| domain | best-supported finding | quantitative/variant detail | suggested ontology terms | evidence type/limitations |
|---|---|---|---|---|
| Disease identity | Defining entity is a recessive OPA1-related mitochondrial disease within the mtDNA maintenance/depletion spectrum, clinically anchored by fatal infantile mitochondrial encephalomyopathy with hypertrophic cardiomyopathy and optic atrophy; it is distinct from dominant OPA1 optic atrophy/ADOA-plus | Causal gene: **OPA1** (OMIM *605290). The 2017 series explicitly cites the earlier homozygous **p.Leu589Arg** case report as the first infantile lethal cardiomyopathic OPA1 phenotype; nomenclature overlap means database identifiers should be verified externally before KB entry finalization (pqac-00000003, pqac-00000005, pqac-00000006) | MONDO: mitochondrial DNA depletion syndrome; NCIT: Mitochondrial Disease; HP: Optic atrophy, Hypertrophic cardiomyopathy, Encephalopathy | Human clinical/genetic evidence; exact MONDO/Orphanet subtype identifier not confirmed in available contexts |
| Inheritance | The cardioencephalomyopathic form is best supported as **autosomal recessive / biallelic OPA1 disease** | Parents carrying single heterozygous variants in reported biallelic cases were unaffected or minimally affected; 2017 paper states this is “in accordance with a recessive mode of inheritance” (pqac-00000000, pqac-00000003) | HP: Autosomal recessive inheritance | Human pedigree evidence; penetrance for this ultra-rare subtype cannot be estimated |
| Defining cardioencephalomyopathic cases | The defining subtype should be kept separate from broader biallelic OPA1 disease because the hallmark includes **infantile lethal encephalomyopathy plus hypertrophic cardiomyopathy and optic atrophy** | Reported as “the first homozygous OPA1 mutation… associated with fatal infantile mitochondrial encephalomyopathy, hypertrophic cardiomyopathy and optic atrophy”; variant cited in 2017 review/discussion is **p.Leu589Arg** (pqac-00000003, pqac-00000005, pqac-00000006) | HP: Infantile onset, Hypertrophic cardiomyopathy, Optic atrophy, Lethal infantile disease; UBERON: heart, brain, retina/optic nerve | Indirectly supported here through discussion of prior primary case; full clinical granularity of the p.Leu589Arg family is not present in the retrieved text |
| Broader biallelic OPA1 spectrum | Broader recessive OPA1 disease includes severe multisystem mitochondrial phenotypes even without cardiomyopathy; optic atrophy may be late or absent early | 2017 series: **P1** c.190_194del (p.Ser64Asnfs*7) + c.1311A>G (p.Ile437Met); **P2** c.2962G>T (p.Val988Phe) + p.Ile437Met; **P3** homozygous c.1180G>A (p.Ala394Thr) (pqac-00000003, pqac-00000001, pqac-00000002) | HP: Ataxia, Peripheral neuropathy, Hypotonia, Developmental regression, Spasticity, Optic atrophy | Human case-series evidence; phenotype spectrum broader than the specific 14B/cardioencephalomyopathic designation |
| Core neurologic phenotype | Early-onset encephalopathic/neurodegenerative disease with hypotonia, ataxia, neuropathy, developmental delay/regression is strongly supported across biallelic OPA1 cases | P1: frequent vomiting from infancy, marked psychomotor delay, seizures, severe axonal sensory neuropathy, lactate peak on MRS, progressive multiorgan failure; P3: ataxic-spastic gait, nystagmus, dysarthria, axonal sensory-motor neuropathy; P2: ataxia and sensory neuropathy (pqac-00000001, pqac-00000004, pqac-00000005) | HP: Global developmental delay, Hypotonia, Ataxia, Seizures, Peripheral axonal neuropathy, Psychomotor regression | Human clinical evidence from 3 patients; no pooled frequency estimates beyond this tiny cohort |
| Ophthalmic phenotype | Optic atrophy is important but may not be the presenting or dominant feature in recessive OPA1 disease | P1 had optic atrophy by age 5; P2 had bilateral optic neuropathy/optic atrophy; P3 had no overt optic atrophy until at least age 10 despite neurologic disease (pqac-00000001, pqac-00000000, pqac-00000005) | HP: Optic atrophy, Ptosis, Ophthalmoparesis, Abnormal visual evoked potentials | Human ophthalmic phenotyping; variability is high, so absence of early optic atrophy does not exclude disease |
| Imaging and electrophysiology | Neuroimaging can show Leigh-like or leukodystrophy-like changes; neurophysiology often shows axonal neuropathy | P1 MRI: bilateral swollen mesencephalon/pons/subthalamic nuclei, putaminal necrosis, cerebellar atrophy; H-MRS: “very high lactate peak”; P3 MRI evolved from white-matter T2 hyperintensities to bilateral putaminal abnormalities; neuropathy shown on NCS (pqac-00000001, pqac-00000005) | HP: Abnormality of basal ganglia MRI, Cerebellar atrophy, Elevated brain lactate peak, Axonal neuropathy; UBERON: pons, putamen, cerebellum | Human clinical evidence; patterns are not pathognomonic |
| mtDNA depletion evidence | Recessive OPA1 disease can include bona fide mtDNA depletion/maintenance defect | In P1 fibroblasts mtDNA content was “≈40% of the mean control value”; in muscle “≈35% of the mean control value” by qPCR (pqac-00000002, pqac-00000000, pqac-00000011) | GO: mitochondrial DNA maintenance; HP: Decreased mitochondrial DNA copy number | Direct patient molecular evidence, but quantified in one proband rather than the cardiomyopathic p.Leu589Arg family |
| Protein dysfunction/mechanism | OPA1 dysfunction causes impaired mitochondrial inner-membrane fusion/cristae organization with downstream mtDNA instability and bioenergetic failure | OPA1 is a dynamin-related GTPase at the inner mitochondrial membrane involved in “mitochondrial dynamics and mtDNA maintenance”; patient fibroblasts showed reduced OPA1 and fragmented mitochondria (pqac-00000003, pqac-00000002) | GO: mitochondrial inner membrane fusion, cristae formation, mitochondrial DNA maintenance; GO CC: mitochondrial inner membrane | Human cellular evidence and disease-mechanism review evidence; exact step linking each variant to cardiomyopathy remains incompletely resolved |
| Causal chain | Best-supported pathogenic chain: biallelic OPA1 variant → reduced/abnormal OPA1 function → impaired fusion/cristae integrity → mtDNA maintenance defect/depletion → OXPHOS inefficiency → high-energy tissue failure in brain/optic nerve/heart | P3 fibroblasts had reduced ATP synthesis with malate and pyruvate+malate, and lower ATP in galactose stress conditions; broader review notes mtDNA maintenance disorders arise from defects in replication, nucleotide metabolism, and mitochondrial dynamics, including OPA1 (pqac-00000000, pqac-00000008) | GO: ATP synthesis coupled electron transport, oxidative phosphorylation, mitochondrial genome maintenance; CL: cardiomyocyte, neuron, retinal ganglion cell | Mixed evidence: direct fibroblast data plus broader mechanistic review; heart-specific downstream pathophysiology inferred partly from defining cardiomyopathic cases |
| Variant functional support | Missense alleles show differential residual function consistent with phenotype severity | Yeast MGM1/OPA1 assay: **p.Val988Phe** virtually abolished respiratory growth, **p.Ala394Thr** markedly reduced growth, **p.Ile437Met** milder defect; the paper states effect “seems to correlate with the clinical presentation” (pqac-00000002, pqac-00000011) | NCIT: Functional assay; GO: respiratory growth / mitochondrial function | Yeast model evidence, not direct human cardiac tissue validation |
| Diagnostic evidence | Recommended diagnosis is genomic testing supported by mitochondrial phenotyping, not single biomarker alone | 2017 cases were solved by targeted resequencing/WES after mitochondrial differential workup; supportive findings included abnormal VEP/OCT, NCS, MRI/MRS, qPCR mtDNA copy number, fibroblast OPA1 immunoblot and morphology (pqac-00000003, pqac-00000004, pqac-00000002) | NCIT: Whole Exome Sequencing, Targeted Next-Generation Sequencing; HP terms as above | Human clinical evidence; no disease-specific formal diagnostic criteria identified in available contexts |
| Differential diagnosis | Can mimic Leigh syndrome, Behr syndrome, leukodystrophy, hereditary ataxia/neuropathy, or isolated optic neuropathy | Authors note P1 course was “reminiscent of Leigh syndrome” and P3 MRI suggested leukodystrophy; P2/P3 resembled Behr syndrome (pqac-00000000, pqac-00000005) | HP: Leigh-like lesions, Behr syndrome-like phenotype | Expert interpretation from case series; no validated diagnostic algorithm specific to this subtype |
| Treatment/management | No disease-modifying therapy is established for recessive cardioencephalomyopathic OPA1 disease; care is supportive | In the 2017 biallelic series, P2 received **idebenone 135 mg/day** with stable short-term follow-up, but efficacy for recessive multisystem OPA1 disease is unproven (pqac-00000001) | NCIT: Idebenone therapy; Supportive care | Single-patient observational use only; no controlled trial evidence for this subtype |
| OPA1-related trials | Current interventional development targets **OPA1-associated dominant optic atrophy**, not the recessive cardioencephalomyopathic subtype | Trials retrieved: **PYC-001** intravitreal studies **NCT06461286** (Phase 1) and **NCT06970106** (Phase 1/2), plus natural-history studies **NCT07729982** and **NCT06140329**; these are for OPA1 mutation-associated ADOA (pqac-00000008) | NCIT: Gene/RNA-targeted therapy, Natural history study | Trial relevance is indirect; no subtype-specific trial for biallelic cardioencephalomyopathic disease identified |
| Prognosis | Prognosis can be severe, including infantile lethality with multiorgan failure; broader biallelic OPA1 disease shows variable severity | P1 died after progressive decline with respiratory failure, sepsis, and multiorgan failure; discussion cites the prior homozygous OPA1 cardiomyopathic sisters with fatal infantile course (pqac-00000001, pqac-00000000, pqac-00000005) | HP: Multiorgan failure, Respiratory failure, Early death | Human evidence is limited to very small numbers; no survival curves or median survival available |
| Anatomy/cell types affected | Highest-burden tissues are those with high energy demand: brain, optic nerve/retinal ganglion cells, peripheral nerve, skeletal muscle, and in the defining subtype the heart | OPA1 disease affects “not only the optic nerve but also several other tissues/organs”; reviews of mtDNA maintenance disorders emphasize high-energy tissues (pqac-00000005, pqac-00000008) | UBERON: brain, optic nerve, retina, peripheral nerve, skeletal muscle, heart; CL: retinal ganglion cell, neuron, cardiomyocyte, skeletal muscle cell | Combination of direct cases and broader mitochondrial-disease biology |
| Model systems | Useful models include patient fibroblasts and yeast MGM1/OPA1 complementation systems | Patient fibroblasts: reduced OPA1, fragmented mitochondrial network, mtDNA depletion; yeast hybrid assay functionally stratified missense alleles (pqac-00000002, pqac-00000011, pqac-00000012) | NCIT: Fibroblast model, Yeast model; GO: mitochondrial network organization | No dedicated mammalian cardiomyopathy model for the exact p.Leu589Arg subtype was available in retrieved contexts |
| Key evidence gaps | Major gaps remain in identifiers, prevalence, heart-specific mechanism, genotype-phenotype correlation, and therapy | No confirmed prevalence/incidence, no validated subtype-specific biomarkers, no curated frequency table for phenotypes, no formal treatment guideline, and limited direct data from the defining p.Leu589Arg cardiomyopathic family in the retrieved texts (pqac-00000003, pqac-00000008) | NCIT: Not Available / Evidence gap | Important for KB curation: avoid assigning unsupported IDs, frequencies, or treatment efficacy claims |


*Table: This table summarizes the best-supported disease knowledge for the biallelic OPA1-associated mtDNA depletion/cardioencephalomyopathic phenotype and clearly distinguishes the defining infantile cardiomyopathic cases from the broader recessive OPA1 spectrum. It is designed for direct use in knowledge-base curation with ontology suggestions and explicit evidence limitations.*