🏷

Classifications

Harrison's Part

Mechanistic Nosology

👪

Inheritance

1

Autosomal recessive HP:0000007

Autosomal recessive; affected individuals are homozygous for a variant at RRM1 Arg381, with parental consanguinity in one family.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:35617047 SUPPORT Human clinical

"2 homozygous recessive variants at p.R381"

The recessive disease is caused by biallelic p.R381 variants.

⚙

Pathophysiology

6

RRM1 Loss-of-Function Variant

A biallelic loss-of-function missense variant at RRM1 Arg381 reduces the catalytic activity of ribonucleotide reductase.

RRM1 hgnc:10451

Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION

ribonucleoside-diphosphate reductase activity GO:0004748 ↓ DECREASED

Downstream

Imbalanced Mitochondrial dNTP Pools Reduced reductase activity impairs de novo dNTP synthesis.

Show evidence (2 references)

PMID:35617047 SUPPORT Human clinical

"We identified 3 RRM1 loss-of-function variants, including a dominant catalytic site variant (NP_001024.1: p.N427K) and 2 homozygous recessive variants at p.R381"

The recessive R381 variants are loss-of-function.

PMID:35617047 SUPPORT In vitro / ex vivo

"Using primary skin fibroblasts from probands, we measured RNR activity and found significantly impaired reduction"

Direct enzymatic evidence that the variants reduce ribonucleotide reductase activity.

Imbalanced Mitochondrial dNTP Pools

Impaired de novo synthesis perturbs mitochondrial nucleoside-diphosphate and dNTP pools and causes ribonucleotide incorporation into mtDNA. The pool changes are allele-dependent: near-normal in the R381H fibroblasts, with reduced dGTP/dTTP reported for R381C.

mitochondrion GO:0005739

Animal models

RNR-subunit overexpressing mouse Mouse partially recapitulates dNTP imbalance drives muscle mtDNA depletion, as inferred for the human disease.

Downstream

Impaired mtDNA Replication Imbalanced and insufficient dNTPs impair mtDNA replication.

Show evidence (2 references)

PMID:35617047 SUPPORT In vitro / ex vivo

"Fibroblasts also exhibited aberrant nucleoside diphosphate and dNTP pools and mtDNA ribonucleotide incorporation"

Patient fibroblasts show the dNTP-pool imbalance and mtDNA ribonucleotide incorporation.

PMID:35617047 SUPPORT In vitro / ex vivo

"mitochondrial dNTP pools of fibroblasts from probands 1a and 1b were generally similar to those of controls, aside from a slight increase of dGTP for proband 1a"

The R381H fibroblast pools were near-normal, so the pool perturbation is allele-dependent rather than uniform.

Impaired mtDNA Replication

Cells that depend on de novo dNTP synthesis cannot replicate mtDNA normally, producing mtDNA depletion in cycling cells.

mitochondrial DNA replication GO:0006264 ↓ DECREASED

mitochondrion GO:0005739

Downstream

Multiple mtDNA Deletions Stalled replication and faulty repair in post-mitotic muscle generate multiple mtDNA deletions.

Show evidence (2 references)

PMID:35617047 SUPPORT In vitro / ex vivo

"Cultured primary skin fibroblasts of probands manifested mtDNA depletion under cycling conditions, indicating impaired de novo nucleotide synthesis"

Patient fibroblasts deplete mtDNA when cycling, showing impaired de novo synthesis.

PMID:35617047 SUPPORT Human clinical

"a muscle biopsy that revealed multiple mtDNA deletions and reduced mtDNA"

Recessive proband 2's muscle shows mtDNA depletion (reduced copy number) in vivo.

Multiple mtDNA Deletions

Post-mitotic skeletal muscle accumulates multiple mtDNA deletions that expand clonally.

skeletal muscle fiber CL:0008002

mitochondrion GO:0005739

skeletal muscle tissue UBERON:0001134 extra-ocular muscle UBERON:0001601

Downstream

Mosaic Respiratory Chain Deficiency Clonal expansion of deleted mtDNA produces mosaic respiratory-chain deficiency.

Enteric Mitochondrial Involvement Gastrointestinal mitochondrial involvement is inferred from the MNGIE-like clinical phenotype in family 1 by analogy with other mtDNA maintenance disorders; gastrointestinal tissue was not tested for mtDNA deletions.

Show evidence (1 reference)

PMID:35617047 SUPPORT Human clinical

"a muscle biopsy that revealed multiple mtDNA deletions"

A recessive proband's muscle carries multiple mtDNA deletions.

Mosaic Respiratory Chain Deficiency

A mosaic of fibres loses respiratory-chain function, seen as COX-deficient and ragged-red fibres, and energy failure strikes high-demand, long-lived muscle.

skeletal muscle fiber CL:0008002

oxidative phosphorylation GO:0006119 ↓ DECREASED

mitochondrion GO:0005739

skeletal muscle tissue UBERON:0001134 extra-ocular muscle UBERON:0001601

Downstream

Progressive external ophthalmoplegia Extraocular-muscle energy failure produces ophthalmoplegia.

Ptosis Levator-muscle involvement produces ptosis.

Diplopia Ophthalmoparesis produces double vision.

Proximal muscle weakness Limb-muscle energy failure produces proximal weakness.

Elevated creatine kinase Muscle fibre damage releases creatine kinase.

Generalized limb muscle atrophy Chronic myopathy produces limb muscle atrophy.

Cytochrome C oxidase-negative muscle fibers Respiratory-chain deficiency is seen as COX-negative fibres.

Ragged-red muscle fibers Mitochondrial proliferation is seen as ragged-red fibres.

Show evidence (1 reference)

PMID:35617047 SUPPORT Human clinical

"A muscle biopsy showed 50%-60% COX-deficient fibers, 3%-4% ragged-red fibers (RRFs), numerous highly atrophic fibers, regenerating central nucleated fibers, and a few fibers with necrotic sarcoplasm"

Muscle biopsy shows the mosaic respiratory-chain deficiency.

Enteric Mitochondrial Involvement

Gastrointestinal mitochondrial involvement is inferred in consanguineous family 1 (homozygous p.R381H) from the MNGIE-like presentation of intestinal dysmotility, vomiting, diarrhea, weight loss, and cachexia, by analogy with other mtDNA maintenance disorders rather than direct demonstration in gastrointestinal tissue.

alimentary part of gastrointestinal system UBERON:0005409

Downstream

Gastrointestinal dysmotility Enteric involvement impairs gut motility.

Diarrhea Dysmotility produces intermittent diarrhea.

Vomiting Enteric involvement produces nausea and vomiting.

Weight loss Gut dysmotility and malabsorption produce weight loss.

Cachexia Chronic gastrointestinal involvement produces cachexia.

Show evidence (1 reference)

PMID:35617047 SUPPORT Human clinical

"developed ptosis, ophthalmoparesis, cachexia, and intestinal dysmotility"

A recessive proband developed intestinal dysmotility and cachexia.

⬡

Pathograph

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

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Phenotypes

15

Digestive 3

Vomiting HP:0002013

Show evidence (1 reference)

PMID:35617047 SUPPORT Human clinical

"healthy until 7 years of age when he developed nausea and occasional vomiting"

Gastrointestinal symptoms in the MNGIE-like family.

Diarrhea HP:0002014

Show evidence (1 reference)

PMID:35617047 SUPPORT Human clinical

"He developed intermittent diarrhea at 14 years of age"

Intermittent diarrhea in a recessive proband.

Gastrointestinal dysmotility HP:0002579

All gastrointestinal manifestations in PMID:35617047 (dysmotility, vomiting, diarrhea, weight loss, and cachexia) come from the single consanguineous p.R381H family (probands 1a and 1b) and were not reported in the two p.R381C families.

Show evidence (1 reference)

PMID:35617047 SUPPORT Human clinical

"developed ptosis, ophthalmoparesis, cachexia, and intestinal dysmotility"

Intestinal dysmotility in the MNGIE-like family.

Eye 3

Progressive external ophthalmoplegia HP:0000590

Show evidence (1 reference)

PMID:35617047 SUPPORT Human clinical

"double vision, ptosis, ophthalmoplegia, and difficulty walking stairs and standing due to muscle weakness"

Ophthalmoplegia is a defining feature.

Ptosis HP:0000508

Show evidence (1 reference)

PMID:35617047 SUPPORT Human clinical

"double vision, ptosis, ophthalmoplegia, and difficulty walking stairs and standing due to muscle weakness"

Ptosis is a presenting feature.

Diplopia HP:0000651

Show evidence (1 reference)

PMID:35617047 SUPPORT Human clinical

"double vision, ptosis, ophthalmoplegia, and difficulty walking stairs and standing due to muscle weakness"

Double vision is often the first symptom in late-onset cases.

Metabolism 1

Elevated creatine kinase Elevated circulating creatine kinase activity HP:0003236

Show evidence (1 reference)

PMID:35617047 SUPPORT Human clinical

"Ptosis and elevated creatine kinase (697 U/L; normal 51-294 U/L) were evident after pneumonia at 31 years of age"

Serum creatine kinase is elevated.

Musculoskeletal 4

Proximal muscle weakness HP:0003701

Show evidence (2 references)

PMID:35617047 SUPPORT Human clinical

"he lost 17 kg and developed moderate proximal limb weakness"

Progressive proximal limb weakness in proband 1a.

PMID:35617047 SUPPORT Human clinical

"Proband 4 was a 61-year-old woman of nonconsanguineous parents with double vision, ptosis, ophthalmoplegia, and difficulty walking stairs and standing due to muscle weakness."

Documents difficulty climbing stairs and standing due to muscle weakness in proband 4.

Generalized limb muscle atrophy HP:0009055

Show evidence (1 reference)

PMID:35617047 SUPPORT Human clinical

"Limb MRI revealed generalized muscle atrophy"

Limb MRI showed generalized muscle atrophy.

Cytochrome C oxidase-negative muscle fibers HP:0003688

Show evidence (1 reference)

PMID:35617047 SUPPORT Human clinical

"A muscle biopsy showed 50%-60% COX-deficient fibers, 3%-4% ragged-red fibers (RRFs), numerous highly atrophic fibers, regenerating central nucleated fibers, and a few fibers with necrotic sarcoplasm"

COX-deficient fibres on muscle biopsy.

Ragged-red muscle fibers HP:0003200

Show evidence (1 reference)

PMID:35617047 SUPPORT Human clinical

"A muscle biopsy showed 50%-60% COX-deficient fibers, 3%-4% ragged-red fibers (RRFs), numerous highly atrophic fibers, regenerating central nucleated fibers, and a few fibers with necrotic sarcoplasm"

Ragged-red fibres on muscle biopsy.

Nervous System 2

Peripheral axonal neuropathy HP:0003477

Sequelae: Areflexia

Show evidence (1 reference)

PMID:35617047 SUPPORT Human clinical

"Absent tendon reflexes, nerve conduction studies, and electromyography indicated a mild axonal sensorimotor peripheral neuropathy"

Nerve conduction studies and EMG show a mild axonal sensorimotor peripheral neuropathy.

Areflexia HP:0001284

Show evidence (1 reference)

PMID:35617047 SUPPORT Human clinical

"Absent tendon reflexes, nerve conduction studies, and electromyography indicated a mild axonal sensorimotor peripheral neuropathy"

Absent tendon reflexes (areflexia) accompanied the neuropathy.

Growth 2

Weight loss HP:0001824

Show evidence (1 reference)

PMID:35617047 SUPPORT Human clinical

"he lost 17 kg and developed moderate proximal limb weakness"

Weight loss, prominent in the MNGIE-like family.

Cachexia HP:0004326

Show evidence (1 reference)

PMID:35617047 SUPPORT Human clinical

"developed ptosis, ophthalmoparesis, cachexia, and intestinal dysmotility"

Cachexia in the MNGIE-like family.

🧬

Genetic Associations

1

RRM1 (Causative)

Gene: RRM1 hgnc:10451 relationship_type: CAUSATIVE variant_origin: GERMLINE

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:35617047 SUPPORT Human clinical

"We identified 3 RRM1 loss-of-function variants, including a dominant catalytic site variant (NP_001024.1: p.N427K) and 2 homozygous recessive variants at p.R381"

Identifies the causal RRM1 loss-of-function variants.

Variants (2)

R381H

c.1142G>A; recessive loss-of-function; the consanguineous family 1 (MNGIE-like picture).

R381C

c.1141C>T; recessive loss-of-function; affects the same residue as R381H, found in family 2 and proband 4.

💊

Medical Actions

2

Supportive care

Category: Therapeutic Action: Supportive Care NCIT:C15747

PMID:35617047 reports no disease-specific therapy or management regimen for the affected families; clinical care is supportive and symptomatic.

Genetic counseling

Category: Counseling / Informational Action: Genetic Counseling NCIT:C15240

Genetic counseling for affected individuals and families addresses the autosomal recessive inheritance of biallelic RRM1 p.R381 loss-of-function variants.

Show evidence (1 reference)

PMID:35617047 SUPPORT Human clinical

"We identified 3 RRM1 loss-of-function variants, including a dominant catalytic site variant (NP_001024.1: p.N427K) and 2 homozygous recessive variants at p.R381"

Establishes homozygous recessive RRM1 p.R381 loss-of-function variants as the genetic basis informing family counseling.

🔬

Diagnosis

2

Molecular genetic testing (Present)

Whole-exome sequencing identifies the biallelic RRM1 R381 variant and confirms the diagnosis.

whole exome sequencing NCIT:C15709

Results: Homozygous or biallelic pathogenic loss-of-function variants in RRM1 (such as p.R381H or p.R381C).

Show evidence (1 reference)

PMID:35617047 SUPPORT Human clinical

"we performed whole exome sequencing (WES) and identified a candidate RRM1 missense variant"

WES identified the causal RRM1 variant.

Muscle biopsy (Present)

Muscle biopsy shows COX-deficient and ragged-red fibres; Southern blot or long-range PCR of muscle DNA detects the multiple mtDNA deletions.

muscle biopsy NCIT:C51895

Results: Mosaic COX-deficient fibers and ragged-red fibers (50%-60% COX-deficient and 3%-4% ragged-red fibers in proband 1a; COX-deficient fibers and 30% ragged-red fibers in proband 4), with multiple mtDNA deletions on Southern blot or long-range PCR.

Show evidence (3 references)

PMID:35617047 SUPPORT Human clinical

"A muscle biopsy showed 50%-60% COX-deficient fibers, 3%-4% ragged-red fibers (RRFs), numerous highly atrophic fibers, regenerating central nucleated fibers, and a few fibers with necrotic sarcoplasm"

Documents 50%-60% COX-deficient fibers and 3%-4% ragged-red fibers on muscle biopsy in proband 1a.

PMID:35617047 SUPPORT Human clinical

"Muscle histopathology showed COX-deficient fibers and 30% RRFs."

Documents COX-deficient fibers and 30% ragged-red fibers on muscle histopathology in proband 4.

PMID:35617047 SUPPORT Human clinical

"Southern blot revealed multiple mtDNA deletions"

Southern blot of a recessive proband's muscle detects the multiple mtDNA deletions.

📈

Progression

2

Onset

Ophthalmoparesis began between adolescence (proband 1a at 17 years) and mid-adulthood (proband 2 at 45 years). In the MNGIE-like family 1, gastrointestinal symptoms began earlier, with nausea and vomiting from 7 years and diarrhea from 14 years.

Progression

Progressive external ophthalmoplegia, proximal myopathy, and, in the MNGIE-like family, cachexia and neuropathy.

📊

Prevalence

1

Worldwide

Cases/families reported in the literature Not yet documented

Ultra-rare. The single source (PMID:35617047) reports 5 probands from 4 families; the recessive R381 disease curated here is seen in three of those families, while the remaining proband (proband 3) carries the dominant p.N427K variant and is a separate disease.

🐁

Animal Models

1

RNR-subunit overexpressing mouse

A mechanistic model: overexpressing two RNR subunits imbalances dNTP pools and depletes muscle mtDNA, supporting dNTP balance (not just quantity) as the driver. The Rrm1 knockout is embryonic-lethal and does not model the disease.

Species

Mouse

Genotype

Transgenic overexpression of RNR subunits (Rrm1/Rrm2/p53R2)

Publication

PMID:20724444

Pathograph links

Imbalanced Mitochondrial dNTP Pools partially recapitulates fidelity: low observes: organism dNTP imbalance drives muscle mtDNA depletion, as inferred for the human disease.

Limitations: An overexpression/imbalance model, not the RRM1 R381 loss-of-function allele, and it produces depletion rather than the deletions seen in patient muscle.

Show evidence (1 reference)

PMID:20724444 SUPPORT Model organism

"simultaneous expression of two RNR subunits leads to imbalanced dNTP pools and progressive mtDNA depletion in the skeletal muscle, without mtDNA mutagenesis"

Shows dNTP imbalance drives muscle mtDNA depletion.

Show evidence (1 reference)

PMID:20724444 SUPPORT Model organism

"simultaneous expression of two RNR subunits leads to imbalanced dNTP pools and progressive mtDNA depletion in the skeletal muscle, without mtDNA mutagenesis"

Establishes the RNR-imbalance mouse as a partial mechanistic model.

{ }

Source YAML

click to show

name: Progressive External Ophthalmoplegia Autosomal Recessive 6
creation_date: "2026-10-29T00:00:00Z"
category: Mendelian
description: >-
  Progressive external ophthalmoplegia with mitochondrial DNA deletions,
  autosomal recessive 6 (PEOB6) is a rare mitochondrial DNA maintenance
  disorder caused by biallelic loss-of-function variants in RRM1, which encodes
  the catalytic subunit of ribonucleotide reductase required for de novo
  deoxyribonucleotide (dNTP) synthesis. Impaired ribonucleotide reductase
  activity perturbs mitochondrial dNTP pools and mtDNA replication, leading to
  accumulation of multiple mtDNA deletions and mosaic respiratory chain
  deficiency in skeletal and extraocular muscle. Affected individuals present
  between childhood and adulthood with progressive external ophthalmoplegia,
  ptosis, diplopia, proximal limb muscle weakness and atrophy, and in some
  families a mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)-like
  multisystem presentation with gastrointestinal dysmotility, vomiting,
  diarrhea, weight loss, cachexia, areflexia, and axonal sensorimotor
  peripheral neuropathy.
disease_term:
  preferred_term: progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 6
  term:
    id: MONDO:0957993
    label: progressive external ophthalmoplegia with mitochondrial dna deletions, autosomal recessive 6
synonyms:
- PEOB6
- RRM1-related progressive external ophthalmoplegia
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
    evidence:
    - reference: PMID:35617047
      reference_title: RRM1 variants cause a mitochondrial DNA maintenance disorder via impaired de novo nucleotide synthesis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Here, we report 5 probands from 4 families who presented with ptosis and ophthalmoplegia as well as other clinical manifestations and multiple mtDNA deletions in muscle."
      explanation: PEOB6 presents primarily as a neuromuscular disorder with ptosis, progressive external ophthalmoplegia, proximal myopathy, and peripheral axonal neuropathy.
    notes: Neuromuscular disorder with progressive external ophthalmoplegia, myopathy, and peripheral neuropathy.
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    evidence:
    - reference: PMID:35617047
      reference_title: RRM1 variants cause a mitochondrial DNA maintenance disorder via impaired de novo nucleotide synthesis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Mitochondrial DNA (mtDNA) depletion/deletions syndromes (MDDS) encompass a clinically and etiologically heterogenous group of mitochondrial disorders caused by impaired mtDNA maintenance."
      explanation: PEOB6 is a monogenic autosomal recessive mitochondrial DNA maintenance disorder caused by biallelic RRM1 loss-of-function variants.
    notes: Autosomal recessive monogenic disorder of de novo nucleotide synthesis and mtDNA maintenance.
  mechanistic_category:
  - classification_value: mitochondrial disease
    evidence:
    - reference: PMID:35617047
      reference_title: RRM1 variants cause a mitochondrial DNA maintenance disorder via impaired de novo nucleotide synthesis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Mitochondrial DNA (mtDNA) depletion/deletions syndromes (MDDS) encompass a clinically and etiologically heterogenous group of mitochondrial disorders caused by impaired mtDNA maintenance."
      explanation: Directly classifies RRM1-related PEOB6 as a mitochondrial DNA maintenance disorder (MDDS) within the mitochondrial disease spectrum.
    notes: Mitochondrial DNA maintenance disorder with multiple mtDNA deletions and mosaic OXPHOS deficiency.
notes: >-
  PEOB6 (OMIM:620647) is an autosomal recessive mitochondrial DNA
  maintenance disorder (an MDDS) caused by biallelic loss-of-function RRM1
  variants that impair de novo deoxyribonucleotide synthesis. The whole entry
  rests on a single multicentre report (PMID:35617047) describing recessive
  probands homozygous for a variant at RRM1 Arg381. The dominant catalytic-site
  variant p.N427K reported in the same paper is a separate (dominant) disease and
  is deliberately not included here. The respiratory-chain node conforms to the
  primary_oxphos_deficiency module's OXPHOS Complex Deficiency node, and the
  multiple mtDNA deletions node to its Mitochondrial DNA Depletion or Deletion
  trigger, following the other MDDS entries; the upstream dNTP-synthesis defect
  itself has no dedicated module. Among the three recessive families reported
  (probands 1a/1b homozygous for p.R381H, family 2 homozygous for p.R381C, and
  proband 4 homozygous for p.R381C), the MNGIE-like gastrointestinal features
  (intestinal dysmotility, vomiting, diarrhea, weight loss, and cachexia) were
  confined to consanguineous family 1 and were not reported in the two p.R381C
  families.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Autosomal recessive; affected individuals are homozygous for a variant at
    RRM1 Arg381, with parental consanguinity in one family.
  evidence:
  - reference: PMID:35617047
    reference_title: RRM1 variants cause a mitochondrial DNA maintenance disorder via impaired de novo nucleotide synthesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "2 homozygous recessive variants at p.R381"
    explanation: The recessive disease is caused by biallelic p.R381 variants.
genetic:
- name: RRM1
  gene_term:
    preferred_term: RRM1
    term:
      id: hgnc:10451
      label: RRM1
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  notes: >-
    RRM1 is the catalytic subunit of ribonucleotide reductase, which makes
    deoxyribonucleotides for mtDNA replication. The two recessive alleles are
    p.R381H (c.1142G>A) and p.R381C (c.1141C>T). The dominant p.N427K
    catalytic-site variant causes a separate dominant disease and is excluded.
  variants:
  - name: R381H
    description: c.1142G>A; recessive loss-of-function; the consanguineous family 1 (MNGIE-like picture).
  - name: R381C
    description: c.1141C>T; recessive loss-of-function; affects the same residue as R381H, found in family 2 and proband 4.
  evidence:
  - reference: PMID:35617047
    reference_title: RRM1 variants cause a mitochondrial DNA maintenance disorder via impaired de novo nucleotide synthesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified 3 RRM1 loss-of-function variants, including a dominant catalytic site variant (NP_001024.1: p.N427K) and 2 homozygous recessive variants at p.R381"
    explanation: Identifies the causal RRM1 loss-of-function variants.
pathophysiology:
- name: RRM1 Loss-of-Function Variant
  biological_scale: MOLECULAR
  description: >-
    A biallelic loss-of-function missense variant at RRM1 Arg381 reduces the
    catalytic activity of ribonucleotide reductase.
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
  genes:
  - preferred_term: RRM1
    term:
      id: hgnc:10451
      label: RRM1
  molecular_functions:
  - preferred_term: ribonucleoside-diphosphate reductase activity
    modifier: DECREASED
    term:
      id: GO:0004748
      label: "ribonucleoside-diphosphate reductase activity, thioredoxin disulfide as acceptor"
  downstream:
  - target: Imbalanced Mitochondrial dNTP Pools
    causal_link_type: DIRECT
    description: Reduced reductase activity impairs de novo dNTP synthesis.
  evidence:
  - reference: PMID:35617047
    reference_title: RRM1 variants cause a mitochondrial DNA maintenance disorder via impaired de novo nucleotide synthesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified 3 RRM1 loss-of-function variants, including a dominant catalytic site variant (NP_001024.1: p.N427K) and 2 homozygous recessive variants at p.R381"
    explanation: The recessive R381 variants are loss-of-function.
  - reference: PMID:35617047
    reference_title: RRM1 variants cause a mitochondrial DNA maintenance disorder via impaired de novo nucleotide synthesis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Using primary skin fibroblasts from probands, we measured RNR activity and found significantly impaired reduction"
    explanation: Direct enzymatic evidence that the variants reduce ribonucleotide reductase activity.
- name: Imbalanced Mitochondrial dNTP Pools
  biological_scale: MOLECULAR
  description: >-
    Impaired de novo synthesis perturbs mitochondrial nucleoside-diphosphate and
    dNTP pools and causes ribonucleotide incorporation into mtDNA. The pool
    changes are allele-dependent: near-normal in the R381H fibroblasts, with
    reduced dGTP/dTTP reported for R381C.
  cellular_components:
  - preferred_term: mitochondrion
    term:
      id: GO:0005739
      label: mitochondrion
  downstream:
  - target: Impaired mtDNA Replication
    causal_link_type: DIRECT
    description: Imbalanced and insufficient dNTPs impair mtDNA replication.
  evidence:
  - reference: PMID:35617047
    reference_title: RRM1 variants cause a mitochondrial DNA maintenance disorder via impaired de novo nucleotide synthesis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Fibroblasts also exhibited aberrant nucleoside diphosphate and dNTP pools and mtDNA ribonucleotide incorporation"
    explanation: Patient fibroblasts show the dNTP-pool imbalance and mtDNA ribonucleotide incorporation.
  - reference: PMID:35617047
    reference_title: RRM1 variants cause a mitochondrial DNA maintenance disorder via impaired de novo nucleotide synthesis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "mitochondrial dNTP pools of fibroblasts from probands 1a and 1b were generally similar to those of controls, aside from a slight increase of dGTP for proband 1a"
    explanation: The R381H fibroblast pools were near-normal, so the pool perturbation is allele-dependent rather than uniform.
- name: Impaired mtDNA Replication
  biological_scale: MOLECULAR
  description: >-
    Cells that depend on de novo dNTP synthesis cannot replicate mtDNA normally,
    producing mtDNA depletion in cycling cells.
  cellular_components:
  - preferred_term: mitochondrion
    term:
      id: GO:0005739
      label: mitochondrion
  biological_processes:
  - preferred_term: mitochondrial DNA replication
    modifier: DECREASED
    term:
      id: GO:0006264
      label: mitochondrial DNA replication
  downstream:
  - target: Multiple mtDNA Deletions
    causal_link_type: DIRECT
    description: Stalled replication and faulty repair in post-mitotic muscle generate multiple mtDNA deletions.
  evidence:
  - reference: PMID:35617047
    reference_title: RRM1 variants cause a mitochondrial DNA maintenance disorder via impaired de novo nucleotide synthesis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Cultured primary skin fibroblasts of probands manifested mtDNA depletion under cycling conditions, indicating impaired de novo nucleotide synthesis"
    explanation: Patient fibroblasts deplete mtDNA when cycling, showing impaired de novo synthesis.
  - reference: PMID:35617047
    reference_title: RRM1 variants cause a mitochondrial DNA maintenance disorder via impaired de novo nucleotide synthesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a muscle biopsy that revealed multiple mtDNA deletions and reduced mtDNA"
    explanation: Recessive proband 2's muscle shows mtDNA depletion (reduced copy number) in vivo.
- name: Multiple mtDNA Deletions
  conforms_to: "primary_oxphos_deficiency#Mitochondrial DNA Depletion or Deletion"
  biological_scale: CELLULAR
  description: >-
    Post-mitotic skeletal muscle accumulates multiple mtDNA deletions that expand
    clonally.
  locations:
  - preferred_term: skeletal muscle tissue
    term:
      id: UBERON:0001134
      label: skeletal muscle tissue
  - preferred_term: extra-ocular muscle
    term:
      id: UBERON:0001601
      label: extra-ocular muscle
  cellular_components:
  - preferred_term: mitochondrion
    term:
      id: GO:0005739
      label: mitochondrion
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  downstream:
  - target: Mosaic Respiratory Chain Deficiency
    causal_link_type: DIRECT
    description: Clonal expansion of deleted mtDNA produces mosaic respiratory-chain deficiency.
  - target: Enteric Mitochondrial Involvement
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Gastrointestinal mitochondrial involvement is inferred from the
      MNGIE-like clinical phenotype in family 1 by analogy with other mtDNA
      maintenance disorders; gastrointestinal tissue was not tested for mtDNA
      deletions.
  evidence:
  - reference: PMID:35617047
    reference_title: RRM1 variants cause a mitochondrial DNA maintenance disorder via impaired de novo nucleotide synthesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a muscle biopsy that revealed multiple mtDNA deletions"
    explanation: A recessive proband's muscle carries multiple mtDNA deletions.
- name: Mosaic Respiratory Chain Deficiency
  conforms_to: "primary_oxphos_deficiency#OXPHOS Complex Deficiency"
  biological_scale: CELLULAR
  description: >-
    A mosaic of fibres loses respiratory-chain function, seen as COX-deficient and
    ragged-red fibres, and energy failure strikes high-demand, long-lived muscle.
  locations:
  - preferred_term: skeletal muscle tissue
    term:
      id: UBERON:0001134
      label: skeletal muscle tissue
  - preferred_term: extra-ocular muscle
    term:
      id: UBERON:0001601
      label: extra-ocular muscle
  cellular_components:
  - preferred_term: mitochondrion
    term:
      id: GO:0005739
      label: mitochondrion
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  biological_processes:
  - preferred_term: oxidative phosphorylation
    modifier: DECREASED
    term:
      id: GO:0006119
      label: oxidative phosphorylation
  downstream:
  - target: Progressive external ophthalmoplegia
    causal_link_type: DIRECT
    description: Extraocular-muscle energy failure produces ophthalmoplegia.
  - target: Ptosis
    causal_link_type: DIRECT
    description: Levator-muscle involvement produces ptosis.
  - target: Diplopia
    causal_link_type: DIRECT
    description: Ophthalmoparesis produces double vision.
  - target: Proximal muscle weakness
    causal_link_type: DIRECT
    description: Limb-muscle energy failure produces proximal weakness.
  - target: Elevated creatine kinase
    causal_link_type: DIRECT
    description: Muscle fibre damage releases creatine kinase.
  - target: Generalized limb muscle atrophy
    causal_link_type: DIRECT
    description: Chronic myopathy produces limb muscle atrophy.
  - target: Cytochrome C oxidase-negative muscle fibers
    causal_link_type: DIRECT
    description: Respiratory-chain deficiency is seen as COX-negative fibres.
  - target: Ragged-red muscle fibers
    causal_link_type: DIRECT
    description: Mitochondrial proliferation is seen as ragged-red fibres.
  evidence:
  - reference: PMID:35617047
    reference_title: RRM1 variants cause a mitochondrial DNA maintenance disorder via impaired de novo nucleotide synthesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A muscle biopsy showed 50%-60% COX-deficient fibers, 3%-4% ragged-red fibers (RRFs), numerous highly atrophic fibers, regenerating central nucleated fibers, and a few fibers with necrotic sarcoplasm"
    explanation: Muscle biopsy shows the mosaic respiratory-chain deficiency.
- name: Enteric Mitochondrial Involvement
  biological_scale: TISSUE
  description: >-
    Gastrointestinal mitochondrial involvement is inferred in consanguineous
    family 1 (homozygous p.R381H) from the MNGIE-like presentation of
    intestinal dysmotility, vomiting, diarrhea, weight loss, and cachexia, by
    analogy with other mtDNA maintenance disorders rather than direct
    demonstration in gastrointestinal tissue.
  locations:
  - preferred_term: alimentary part of gastrointestinal system
    term:
      id: UBERON:0005409
      label: alimentary part of gastrointestinal system
  downstream:
  - target: Gastrointestinal dysmotility
    causal_link_type: DIRECT
    description: Enteric involvement impairs gut motility.
  - target: Diarrhea
    causal_link_type: DIRECT
    description: Dysmotility produces intermittent diarrhea.
  - target: Vomiting
    causal_link_type: DIRECT
    description: Enteric involvement produces nausea and vomiting.
  - target: Weight loss
    causal_link_type: DIRECT
    description: Gut dysmotility and malabsorption produce weight loss.
  - target: Cachexia
    causal_link_type: DIRECT
    description: Chronic gastrointestinal involvement produces cachexia.
  evidence:
  - reference: PMID:35617047
    reference_title: RRM1 variants cause a mitochondrial DNA maintenance disorder via impaired de novo nucleotide synthesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "developed ptosis, ophthalmoparesis, cachexia, and intestinal dysmotility"
    explanation: A recessive proband developed intestinal dysmotility and cachexia.
phenotypes:
- category: Ophthalmologic
  name: Progressive external ophthalmoplegia
  diagnostic: true
  description: >-
    Progressive weakness and paralysis of the extraocular muscles, a core
    manifestation across all reported families with RRM1-related mitochondrial
    DNA maintenance disorder.
  phenotype_term:
    preferred_term: Progressive external ophthalmoplegia
    term:
      id: HP:0000590
      label: Progressive external ophthalmoplegia
  evidence:
  - reference: PMID:35617047
    reference_title: RRM1 variants cause a mitochondrial DNA maintenance disorder via impaired de novo nucleotide synthesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "double vision, ptosis, ophthalmoplegia, and difficulty walking stairs and standing due to muscle weakness"
    explanation: Ophthalmoplegia is a defining feature.
- category: Ophthalmologic
  name: Ptosis
  diagnostic: true
  description: >-
    Drooping of the upper eyelids due to levator palpebrae superioris weakness,
    presenting alongside progressive external ophthalmoplegia.
  phenotype_term:
    preferred_term: Ptosis
    term:
      id: HP:0000508
      label: Ptosis
  evidence:
  - reference: PMID:35617047
    reference_title: RRM1 variants cause a mitochondrial DNA maintenance disorder via impaired de novo nucleotide synthesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "double vision, ptosis, ophthalmoplegia, and difficulty walking stairs and standing due to muscle weakness"
    explanation: Ptosis is a presenting feature.
- category: Ophthalmologic
  name: Diplopia
  description: >-
    Double vision resulting from extraocular muscle paresis and ocular
    misalignment.
  phenotype_term:
    preferred_term: Diplopia
    term:
      id: HP:0000651
      label: Diplopia
  evidence:
  - reference: PMID:35617047
    reference_title: RRM1 variants cause a mitochondrial DNA maintenance disorder via impaired de novo nucleotide synthesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "double vision, ptosis, ophthalmoplegia, and difficulty walking stairs and standing due to muscle weakness"
    explanation: Double vision is often the first symptom in late-onset cases.
- category: Musculoskeletal
  name: Proximal muscle weakness
  description: >-
    Progressive weakness of the proximal limb musculature causing difficulty
    climbing stairs and rising from a seated position.
  phenotype_term:
    preferred_term: Proximal muscle weakness
    term:
      id: HP:0003701
      label: Proximal muscle weakness
  evidence:
  - reference: PMID:35617047
    reference_title: RRM1 variants cause a mitochondrial DNA maintenance disorder via impaired de novo nucleotide synthesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "he lost 17 kg and developed moderate proximal limb weakness"
    explanation: Progressive proximal limb weakness in proband 1a.
  - reference: PMID:35617047
    reference_title: RRM1 variants cause a mitochondrial DNA maintenance disorder via impaired de novo nucleotide synthesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Proband 4 was a 61-year-old woman of nonconsanguineous parents with double vision, ptosis, ophthalmoplegia, and difficulty walking stairs and standing due to muscle weakness."
    explanation: Documents difficulty climbing stairs and standing due to muscle weakness in proband 4.
- category: Laboratory
  name: Elevated creatine kinase
  description: >-
    Mildly to moderately elevated serum creatine kinase activity reflecting
    skeletal muscle fiber injury.
  phenotype_term:
    preferred_term: Elevated creatine kinase
    term:
      id: HP:0003236
      label: Elevated circulating creatine kinase activity
  evidence:
  - reference: PMID:35617047
    reference_title: RRM1 variants cause a mitochondrial DNA maintenance disorder via impaired de novo nucleotide synthesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ptosis and elevated creatine kinase (697 U/L; normal 51-294 U/L) were evident after pneumonia at 31 years of age"
    explanation: Serum creatine kinase is elevated.
- category: Gastrointestinal
  name: Vomiting
  description: >-
    Recurrent nausea and vomiting beginning in childhood in patients with
    enteric mitochondrial involvement.
  phenotype_term:
    preferred_term: Vomiting
    term:
      id: HP:0002013
      label: Vomiting
  evidence:
  - reference: PMID:35617047
    reference_title: RRM1 variants cause a mitochondrial DNA maintenance disorder via impaired de novo nucleotide synthesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "healthy until 7 years of age when he developed nausea and occasional vomiting"
    explanation: Gastrointestinal symptoms in the MNGIE-like family.
- category: Constitutional
  name: Weight loss
  description: >-
    Substantial progressive weight loss secondary to chronic gastrointestinal
    dysmotility.
  phenotype_term:
    preferred_term: Weight loss
    term:
      id: HP:0001824
      label: Weight loss
  evidence:
  - reference: PMID:35617047
    reference_title: RRM1 variants cause a mitochondrial DNA maintenance disorder via impaired de novo nucleotide synthesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "he lost 17 kg and developed moderate proximal limb weakness"
    explanation: Weight loss, prominent in the MNGIE-like family.
- category: Gastrointestinal
  name: Diarrhea
  description: >-
    Intermittent chronic diarrhea associated with gastrointestinal dysmotility.
  phenotype_term:
    preferred_term: Diarrhea
    term:
      id: HP:0002014
      label: Diarrhea
  evidence:
  - reference: PMID:35617047
    reference_title: RRM1 variants cause a mitochondrial DNA maintenance disorder via impaired de novo nucleotide synthesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He developed intermittent diarrhea at 14 years of age"
    explanation: Intermittent diarrhea in a recessive proband.
- category: Gastrointestinal
  name: Gastrointestinal dysmotility
  description: >-
    Impaired intestinal motility presenting as part of an MNGIE-like clinical
    phenotype in consanguineous family 1 (homozygous p.R381H); gastrointestinal
    features were confined to this family among the three recessive families
    reported.
  notes: >-
    All gastrointestinal manifestations in PMID:35617047 (dysmotility,
    vomiting, diarrhea, weight loss, and cachexia) come from the single
    consanguineous p.R381H family (probands 1a and 1b) and were not reported in
    the two p.R381C families.
  phenotype_term:
    preferred_term: intestinal dysmotility
    term:
      id: HP:0002579
      label: Gastrointestinal dysmotility
  evidence:
  - reference: PMID:35617047
    reference_title: RRM1 variants cause a mitochondrial DNA maintenance disorder via impaired de novo nucleotide synthesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "developed ptosis, ophthalmoparesis, cachexia, and intestinal dysmotility"
    explanation: Intestinal dysmotility in the MNGIE-like family.
- category: Constitutional
  name: Cachexia
  description: >-
    Severe wasting and loss of body mass accompanying chronic intestinal
    dysmotility in the MNGIE-like presentation.
  phenotype_term:
    preferred_term: Cachexia
    term:
      id: HP:0004326
      label: Cachexia
  evidence:
  - reference: PMID:35617047
    reference_title: RRM1 variants cause a mitochondrial DNA maintenance disorder via impaired de novo nucleotide synthesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "developed ptosis, ophthalmoparesis, cachexia, and intestinal dysmotility"
    explanation: Cachexia in the MNGIE-like family.
- category: Musculoskeletal
  name: Generalized limb muscle atrophy
  description: >-
    Diffuse atrophy of the limb musculature demonstrated on clinical
    examination and muscle MRI.
  phenotype_term:
    preferred_term: Generalized limb muscle atrophy
    term:
      id: HP:0009055
      label: Generalized limb muscle atrophy
  evidence:
  - reference: PMID:35617047
    reference_title: RRM1 variants cause a mitochondrial DNA maintenance disorder via impaired de novo nucleotide synthesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Limb MRI revealed generalized muscle atrophy"
    explanation: Limb MRI showed generalized muscle atrophy.
- category: Neurologic
  name: Peripheral axonal neuropathy
  description: >-
    Mild axonal sensorimotor peripheral neuropathy documented by nerve
    conduction studies and electromyography.
  phenotype_term:
    preferred_term: axonal sensorimotor peripheral neuropathy
    term:
      id: HP:0003477
      label: Peripheral axonal neuropathy
  evidence:
  - reference: PMID:35617047
    reference_title: RRM1 variants cause a mitochondrial DNA maintenance disorder via impaired de novo nucleotide synthesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Absent tendon reflexes, nerve conduction studies, and electromyography indicated a mild axonal sensorimotor peripheral neuropathy"
    explanation: Nerve conduction studies and EMG show a mild axonal sensorimotor peripheral neuropathy.
  sequelae:
  - target: Areflexia
    description: Axonal sensorimotor peripheral neuropathy leads to loss of deep tendon reflexes.
- category: Neurologic
  name: Areflexia
  description: >-
    Absence of deep tendon reflexes on neurologic examination, associated with
    peripheral axonal neuropathy.
  phenotype_term:
    preferred_term: Areflexia
    term:
      id: HP:0001284
      label: Areflexia
  evidence:
  - reference: PMID:35617047
    reference_title: RRM1 variants cause a mitochondrial DNA maintenance disorder via impaired de novo nucleotide synthesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Absent tendon reflexes, nerve conduction studies, and electromyography indicated a mild axonal sensorimotor peripheral neuropathy"
    explanation: Absent tendon reflexes (areflexia) accompanied the neuropathy.
- category: Histopathologic
  name: Cytochrome C oxidase-negative muscle fibers
  diagnostic: true
  description: >-
    Mosaic cytochrome c oxidase (COX)-deficient skeletal muscle fibers on
    histochemical staining, reflecting clonal expansion of mtDNA deletions.
  phenotype_term:
    preferred_term: Cytochrome C oxidase-negative muscle fibers
    term:
      id: HP:0003688
      label: Cytochrome C oxidase-negative muscle fibers
  evidence:
  - reference: PMID:35617047
    reference_title: RRM1 variants cause a mitochondrial DNA maintenance disorder via impaired de novo nucleotide synthesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A muscle biopsy showed 50%-60% COX-deficient fibers, 3%-4% ragged-red fibers (RRFs), numerous highly atrophic fibers, regenerating central nucleated fibers, and a few fibers with necrotic sarcoplasm"
    explanation: COX-deficient fibres on muscle biopsy.
- category: Histopathologic
  name: Ragged-red muscle fibers
  diagnostic: true
  description: >-
    Ragged-red skeletal muscle fibers on modified Gomori trichrome staining,
    representing subsarcolemmal accumulation of abnormal mitochondria.
  phenotype_term:
    preferred_term: Ragged-red muscle fibers
    term:
      id: HP:0003200
      label: Ragged-red muscle fibers
  evidence:
  - reference: PMID:35617047
    reference_title: RRM1 variants cause a mitochondrial DNA maintenance disorder via impaired de novo nucleotide synthesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A muscle biopsy showed 50%-60% COX-deficient fibers, 3%-4% ragged-red fibers (RRFs), numerous highly atrophic fibers, regenerating central nucleated fibers, and a few fibers with necrotic sarcoplasm"
    explanation: Ragged-red fibres on muscle biopsy.
diagnosis:
- name: Molecular genetic testing
  presence: Present
  diagnosis_term:
    preferred_term: whole exome sequencing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  description: >-
    Whole-exome sequencing identifies the biallelic RRM1 R381 variant and
    confirms the diagnosis.
  results: >-
    Homozygous or biallelic pathogenic loss-of-function variants in RRM1 (such
    as p.R381H or p.R381C).
  evidence:
  - reference: PMID:35617047
    reference_title: RRM1 variants cause a mitochondrial DNA maintenance disorder via impaired de novo nucleotide synthesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we performed whole exome sequencing (WES) and identified a candidate RRM1 missense variant"
    explanation: WES identified the causal RRM1 variant.
- name: Muscle biopsy
  presence: Present
  diagnosis_term:
    preferred_term: muscle biopsy
    term:
      id: NCIT:C51895
      label: Muscle Biopsy
  description: >-
    Muscle biopsy shows COX-deficient and ragged-red fibres; Southern blot or
    long-range PCR of muscle DNA detects the multiple mtDNA deletions.
  results: >-
    Mosaic COX-deficient fibers and ragged-red fibers (50%-60% COX-deficient
    and 3%-4% ragged-red fibers in proband 1a; COX-deficient fibers and 30%
    ragged-red fibers in proband 4), with multiple mtDNA deletions on Southern
    blot or long-range PCR.
  evidence:
  - reference: PMID:35617047
    reference_title: RRM1 variants cause a mitochondrial DNA maintenance disorder via impaired de novo nucleotide synthesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A muscle biopsy showed 50%-60% COX-deficient fibers, 3%-4% ragged-red fibers (RRFs), numerous highly atrophic fibers, regenerating central nucleated fibers, and a few fibers with necrotic sarcoplasm"
    explanation: Documents 50%-60% COX-deficient fibers and 3%-4% ragged-red fibers on muscle biopsy in proband 1a.
  - reference: PMID:35617047
    reference_title: RRM1 variants cause a mitochondrial DNA maintenance disorder via impaired de novo nucleotide synthesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Muscle histopathology showed COX-deficient fibers and 30% RRFs."
    explanation: Documents COX-deficient fibers and 30% ragged-red fibers on muscle histopathology in proband 4.
  - reference: PMID:35617047
    reference_title: RRM1 variants cause a mitochondrial DNA maintenance disorder via impaired de novo nucleotide synthesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Southern blot revealed multiple mtDNA deletions"
    explanation: Southern blot of a recessive proband's muscle detects the multiple mtDNA deletions.
treatments:
- name: Supportive care
  description: >-
    PMID:35617047 reports no disease-specific therapy or management regimen for
    the affected families; clinical care is supportive and symptomatic.
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  notes: >-
    Recorded without evidence or target_mechanisms because PMID:35617047
    reports no management for the affected families.
- name: Genetic counseling
  description: >-
    Genetic counseling for affected individuals and families addresses the
    autosomal recessive inheritance of biallelic RRM1 p.R381 loss-of-function
    variants.
  action_category: COUNSELING_INFORMATIONAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:35617047
    reference_title: RRM1 variants cause a mitochondrial DNA maintenance disorder via impaired de novo nucleotide synthesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified 3 RRM1 loss-of-function variants, including a dominant catalytic site variant (NP_001024.1: p.N427K) and 2 homozygous recessive variants at p.R381"
    explanation: Establishes homozygous recessive RRM1 p.R381 loss-of-function variants as the genetic basis informing family counseling.
animal_models:
- name: RNR-subunit overexpressing mouse
  species: Mouse
  genotype: Transgenic overexpression of RNR subunits (Rrm1/Rrm2/p53R2)
  publication: PMID:20724444
  description: >-
    A mechanistic model: overexpressing two RNR subunits imbalances dNTP pools
    and depletes muscle mtDNA, supporting dNTP balance (not just quantity) as the
    driver. The Rrm1 knockout is embryonic-lethal and does not model the disease.
  modeled_mechanisms:
  - target: Imbalanced Mitochondrial dNTP Pools
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: ORGANISM
    description: dNTP imbalance drives muscle mtDNA depletion, as inferred for the human disease.
    limitations: >-
      An overexpression/imbalance model, not the RRM1 R381 loss-of-function
      allele, and it produces depletion rather than the deletions seen in patient
      muscle.
    evidence:
    - reference: PMID:20724444
      reference_title: Ribonucleotide reductase is not limiting for mitochondrial DNA copy number in mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "simultaneous expression of two RNR subunits leads to imbalanced dNTP pools and progressive mtDNA depletion in the skeletal muscle, without mtDNA mutagenesis"
      explanation: Shows dNTP imbalance drives muscle mtDNA depletion.
  evidence:
  - reference: PMID:20724444
    reference_title: Ribonucleotide reductase is not limiting for mitochondrial DNA copy number in mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "simultaneous expression of two RNR subunits leads to imbalanced dNTP pools and progressive mtDNA depletion in the skeletal muscle, without mtDNA mutagenesis"
    explanation: Establishes the RNR-imbalance mouse as a partial mechanistic model.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    Ultra-rare. The single source (PMID:35617047) reports 5 probands from 4
    families; the recessive R381 disease curated here is seen in three of those
    families, while the remaining proband (proband 3) carries the dominant
    p.N427K variant and is a separate disease.
progression:
- phase: Onset
  notes: >-
    Ophthalmoparesis began between adolescence (proband 1a at 17 years) and
    mid-adulthood (proband 2 at 45 years). In the MNGIE-like family 1,
    gastrointestinal symptoms began earlier, with nausea and vomiting from 7
    years and diarrhea from 14 years.
- phase: Progression
  notes: >-
    Progressive external ophthalmoplegia, proximal myopathy, and, in the
    MNGIE-like family, cachexia and neuropathy.

📚

References & Deep Research

Deep Research

1

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

Claude Code ▸

Progressive External Ophthalmoplegia, Autosomal Recessive 6 (PEOB6; RRM1): Research Report

claude-haiku-5-5, claude-opus-5-5 15 citations 2026-10-29T06:10:37.769810

Progressive External Ophthalmoplegia, Autosomal Recessive 6 (PEOB6; RRM1): Research Report

Summary

The disease and its gene. PEOB6 (MONDO:0957993; OMIM #620647) is an autosomal recessive mitochondrial DNA (mtDNA) maintenance disorder. It is caused by homozygous variants in RRM1 (hgnc:10451; OMIM *180410; 11p15.4). RRM1 is the catalytic subunit of ribonucleotide reductase (RNR), the enzyme that makes DNA building blocks (dNTPs) from scratch.
The evidence base is one paper. It rests entirely on Shintaku et al., J Clin Invest 2022, PMID:35617047 (PMC9246377). The recessive disease covers 5 patients from 3 families, all homozygous for a change at arginine 381.
The search found no later case reports or treatment studies (2023–2026).
Dominant p.N427K is a separate disease. The same paper reports a heterozygous catalytic-site variant, p.N427K, in one British family. OMIM's gene-map row for RRM1 lists both AD and AR inheritance. That dominant family is not PEOB6 and should not be lumped into this entry.

Before any of this goes into the KB:

Snippets. The fetch tools would not return abstracts word for word, so only short fragments from the PMID:35617047 abstract are quoted here. Use just fetch-reference PMID:35617047 and copy snippets from the cached text.
Ontology IDs. Every HP, GO, CL, UBERON and NCIT ID below is a lead written from memory. Look each one up before binding it, as the repo's CURIE rule requires.

1. Disease information

What it is. Adult-onset (in one patient, childhood-onset) ptosis and progressive external ophthalmoplegia. It comes with variable myopathy, gut dysmotility and cachexia, neuropathy, and multiple mtDNA deletions in skeletal muscle.

Identifier	Value	Source
MONDO	MONDO:0957993	MedGen C5882731
OMIM	#620647	MedGen / OMIM
MedGen	UID 1847098; CUI C5882731	MedGen
Orphanet	None specific to PEOB6 was found. The broader autosomal recessive PEO class applies (ORPHA:254892 — verify).	—
ICD-10	H49.4 (progressive external ophthalmoplegia, nonspecific)	—
ICD-11	No specific code	—
MeSH	D017246 Ophthalmoplegia, Chronic Progressive External (broader term — verify)	—
KEGG	H01395, autosomal recessive PEO (lists RRM1 among its genes)	KEGG

Synonyms: PEOB6; progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 6.

Type of source. All information comes from individual patient case descriptions in one multicentre paper. There are no registry or EHR data.

Key abstract statements (PMID:35617047): - "5 probands from 4 families who presented with ptosis and ophthalmoplegia as well as other clinical manifestations and multiple mtDNA deletions in muscle" - "Our data reveal that primary RRM1 deficiency and, by extension, impaired de novo nucleotide synthesis are causes of MDDS."

2. Etiology

Cause. Biallelic (homozygous) loss-of-function missense variants in RRM1. Both known recessive variants change arginine 381:
c.1142G>A, p.R381H
c.1141C>T, p.R381C
The abstract describes them as "RRM1 loss-of-function variants … 2 homozygous recessive variants at p.R381."
Risk factors.
Parental consanguinity: the Saudi family 1 (probands 1a and 1b) is consanguineous.
Recurrence of p.R381C in two apparently unrelated Northern European families (Dutch family 2; family 4).
Environmental risk factors: none known.
Protective factors and gene–environment interactions: none reported.
Plausible but unproven modifier: factors that raise dNTP demand or block de novo synthesis. Hydroxyurea and gemcitabine directly inhibit RNR. This is an inference, not a documented interaction (see §5).

3. Phenotypes

The 5 recessive patients are 1a, 1b, proband 2, proband 2's brother, and proband 4. Clinical detail is from the JCI full text; proband 2's brother is described only as "similarly affected."

Phenotype	Suggested HP term (verify)	Frequency	Onset and course
Ptosis	HP:0000508 Ptosis	5/5	Adult; progressive
External ophthalmoplegia / ophthalmoparesis	HP:0000590 Progressive external ophthalmoplegia; HP:0000602 Ophthalmoplegia	5/5	Adolescence (1a, age 17) to age 61
Diplopia	HP:0000651 Diplopia	Probands 2 and 4 (and proband 3 in the dominant family)	Often the first symptom in late-onset cases
Myopathy / proximal limb weakness (trouble climbing stairs or standing; gait impairment)	HP:0003701 Proximal muscle weakness; HP:0003198 Myopathy	1a, 2, 4	Progressive. Proband 4 recalled weakness since childhood
Muscle atrophy	HP:0003202 Skeletal muscle atrophy	1a	—
Nausea, vomiting, diarrhea; intestinal dysmotility	HP:0002018 Nausea; HP:0002013 Vomiting; HP:0002014 Diarrhea; HP:0002579 Gastrointestinal dysmotility	1a, 1b	1a: vomiting from age 7, diarrhea from age 14. The family 1 picture resembles MNGIE
Weight loss / cachexia	HP:0001824 Weight loss; HP:0004326 Cachexia	1a (17 kg lost), 1b	—
Axonal sensorimotor neuropathy; areflexia	HP:0007141 Sensorimotor neuropathy (or the axonal term); HP:0001284 Areflexia	1a (mild, confirmed by nerve conduction and EMG)	—
Raised CK (697 U/L in 1a) and raised AST/ALT (OMIM synopsis)	HP:0003236 Elevated circulating creatine kinase concentration; transaminase terms	1a	—
COX-deficient fibers	HP:0003688 Cytochrome C oxidase-negative muscle fibers	1a (50–60%), 4	—
Ragged-red fibers	HP:0003200 Ragged-red muscle fibers	1a (3–4%), 4 (30%)	—
Central nuclei, regenerating and necrotic fibers	Centrally nucleated fibers term	1a	—
Multiple mtDNA deletions in muscle	HPO term to be identified	4/4 biopsied recessive probands	—
Muscle mtDNA depletion (10–30% of control)	—	Proband 2	—
Dysphagia	HP:0002015 Dysphagia	Listed in the MedGen/OMIM synopsis; in the paper it is clearly in proband 3 (dominant)	—
Sensorineural hearing loss	HP:0000407 Sensorineural hearing loss	Listed by MedGen; in the paper it is in proband 3 (dominant)	—
Gastroparesis, loss of ambulation, intellectual disability	—	Listed in the MedGen HPO annotation, but not found in the JCI text that was read	Treat as low-confidence until checked against the OMIM synopsis

Quality of life. The main burdens are visual (diplopia, ptosis), mobility (proximal weakness, gait), and nutrition (cachexia in family 1). No validated quality-of-life instrument data exist.

4. Genetic and molecular information

Gene. RRM1, ribonucleotide reductase catalytic subunit M1. - IDs: hgnc:10451; NCBI Gene 6240; UniProt P23921; Ensembl ENSG00000167325; OMIM 180410; 11p15.4 (HGNC REST). - The protein is the large R1 subunit of class Ia RNR. It holds: - the catalytic site; - the allosteric specificity site (loop 2), which sets the dNTP balance; - the activity (ATP-cone) site. - It pairs with RRM2 (in S phase) or with RRM2B/p53R2 (outside S phase and in post-mitotic tissues).

Variants (transcript NM_001033; protein NP_001024.1):

Variant	Zygosity	Families	gnomAD	ClinVar (per GeneCards)	Structural effect
c.1142G>A p.(Arg381His)	Homozygous	Family 1: Saudi, consanguineous (1a, 1b)	Absent (v2.1.1)	Likely pathogenic	Breaks a hydrogen-bond network linking R381 to the catalytic-site "gating" residue R293. R293 swings away from GDP. TTP binding and dimer-interface contact are predicted to drop.
c.1141C>T p.(Arg381Cys)	Homozygous	Family 2: Dutch (proband + brother); Family 4	1 × 10⁻⁴ heterozygous; no homozygotes	Pathogenic	Hydrogen-bond network intact, but flexibility falls and inter-protomer buried surface area drops by about 100 Å². Predicted to impair dimerization.
c.1281C>A p.(Asn427Lys)	Heterozygous	Family 3: White British	Absent	—	In the catalytic site; N427 hydrogen-bonds the substrate ribose 2′/3′-OH. Belongs to the dominant phenotype, not PEOB6.

Where R381 sits. R381 lies near the specificity site, as "an extension of loop 1." It interacts with S260.
Functional effect. Loss of function: RNR activity ([¹⁴C]CDP → dCDP) was reduced in patient fibroblasts, while RRM1 protein levels were normal. That means reduced catalytic function, not protein instability.
Variant class: missense only. All variants are germline.
Modifier genes: none known.
Epigenetics and chromosomal abnormalities: none reported or relevant.

5. Environmental information

No environmental, lifestyle or infectious causes are known.
Inferred pharmacological concern: RNR inhibitors (hydroxyurea, gemcitabine, clofarabine, cladribine) act on RRM1. In theory they could worsen dNTP depletion in carriers or patients. This is not documented.

6. Mechanism and pathophysiology

Causal chain:

Lesion. Homozygous missense at RRM1 Arg381 (p.R381H or p.R381C) changes the local structure near loop 1, the specificity site and the dimer interface. This step is inferred from molecular dynamics simulations (computational evidence).
→ Reduced RNR catalytic activity. Less ribonucleoside diphosphate (NDP) is turned into deoxyribonucleoside diphosphate (dNDP). This was shown in patient fibroblasts (in vitro).
→ Abnormal nucleotide pools. NDPs are raised and mitochondrial dGTP and dTTP are lowered. Shown in fibroblasts: the pool changes were clearest in probands 2 and 3 and were not seen in 1a/1b.
→ More ribonucleotides built into mtDNA, because the dNTP:rNTP ratio falls. Shown by alkaline hydrolysis and denaturing Southern blot.
→ Impaired mtDNA replication in cells that depend on de novo dNTP synthesis. mtDNA depletion appears in proliferating fibroblasts, but not in quiescent ones, which rely on the salvage pathway. Expression of salvage-pathway genes was normal.
→ Stalled replication and faulty repair in post-mitotic muscle produce multiple mtDNA deletions. This step is inferred by analogy with RRM2B, TK2 and POLG. Long-range PCR found no deletions in cultured fibroblasts; deletions were found only in muscle.
→ Clonal build-up of deleted mtDNA gives mosaic respiratory chain deficiency: COX-negative and ragged-red fibers, and reduced activity of complex IV and complexes II+III.
→ Energy failure in high-demand, long-lived cells, branching into three outcomes:
8a. extraocular and levator muscles → ptosis and progressive external ophthalmoplegia;
8b. limb skeletal muscle → proximal myopathy, atrophy, raised CK;
8c. enteric smooth muscle or neurons, and peripheral nerve → GI dysmotility, cachexia, axonal neuropathy. This branch was seen only in family 1 (R381H) and is a mechanistic inference.

Mechanism categories:

Molecular pathway: de novo dNTP synthesis (Reactome "Synthesis of dNTPs"; KEGG purine and pyrimidine metabolism).
Suggested GO terms:
GO:0009263 deoxyribonucleotide biosynthetic process (DECREASED);
GO:0004748 ribonucleoside-diphosphate reductase activity, thioredoxin disulfide as acceptor (DECREASED);
GO:0000002 mitochondrial genome maintenance;
GO:0006264 mitochondrial DNA replication;
cellular component GO:0005971 ribonucleoside-diphosphate reductase complex; GO:0005829 cytosol; GO:0005739 mitochondrion (where the defect shows).
Cell types (CL): skeletal muscle fiber (CL:0008002 or CL:0000188); extraocular muscle fibers; fibroblast (CL:0000057; the in vitro model); possibly enteric neurons or smooth muscle.
Immune involvement: none.
Tissue damage: respiratory chain failure, fiber necrosis and regeneration, atrophy.
Omics, single-cell, CRISPR screens: none disease-specific. RRM1 is pan-essential in DepMap, which fits the total-knockout lethality below.
Context from mouse (PMID:20724444, Ylikallio 2010). Overexpressing RNR subunits does not raise mtDNA copy number. Imbalanced dNTP pools from overexpressing two subunits caused progressive mtDNA depletion in muscle. This supports dNTP balance, not just quantity, as the critical variable.

7. Anatomical structures affected

Primary:
extraocular muscles (UBERON:0001601 extra-ocular muscle);
levator palpebrae superioris / upper eyelid;
skeletal muscle (UBERON:0001134 skeletal muscle tissue).
Secondary:
gastrointestinal tract (small intestine motility);
peripheral nerves (UBERON:0001021 nerve);
inner ear / cochlea (only in the dominant family).
Subcellular: mitochondrion and mitochondrial nucleoid (GO:0042645).
Laterality: bilateral, symmetric ptosis and ophthalmoplegia.

8. Temporal development

Onset:
usually adulthood (early 40s to 61);
adolescence in family 1 (GI symptoms at 7, ophthalmoparesis at 17);
proband 4 reported subjective weakness since childhood.
Course: insidious, slowly progressive, and lifelong. Diplopia → ptosis → complete ophthalmoplegia → limb weakness and gait difficulty.
Remission: none.
Natural-history data: none.

9. Inheritance and population

Inheritance: autosomal recessive (HP:0000007).
Penetrance: apparently complete in homozygotes; no heterozygous carrier was affected.
Expressivity: variable. R381H (family 1) gives an earlier, more multisystem, MNGIE-like picture. R381C gives late-onset ocular myopathy.
Anticipation and germline mosaicism: none.
Founder effect: possible for R381C in Northern Europeans (two families). Not formally tested.
Consanguinity: present in family 1.
Prevalence: unknown. Ultra-rare, with 5 patients reported (Orphanet-style class "<1/1,000,000"; measure type CASES_IN_LITERATURE). Carrier frequency of R381C is about 1 in 10,000.
Sex: both affected (3 men, including the brother; 2 women).
Geography: Saudi Arabia; the Netherlands; family 4 of unstated ancestry.

10. Diagnostics

Clinical and laboratory: - CK, which may be raised. - Lactate. - Muscle biopsy with COX/SDH histochemistry (COX-negative and ragged-red fibers). - Respiratory chain enzyme assays. - Long-range PCR or Southern blot of muscle mtDNA for multiple deletions: the hallmark. - qPCR for mtDNA copy number.

Electrophysiology: nerve conduction and EMG (axonal sensorimotor neuropathy, myopathic EMG).

Genetic testing: - Exome or genome sequencing, or a nuclear mtDNA-maintenance gene panel. - RRM1 is on PanelApp Australia's mitochondrial disease panel (#203). - Analyse a blood sample for nuclear genes. Muscle mtDNA analysis shows the deletions, but blood mtDNA testing will be normal.

Supporting functional assays (research): - RNR activity in fibroblasts; - dNTP pools; - mtDNA depletion in proliferating, but not quiescent, fibroblasts; - mtDNA ribonucleotide content.

Differential diagnosis (other nuclear causes of PEO with multiple mtDNA deletions):

Gene	Disease	Distinguishing note
POLG	PEOA1 / PEOB1	Commonest cause
TWNK	PEOA3	—
SLC25A4	PEOA2	—
RRM2B	PEOA5 / PEOB5	Same enzyme complex as RRM1
TK2	PEOB3	Has a deoxynucleoside therapy
DGUOK	PEOB4	—
TYMP	MNGIE	Closest mimic of family 1. Plasma thymidine and deoxyuridine are raised in MNGIE and not expected in RRM1 disease
POLG2, OPA1, MGME1, DNA2, others	—	—
—	Myasthenia gravis; oculopharyngeal muscular dystrophy (PABPN1)	Non-mitochondrial mimics

Screening: no newborn or population screening. Carrier and cascade testing is possible within families.

11. Outcome and prognosis

No survival data exist. Patients survive into their 30s–60s with progressive disability.
Cachexia and GI dysmotility (family 1) are the probable life-limiting complications.
Other complications: aspiration from dysphagia, falls, and exposure keratopathy from ptosis.
No prognostic biomarkers are known.

12. Treatment

No disease-specific therapy has been reported. Management is supportive, following general guidance for primary mitochondrial myopathy.

Intervention	Suggested NCIT term (verify)	Notes
Ptosis surgery (frontalis sling or levator resection)	NCIT:C15329 Surgical Procedure (no specific term identified)	Avoid overcorrection because of poor eye closure
Prisms for diplopia	Supportive care	—
Physical therapy / exercise	NCIT:C15302 Physical Therapy	Endurance training is used in mitochondrial myopathy generally
Nutritional support / enteral feeding for cachexia	NCIT:C15433 Nutritional Support	Relevant to the family 1 phenotype
Genetic counseling	NCIT:C15240 Genetic Counseling	25% recurrence risk for siblings of a patient
Supportive care	NCIT:C15747 Supportive Care	—

Experimental / theoretical: deoxynucleoside supplementation. dC/dT therapy is effective in TK2 deficiency (doxecitine/doxribtimine). It might bypass the de novo block through salvage enzymes, which stay intact in RRM1 patient cells. This is a hypothesis that has not been tested; the search found no trials or case reports.
Clinical trials: none for RRM1 (ClinicalTrials.gov search for "RRM1 ophthalmoplegia" returns none).
Pharmacogenomics: avoid RNR inhibitors where possible. This is inferred, not established.

13. Prevention

Primary prevention: carrier testing in at-risk relatives, especially in the consanguineous family. Prenatal or preimplantation diagnosis once both variants in a family are known.
Tertiary prevention:
watch for dysphagia, nutrition, cardiac and respiratory status (generic mitochondrial surveillance);
corneal protection after ptosis surgery.
Vaccination, public health and environmental measures: not applicable.

14. Other species and natural disease

OMIA: no naturally occurring RRM1 disease is known in animals.
Orthologs:
mouse Rrm1 (MGI:98180; NCBITaxon:10090);
zebrafish rrm1 (ZFIN:ZDB-GENE-990415-247; NCBITaxon:7955);
Drosophila RnrL;
yeast RNR1 and RNR3 (NCBITaxon:4932).
RRM1 is highly conserved: the class Ia R1 catalytic machinery is shared from E. coli NrdA to humans.
Zoonotic relevance: none.

15. Model organisms

Model	Phenotype	Fit to human disease
Mouse Rrm1 knockout (MGI / IMPC)	Embryonic lethal before E3.5 / pre-implantation, complete penetrance	Shows the gene is essential. Fails to recapitulate the disease: total loss is lethal, whereas patients carry hypomorphic missense alleles
Mouse Rrm1-W688G knock-in (Specks et al., Mol Cell Biol 2015)	Loses RRM2 binding; embryonic lethal	Fails to recapitulate; mechanistic only
Transgenic Rrm1 / Rrm2 / p53R2 overexpressing mice (PMID:20724444)	No rise in mtDNA copy number. dNTP imbalance → progressive muscle mtDNA depletion	Supports dNTP imbalance as the driver of mtDNA loss; partial mechanistic model
Patient primary skin fibroblasts (PMID:35617047)	Reduced RNR activity, abnormal NDP/dNTP pools, mtDNA depletion only when cycling, mtDNA ribonucleotide incorporation, complex II+III defect	Best existing model. Lacks deletions and post-mitotic muscle biology

Main gap: no knock-in mouse or zebrafish model carries R381H or R381C. A homozygous R381 knock-in, or patient iPSC-derived myotubes, would be the natural next model.
Resources: MGI, IMPC, ZFIN, Cellosaurus (no patient lines deposited).

Knowledge gaps

Only 5 patients are known; the phenotype spectrum and natural history are undefined.
How depletion in proliferating cells leads to deletions in post-mitotic muscle has not been demonstrated (§6, step 6).
Why only family 1 has GI involvement (R381H versus R381C, or background) is unexplained.
Whether deoxynucleoside therapy rescues the defect, in fibroblasts or in patients, has not been tested.
The source of several MedGen/OMIM-listed features (intellectual disability, gastroparesis, loss of ambulation) is unclear; they may belong to the dominant family.

Sources

Shintaku J, Pernice WM, Eyaid W, … Taylor RW, Hirano M. "RRM1 variants cause a mitochondrial DNA maintenance disorder via impaired de novo nucleotide synthesis." J Clin Invest. 2022 Jul 1;132(13):e145660. PMID:35617047; PMC9246377. JCI · PubMed · PMC
Ylikallio E, et al. "Ribonucleotide reductase is not limiting for mitochondrial DNA copy number in mice." Nucleic Acids Res. 2010;38(22). PMID:20724444.
MedGen C5882731 / UID 1847098 (PEOB6)
OMIM Clinical Synopsis #620647 (blocked by HTTP 403; content seen through search snippets only)
OMIM *180410 RRM1
HGNC REST: RRM1
KEGG H01395
PanelApp Australia, panel 203, RRM1
GeneCards RRM1
NIH GTR RRM1
MGI Rrm1 · IMPC Rrm1 · Alliance
ZFIN rrm1
Specks J, et al. Mol Cell Biol 2015 (Rrm1-W688G knock-in; PMID not retrieved)

Reference Validation

Checked with linkml-reference-validator 0.4.0.

Outcome	Count
References checked	3
Resolved	3
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	3
On topic	3
Off topic	0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	46
Resolved	43
Unresolved (possible confabulation)	0
Obsolete	1
Unverifiable	2
Terms whose name was checked	4
Terms named correctly	1
Terms named as a different term	2
Terms whose name is worth a second look	1

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

MONDO:0957993 (2 mentions) - the report calls it "MONDO"; MONDO calls it progressive external ophthalmoplegia with mitochondrial dna deletions, autosomal recessive 6
NCBITaxon:4932 (1 mention) - the report calls it "yeast RNR1 and RNR3"; NCBITaxon calls it Saccharomyces cerevisiae

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

GO:0000002 (obsolete mitochondrial genome maintenance) (1 mention)

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

GO:0042645 (1 mention) - the report calls it "Subcellular: mitochondrion and mitochondrial nucleoid"; GO calls it mitochondrial nucleoid**

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA, MGI.

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References & Deep Research

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Progressive External Ophthalmoplegia, Autosomal Recessive 6 (PEOB6; RRM1): Research Report

Summary

1. Disease information

2. Etiology

3. Phenotypes

4. Genetic and molecular information

5. Environmental information

6. Mechanism and pathophysiology

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

10. Diagnostics

11. Outcome and prognosis

12. Treatment

13. Prevention

14. Other species and natural disease

15. Model organisms

Knowledge gaps

Sources

Reference Validation

Term Validation

Terms the report names something else

Obsolete terms

Terms whose name is worth a second look

Prefixes with no resolver