 (19q13)	Mitochondrial outer-membrane protein	258501 (3-MGA III)	Autosomal recessive	c.143-1G>C (Iraqi-Jewish founder)
C19orf12	HGNC:25443 (19q12)	Mitochondria-associated (MPAN/NBIA)	614298	Biallelic (homozygous reported)	LoF variants
UCHL1	HGNC:12513 (4p13)	Ubiquitin C-terminal hydrolase	—	Biallelic (novel deletion)	Deletion → HCM

Variant classification: Reported variants are largely pathogenic/likely pathogenic (ACMG/AMP), often novel and private to families; many are absent from population controls (e.g., novel OPA1 compound heterozygous variants not seen in n=300 controls). Variant types span missense, frameshift, nonsense, splice-site, and structural/CNV (3q deletion). Allele frequencies are very low/absent in gnomAD for pathogenic alleles; the OPA1 p.Ile382Met modifier is more common and asymptomatic in heterozygotes. Origin is germline. Functional consequence is predominantly loss of function converging on OXPHOS deficiency; domain-specific OPA1 effects (GTPase vs. BSE) modulate fusion and apoptosis severity.

Modifier genes: OPA1 p.Ile382Met and co-occurring mtDNA variants modify severity. Epigenetics/chromosomal: No disease-specific epigenetic signature is established; a de novo 3q deletion co-occurring with an OPA1 missense variant produced a severe Behr-like phenotype.

5. Environmental Information

No environmental, lifestyle, or infectious agents are implicated in Behr syndrome causation. This is a monogenic mitochondrial disorder. The only environmental relevance is the advisory to avoid mitochondrial toxins that could exacerbate an already compromised OXPHOS system.

6. Mechanism / Pathophysiology

Causal chain (upstream → downstream):

Biallelic LoF variant (OPA1 / C12orf65 / OPA3 / C19orf12 / UCHL1)
│
▼
Impaired mitochondrial fusion / translation / integrity
│
▼
OXPHOS deficiency → ATP failure, ↑ROS, cristae disruption,
   mtDNA instability, Ca²⁺ dysregulation, cytochrome c release
│
▼
Selective stress on high-demand neurons (retinal ganglion cells;
   long CNS/PNS axons)  ── mitochondrial fragmentation, mitophagy
│
▼
SARM1-dependent axon self-destruction (executioner step)
│
▼
RGC/axon loss → optic atrophy; cerebellar, corticospinal,
   peripheral-nerve degeneration → ataxia, spasticity, neuropathy

Molecular pathways: Mitochondrial fusion/dynamics; mitochondrial translation; intrinsic apoptosis (cytochrome c/caspase); SARM1/NAD⁺ axon-death pathway; calcium-mediated mitophagy.
Cellular processes: Apoptosis, mitophagy, oxidative stress, energy failure (GO:0006915 apoptotic process; GO:0000422 mitophagy; GO:0006119 oxidative phosphorylation; GO:0008053 mitochondrial fusion).
Protein dysfunction: Loss of function of OPA1 GTPase; domain-specific defects (GTPase β-fold vs. BSE α-helix) differentially impair fusion, membrane-potential maintenance, and apoptosis.
Metabolic changes: OXPHOS/complex I deficiency; elevated lactate (metabolic strokes, MRS peak); elevated urinary 3-methylglutaconic/3-methylglutaric acid (OPA3/Costeff).
Cell types / compartments: Retinal ganglion cells (CL:0000740); neurons broadly; mitochondrion (GO:0005739) and inner mitochondrial membrane (GO:0005743).
Immune involvement: None; this is a primary energetic/neurodegenerative disorder.

7. Anatomical Structures Affected

Organ level: Eye/optic nerve (primary), brain (cerebellum, basal ganglia, corticospinal tracts), spinal cord, peripheral nerves; heart (UCHL1, HCM) and skeletal muscle (severe forms) as secondary/variable.
Body systems: Visual/nervous system (central and peripheral), with cardiovascular involvement in the UCHL1 form.
UBERON/CL terms: optic nerve UBERON:0000941; retina UBERON:0000966; retinal ganglion cell CL:0000740; cerebellum UBERON:0002037; spinal cord/corticospinal tract UBERON:0002240; basal ganglia UBERON:0002420; peripheral nerve UBERON:0001021; skeletal muscle UBERON:0001134.
Subcellular: mitochondrion GO:0005739; inner membrane GO:0005743.
Localization/laterality: Bilateral and largely symmetric optic and neurological involvement.

8. Temporal Development

Onset: Congenital to early childhood; insidious, chronic.
Progression: Slowly progressive; in Costeff, ataxia/chorea appear early and stabilize while pyramidal dysfunction appears later and worsens with age (r=0.71, p<0.001). Severe biallelic OPA1 can present acutely with status epilepticus/metabolic stroke episodes.
Course: Chronic, lifelong; visual loss permanent. No spontaneous remission.
Critical periods: Early childhood is the key window; therapeutic intervention (idebenone, gene therapy) is hypothesized to be most beneficial before extensive RGC loss.

9. Inheritance and Population

Epidemiology: Ultra-rare; no precise prevalence. Fewer than ~25 biallelic OPA1-Behr cases by 2022. Parent disorder ADOA prevalence ~1/10,000 (Denmark, founder) to ~1/30,000–1/50,000 elsewhere; ~20% of ADOA is syndromic.
Inheritance: Autosomal recessive/biallelic (OPA1, C12orf65, C19orf12, UCHL1); AR for OPA3/Costeff. Penetrance of biallelic genotypes is high; expressivity is highly variable. Heterozygous carriers are typically asymptomatic.
Founder effects / consanguinity: OPA3 c.143-1G>C is an Iraqi-Jewish founder mutation; consanguinity increases recessive-disease risk.
Demographics: Costeff concentrated in Iraqi Jews. No strong sex bias reported for Behr syndrome overall.

10. Diagnostics

See Finding 10. Diagnosis rests on clinical recognition of optic atrophy plus neurological signs, confirmed by gene panel/WES/WGS. Supportive workup: OCT (RNFL/GCL thinning), VEP, visual fields, fundoscopy; brain MRI/MRS (cerebellar atrophy, basal ganglia changes, Leigh-like lesions, lactate peak); NCS/EMG (axonal sensorimotor polyneuropathy); muscle biopsy (reduced COX staining) and OXPHOS assays; urine organic acids (3-MGA in OPA3); chromosomal microarray for CNVs. Key differential diagnoses: NBIA (basal ganglia iron), hereditary spastic paraplegias, other mitochondrial optic neuropathies (LHON, DOA), and spinocerebellar ataxias.

11. Outcome / Prognosis

Prognosis is gene- and severity-dependent. OPA3/Costeff: slow neurological deterioration, ambulation preserved beyond the fifth decade, intact-to-low-average cognition, near-normal lifespan. Severe biallelic OPA1: early severe visual loss, intractable seizures, metabolic strokes, possible multiorgan failure and early death. UCHL1: hypertrophic cardiomyopathy with sudden cardiac death (ages 40–43). Visual impairment is permanent (often legal blindness); morbidity accrues from progressive motor disability. Prognostic factors: causal gene, biallelic dosage/variant severity, age of onset, presence of seizures/metabolic strokes/cardiomyopathy.

12. Treatment

Pharmacotherapy: No disease-specific drug. Idebenone (short-chain CoQ10 analogue, complex I bypass) used in the broader class; the metabolite QS10 restores respiration in complex I/CoQ defects in cellular and zebrafish models. Symptomatic drugs for seizures, spasticity, and neuropathic pain.
Advanced therapeutics: Gene therapy (allotopic expression, Phase III in LHON); variant-agnostic gene-expression modulation trials underway for OPA1-DOA. SARM1 inhibition is a mechanistically supported preclinical target.
Surgical/supportive/rehabilitative: Low-vision aids; physiotherapy/occupational/speech therapy; orthopedic management of scoliosis/spasticity; cardiac management in UCHL1 form.
MAXO suggestions: pharmacotherapy (MAXO:0000058), gene therapy (MAXO:0000004), physiotherapy/rehabilitation (MAXO:0000506), surveillance/monitoring (MAXO:0000644), dietary/supportive care.

13. Prevention

Genetic prevention (counseling, carrier/cascade testing, prenatal diagnosis, PGD) is the mainstay, plus genotype-guided tertiary prevention (cardiac surveillance in UCHL1). No immunization, newborn screening, or behavioral prevention applies.

14. Other Species / Natural Disease

Taxonomy/orthologs: Human genes have conserved orthologs — mouse Opa1, Opa3, C12orf65, Uchl1 (NCBI Taxon 10090); zebrafish Danio rerio (7955); C. elegans (6239).
Natural disease: No well-documented naturally occurring Behr syndrome equivalent in companion animals/wildlife (OMIA not specifically implicated); disease knowledge comes from engineered models rather than natural animal disease.
Comparative biology: Mitochondrial fusion/OXPHOS mechanisms are deeply evolutionarily conserved, underpinning the utility of cross-species models.
Zoonotic potential: Not applicable (non-infectious genetic disease).

15. Model Organisms

Model	Type	Gene	Phenotype recapitulation	Key use
Opa1^R290Q/+ mouse	Mammalian, knock-in	Opa1	Mitochondrial defects, age-related RGC loss, optic nerve degeneration, reduced RGC function	ADOA/Behr mechanism; SARM1 rescue
Opa3^L122P mouse	Mammalian, point mutant	Opa3	Disrupted mitochondrial function; impaired skeletal integrity	Costeff modeling
iPS-OPA1-BEHR	Cellular, iPSC	OPA1 (compound het)	Patient-specific mitochondrial phenotype	Behr-specific disease modeling
Patient fibroblasts	In vitro	OPA1	Fragmented mitochondria under galactose stress; reduced OPA1 protein	Biochemical validation
Zebrafish / C. elegans	Vertebrate / invertebrate	OPA1/mito	Respiration/mitophagy phenotypes	Idebenone/QS10 rescue; Ca²⁺-mitophagy

Limitations: Most models capture mitochondrial/RGC pathology (dominant ADOA) rather than the full recessive multisystem Behr tetrad; the iPSC model is early-stage; no model fully reproduces the human seizure/metabolic-stroke/cardiomyopathy spectrum.

Mechanistic Model / Interpretation

Behr syndrome exemplifies phenotypic convergence from genetic heterogeneity: several distinct genes, all touching mitochondrial biology (fusion via OPA1, translation via C12orf65, outer-membrane integrity via OPA3, mitochondria-associated function via C19orf12, and protein homeostasis via UCHL1), produce a shared clinical picture because they all cause a cellular energy deficit that most severely afflicts the body's most metabolically demanding, longest-axon neurons. Retinal ganglion cells are the sentinel casualty (optic atrophy), followed by cerebellar, corticospinal, and peripheral-nerve degeneration.

The dosage principle is central: monoallelic OPA1 → dominant optic atrophy; biallelic OPA1 → syndromic Behr, with hypomorphic modifier alleles (p.Ile382Met) tuning severity. The recent demonstration that SARM1 knockout suppresses degeneration downstream of persistent mitochondrial fragmentation reframes therapy: even without correcting the primary mitochondrial defect, blocking the axon-death executioner may preserve neurons. This dovetails with the two clinically advanced strategies—idebenone (energetic rescue upstream) and gene therapy (correcting the primary lesion)—to define a three-tier therapeutic map: (1) fix the gene, (2) bypass/boost mitochondrial energetics, (3) block SARM1-mediated axon death.

Evidence Base

PMID	Contribution	Supports
26187298	Historical definition; C19orf12; NBIA differential	F001, F002, F010, F013
26380172	Full phenotype; mitochondrial translation (C12orf65)	F001, F002, F009
40993840	C12orf65 mitochondrial translation/OXPHOS mechanism	F002
35741767	Biallelic OPA1 → Behr; 21-case review	F003, F011
30972688	Biallelic dosage; metabolic stroke; Ile382Met carriers	F003, F012
25201222	Costeff natural history (n=28); founder population	F004, F007, F011
26190011	OPA3/Costeff clinical/metabolic definition	F004
40344041	SARM1 KO suppresses degeneration; Opa1^R290Q mouse	F005, F008
33340656	OPA1 protein function	F005
36813316	Selective RGC vulnerability	F005
41318849	Idebenone efficacy; gene-therapy trials	F006
33159657	Idebenone established in class	F006
22776096	ADOA prevalence; 20% syndromic	F007
27879217	iPS-OPA1-BEHR model; OMIM #210000	F008, F012
28494813	Variable expressivity (optic atrophy not obligate)	F009
32656641	UCHL1 form; HCM; diagnostic modality	F009, F010, F011, F013
28442211	Muscle biopsy COX reduction; Leigh-like MRI	F010
27106103	Opa3^L122P Costeff mouse	F008

Supporting/contextual papers: OPA1 domain-specific defects PMID: 40275276; Ca²⁺-mediated mitophagy PMID: 34389813; idebenone metabolite QS10 PMID: 29694828; OPA1 recessive cataract/neuropathy case PMID: 27150940; OPA1 + 3q deletion PMID: 32883255; OPA3 neuro-ophthalmic phenotype PMID: 33870938; Costeff neuropsychology PMID: 25657044.

Limitations and Knowledge Gaps

No precise epidemiology. Behr syndrome prevalence/incidence is unknown; estimates are extrapolated from the parent ADOA disorder and small case counts (<25 biallelic OPA1 cases).
Definitional ambiguity. "Behr syndrome" is a clinical descriptor spanning multiple genes; boundaries with ADOA-plus, Costeff, MPAN, and other mitochondrial optic neuropathies are blurred, complicating annotation.
Variable expressivity obscures genotype–phenotype correlations, and some cases lack the "obligate" optic atrophy.
Model gaps. Existing models chiefly capture dominant ADOA/RGC pathology; none fully reproduces the recessive multisystem Behr tetrad or the severe seizure/metabolic-stroke/cardiomyopathy manifestations.
No disease-specific trials. Therapeutic evidence (idebenone, gene therapy, SARM1) is borrowed from LHON/ADOA; efficacy in Behr syndrome specifically is unproven.
Limited omics. No transcriptomic/proteomic/metabolomic profiling specific to Behr-syndrome patient tissue beyond fibroblast/iPSC OXPHOS assays.

Proposed Follow-up Experiments / Actions

Establish an international Behr-syndrome registry with harmonized gene panels to derive real prevalence, gene-frequency, and natural-history data.
Deep phenotyping + longitudinal OCT/MRS to define gene-specific progression biomarkers (e.g., RNFL/GCL thinning rates; lactate dynamics) suitable as trial endpoints.
Test SARM1 inhibitors in the Opa1^R290Q/+ mouse and biallelic-OPA1 iPSC-RGC organoids to determine whether axon-death blockade preserves vision independent of mitochondrial correction.
Genotype-stratified idebenone/QS10 trials in biallelic-OPA1 and C12orf65 Behr patients, prioritizing early (pre-severe-loss) intervention windows.
Systematic cardiac and metabolic-stroke surveillance protocols, particularly UCHL1 (echocardiography) and biallelic OPA1 (lactate, seizure monitoring), to reduce mortality.
Multi-omics of patient iPSC-derived neurons (transcriptomics/proteomics/metabolomics) to identify convergent, druggable nodes across the heterogeneous genetic causes.
Expand carrier screening in founder/consanguineous populations (Iraqi-Jewish OPA3 c.143-1G>C) with reproductive counseling and PGD access.

Report compiled from 13 confirmed findings and 33 reviewed papers across 5 investigation iterations. Evidence sources span human clinical case series, model-organism studies (mouse, zebrafish, C. elegans), in vitro/iPSC work, and aggregated disease-level resources (OMIM, Orphanet).

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Discussions and Knowledge Gaps

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Medical Actions

Biochemical Markers

Diagnosis

Prevalence

Differential Diagnoses

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References

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Behr Syndrome: Comprehensive Disease-Characteristics Report

Executive summary

1. Disease information

Definition and nosology

2. Etiology, causal factors, and risks

Genetic cause

Environmental, lifestyle, infectious, and protective factors

3. Phenotypes

Quality-of-life impact

4. Genetic and molecular information

5. Environmental information

6. Mechanism and pathophysiology

Causal chain

Molecular profiling and advanced technologies

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

10. Diagnostics

Clinical evaluation

Genetic testing strategy

Differential diagnosis

11. Outcome and prognosis

12. Treatment

Current real-world management

Experimental therapy and trials

13. Prevention

14. Other species and natural disease

15. Model organisms and experimental systems

Recent developments and expert assessment

Ontology-ready summary

Evidence limitations

Artifacts

Behr Syndrome: Comprehensive Disease Characteristics Report

Summary

Key Findings

1. Disease Definition and Core Clinical Tetrad (F001)

2. Genetic Heterogeneity with a Shared Mitochondrial Pathomechanism (F002)

3. Biallelic OPA1 Causes Severe Early-Onset Behr Syndrome with Metabolic Strokes (F003)

4. OPA3-Related Costeff Syndrome: A Behr-Overlapping Founder Disorder (F004)

5. RGC Degeneration Proceeds via Mitochondrial Dysfunction and SARM1-Dependent Axon Death (F005)

6. No Cure Exists; Management Is Supportive with Emerging Therapies (F006)

7. Ultra-Rare Recessive Disorder with Founder Effects and Consanguinity Contribution (F007)

8. Animal and Cellular Models Recapitulate Behr-Spectrum Pathology (F008)

9. Phenotype Spectrum with HPO Terms and Variable Expressivity (F009)

10. Diagnosis: Clinical Recognition Plus NGS, with Supportive Testing (F010)

11. Chronic Progressive Course; Prognosis Varies by Gene and Severity (F011)

12. Identifiers, Synonyms, and Purely Genetic Etiology (F012)

13. Prevention Is Genetic (F013)

Detailed Section-by-Section Report

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development