NARP syndrome

Mendelian MONDO:0010794 Pathograph 19 Show in embeddings browser hereditary disease mitochondrial disease

NARP syndrome is a maternally inherited mitochondrial disease caused most often by pathogenic MT-ATP6 variants, including canonical nucleotide 8993 substitutions. The syndrome is characterized by impaired oxidative phosphorylation with prominent neurologic and retinal vulnerability, classically manifesting with neuropathy, ataxia, and retinitis pigmentosa. Clinical severity varies with heteroplasmy and may overlap with Leigh syndrome.

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8
Pathophys.
6
Phenotypes
19
Pathograph
1
Genes
3
Medical Actions
2
Differentials
1
References
1
Deep Research
⚙

Pathophysiology

8
MT-ATP6 ATP synthase dysfunction
Canonical MT-ATP6 nucleotide 8993 variants and other pathogenic MT-ATP6 variants impair the proton-translocating membrane sector of mitochondrial ATP synthase.
MT-ATP6 hgnc:7414
proton motive force-driven ATP synthesis GO:0015986 ⚠ ABNORMAL
proton-transporting ATP synthase activity, rotational mechanism GO:0046933 ↓ DECREASED
proton-transporting ATP synthase complex GO:0045259
Downstream
Mitochondrial complex V assembly defect The atypical m.8561C>G MT-ATP6/8 variant disrupts assembly of mitochondrial ATP synthase complex V in patient-derived myoblasts.
Reduced mitochondrial ATP production Defective ATP synthase coupling decreases efficient ATP generation.
Show evidence (3 references)
PMID:27502083 SUPPORT Human Clinical
"Pathogenic mutations in MT-ATP6 are associated with the Leigh syndrome, the syndrome of neuropathy, ataxia, and retinitis pigmentosa (NARP), as well as with non-classical phenotypes, while MT-ATP8 is less frequently mutated in patients with mitochondrial disease."
This directly supports MT-ATP6 dysfunction as the canonical initiating lesion in NARP-spectrum mitochondrial disease.
PMID:16525806 SUPPORT Human Clinical
"The 8993 T>G mutation in mitochondrial DNA has been associated with variable syndromes of differing severity ranging from maternally inherited Leigh's syndrome (MILS) to neuropathy, ataxia, retinitis pigmentosa (NARP), depending on the mutation loads in affected patients."
This supports canonical 8993 T>G MT-ATP6-associated NARP/MILS as a heteroplasmy-dependent clinical spectrum.
PMID:22819295 SUPPORT Human Clinical
"Mutations in mitochondrial DNA (mtDNA) encoded nucleotide 8993 can cause NARP syndrome (neuropathy, ataxia, and retinitis pigmentosa) or MILS (maternally inherited Leigh syndrome)."
This family report supports m.8993T>C as another canonical MT-ATP6 nucleotide 8993 variant in the NARP/MILS spectrum.
Mitochondrial complex V assembly defect
In the atypical m.8561C>G MT-ATP6/8 sibling report, patient-derived myoblasts showed abnormal complex V assembly, with accumulation of an assembly intermediate and excess F1 subcomplex despite unchanged total complex V abundance.
mitochondrial proton-transporting ATP synthase complex assembly GO:0033615 ⚠ ABNORMAL
proton-transporting ATP synthase complex GO:0045259
Downstream
Reduced mitochondrial ATP production Abnormal complex V assembly reduces ATP production in m.8561C>G patient-derived myoblasts.
Show evidence (1 reference)
PMID:27502083 SUPPORT In Vitro
"An additional assembly intermediate of complex V and increased amount of subcomplex F1 were observed in myoblasts of the two patients, but the total amount of complex V was unaffected."
This patient-derived myoblast study identifies abnormal complex V assembly as a biochemical lesion of the m.8561C>G MT-ATP6/8 variant.
Reduced mitochondrial ATP production
Inefficient oxidative phosphorylation limits ATP availability in tissues with high metabolic demand.
oxidative phosphorylation GO:0006119 ⚠ ABNORMAL
Downstream
Neuroretinal energy failure Neurons, peripheral nerves, and retinal cells are especially vulnerable.
Sensorineural hearing impairment Auditory sensory cells and auditory neurons are vulnerable to impaired mitochondrial ATP production, producing sensorineural hearing impairment.
Endocrine energy vulnerability Impaired ATP production can also involve endocrine tissues in the MT-ATP6/8 phenotype, producing diabetes and primary hypogonadism.
Intracellular ATP concentration Reduced ATP production is directly measurable as lower intracellular ATP concentration in patient-derived myoblasts.
Show evidence (2 references)
PMID:27502083 SUPPORT In Vitro
"Furthermore, intracellular ATP concentration was lower in patient myoblasts indicating defective energy production."
Patient-derived myoblast data directly supports reduced ATP production downstream of MT-ATP6/8 dysfunction.
PMID:31276579 SUPPORT In Vitro
"The m.8993T>G mutation of the mitochondrial MT-ATP6 gene has been associated with numerous cases of neuropathy, ataxia and retinitis pigmentosa and maternally inherited Leigh syndrome, which are diseases known to result from abnormalities affecting mitochondrial energy transduction."
This NARP cellular-model paper connects the canonical m.8993T>G MT-ATP6 variant with mitochondrial energy-transduction abnormalities.
Neuroretinal energy failure
Energy failure in the nervous system and retina drives the core neurologic and ophthalmologic phenotype.
neuron CL:0000540 photoreceptor cell CL:0000210
oxidative phosphorylation GO:0006119 ⚠ ABNORMAL
Downstream
Cerebellar dysfunction Cerebellar energy failure contributes to gait instability.
Peripheral nerve dysfunction Peripheral nerve energy failure produces sensory and motor neuropathy.
Retinal degeneration Retinal energy failure leads to pigmentary retinopathy and vision loss.
Show evidence (2 references)
PMID:27502083 SUPPORT Human Clinical
"We suggest that the m.8561C>G mutation in MT-ATP6/8 is pathogenic, leads biochemically to impaired assembly and decreased ATP production of complex V, and results clinically in a phenotype with the core features of cerebellar ataxia, peripheral neuropathy, diabetes mellitus, and..."
This links impaired complex V energy production to the characteristic multisystem neurologic phenotype.
PMID:16525806 SUPPORT Human Clinical
"We report a kindred with several members in the same generation suffering NARP or Leigh's syndrome due to a 8993 T>G mutation."
This canonical 8993 T>G kindred supports neuroretinal NARP manifestations within the MT-ATP6 disease spectrum.
Endocrine energy vulnerability
The atypical m.8561C>G MT-ATP6/8 complex V defect can involve endocrine tissues, producing diabetes mellitus and hypergonadotropic hypogonadism in addition to the neurologic and retinal syndrome.
oxidative phosphorylation GO:0006119 ⚠ ABNORMAL
Downstream
Diabetes mellitus Endocrine involvement includes diabetes mellitus.
Hypergonadotropic hypogonadism Endocrine involvement also includes primary gonadal failure.
Show evidence (1 reference)
PMID:27502083 SUPPORT Human Clinical
"We investigated two adult siblings presenting with features of cerebellar ataxia, peripheral neuropathy, diabetes mellitus, sensorineural hearing impairment, and hypergonadotropic hypogonadism."
The patient phenotype directly documents endocrine involvement in the MT-ATP6/8-related NARP-overlap presentation.
Cerebellar dysfunction
Energetic failure within cerebellar systems produces impaired coordination and gait instability.
Downstream
Ataxia Cerebellar system involvement manifests clinically as ataxia in NARP-spectrum disease.
Peripheral nerve dysfunction
Mitochondrial failure in peripheral nerves contributes to sensory and motor neuropathy.
Downstream
Peripheral neuropathy Peripheral nerve involvement is represented clinically by peripheral neuropathy.
Retinal degeneration
Retinal energetic vulnerability contributes to pigmentary retinopathy and progressive visual dysfunction.
Downstream
Retinitis pigmentosa Retinal degeneration is represented clinically by retinitis pigmentosa in the NARP phenotype.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for NARP syndrome Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

6
Ear 1
Sensorineural hearing impairment Sensorineural hearing impairment HP:0000407
Show evidence (1 reference)
PMID:27502083 SUPPORT Human Clinical
"We investigated two adult siblings presenting with features of cerebellar ataxia, peripheral neuropathy, diabetes mellitus, sensorineural hearing impairment, and hypergonadotropic hypogonadism."
This directly documents sensorineural hearing impairment in an MT-ATP6/8 NARP-overlap phenotype.
Endocrine 2
Diabetes mellitus Diabetes mellitus HP:0000819
Show evidence (1 reference)
PMID:27502083 SUPPORT Human Clinical
"We investigated two adult siblings presenting with features of cerebellar ataxia, peripheral neuropathy, diabetes mellitus, sensorineural hearing impairment, and hypergonadotropic hypogonadism."
This directly documents diabetes mellitus in an MT-ATP6/8 NARP-overlap phenotype.
Hypergonadotropic hypogonadism Hypergonadotropic hypogonadism HP:0000815
Show evidence (1 reference)
PMID:27502083 SUPPORT Human Clinical
"We investigated two adult siblings presenting with features of cerebellar ataxia, peripheral neuropathy, diabetes mellitus, sensorineural hearing impairment, and hypergonadotropic hypogonadism."
This directly documents hypergonadotropic hypogonadism in an MT-ATP6/8-related NARP-overlap phenotype.
Eye 1
Retinitis pigmentosa Rod-cone dystrophy HP:0000510
Show evidence (2 references)
PMID:27502083 SUPPORT Human Clinical
"Pathogenic mutations in MT-ATP6 are associated with the Leigh syndrome, the syndrome of neuropathy, ataxia, and retinitis pigmentosa (NARP), as well as with non-classical phenotypes, while MT-ATP8 is less frequently mutated in patients with mitochondrial disease."
This directly names retinitis pigmentosa within the canonical NARP phenotype.
PMID:22819295 SUPPORT Human Clinical
"Mutations in mitochondrial DNA (mtDNA) encoded nucleotide 8993 can cause NARP syndrome (neuropathy, ataxia, and retinitis pigmentosa) or MILS (maternally inherited Leigh syndrome)."
This canonical nucleotide 8993 family report explicitly includes retinitis pigmentosa in the NARP syndrome definition.
Nervous System 2
Ataxia Ataxia HP:0001251
Show evidence (2 references)
PMID:27502083 SUPPORT Human Clinical
"We investigated two adult siblings presenting with features of cerebellar ataxia, peripheral neuropathy, diabetes mellitus, sensorineural hearing impairment, and hypergonadotropic hypogonadism."
This directly documents ataxia in MT-ATP6/8-related NARP-spectrum disease.
PMID:22819295 SUPPORT Human Clinical
"Mutations in mitochondrial DNA (mtDNA) encoded nucleotide 8993 can cause NARP syndrome (neuropathy, ataxia, and retinitis pigmentosa) or MILS (maternally inherited Leigh syndrome)."
This canonical nucleotide 8993 family report explicitly includes ataxia in the NARP syndrome definition.
Peripheral neuropathy Peripheral neuropathy HP:0009830
Show evidence (2 references)
PMID:27502083 SUPPORT Human Clinical
"We investigated two adult siblings presenting with features of cerebellar ataxia, peripheral neuropathy, diabetes mellitus, sensorineural hearing impairment, and hypergonadotropic hypogonadism."
This directly documents peripheral neuropathy as a core NARP-spectrum manifestation.
PMID:22819295 SUPPORT Human Clinical
"Mutations in mitochondrial DNA (mtDNA) encoded nucleotide 8993 can cause NARP syndrome (neuropathy, ataxia, and retinitis pigmentosa) or MILS (maternally inherited Leigh syndrome)."
This canonical nucleotide 8993 family report explicitly includes neuropathy in the NARP syndrome definition.
🧬

Genetic Associations

1
MT-ATP6 (Causal pathogenic mitochondrial DNA variants, including canonical nucleotide 8993 substitutions, with heteroplasmy-dependent NARP/MILS severity)
Gene: MT-ATP6 hgnc:7414
Mitochondrial inheritance
Show evidence (3 references)
PMID:27502083 SUPPORT Human Clinical
"Pathogenic mutations in MT-ATP6 are associated with the Leigh syndrome, the syndrome of neuropathy, ataxia, and retinitis pigmentosa (NARP), as well as with non-classical phenotypes, while MT-ATP8 is less frequently mutated in patients with mitochondrial disease."
This directly supports MT-ATP6 as the established causal gene for NARP-spectrum disease.
PMID:16525806 SUPPORT Human Clinical
"We report a kindred with several members in the same generation suffering NARP or Leigh's syndrome due to a 8993 T>G mutation."
This kindred directly supports the canonical 8993 T>G mitochondrial DNA mutation as a cause of NARP/Leigh-spectrum disease.
PMID:22819295 SUPPORT Human Clinical
"Here, we report the results of whole mitochondrial genome analysis of a family with m.8993T>C mutation in the MT-ATP6 gene and associated with NARP/MILS, and discuss the familial inheritance, effects of variation in combinations and heteroplasmy levels on the clinical findings."
This supports m.8993T>C in MT-ATP6 as another familial NARP/MILS variant with heteroplasmy-dependent clinical expression.
💊

Medical Actions

3
Supportive mitochondrial disease management
Action: supportive care MAXO:0000950
Management is supportive and includes symptom-based neurologic, ophthalmologic, rehabilitation, and medication-avoidance care.
Target Phenotypes: Ataxia HP:0001251 Peripheral neuropathy HP:0009830 Retinitis pigmentosa HP:0000510 Sensorineural hearing impairment HP:0000407 Diabetes mellitus HP:0000819
Show evidence (2 references)
PMID:20301352 SUPPORT Human Clinical
"Treatment of manifestations: Treatment is supportive."
GeneReviews supports supportive, symptom-directed management for mtDNA-associated Leigh-spectrum disease overlapping NARP/MILS.
PMID:20301352 SUPPORT Human Clinical
"Sodium valproate, medications that cause acidosis, and dichloroacetate should be avoided or used with caution;"
GeneReviews supports avoiding mitochondrial stressors such as valproate and acidosis-provoking medications in this spectrum.
Physical therapy
Action: physical therapy MAXO:0000011
Rehabilitation is used to preserve mobility, balance, and function in progressive neuromuscular disease.
Target Phenotypes: Ataxia HP:0001251
Show evidence (1 reference)
PMID:20301352 SUPPORT Human Clinical
"developmental and educational support; physical therapy and occupational therapy; standard treatment of eye movement disorders;"
GeneReviews includes physical therapy among supportive interventions for mtDNA-associated Leigh-spectrum manifestations.
Genetic counseling
Action: Genetic Counseling NCIT:C15240
Genetic counseling addresses maternal mtDNA inheritance, heteroplasmy, recurrence-risk uncertainty, and reproductive options.
Show evidence (1 reference)
PMID:20301352 SUPPORT Human Clinical
"Reproductive options for the family members of a proband with an mtDNA pathogenic variant may include prenatal testing, preimplantation genetic testing, and oocyte donation."
GeneReviews supports genetic counseling and reproductive planning for families with pathogenic mtDNA variants.
🔬

Biochemical Markers

2
Intracellular ATP concentration (DECREASED)
Context: In the m.8561C>G report, patient-derived myoblasts show reduced intracellular ATP concentration, reflecting defective complex V energy production.
Pathograph Readouts
Readout Of Reduced mitochondrial ATP production Negative Diagnostic
Lower intracellular ATP concentration reports the reduced ATP production node caused by impaired ATP synthase complex V in the m.8561C>G myoblast model.
Show evidence (1 reference)
PMID:27502083 SUPPORT In Vitro
"Furthermore, intracellular ATP concentration was lower in patient myoblasts indicating defective energy production."
The study directly supports lower intracellular ATP concentration as a biochemical readout of defective energy production.
Show evidence (1 reference)
PMID:27502083 SUPPORT In Vitro
"Furthermore, intracellular ATP concentration was lower in patient myoblasts indicating defective energy production."
Patient myoblast measurements document decreased intracellular ATP.
Complex V assembly intermediate and F1 subcomplex accumulation (ABNORMAL)
Context: In the m.8561C>G report, patient myoblasts show an additional complex V assembly intermediate and increased F1 subcomplex despite unchanged total complex V.
Pathograph Readouts
Readout Of Mitochondrial complex V assembly defect Positive Diagnostic
Abnormal complex V assembly intermediates report the mitochondrial ATP synthase assembly defect in the m.8561C>G patient-derived myoblast model.
Show evidence (1 reference)
PMID:27502083 SUPPORT In Vitro
"An additional assembly intermediate of complex V and increased amount of subcomplex F1 were observed in myoblasts of the two patients, but the total amount of complex V was unaffected."
Patient myoblast data directly document the complex V assembly readout.
Show evidence (1 reference)
PMID:27502083 SUPPORT In Vitro
"An additional assembly intermediate of complex V and increased amount of subcomplex F1 were observed in myoblasts of the two patients, but the total amount of complex V was unaffected."
This supports abnormal complex V assembly intermediates as a biochemical readout of the ATP synthase defect.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from NARP syndrome:

Leigh syndrome MONDO:0009723
Overlapping Features The same canonical MT-ATP6 nucleotide 8993 variants can produce NARP or maternally inherited Leigh syndrome, with severity related to mutant load.
Show evidence (1 reference)
PMID:16525806 SUPPORT Human Clinical
"The 8993 T>G mutation in mitochondrial DNA has been associated with variable syndromes of differing severity ranging from maternally inherited Leigh's syndrome (MILS) to neuropathy, ataxia, retinitis pigmentosa (NARP), depending on the mutation loads in affected patients."
This supports Leigh syndrome as a heteroplasmy-related presentation of the same canonical MT-ATP6 variant spectrum.
MELAS syndrome MONDO:0010789
Overlapping Features Other mitochondrial DNA disorders can overlap with neurologic impairment and ophthalmologic findings.
{ }

Source YAML

click to show 
name: NARP syndrome
creation_date: '2026-04-13T04:00:00Z'
updated_date: '2026-05-20T15:30:55Z'
description: >-
  NARP syndrome is a maternally inherited mitochondrial disease caused most
  often by pathogenic MT-ATP6 variants, including canonical nucleotide 8993
  substitutions. The syndrome is characterized by impaired oxidative
  phosphorylation with prominent neurologic and retinal vulnerability,
  classically manifesting with neuropathy, ataxia, and retinitis pigmentosa.
  Clinical severity varies with heteroplasmy and may overlap with Leigh
  syndrome.
category: Mendelian
parents:
- hereditary disease
- mitochondrial disease
disease_term:
  preferred_term: NARP syndrome
  term:
    id: MONDO:0010794
    label: NARP syndrome
pathophysiology:
- name: MT-ATP6 ATP synthase dysfunction
  description: >-
    Canonical MT-ATP6 nucleotide 8993 variants and other pathogenic MT-ATP6
    variants impair the proton-translocating membrane sector of mitochondrial
    ATP synthase.
  genes:
  - preferred_term: MT-ATP6
    term:
      id: hgnc:7414
      label: MT-ATP6
  molecular_functions:
  - preferred_term: proton-transporting ATP synthase activity, rotational mechanism
    modifier: DECREASED
    term:
      id: GO:0046933
      label: proton-transporting ATP synthase activity, rotational mechanism
  cellular_components:
  - preferred_term: proton-transporting ATP synthase complex
    term:
      id: GO:0045259
      label: proton-transporting ATP synthase complex
  biological_processes:
  - preferred_term: proton motive force-driven ATP synthesis
    modifier: ABNORMAL
    term:
      id: GO:0015986
      label: proton motive force-driven ATP synthesis
  evidence:
  - reference: PMID:27502083
    reference_title: A novel mutation m.8561C>G in MT-ATP6/8 causing a mitochondrial syndrome with ataxia, peripheral neuropathy, diabetes mellitus, and hypergonadotropic hypogonadism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pathogenic mutations in MT-ATP6 are associated with the Leigh syndrome, the syndrome of neuropathy, ataxia, and retinitis pigmentosa (NARP), as well as with non-classical phenotypes, while MT-ATP8 is less frequently mutated in patients with mitochondrial disease.
    explanation: This directly supports MT-ATP6 dysfunction as the canonical initiating lesion in NARP-spectrum mitochondrial disease.
  - reference: PMID:16525806
    reference_title: "NARP-MILS syndrome caused by 8993 T>G mitochondrial DNA mutation: a clinical, genetic and neuropathological study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The 8993 T>G mutation in mitochondrial DNA has been associated with
      variable syndromes of differing severity ranging from maternally inherited
      Leigh's syndrome (MILS) to neuropathy, ataxia, retinitis pigmentosa
      (NARP), depending on the mutation loads in affected patients.
    explanation: >-
      This supports canonical 8993 T>G MT-ATP6-associated NARP/MILS as a
      heteroplasmy-dependent clinical spectrum.
  - reference: PMID:22819295
    reference_title: Whole mitochondrial genome analysis of a family with NARP/MILS caused by m.8993T>C mutation in the MT-ATP6 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations in mitochondrial DNA (mtDNA) encoded nucleotide 8993 can cause
      NARP syndrome (neuropathy, ataxia, and retinitis pigmentosa) or MILS
      (maternally inherited Leigh syndrome).
    explanation: >-
      This family report supports m.8993T>C as another canonical MT-ATP6
      nucleotide 8993 variant in the NARP/MILS spectrum.
  downstream:
  - target: Mitochondrial complex V assembly defect
    causal_link_type: DIRECT
    description: >-
      The atypical m.8561C>G MT-ATP6/8 variant disrupts assembly of
      mitochondrial ATP synthase complex V in patient-derived myoblasts.
    evidence:
    - reference: PMID:27502083
      reference_title: A novel mutation m.8561C>G in MT-ATP6/8 causing a mitochondrial syndrome with ataxia, peripheral neuropathy, diabetes mellitus, and hypergonadotropic hypogonadism.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        An additional assembly intermediate of complex V and increased amount of
        subcomplex F1 were observed in myoblasts of the two patients, but the
        total amount of complex V was unaffected.
      explanation: >-
        Patient myoblast data directly support complex V assembly disruption
        downstream of the MT-ATP6/8 variant.
  - target: Reduced mitochondrial ATP production
    causal_link_type: DIRECT
    description: Defective ATP synthase coupling decreases efficient ATP generation.
- name: Mitochondrial complex V assembly defect
  description: >-
    In the atypical m.8561C>G MT-ATP6/8 sibling report, patient-derived
    myoblasts showed abnormal complex V assembly, with accumulation of an
    assembly intermediate and excess F1 subcomplex despite unchanged total
    complex V abundance.
  cellular_components:
  - preferred_term: proton-transporting ATP synthase complex
    term:
      id: GO:0045259
      label: proton-transporting ATP synthase complex
  biological_processes:
  - preferred_term: mitochondrial proton-transporting ATP synthase complex assembly
    modifier: ABNORMAL
    term:
      id: GO:0033615
      label: mitochondrial proton-transporting ATP synthase complex assembly
  evidence:
  - reference: PMID:27502083
    reference_title: A novel mutation m.8561C>G in MT-ATP6/8 causing a mitochondrial syndrome with ataxia, peripheral neuropathy, diabetes mellitus, and hypergonadotropic hypogonadism.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      An additional assembly intermediate of complex V and increased amount of
      subcomplex F1 were observed in myoblasts of the two patients, but the
      total amount of complex V was unaffected.
    explanation: >-
      This patient-derived myoblast study identifies abnormal complex V
      assembly as a biochemical lesion of the m.8561C>G MT-ATP6/8 variant.
  downstream:
  - target: Reduced mitochondrial ATP production
    causal_link_type: DIRECT
    description: >-
      Abnormal complex V assembly reduces ATP production in m.8561C>G
      patient-derived myoblasts.
    evidence:
    - reference: PMID:27502083
      reference_title: A novel mutation m.8561C>G in MT-ATP6/8 causing a mitochondrial syndrome with ataxia, peripheral neuropathy, diabetes mellitus, and hypergonadotropic hypogonadism.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        We suggest that the m.8561C>G mutation in MT-ATP6/8 is pathogenic,
        leads biochemically to impaired assembly and decreased ATP production
        of complex V, and results clinically in a phenotype with the core
        features of cerebellar ataxia, peripheral neuropathy, diabetes
        mellitus, and hypergonadotropic hypogonadism.
      explanation: >-
        The authors directly link impaired complex V assembly with decreased
        ATP production.
- name: Reduced mitochondrial ATP production
  description: >-
    Inefficient oxidative phosphorylation limits ATP availability in tissues
    with high metabolic demand.
  chemical_entities:
  - preferred_term: ATP
    modifier: DECREASED
    term:
      id: CHEBI:15422
      label: ATP
  biological_processes:
  - preferred_term: oxidative phosphorylation
    modifier: ABNORMAL
    term:
      id: GO:0006119
      label: oxidative phosphorylation
  evidence:
  - reference: PMID:27502083
    reference_title: A novel mutation m.8561C>G in MT-ATP6/8 causing a mitochondrial syndrome with ataxia, peripheral neuropathy, diabetes mellitus, and hypergonadotropic hypogonadism.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Furthermore, intracellular ATP concentration was lower in patient myoblasts indicating defective energy production.
    explanation: Patient-derived myoblast data directly supports reduced ATP production downstream of MT-ATP6/8 dysfunction.
  - reference: PMID:31276579
    reference_title: Deregulating mitochondrial metabolite and ion transport has beneficial effects in yeast and human cellular models for NARP syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The m.8993T>G mutation of the mitochondrial MT-ATP6 gene has been
      associated with numerous cases of neuropathy, ataxia and retinitis
      pigmentosa and maternally inherited Leigh syndrome, which are diseases
      known to result from abnormalities affecting mitochondrial energy
      transduction.
    explanation: >-
      This NARP cellular-model paper connects the canonical m.8993T>G MT-ATP6
      variant with mitochondrial energy-transduction abnormalities.
  downstream:
  - target: Neuroretinal energy failure
    causal_link_type: DIRECT
    description: Neurons, peripheral nerves, and retinal cells are especially vulnerable.
  - target: Sensorineural hearing impairment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >
      Auditory sensory cells and auditory neurons are vulnerable to impaired
      mitochondrial ATP production, producing sensorineural hearing impairment.
  - target: Endocrine energy vulnerability
    causal_link_type: DIRECT
    description: >-
      Impaired ATP production can also involve endocrine tissues in the
      MT-ATP6/8 phenotype, producing diabetes and primary hypogonadism.
    evidence:
    - reference: PMID:27502083
      reference_title: A novel mutation m.8561C>G in MT-ATP6/8 causing a mitochondrial syndrome with ataxia, peripheral neuropathy, diabetes mellitus, and hypergonadotropic hypogonadism.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We suggest that the m.8561C>G mutation in MT-ATP6/8 is pathogenic,
        leads biochemically to impaired assembly and decreased ATP production
        of complex V, and results clinically in a phenotype with the core
        features of cerebellar ataxia, peripheral neuropathy, diabetes
        mellitus, and hypergonadotropic hypogonadism.
      explanation: >-
        The clinical report connects reduced complex V ATP production with
        endocrine manifestations including diabetes and hypergonadotropic
        hypogonadism.
  - target: Intracellular ATP concentration
    causal_link_type: DIRECT
    description: >-
      Reduced ATP production is directly measurable as lower intracellular ATP
      concentration in patient-derived myoblasts.
    evidence:
    - reference: PMID:27502083
      reference_title: A novel mutation m.8561C>G in MT-ATP6/8 causing a mitochondrial syndrome with ataxia, peripheral neuropathy, diabetes mellitus, and hypergonadotropic hypogonadism.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Furthermore, intracellular ATP concentration was lower in patient
        myoblasts indicating defective energy production.
      explanation: >-
        Patient-derived myoblast data support intracellular ATP concentration as
        a biochemical readout of reduced mitochondrial ATP production.
- name: Neuroretinal energy failure
  description: >-
    Energy failure in the nervous system and retina drives the core neurologic
    and ophthalmologic phenotype.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  - preferred_term: photoreceptor cell
    term:
      id: CL:0000210
      label: photoreceptor cell
  biological_processes:
  - preferred_term: oxidative phosphorylation
    modifier: ABNORMAL
    term:
      id: GO:0006119
      label: oxidative phosphorylation
  evidence:
  - reference: PMID:27502083
    reference_title: A novel mutation m.8561C>G in MT-ATP6/8 causing a mitochondrial syndrome with ataxia, peripheral neuropathy, diabetes mellitus, and hypergonadotropic hypogonadism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We suggest that the m.8561C>G mutation in MT-ATP6/8 is pathogenic, leads biochemically to impaired assembly and decreased ATP production of complex V, and results clinically in a phenotype with the core features of cerebellar ataxia, peripheral neuropathy, diabetes mellitus, and hypergonadotropic hypogonadism.
    explanation: This links impaired complex V energy production to the characteristic multisystem neurologic phenotype.
  - reference: PMID:16525806
    reference_title: "NARP-MILS syndrome caused by 8993 T>G mitochondrial DNA mutation: a clinical, genetic and neuropathological study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report a kindred with several members in the same generation suffering
      NARP or Leigh's syndrome due to a 8993 T>G mutation.
    explanation: >-
      This canonical 8993 T>G kindred supports neuroretinal NARP manifestations
      within the MT-ATP6 disease spectrum.
  downstream:
  - target: Cerebellar dysfunction
    causal_link_type: DIRECT
    description: Cerebellar energy failure contributes to gait instability.
  - target: Peripheral nerve dysfunction
    causal_link_type: DIRECT
    description: Peripheral nerve energy failure produces sensory and motor neuropathy.
  - target: Retinal degeneration
    causal_link_type: DIRECT
    description: Retinal energy failure leads to pigmentary retinopathy and vision loss.
- name: Endocrine energy vulnerability
  description: >-
    The atypical m.8561C>G MT-ATP6/8 complex V defect can involve endocrine
    tissues, producing diabetes mellitus and hypergonadotropic hypogonadism in
    addition to the neurologic and retinal syndrome.
  biological_processes:
  - preferred_term: oxidative phosphorylation
    modifier: ABNORMAL
    term:
      id: GO:0006119
      label: oxidative phosphorylation
  evidence:
  - reference: PMID:27502083
    reference_title: A novel mutation m.8561C>G in MT-ATP6/8 causing a mitochondrial syndrome with ataxia, peripheral neuropathy, diabetes mellitus, and hypergonadotropic hypogonadism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We investigated two adult siblings presenting with features of cerebellar
      ataxia, peripheral neuropathy, diabetes mellitus, sensorineural hearing
      impairment, and hypergonadotropic hypogonadism.
    explanation: >-
      The patient phenotype directly documents endocrine involvement in the
      MT-ATP6/8-related NARP-overlap presentation.
  downstream:
  - target: Diabetes mellitus
    causal_link_type: DIRECT
    description: Endocrine involvement includes diabetes mellitus.
    evidence:
    - reference: PMID:27502083
      reference_title: A novel mutation m.8561C>G in MT-ATP6/8 causing a mitochondrial syndrome with ataxia, peripheral neuropathy, diabetes mellitus, and hypergonadotropic hypogonadism.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We investigated two adult siblings presenting with features of
        cerebellar ataxia, peripheral neuropathy, diabetes mellitus,
        sensorineural hearing impairment, and hypergonadotropic hypogonadism.
      explanation: >-
        Diabetes mellitus is reported in the affected siblings with the
        MT-ATP6/8 complex V defect.
  - target: Hypergonadotropic hypogonadism
    causal_link_type: DIRECT
    description: Endocrine involvement also includes primary gonadal failure.
    evidence:
    - reference: PMID:27502083
      reference_title: A novel mutation m.8561C>G in MT-ATP6/8 causing a mitochondrial syndrome with ataxia, peripheral neuropathy, diabetes mellitus, and hypergonadotropic hypogonadism.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We investigated two adult siblings presenting with features of
        cerebellar ataxia, peripheral neuropathy, diabetes mellitus,
        sensorineural hearing impairment, and hypergonadotropic hypogonadism.
      explanation: >-
        Hypergonadotropic hypogonadism is reported in the same affected
        siblings.
- name: Cerebellar dysfunction
  description: >-
    Energetic failure within cerebellar systems produces impaired coordination
    and gait instability.
  downstream:
  - target: Ataxia
    description: Cerebellar system involvement manifests clinically as ataxia in NARP-spectrum disease.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:27502083
      reference_title: A novel mutation m.8561C>G in MT-ATP6/8 causing a mitochondrial syndrome with ataxia, peripheral neuropathy, diabetes mellitus, and hypergonadotropic hypogonadism.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We suggest that the m.8561C>G mutation in MT-ATP6/8 is pathogenic, leads biochemically to impaired assembly and decreased ATP production of complex V, and results clinically in a phenotype with the core features of cerebellar ataxia, peripheral neuropathy, diabetes mellitus, and hypergonadotropic hypogonadism.
      explanation: The MT-ATP6/8 family report connects impaired complex V ATP production with cerebellar ataxia as a core clinical feature.
- name: Peripheral nerve dysfunction
  description: >-
    Mitochondrial failure in peripheral nerves contributes to sensory and motor
    neuropathy.
  downstream:
  - target: Peripheral neuropathy
    description: Peripheral nerve involvement is represented clinically by peripheral neuropathy.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:27502083
      reference_title: A novel mutation m.8561C>G in MT-ATP6/8 causing a mitochondrial syndrome with ataxia, peripheral neuropathy, diabetes mellitus, and hypergonadotropic hypogonadism.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We suggest that the m.8561C>G mutation in MT-ATP6/8 is pathogenic, leads biochemically to impaired assembly and decreased ATP production of complex V, and results clinically in a phenotype with the core features of cerebellar ataxia, peripheral neuropathy, diabetes mellitus, and hypergonadotropic hypogonadism.
      explanation: The clinical report identifies peripheral neuropathy among the core MT-ATP6/8 phenotype features downstream of complex V dysfunction.
- name: Retinal degeneration
  description: >-
    Retinal energetic vulnerability contributes to pigmentary retinopathy and
    progressive visual dysfunction.
  downstream:
  - target: Retinitis pigmentosa
    description: Retinal degeneration is represented clinically by retinitis pigmentosa in the NARP phenotype.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:27502083
      reference_title: A novel mutation m.8561C>G in MT-ATP6/8 causing a mitochondrial syndrome with ataxia, peripheral neuropathy, diabetes mellitus, and hypergonadotropic hypogonadism.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Pathogenic mutations in MT-ATP6 are associated with the Leigh syndrome, the syndrome of neuropathy, ataxia, and retinitis pigmentosa (NARP), as well as with non-classical phenotypes, while MT-ATP8 is less frequently mutated in patients with mitochondrial disease.
      explanation: The report explicitly names retinitis pigmentosa as one of the defining NARP phenotype components associated with MT-ATP6 mutations.
phenotypes:
- name: Ataxia
  category: Neurologic
  description: Progressive gait and coordination impairment is a core clinical feature.
  phenotype_term:
    preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
  evidence:
  - reference: PMID:27502083
    reference_title: A novel mutation m.8561C>G in MT-ATP6/8 causing a mitochondrial syndrome with ataxia, peripheral neuropathy, diabetes mellitus, and hypergonadotropic hypogonadism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We investigated two adult siblings presenting with features of cerebellar ataxia, peripheral neuropathy, diabetes mellitus, sensorineural hearing impairment, and hypergonadotropic hypogonadism.
    explanation: This directly documents ataxia in MT-ATP6/8-related NARP-spectrum disease.
  - reference: PMID:22819295
    reference_title: Whole mitochondrial genome analysis of a family with NARP/MILS caused by m.8993T>C mutation in the MT-ATP6 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations in mitochondrial DNA (mtDNA) encoded nucleotide 8993 can cause
      NARP syndrome (neuropathy, ataxia, and retinitis pigmentosa) or MILS
      (maternally inherited Leigh syndrome).
    explanation: >-
      This canonical nucleotide 8993 family report explicitly includes ataxia
      in the NARP syndrome definition.
- name: Peripheral neuropathy
  category: Neurologic
  description: Peripheral neuropathy contributes to sensory loss, weakness, and areflexia.
  phenotype_term:
    preferred_term: Peripheral neuropathy
    term:
      id: HP:0009830
      label: Peripheral neuropathy
  evidence:
  - reference: PMID:27502083
    reference_title: A novel mutation m.8561C>G in MT-ATP6/8 causing a mitochondrial syndrome with ataxia, peripheral neuropathy, diabetes mellitus, and hypergonadotropic hypogonadism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We investigated two adult siblings presenting with features of cerebellar ataxia, peripheral neuropathy, diabetes mellitus, sensorineural hearing impairment, and hypergonadotropic hypogonadism.
    explanation: This directly documents peripheral neuropathy as a core NARP-spectrum manifestation.
  - reference: PMID:22819295
    reference_title: Whole mitochondrial genome analysis of a family with NARP/MILS caused by m.8993T>C mutation in the MT-ATP6 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations in mitochondrial DNA (mtDNA) encoded nucleotide 8993 can cause
      NARP syndrome (neuropathy, ataxia, and retinitis pigmentosa) or MILS
      (maternally inherited Leigh syndrome).
    explanation: >-
      This canonical nucleotide 8993 family report explicitly includes
      neuropathy in the NARP syndrome definition.
- name: Retinitis pigmentosa
  category: Ophthalmologic
  description: Pigmentary retinal degeneration causes progressive visual impairment.
  phenotype_term:
    preferred_term: Retinitis pigmentosa
    term:
      id: HP:0000510
      label: Rod-cone dystrophy
  evidence:
  - reference: PMID:27502083
    reference_title: A novel mutation m.8561C>G in MT-ATP6/8 causing a mitochondrial syndrome with ataxia, peripheral neuropathy, diabetes mellitus, and hypergonadotropic hypogonadism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pathogenic mutations in MT-ATP6 are associated with the Leigh syndrome, the syndrome of neuropathy, ataxia, and retinitis pigmentosa (NARP), as well as with non-classical phenotypes, while MT-ATP8 is less frequently mutated in patients with mitochondrial disease.
    explanation: This directly names retinitis pigmentosa within the canonical NARP phenotype.
  - reference: PMID:22819295
    reference_title: Whole mitochondrial genome analysis of a family with NARP/MILS caused by m.8993T>C mutation in the MT-ATP6 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations in mitochondrial DNA (mtDNA) encoded nucleotide 8993 can cause
      NARP syndrome (neuropathy, ataxia, and retinitis pigmentosa) or MILS
      (maternally inherited Leigh syndrome).
    explanation: >-
      This canonical nucleotide 8993 family report explicitly includes
      retinitis pigmentosa in the NARP syndrome definition.
- name: Sensorineural hearing impairment
  category: Otolaryngologic
  description: Sensorineural hearing impairment is part of the broader MT-ATP6-associated neurologic phenotype.
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:27502083
    reference_title: A novel mutation m.8561C>G in MT-ATP6/8 causing a mitochondrial syndrome with ataxia, peripheral neuropathy, diabetes mellitus, and hypergonadotropic hypogonadism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We investigated two adult siblings presenting with features of cerebellar ataxia, peripheral neuropathy, diabetes mellitus, sensorineural hearing impairment, and hypergonadotropic hypogonadism.
    explanation: This directly documents sensorineural hearing impairment in an MT-ATP6/8 NARP-overlap phenotype.
- name: Diabetes mellitus
  category: Endocrine
  description: >-
    Diabetes mellitus was reported in the atypical m.8561C>G MT-ATP6/8
    NARP-overlap phenotype.
  phenotype_term:
    preferred_term: Diabetes mellitus
    term:
      id: HP:0000819
      label: Diabetes mellitus
  evidence:
  - reference: PMID:27502083
    reference_title: A novel mutation m.8561C>G in MT-ATP6/8 causing a mitochondrial syndrome with ataxia, peripheral neuropathy, diabetes mellitus, and hypergonadotropic hypogonadism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We investigated two adult siblings presenting with features of cerebellar ataxia, peripheral neuropathy, diabetes mellitus, sensorineural hearing impairment, and hypergonadotropic hypogonadism.
    explanation: This directly documents diabetes mellitus in an MT-ATP6/8 NARP-overlap phenotype.
- name: Hypergonadotropic hypogonadism
  category: Endocrine
  description: >-
    Hypergonadotropic hypogonadism was reported in the atypical m.8561C>G
    MT-ATP6/8 NARP-overlap phenotype.
  phenotype_term:
    preferred_term: Hypergonadotropic hypogonadism
    term:
      id: HP:0000815
      label: Hypergonadotropic hypogonadism
  evidence:
  - reference: PMID:27502083
    reference_title: A novel mutation m.8561C>G in MT-ATP6/8 causing a mitochondrial syndrome with ataxia, peripheral neuropathy, diabetes mellitus, and hypergonadotropic hypogonadism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We investigated two adult siblings presenting with features of cerebellar
      ataxia, peripheral neuropathy, diabetes mellitus, sensorineural hearing
      impairment, and hypergonadotropic hypogonadism.
    explanation: >-
      This directly documents hypergonadotropic hypogonadism in an
      MT-ATP6/8-related NARP-overlap phenotype.
biochemical:
- name: Intracellular ATP concentration
  biomarker_term:
    preferred_term: adenosine triphosphate measurement
    term:
      id: NCIT:C147307
      label: Adenosine Triphosphate Measurement
  presence: DECREASED
  context: >-
    In the m.8561C>G report, patient-derived myoblasts show reduced
    intracellular ATP concentration, reflecting defective complex V energy
    production.
  readouts:
  - target: Reduced mitochondrial ATP production
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Lower intracellular ATP concentration reports the reduced ATP production
      node caused by impaired ATP synthase complex V in the m.8561C>G myoblast
      model.
    evidence:
    - reference: PMID:27502083
      reference_title: A novel mutation m.8561C>G in MT-ATP6/8 causing a mitochondrial syndrome with ataxia, peripheral neuropathy, diabetes mellitus, and hypergonadotropic hypogonadism.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Furthermore, intracellular ATP concentration was lower in patient
        myoblasts indicating defective energy production.
      explanation: >-
        The study directly supports lower intracellular ATP concentration as a
        biochemical readout of defective energy production.
  evidence:
  - reference: PMID:27502083
    reference_title: A novel mutation m.8561C>G in MT-ATP6/8 causing a mitochondrial syndrome with ataxia, peripheral neuropathy, diabetes mellitus, and hypergonadotropic hypogonadism.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Furthermore, intracellular ATP concentration was lower in patient
      myoblasts indicating defective energy production.
    explanation: >-
      Patient myoblast measurements document decreased intracellular ATP.
- name: Complex V assembly intermediate and F1 subcomplex accumulation
  presence: ABNORMAL
  context: >-
    In the m.8561C>G report, patient myoblasts show an additional complex V
    assembly intermediate and increased F1 subcomplex despite unchanged total
    complex V.
  readouts:
  - target: Mitochondrial complex V assembly defect
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Abnormal complex V assembly intermediates report the mitochondrial ATP
      synthase assembly defect in the m.8561C>G patient-derived myoblast model.
    evidence:
    - reference: PMID:27502083
      reference_title: A novel mutation m.8561C>G in MT-ATP6/8 causing a mitochondrial syndrome with ataxia, peripheral neuropathy, diabetes mellitus, and hypergonadotropic hypogonadism.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        An additional assembly intermediate of complex V and increased amount
        of subcomplex F1 were observed in myoblasts of the two patients, but
        the total amount of complex V was unaffected.
      explanation: >-
        Patient myoblast data directly document the complex V assembly readout.
  evidence:
  - reference: PMID:27502083
    reference_title: A novel mutation m.8561C>G in MT-ATP6/8 causing a mitochondrial syndrome with ataxia, peripheral neuropathy, diabetes mellitus, and hypergonadotropic hypogonadism.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      An additional assembly intermediate of complex V and increased amount of
      subcomplex F1 were observed in myoblasts of the two patients, but the
      total amount of complex V was unaffected.
    explanation: >-
      This supports abnormal complex V assembly intermediates as a biochemical
      readout of the ATP synthase defect.
genetic:
- name: MT-ATP6
  gene_term:
    preferred_term: MT-ATP6
    term:
      id: hgnc:7414
      label: MT-ATP6
  association: >-
    Causal pathogenic mitochondrial DNA variants, including canonical nucleotide
    8993 substitutions, with heteroplasmy-dependent NARP/MILS severity
  inheritance:
  - name: Mitochondrial inheritance
    inheritance_term:
      preferred_term: Mitochondrial inheritance
      term:
        id: HP:0001427
        label: Mitochondrial inheritance
    evidence:
    - reference: PMID:27502083
      reference_title: A novel mutation m.8561C>G in MT-ATP6/8 causing a mitochondrial syndrome with ataxia, peripheral neuropathy, diabetes mellitus, and hypergonadotropic hypogonadism.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Mutation heteroplasmy correlated with the disease phenotype in five family members.
      explanation: Maternal mitochondrial inheritance with heteroplasmy-dependent expression is directly supported by family-based genotype-phenotype correlation.
  evidence:
  - reference: PMID:27502083
    reference_title: A novel mutation m.8561C>G in MT-ATP6/8 causing a mitochondrial syndrome with ataxia, peripheral neuropathy, diabetes mellitus, and hypergonadotropic hypogonadism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pathogenic mutations in MT-ATP6 are associated with the Leigh syndrome, the syndrome of neuropathy, ataxia, and retinitis pigmentosa (NARP), as well as with non-classical phenotypes, while MT-ATP8 is less frequently mutated in patients with mitochondrial disease.
    explanation: This directly supports MT-ATP6 as the established causal gene for NARP-spectrum disease.
  - reference: PMID:16525806
    reference_title: "NARP-MILS syndrome caused by 8993 T>G mitochondrial DNA mutation: a clinical, genetic and neuropathological study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report a kindred with several members in the same generation suffering
      NARP or Leigh's syndrome due to a 8993 T>G mutation.
    explanation: >-
      This kindred directly supports the canonical 8993 T>G mitochondrial DNA
      mutation as a cause of NARP/Leigh-spectrum disease.
  - reference: PMID:22819295
    reference_title: Whole mitochondrial genome analysis of a family with NARP/MILS caused by m.8993T>C mutation in the MT-ATP6 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we report the results of whole mitochondrial genome analysis of a
      family with m.8993T>C mutation in the MT-ATP6 gene and associated with
      NARP/MILS, and discuss the familial inheritance, effects of variation in
      combinations and heteroplasmy levels on the clinical findings.
    explanation: >-
      This supports m.8993T>C in MT-ATP6 as another familial NARP/MILS variant
      with heteroplasmy-dependent clinical expression.
environmental: []
treatments:
- name: Supportive mitochondrial disease management
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  description: >-
    Management is supportive and includes symptom-based neurologic,
    ophthalmologic, rehabilitation, and medication-avoidance care.
  target_phenotypes:
  - preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
  - preferred_term: Peripheral neuropathy
    term:
      id: HP:0009830
      label: Peripheral neuropathy
  - preferred_term: Retinitis pigmentosa
    term:
      id: HP:0000510
      label: Rod-cone dystrophy
  - preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  - preferred_term: Diabetes mellitus
    term:
      id: HP:0000819
      label: Diabetes mellitus
  evidence:
  - reference: PMID:20301352
    reference_title: Mitochondrial DNA-Associated Leigh Syndrome Spectrum.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment of manifestations: Treatment is supportive."
    explanation: >-
      GeneReviews supports supportive, symptom-directed management for
      mtDNA-associated Leigh-spectrum disease overlapping NARP/MILS.
  - reference: PMID:20301352
    reference_title: Mitochondrial DNA-Associated Leigh Syndrome Spectrum.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sodium valproate, medications that cause acidosis, and dichloroacetate
      should be avoided or used with caution;
    explanation: >-
      GeneReviews supports avoiding mitochondrial stressors such as valproate
      and acidosis-provoking medications in this spectrum.
- name: Physical therapy
  treatment_term:
    preferred_term: physical therapy
    term:
      id: MAXO:0000011
      label: physical therapy
  description: >-
    Rehabilitation is used to preserve mobility, balance, and function in
    progressive neuromuscular disease.
  target_phenotypes:
  - preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
  evidence:
  - reference: PMID:20301352
    reference_title: Mitochondrial DNA-Associated Leigh Syndrome Spectrum.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      developmental and educational support; physical therapy and occupational
      therapy; standard treatment of eye movement disorders;
    explanation: >-
      GeneReviews includes physical therapy among supportive interventions for
      mtDNA-associated Leigh-spectrum manifestations.
- name: Genetic counseling
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  description: >-
    Genetic counseling addresses maternal mtDNA inheritance, heteroplasmy,
    recurrence-risk uncertainty, and reproductive options.
  evidence:
  - reference: PMID:20301352
    reference_title: Mitochondrial DNA-Associated Leigh Syndrome Spectrum.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Reproductive options for the family members of a proband with an mtDNA
      pathogenic variant may include prenatal testing, preimplantation genetic
      testing, and oocyte donation.
    explanation: >-
      GeneReviews supports genetic counseling and reproductive planning for
      families with pathogenic mtDNA variants.
diagnosis:
- name: Mitochondrial DNA testing
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: MAXO:0000127
      label: genetic testing
  description: >-
    Molecular diagnosis is established by identification of a pathogenic
    MT-ATP6 variant and heteroplasmy assessment.
  results: Pathogenic MT-ATP6 variant supports the diagnosis of NARP syndrome.
- name: Ophthalmologic evaluation
  diagnosis_term:
    preferred_term: clinical assessment
    term:
      id: MAXO:0000487
      label: clinical assessment
  description: >-
    Retinal examination helps document pigmentary retinopathy and disease
    severity.
  results: Pigmentary retinopathy supports the syndromic diagnosis.
differential_diagnoses:
- name: Leigh syndrome
  disease_term:
    preferred_term: Leigh syndrome
    term:
      id: MONDO:0009723
      label: Leigh syndrome
  description: >-
    The same canonical MT-ATP6 nucleotide 8993 variants can produce NARP or
    maternally inherited Leigh syndrome, with severity related to mutant load.
  evidence:
  - reference: PMID:16525806
    reference_title: "NARP-MILS syndrome caused by 8993 T>G mitochondrial DNA mutation: a clinical, genetic and neuropathological study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The 8993 T>G mutation in mitochondrial DNA has been associated with
      variable syndromes of differing severity ranging from maternally inherited
      Leigh's syndrome (MILS) to neuropathy, ataxia, retinitis pigmentosa
      (NARP), depending on the mutation loads in affected patients.
    explanation: >-
      This supports Leigh syndrome as a heteroplasmy-related presentation of
      the same canonical MT-ATP6 variant spectrum.
- name: MELAS syndrome
  disease_term:
    preferred_term: MELAS syndrome
    term:
      id: MONDO:0010789
      label: MELAS syndrome
  description: >-
    Other mitochondrial DNA disorders can overlap with neurologic impairment and
    ophthalmologic findings.
references:
- reference: PMID:20301352
  title: Mitochondrial DNA-Associated Leigh Syndrome Spectrum.
  tags:
  - GeneReviews
  findings: []
clinical_trials: []
datasets: []
📚

References & Deep Research

References

1
PMID:20301352
Mitochondrial DNA-Associated Leigh Syndrome Spectrum.
No top-level findings curated for this source.

Deep Research

1
Asta ▸
Asta Literature Retrieval: Pathophysiology and clinical mechanisms of NARP syndrome. Core disease mechanisms, molecular and cellular pathways, i...
Asta Scientific Corpus Retrieval 20 citations 2026-04-13T13:49:48.432029

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of NARP syndrome. Core disease mechanisms, molecular and cellular pathways, i...

This report is retrieval-only and is generated directly from Asta results.

  • Papers retrieved: 20
  • Snippets retrieved: 20

Relevant Papers

[1] Drug repurposing in Rett and Rett-like syndromes: a promising yet underrated opportunity?

  • Authors: Claudia Fuchs, P. A. ‛. ’t Hoen, A. Müller, Friederike Ehrhart, C. V. van Karnebeek
  • Year: 2024
  • Venue: Frontiers in Medicine
  • URL: https://www.semanticscholar.org/paper/b00d0859458647edeebf3cf53f9b39c79311d5ed
  • DOI: 10.3389/fmed.2024.1425038
  • PMID: 39135718
  • PMCID: 11317438
  • Citations: 1
  • Summary: The potential of drug repurposing (DR) as a promising avenue for addressing the unmet medical needs of individuals with RTT and related disorders is explored and Leveraging existing drugs for new therapeutic purposes presents an attractive strategy.
  • Evidence snippets:
  • Snippet 1 (score: 0.425) > Rigorous preclinical and clinical studies are also crucial for better understanding the complex pathophysiology of these syndromes. To date, the precise molecular mechanisms underlying these complex disorders are still not fully understood; hindering the identification and validation of potential drug targets. This specifically applies to CDD and FOXG1-syndrome: both conditions were identified as distinct clinical entities only recently and it is understandable that research efforts initially focused primarily on "classical" RTT. This discrepancy is reflected also in the very different numbers of repurposing studies highlighted in Figure 1. Continued efforts in pre-clinical (identification of valuable cell and animal models etc.) and clinical research (better understanding of the natural history, clinical manifestations, disease progression, biomarkers etc.) will be essential for advancing our understanding and improving outcomes for individuals affected by these syndromes. In particular, better characterizing the shared symptoms and pathways across these entities, will provide valuable insights into the underlying biology and potentially uncover new common mechanisms and targeted therapies. If the disorders demonstrate convergence in their underlying molecular pathways, this provides an opportunity for designing joint DR 10.3389/fmed.2024.1425038 strategies across RTT and RTT-like disorders. This could reduce the time needed for the development of DR and increase the number of patients benefiting from the treatments, resulting in more attractive business models. > Despite promising DR results in preclinical or early-phase clinical trials for RTT and related disorders in our opinion DR is still underrated and underutilized in this kind of disorders. DR holds immense potential for addressing the unmet medical needs and therapeutic challenges posed by such complex NDDs, and recent advancements screening and computational techniques, offer the unique opportunity to predict drug-disease interactions and prioritize candidate compounds for further investigation. By leveraging existing drugs and repurposing them for new indications, this approach offers a pragmatic and efficient strategy to accelerate the development of treatments for individuals affected by these debilitating conditions.

[2] Novel Approaches to Studying SLC13A5 Disease

  • Authors: Adriana S. Beltran
  • Year: 2024
  • Venue: Metabolites
  • URL: https://www.semanticscholar.org/paper/8469c534cd81d96f84b61e2d963dead12088feb7
  • DOI: 10.3390/metabo14020084
  • PMID: 38392976
  • PMCID: 10890222
  • Citations: 2
  • Summary: Current technologies for generating patient-specific induced pluripotent stem cells (iPSCs) and their inherent advantages and limitations are discussed, followed by a summary of the methods for differentiating iPSCs into neurons, hepatocytes, and organoids.
  • Evidence snippets:
  • Snippet 1 (score: 0.415) > The precise pathophysiology underlying how SLC13A5 loss-of-function results in epilepsy refractory to treatment is a subject of open and ongoing research. Several hypotheses suggest SLC13A5 alters metabolic pathways, leading to neuronal dysfunction. Conversely, therapeutic inhibition of NaCT in the liver is a target to improve metabolic diseases, including non-alcoholic fatty liver disease, obesity, and insulin resistance. Thus, functionally accurate modeling and characterization of the mechanisms involved in citrate transport disruption are critical for understanding its role in human disease. > IPSC-derived cellular systems are a powerful tool for modeling rare human genetic diseases, such as SLC13A5 (Figure 5). IPSCs derived from patients containing the genetic information of the disease can overcome the limitations of animal models, providing access to relevant human cell types that recapitulate the disease phenotype. For instance, patient-derived iPSCs differentiated into neurons or hepatocytes can be used to investigate molecular and cellular mechanisms, including citrate transport and accumulation, energy metabolism, oxidative stress, and other cellular processes. They can also be used to define the spectrum of the disease and how different mutations might lead to various disease severities, screen for potential therapeutic compounds that can restore the transporter function or ameliorate the symptoms, and enable personalized medicine approaches that can tailor treatments to individual patients based on their genetic background and disease severity. > transport disruption are critical for understanding its role in human disease. > IPSC-derived cellular systems are a powerful tool for modeling rare human genetic diseases, such as SLC13A5 (Figure 5). IPSCs derived from patients containing the genetic information of the disease can overcome the limitations of animal models, providing access to relevant human cell types that recapitulate the disease phenotype. For instance, patient-derived iPSCs differentiated into neurons or hepatocytes can be used to investigate molecular and cellular mechanisms, including citrate transport and accumulation, energy metabolism, oxidative stress, and other cellular processes.

[3] Aberrant NLRP3 Inflammasome Activation Ignites the Fire of Inflammation in Neuromuscular Diseases

  • Authors: Christine Péladeau, J. Sandhu
  • Year: 2021
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/763a36db080236fca8cde89b2afcdf056f3584d0
  • DOI: 10.3390/ijms22116068
  • PMID: 34199845
  • PMCID: 8200055
  • Citations: 18
  • Influential citations: 1
  • Summary: Whether therapeutic targeting of the NLRP3 inflammasome components is a viable approach to alleviating the detrimental phenotype of neuromuscular diseases and improving clinical outcomes is examined.
  • Evidence snippets:
  • Snippet 1 (score: 0.413) > Despite a large number of mechanisms that have been identified in muscle degeneration and nerve cell loss, none have proven to be the primary cause of the disease. There is much need for a deeper understanding of the biology of the pathogeneses and the molecular mechanisms that are activated early in the diseases in order to identify "druggable" targets and disease-modifying treatments for these devastating diseases. > Human iPSC technologies are emerging as useful platforms for disease modeling to study pathogenic mechanisms and discover novel therapeutics for neuromuscular diseases [211,237]. Indeed, patient-derived iPSCs are being used to create a "patient-in-adish" disease model to derive relevant cell types for testing potential therapeutics, paving the way towards personalized medicine. This approach allows drug screening in a dish prior to administration to patients and "bench-to-bedside" translation of potential therapies. Additionally, iPSCs may also be used to stratify patients with various phenotypes and guide future clinical trials for bringing improved therapies to patients. Since multiple cell types are involved in disease pathogenesis, future research efforts need to be focused on deciphering "disease-specific signatures" at single-cell resolution, and not only in neuronal cells but also in non-neuronal cells. The application of modern technologies, including single-cell RNA sequencing and spatial transcriptomics, to neuromuscular diseases, will allow to ascertain cellular vulnerability and cell-specific mechanisms during various stages of disease progression. > The vital roles of the NLRP3 inflammasome in neuromuscular diseases such as DMD, LGMD and ALS, reveal that targeting this pathway is indeed a promising therapeutic strategy. Dysregulation of the NLRP3 inflammasome in muscle tissues by muscle damage, membrane instability, extracellular ATP and Ca 2+ ions or signals from infiltrating immune cells, clearly impacts the progression of neuromuscular and neurodegenerative disorders. Thus, modulation of these pathways involved with activation and assembly of NLRP3 inflammasome could be truly beneficial.

[4] Targeting Hepatic Stellate Cells for the Prevention and Treatment of Liver Cirrhosis and Hepatocellular Carcinoma: Strategies and Clinical Translation

  • Authors: Hao Xiong, Jinsheng Guo
  • Year: 2025
  • Venue: Pharmaceuticals
  • URL: https://www.semanticscholar.org/paper/76e92127053136900f7e3f10e2c9278251ced5d2
  • DOI: 10.3390/ph18040507
  • PMID: 40283943
  • PMCID: 12030350
  • Citations: 8
  • Summary: HSC-targeted approaches using specific surface markers and receptors may enable the selective delivery of drugs, oligonucleotides, and therapeutic peptides that exert optimized anti-fibrotic and anti-HCC effects.
  • Evidence snippets:
  • Snippet 1 (score: 0.406) > Significant progress has been made in elucidating the cellular and molecular mechanisms of liver fibrosis; however, only a few findings have been successfully translated into clinical applications. Firstly, the high cost of drug development and target validation necessitates prolonged timelines and substantial financial investment. Secondly, as regulatory requirements become more stringent, there is an increasing demand for drugs with well-defined clinical efficacy and safety profiles. Moreover, the efficacy observed in animal models often fails to fully translate to clinical settings due to differences in pharmacokinetics, extracellular matrix (ECM) cross-linking, and disease pathophysiology. Despite advancements in anti-fibrotic drug development, accurately identifying ideal noninvasive biomarkers for fibrotic activity and establishing consensus on optimal clinical endpoints remain significant challenges [113,114]. > Currently, addressing the underlying cause remains the only proven strategy to halt or reverse liver fibrosis progression, while the development of effective anti-fibrotic therapies continues to pose a major challenge in liver disease management. Over the past few decades, substantial progress has been made in elucidating the cellular and molecular mechanisms underlying liver fibrosis. Liver fibrosis is a complex pathological change involving multiple cells, factors, and pathways, and the study of the cellular and molecular mechanisms of its occurrence and development provides an important theoretical basis and therapeutic target for clinical drug development. It is anticipated that improved animal models and well-designed clinical trials will facilitate the successful translation of anti-fibrotic research into effective clinical treatments in the near future.

[5] Conceptualizing Epigenetics and the Environmental Landscape of Autism Spectrum Disorders

  • Authors: G. Torres, Mervat Mourad, Saba Iqbal, Emmanuel Moses-Fynn, Ashani Pandita et al.
  • Year: 2023
  • Venue: Genes
  • URL: https://www.semanticscholar.org/paper/bf76f0682a8a1986ce889cee1fef818480abc83b
  • DOI: 10.3390/genes14091734
  • PMID: 37761876
  • PMCID: 10531442
  • Citations: 11
  • Summary: The present work reviews recent evolutionary, molecular, and epigenetic mechanisms potentially linked to the etiology of autism, and presents a clinical vignette to describe clusters of maladaptive behaviors frequently diagnosed in autistic patients.
  • Evidence snippets:
  • Snippet 1 (score: 0.406) > Currently, there are hundreds of gene variants associated with the onset of ASD. Thus, the clinical presentation of the disease is highly variable, as one or more behavioral symptoms may be related to other comorbid conditions (e.g., anxiety disorder, seizure disorder) besides autism. In addition, antagonistic pleiotropy and dosage-sensitive genes further fragment the phenotypic characteristics of ASD. Regardless, here, we present a prototypical autism clinical vignette with five behavioral specifiers: cognitive disability; deficits in social-emotional reciprocity; repetitive or stereotyped motor behavior; improper coordinated language communication; and gastrointestinal distress. Underneath this clinical vignette, we microdissected and correlated a particular phenotype of the disease to functionally and anatomically related regions of the brain and bilateral body plan. The structural organization imposed here will not only identify a wide network of cells, but also specific clusters of genes targeting a particular symptom within behaviorally relevant regions. It is expected that such structural organization will help lay a solid foundation in psychiatry and point to more focused approaches to a deeper understanding of ASD and its individualized treatment (Table 2). Autism Spectrum Disorders can be managed with appropriate pharmacotherapy. Selective dopamine (DA) and serotonin (5HT) based drugs are the mainstay of pharmacological treatment [43,44]. Additional neurotransmitter systems (e.g., norepinephrine (NE) and histamine) are also drug targets. It is not known whether the listed drugs regulate epigenetic mechanisms to counteract autistic symptoms. What is broadly known is that atypical, typical and psychoactive drugs act on DA and 5HT signaling pathways within regions of the human brain (e.g., cortex and basal ganglia) that are behaviorally relevant to the pathophysiology of ASD. Attention Deficit Hyperactivity Disorder (ADHD) and Fragile X Syndrome are debilitating neuropsychiatric conditions commonly diagnosed in pediatric populations. Fragile X Syndrome is a monogenic inherited disease leading to cognitive disability and ASD.

[6] Human Dermal Fibroblast: A Promising Cellular Model to Study Biological Mechanisms of Major Depression and Antidepressant Drug Response

  • Authors: P. Mesdom, R. Colle, É. Lebigot, S. Trabado, Eric Deflesselle et al.
  • Year: 2020
  • Venue: Current Neuropharmacology
  • URL: https://www.semanticscholar.org/paper/79368e365458486de96794333613c12a6063bf54
  • DOI: 10.2174/1570159X17666191021141057
  • PMID: 31631822
  • PMCID: 7327943
  • Citations: 12
  • Summary: This review highlights the great and still underused potential of HDF, which stands out as a very promising tool in the understanding of MDD and AD mechanisms of action.
  • Evidence snippets:
  • Snippet 1 (score: 0.404) > Background: Human dermal fibroblasts (HDF) can be used as a cellular model relatively easily and without genetic engineering. Therefore, HDF represent an interesting tool to study several human diseases including psychiatric disorders. Despite major depressive disorder (MDD) being the second cause of disability in the world, the efficacy of antidepressant drug (AD) treatment is not sufficient and the underlying mechanisms of MDD and the mechanisms of action of AD are poorly understood. Objective The aim of this review is to highlight the potential of HDF in the study of cellular mechanisms involved in MDD pathophysiology and in the action of AD response. Methods The first part is a systematic review following PRISMA guidelines on the use of HDF in MDD research. The second part reports the mechanisms and molecules both present in HDF and relevant regarding MDD pathophysiology and AD mechanisms of action. Results HDFs from MDD patients have been investigated in a relatively small number of works and most of them focused on the adrenergic pathway and metabolism-related gene expression as compared to HDF from healthy controls. The second part listed an important number of papers demonstrating the presence of many molecular processes in HDF, involved in MDD and AD mechanisms of action. Conclusion The imbalance in the number of papers between the two parts highlights the great and still underused potential of HDF, which stands out as a very promising tool in our understanding of MDD and AD mechanisms of action

[7] Patient-Derived Induced Pluripotent Stem Cell Models for Phenotypic Screening in the Neuronal Ceroid Lipofuscinoses

  • Authors: A. Morsy, Angelica V Carmona, P. Trippier
  • Year: 2021
  • Venue: Molecules
  • URL: https://www.semanticscholar.org/paper/d510bd31c2c0312641423e0a06892605943439bc
  • DOI: 10.3390/molecules26206235
  • PMID: 34684815
  • PMCID: 8538546
  • Citations: 10
  • Influential citations: 2
  • Summary: An overview of available iPSC models for a number of different NCLs is provided and findings in these models that may spur target identification and drug development are highlighted.
  • Evidence snippets:
  • Snippet 1 (score: 0.404) > The NCLs encompasses a group of rare, fatal, pediatric neurodegenerative lysosomal storage disorders.Several gene mutations (CLN1-CLN8, CLN10-CLN14) can lead to NCL; however, a partial understanding of the function of the disease-associated proteins has hindered therapy development.Current treatment options are only symptomatic and focus on delaying progression.To date, there are only two clinically approved drugs, Brineuria, for the treatment of CLN2 disease, and Neurogene's recently approved gene therapy to treat CLN5 disease.Different organism models have become available for NCL disease research which have provided a myriad of important information about the protein function or dysfunction for each of the associated genes, possible disease mechanisms, and have enabled detailed preclinical studies and in a small number of cases, clinical trials. > Herein, we have highlighted the contributions of different disease models to NCL research, focusing on the established patient-derived iPSC phenotypic screening models.The ability of iPSCs to encompass the precise pattern of genetic variants, along with acquiring disease pathogenesis and phenotype makes them a more translational model compared to mice and eliminates the problem of species difference.However, compared to animal models, fewer iPSC models currently exist. > The brain is a complex network of many different cellular phenotypes and screening compounds in just one phenotype, i.e., neurons, is not a complete representation of the environment in the brain.While most studies in NCL patient-derived iPSCs employ either NPCs or neurons there are emerging studies looking at biochemical and pathophysiology effects of NCL on other cell phenotypes, one such example is the use of BMECs to model the blood-brain barrier that identified an impaired barrier phenotype in CLN3.Differentiation of iPSCs into other phenotypes including oligodendrocytes, astrocytes, microglia etc. is ongoing and results are expected in due course.These cell types will allow the construction of increasingly complex co-culture models that more readily represent the human brain and thus allow a greater understanding of the disease.

[8] Cardiomyocytes Derived from Induced Pluripotent Stem Cells as a Disease Model for Propionic Acidemia

  • Authors: Esmeralda Alonso-Barroso, B. Pérez, L. Desviat, E. Richard
  • Year: 2021
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/da649a0f04477c53b448c5ac5f873f8762235290
  • DOI: 10.3390/ijms22031161
  • PMID: 33503868
  • PMCID: 7865492
  • Citations: 16
  • Influential citations: 1
  • Summary: The novel results show that PA iPSC-cardiomyocytes represent a promising model for investigating the pathological mechanisms underlying PA cardiomyopathies, also serving as an ex vivo platform for therapeutic evaluation.
  • Evidence snippets:
  • Snippet 1 (score: 0.404) > The study of the mechanisms involved in disease physiopathology has been mainly performed using the hypomorphic PA mouse model that mimics the biochemical and clinical phenotype [5]. Using this model, bioenergetic failure, oxidative damage and deregulation of miRNAs induced by accumulating propionyl-CoA have been described as potential mechanisms contributing to PA physiopathology [6][7][8]. The limitations of animal models for the study of cardiac energy metabolism [9] and of the commonly available cellular human models such as fibroblasts, underline the importance of generating new relevant cell models to provide deeper insight into the underlying mechanisms of disease. The use of in vitro models with human cellular context is highly recommended and, in this sense, induced pluripotent stem cells (iPSCs) have certain advantages since they provide the genetic background of the patient and represent an unlimited source of biological material for the study of pathophysiology and treatment effectiveness [10]. We have previously generated an iPSC line from a PA patient with defects in the PCCA gene that showed full pluripotency, differentiation capacity and genetic stability [11]. > In the present study, we aimed to establish a platform that served as a disease model to study the cellular and molecular alterations operating in cardiac tissue affected by PA disease. We described the characterization of cardiomyocytes derived from the PCCA iPSC line (PCCA iPSC-CMs) and the analysis of specific pathways potentially involved in cardiac PA physiopathology.

[9] Therapies for Mitochondrial Disease: Past, Present, and Future

  • Authors: Megan Ball, Nicole J. Van Bergen, A. Compton, David R Thorburn, S. Rahman et al.
  • Year: 2025
  • Venue: Journal of Inherited Metabolic Disease
  • URL: https://www.semanticscholar.org/paper/196ee50a950f29bc4134cfb8fe6bdfa9a3a1468b
  • DOI: 10.1002/jimd.70065
  • PMID: 40714961
  • PMCID: 12301291
  • Citations: 2
  • Summary: The latest developments in the pursuit to identify effective treatments for mitochondrial disease are examined and the barriers impeding their success in translation to clinical practice are discussed.
  • Evidence snippets:
  • Snippet 1 (score: 0.403) > Mitochondrial disease is a diverse group of clinically and genetically complex disorders caused by pathogenic variants in nuclear or mitochondrial DNA‐encoded genes that disrupt mitochondrial energy production or other important mitochondrial pathways. Mitochondrial disease can present with a wide spectrum of clinical features and can often be difficult to recognize. These conditions can be devastating; however, for the majority, there is no targeted treatment. In the last 60 years, mitochondrial medicine has experienced significant evolution, moving from the pre‐molecular era to the Age of Genomics in which considerable gene discovery and advancement in our understanding of the pathophysiology of mitochondrial disease have been made. In the last decade, in response to the urgent need for effective treatments, a wide range of emerging therapies have been developed, driven by innovative approaches addressing both the genetic and cellular mechanisms underpinning the diseases. Emerging therapies include dietary intervention, small molecule therapies aimed to restore mitochondrial function, stem cell or liver transplantation, and gene or RNA‐based therapies. However, despite these advances, translation to clinical practice is complicated by the sheer genetic and clinical complexity of mitochondrial disease, difficulty in efficient and precise delivery of therapies to affected tissues, rarity of individual genetic conditions, lack of reliable biomarkers and clinically relevant outcome measures, and the dearth of natural history data. This review examines the latest developments in the pursuit to identify effective treatments for mitochondrial disease and discusses the barriers impeding their success in translation to clinical practice. While treatment for mitochondrial disease may be on the horizon, many challenges must be addressed before it can become a reality.

[10] Changes in Serum Proteomic Profiles at Different Stages of Pregnancy Toxemia in Goats

  • Authors: M. Uzti̇mür, C. N. Ünal, Gurler Akpinar
  • Year: 2025
  • Venue: Journal of Veterinary Internal Medicine
  • URL: https://www.semanticscholar.org/paper/4b9c488b5dbd65d7b26fd2ad9aed70e8c4b59942
  • DOI: 10.1111/jvim.70139
  • PMID: 40492724
  • PMCID: 12150350
  • Summary: Understanding the serum proteome profiles of goats with pregnancy toxemia might help identify the proteomes and pathways responsible for the development of this disease and improve diagnosis and treatment.
  • Evidence snippets:
  • Snippet 1 (score: 0.394) > The pathophysiology and progression of this disease are not fully understood. > Traditional biomedical research has focused on the analysis of single genes, proteins, metabolites, or metabolic pathways in diseases. This molecular reductionist approach is based on the assumption that identifying genetic variations and molecular components will lead to new treatments for diseases [13][14][15][16]. However, many diseases are complex and multifactorial, and in order to determine the phenotype of such diseases, it is necessary to understand the changes that occur in more than one gene, pathway, protein, or metabolite at the cellular, tissue, and organismal levels [17][18][19]. Therefore, in recent years, proteomics, as one field of multi-omics technologies, has helped in evaluating the complex pathogenetic mechanisms of different diseases from a broad perspective and has made substantial contributions [20,21]. In veterinary medicine, proteomic analysis of metabolic diseases such as ketosis [16], hypocalcemia [22], and fatty liver [23] in dairy cows has contributed valuable insights for the definition of new pathophysiological pathways and new diagnosis and treatment protocols for these diseases. The proteomic approach can contribute importantly to a broad and detailed understanding of the changes that occur at the organismal level associated with the increase in BHBA concentration in goats with pregnancy toxemia. Our aim was to evaluate the serum protein profiles of goats with SPT or CPT using proteomic techniques to determine the proteomic profiles of these animals and to identify the relevant pathophysiological mechanisms.

[11] Mitochondrial Dysfunction in Diabetes: Shedding Light on a Widespread Oversight

  • Authors: F. Iheagwam, A. J. Joseph, E. D. Adedoyin, Olawumi Toyin Iheagwam, Samuel Akpoyowvare Ejoh
  • Year: 2025
  • Venue: Pathophysiology
  • URL: https://www.semanticscholar.org/paper/dbf8042761c1a5fc50f8cd894cc498505abac7cb
  • DOI: 10.3390/pathophysiology32010009
  • PMID: 39982365
  • PMCID: 12077258
  • Citations: 24
  • Summary: This review aims to elucidate the complex link between mitochondrial dysfunction and diabetes, covering the spectrum of diabetes types, the role of mitochondria in insulin resistance, highlighting pathophysiological mechanisms, mitochondrial DNA damage, and altered mitochondrial biogenesis and dynamics.
  • Evidence snippets:
  • Snippet 1 (score: 0.394) > The landscape of DM research is continuously evolving, with emerging technologies and approaches offering new insights into the pathophysiology of the disease and potential therapeutic targets. Advancements in omics technologies, encompassing genomes, transcriptomics, proteomics, and metabolomics, have transformed the molecular mechanisms underlying DM [134]. High-throughput sequencing techniques enable comprehensive analysis of genetic variants, gene expression profiles, protein abundance, and metabolite levels associated with DM and its complications [135]. Single-cell omics approaches provide unprecedented resolution and granularity, allowing researchers to dissect cellular heterogeneity and identify novel cell types, subpopulations, and signalling pathways involved in DM pathogenesis. Integrating multi-omics data sets offers a systems-level perspective of DM, unravelling complex networks of molecular interactions and regulatory circuits underlying disease progression [136]. > In addition to omics technologies, advances in imaging modalities, such as MRI, PET, and optical imaging, enable non-invasive visualisation and quantification of metabolic, functional, and structural changes. Molecular imaging probes targeting specific biomarkers and metabolic pathways provide valuable insights into disease mechanisms and treatment responses in preclinical and clinical settings [85]. Despite significant progress in DM research, numerous unanswered questions and knowledge gaps persist, hindering the ability to develop effective prevention and treatment strategies. Key areas requiring further investigation include the role of epigenetics, environmental factors, and the microbiome in DM susceptibility and progression. Moreover, the interaction between environmental cues and genetic predisposition remains incompletely understood, highlighting the need for comprehensive multi-omics studies and large-scale epidemiological analyses to identify gene-environment interactions and modifiable risk factors for DM [137]. Furthermore, the heterogeneity of DM phenotypes and clinical outcomes poses a challenge for personalised medicine approaches, necessitating robust biomarkers and predictive models to stratify patients based on disease subtypes, prognosis, and treatment response [138].

[12] 18O-assisted dynamic metabolomics for individualized diagnostics and treatment of human diseases

  • Authors: E. Nemutlu, Song Zhang, N. Juranic, A. Terzic, S. Macura et al.
  • Year: 2012
  • Venue: Croatian Medical Journal
  • URL: https://www.semanticscholar.org/paper/880f053c7f060db4b990e447d0a22c4b69372ddb
  • DOI: 10.3325/cmj.2012.53.529
  • PMID: 23275318
  • PMCID: 3541579
  • Citations: 28
  • Summary: The potential use of dynamic phosphometabolomic platform for disease diagnostics currently under development at Mayo Clinic is described and discussed briefly.
  • Evidence snippets:
  • Snippet 1 (score: 0.391) > Living cells represent an integrated and interacting network of genes, transcripts, proteins, small signaling molecules, and metabolites that define cellular phenotype and function. Traditionally the focus of biomedical research was on individual genes, single protein targets, single metabolites, and metabolic or signaling pathways. This "molecular reductionist" paradigm was based on the assumption that identifying genetic variations and molecular components would lead to discovery of cures for human diseases. However, most of diseases are complex and multi-factorial and the disease phenotype is determined by the alterations of multiple genes, pathways, proteins and metabolites (at cellular, tissue, and organismal levels). Therefore, an integrated "omics" approach is more viable direction for uncovering alterations in metabolic networks, disease mechanisms, and mechanisms of drug effects. > Recent advent of large-scale metabolomics and fluxomic (metabolite dynamics and metabolic flux analysis) completed the "omics revolution" (Figure 1), where genomics, transcriptomics, proteomics, metabolomics, and fluxomics all together complement phenotype determination of living organism. Such integrated "omics" cascades provide a framework for advances in system and network biology, integrative physiology, and system medicine as well as system pharmacology and regenerative medicine. Noteworthy is the "reverse omic" approach or "metabolomicsinformed pharmacogenomics, " where discovery of specific metabolite changes have led to discovery of genetic alterations (2). Therefore, bringing new "omics" technologies to clinical practice will improve disease diagnostics and treatment by targeting drugs and procedures for each unique transcriptomic and metabolomic profiles.

[13] Sanfilippo Syndrome: Molecular Basis, Disease Models and Therapeutic Approaches

  • Authors: Noelia Benetó, L. Vilageliu, D. Grinberg, I. Canals
  • Year: 2020
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/80f8e4e1b87f7a316de9bd4e7fbd5ac14ed7af1c
  • DOI: 10.3390/ijms21217819
  • PMID: 33105639
  • PMCID: 7659972
  • Citations: 41
  • Influential citations: 2
  • Summary: An update in advances regarding the different and most successful therapeutic approaches that are currently under study to treat Sanfilippo syndrome patients and the potential of new tools such as induced pluripotent stem cells to be used for disease modeling and therapy development are discussed.
  • Evidence snippets:
  • Snippet 1 (score: 0.390) > With this review, we provided an overview of the molecular basis of Sanfilippo syndrome and a summary of the main animal and cellular models available to date, which can be used to test the different therapeutic approaches.For many years, animal models have been the gold-standard to investigate disease mechanisms and to develop and test therapeutic options.However, the fundamental differences between animal and human brain structure and development, as well as the higher complexity of human organs and cells, are major factors that should be taken into account when performing a study.Findings relevant in animal models might not be important in the context of human physiology, pointing out the importance of generating human cellular models to complement the existing animal models.In the last years, several Sanfilippo-iPSC lines have been established and, in combination with faster and improved protocols to generate relevant cell types in 2D and 3D cultures [125][126][127], will contribute to expand our understanding of the molecular and cellular mechanisms of the disease.In addition, iPSC-derived brain cells will be very useful in drug screening studies to identify possible drug candidates with the potential to treat human brain cells.To date, several potential therapies have been tested, however gene therapy seems to be the approach generating a better outcome.It is crucial to follow the ongoing clinical trials for this therapy considering the very promising results of previous studies.Nevertheless, efforts should also be made to develop and assess other possible approaches for the treatment of patients suffering from this devastating disorder.

[14] Common immunopathogenesis of central nervous system diseases: the protein-homeostasis-system hypothesis

  • Authors: Kyung-Yil Lee
  • Year: 2022
  • Venue: Cell & Bioscience
  • URL: https://www.semanticscholar.org/paper/2984270ae67451b93007040848d9694d19714c9f
  • DOI: 10.1186/s13578-022-00920-5
  • PMID: 36384812
  • PMCID: 9668226
  • Citations: 9
  • Influential citations: 1
  • Summary: This article proposes a common immunopathogenesis of CNS diseases, including prion diseases, Alzheimer’s disease, and genetic diseases, through the PHS hypothesis, which proposes that the immune systems in the host control those substances according to the size and biochemical properties of the substances.
  • Evidence snippets:
  • Snippet 1 (score: 0.390) > There are hundreds of genetic diseases of the CNS. The defective proteins in genetic disorders include structural proteins for neurotransmitter receptors and other receptors or ion channels on CNS cells, and proteins involved in enzymatic process, metabolism (transport), or signal transduction pathways in various communication systems [98]. Because a discussion of each genetic disease is beyond the scope of this review, only crucial points about the pathogenesis of genetic diseases are discussed. Singlegene defect diseases of the CNS can be caused by a defective product from a gene, i.e., a protein deficiency or a malfunctioning protein. In general, autosomal dominant genetic diseases are caused by structural protein defects, and autosomal recessive diseases are caused by defects in enzymatic proteins. However, certain genetic diseases that involve an enzymatic or multifunctional protein defect can induce structural cell injury during the natural course of the illness. > Patients with genetic diseases, including HD, familial JCD, GSS, and the genetic forms of AD and PD, show different clinical manifestations from other affected people in their family, including the time of onset of neurological symptoms, speed of progression of the disease, and prognosis, suggesting that phenotypes can vary even when the genotypes are identical. Likewise, similar phenotypes of CNS symptoms can be found in different genetic diseases. In genetic animal models, the phenotypes of single gene knockout can vary by strain in mice, and the clinical manifestations of a gene defect can differ between mice and humans, and mice null for some genes have also no observable phenotypic abnormalities compared with controls [99]. These findings suggest that default of a protein might be at least partly controlled by individual's control systems and that there might exist a similar immune/repair system against cell injury in genetic diseases. > The pathophysiology of most genetic diseases in the CNS is complex because any affected gene is associated with numerous proteins and their corresponding activations of genes and epigenetic changes that occur during disease processes. Thus, the use of a genetic marker for diagnosing or predicting a prognosis remains impractical in clinical settings [100].

[15] Copy number variants (CNVs): a powerful tool for iPSC-based modelling of ASD

  • Authors: D. Drakulić, S. Djurovic, Y. A. Syed, Sebastiano Trattaro, N. Caporale et al.
  • Year: 2020
  • Venue: Molecular Autism
  • URL: https://www.semanticscholar.org/paper/c6cac51304043d34c93254007adca11883e387cd
  • DOI: 10.1186/s13229-020-00343-4
  • PMID: 32487215
  • PMCID: 7268297
  • Citations: 23
  • Influential citations: 1
  • Summary: Here, it is examined how iPSCs derived from ASD patients with an associated CNV inform the understanding of the genetic and biological mechanisms underlying the aetiology of ASD.
  • Evidence snippets:
  • Snippet 1 (score: 0.388) > external factors. These complications hinder identification of the basic pathophysiological mechanisms that lead to ASD and hence hamper development of effective therapies. > Molecular and cellular analysis of human patients is generally prospective with data mostly derived from post-mortem tissue. As mentioned above, such studies are subject to the confounds of secondary effects and record the outcomes of underlying disease mechanism rather than directly probe the causative mechanisms. Animal models can be highly informative for the study of a basic mechanism; however, it is difficult to directly translate between observed patient phenotype and animal models. A particular weakness is the ability to capture the phenotypic variation across the patient population. > Human stem cell models offer an opportunity to directly study the molecular and cellular mechanisms of diseases. Key to this approach is the generation of human-induced pluripotent stem cells (iPSCs) derived from patient cells. These are generated by reprogramming of somatic cells into pluripotent stem cells from which many cell types can be differentiated, including neurons and glial cells. Importantly, they can be easily obtained in the clinic from fibroblasts (skin biopsies), keratinocytes (hair roots) [3], T lymphocytes (peripheral blood) [4,5] and exfoliated renal epithelial cells from urine samples [6,7]. Importantly, patient iPSCs enable the in vitro study of different cells types in isolation or co-culture in order to investigate cell function. Uniquely they can track the development profile of patient cell differentiation. More recently the capacity of iPSCs to form 3D organoids has opened up the possibility to investigate the interaction of multiple cell types in a more brain-like microenvironment. Methods for increasing reproducibility of brain organoid differentiation are improving substantially [8,9] and being exploited to mechanistically dissect the effect of genetic lesions causing ASD and ID [10][11][12], as well as the role of specific genes and molecular modules key to human-specific neuronal differentiation trajectories and pathophysiology [13]. > The major question is how to identify the relevant cellular phenotypes that converge on the common pathophysiological mechanisms underlying patient aeti

[16] Nasopharyngeal Carcinoma Signaling Pathway: An Update on Molecular Biomarkers

  • Authors: W. Tulalamba, T. Janvilisri
  • Year: 2012
  • Venue: International Journal of Cell Biology
  • URL: https://www.semanticscholar.org/paper/307cb9186444d9dad6e2e3b53763be0de76de186
  • DOI: 10.1155/2012/594681
  • PMID: 22500174
  • PMCID: 3303613
  • Citations: 93
  • Influential citations: 5
  • Summary: The molecular signaling pathways in the NPC are discussed for the holistic view of NPC development and progression and the important insights toward NPC pathogenesis may offer strategies for identification of novel biomarkers for diagnosis and prognosis.
  • Evidence snippets:
  • Snippet 1 (score: 0.388) > In the pregenomic eras, highly integrated and complex circuitry of molecular signaling in NPC pathogenesis was only partially understood. Over the past decade, the knowledge of the molecular mechanisms in NPC carcinogenesis has been rapidly accumulated. Dysregulation and abnormal protein expression of molecules in certain signaling pathways involved in cellular functions including proliferation, adhesion, survival, and apoptosis has been demonstrated in the NPC cells. Detailed information on the complex network in signaling pathway leading to a coordinated pattern of gene expression and regulation in NPC will undoubtedly provide important clues to develop novel prognostic and therapeutic strategies for this cancer. Refining molecular markers into clinically relevant assays may assist in the detection of NPC in asymptomatic patients, as well as stage classification and monitoring disease progression and treatments. Furthermore, selective regulation of particular proteins targeting cancer cell proliferation, invasion, and apoptosis is a hopeful prospect for future anticancer therapy that slow disease progression and improve survival.

[17] New therapeutic targets in rare genetic skeletal diseases

  • Authors: M. Briggs, Peter A. Bell, M. Wright, K. A. Pirog
  • Year: 2015
  • Venue: Expert Opinion on Orphan Drugs
  • URL: https://www.semanticscholar.org/paper/1363107f71ae6d2d60abca471cddf3da5d13644b
  • DOI: 10.1517/21678707.2015.1083853
  • PMID: 26635999
  • PMCID: 4643203
  • Citations: 37
  • Influential citations: 1
  • Summary: An overview of disease mechanisms that are shared amongst groups of different GSDs and potential therapeutic approaches that are under investigation are described to generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.
  • Evidence snippets:
  • Snippet 1 (score: 0.386) > proteins of the cartilage ECM such as type II collagen [50]. However, emerging knowledge suggests that the primary genetic defect may be less important than the cells' response to the expression of the mutant gene product [107]. Moreover, the largely overlooked response of a cell (i.e. chondrocyte) to the abnormal extracellular environment is also important for disease progression as illustrated by several GSDs discussed in this review. > It is important that 'omics'-based approaches and technologies are systematically applied to the study of rare GSDs so that definitive reference profiles and disease signatures are generated for each phenotype. These can then be used in a Systems Biology approach to identify both common and dissimilar pathological signatures and disease mechanisms. This approach is entirely dependent upon relevant in vitro and in vivo models (and also novel 'disease-mechanism phenocopies' [107]) for testing new diagnostic and prognostic tools and for determining the molecular mechanisms that underpin the pathophysiology so that effective therapeutic treatments can be developed and validated. This approach will eventually lead to personalized treatments and care strategies centred on shared disease mechanisms with the use of relevant biomarkers to monitor the efficacy of treatment and disease progression. > It is vital that all relevant stakeholders are involved from the outset in defining the appropriate outcomes of any potential therapeutic regime. The perceptions of a successful therapy can differ widely between the clinical academic community and the relevant patient-support groups and it is vital that there is engagement on all these issues. > In summary, the identification of causative genes and mutations for GSDs over the last 20 years, coupled with the generation and in-depth analysis of a plethora of relevant cell and mouse models, has derived new knowledge on disease mechanisms and suggested potential therapeutic targets. The fast-evolving hypothesis that clinically disparate diseases can share common disease mechanisms is a powerful concept that will generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.

[18] Probing disorders of the nervous system using reprogramming approaches

  • Authors: J. Ichida, E. Kiskinis
  • Year: 2015
  • Venue: The EMBO Journal
  • URL: https://www.semanticscholar.org/paper/07c84453351dfc9065d2f4870f5c534a96e63282
  • DOI: 10.15252/embj.201591267
  • PMID: 25925386
  • PMCID: 4474524
  • Citations: 4
  • Summary: Tables listing the various human neural cell types that can be generated and the neurological disease modeling studies that have been reported are presented, the current state of the field is described, important breakthroughs are highlighted and the next steps and future challenges are discussed.
  • Evidence snippets:
  • Snippet 1 (score: 0.384) > Neurological disorders including schizophrenia, ALS, PD, FTD and epilepsy are often characterized by a profound clinical and genetic heterogeneity, suggesting that they might represent a syndrome rather than a single nosological entity (Fanous & Kendler, 2005;Tremblay et al, 2013;Jeste & Geschwind, 2014). The variable combination of positive and negative symptoms in schizophrenia, the variable degree of upper and lower motor neuron dysfunction in ALS, the heterogeneity of cognitive symptoms in PD, the variable rate of progression in FTD and the differential response to anti-epileptic treatments in epileptic syndromes are some examples of the clinical diversity in neurological disorders. In addition, genetic studies in ALS, for example, have demonstrated that the disease can be caused by mutations in genes that encode proteins involved in diverse cellular functions ranging from RNA metabolism, vesicle transport, cytoskeletal homeostasis and the processing of unfolded proteins (Cleveland & Rothstein, 2001;Pasinelli & Brown, 2006;Sreedharan & Brown, 2013). While progress has been achieved in terms of genetic taxonomy, pathological stratification and the classification of patients based on their clinical presentation, little is known about how similar or different patients are, in terms of the molecular pathways that mediate their disease processes. Reprogramming technologies can be used to develop in vitro models of genetic and sporadic disease cases and effectively stratify patients, based on (i) the neuronal subtype that exhibits a disease-associated phenotype and (ii) the pathway that leads to this phenotype in each case (Fig 3). This approach may lead to the identification of overlapping disease mechanisms that will be broadly relevant and represent the best therapeutic opportunities, or toward a personalized approach to clinical trials and therapeutic treatments.

[19] Modeling psychiatric disorders: from genomic findings to cellular phenotypes

  • Authors: Anna Falk, Vivi M. Heine, A. Harwood, Patrick F. Sullivan, M. Peitz et al.
  • Year: 2016
  • Venue: Molecular Psychiatry
  • URL: https://www.semanticscholar.org/paper/235b41240d78140de7ab06a3ad8a7d0b1bdff1a5
  • DOI: 10.1038/mp.2016.89
  • PMID: 27240529
  • PMCID: 4995546
  • Citations: 77
  • Influential citations: 2
  • Summary: The challenges for modeling of psychiatric disorders, potential solutions and how iPSC technology can be used to develop an analytical framework for the evaluation and therapeutic manipulation of fundamental disease processes are critically reviewed.
  • Evidence snippets:
  • Snippet 1 (score: 0.384) > The key challenge for iPSC-based disease modeling is to identify one or more relevant cellular phenotypes that accurately represent the disease pathophysiology. Increasing numbers of reports have demonstrated that for many diseases specific pathophysiology can be captured in human iPSC-based disease models. These range from cardiovascular disease, 44,45 cancer, 46,47 ocular disease, 48,49 diabetes mellitus 50,51 and neurological disorders of the brain. 52,53 Can the same approach be applied to complex psychiatric disorders? > The problem is that almost all psychiatric disorders are characterized by clinical signs and symptoms, but lack independent verification from objective biomarkers. Thus, how might these clinical phenotypes manifest themselves in terms of cell behavior? The identity of robust cellular 'readouts', which typify any psychiatric disorder, is a crucial unsolved problem and an area of intense study 54 (Table 2). When satisfactorily answered, this will herald a new degree of biological objectivity and quantification for the study of psychiatric disorders. > The aim is to find a single or small number of cell phenotypes or parameters that strongly associate with psychiatric disorders, and establish a cellular profile characteristic of cells derived from the general patient population. Although a consensus set of cellular phenotypes for psychiatric disorder is yet to be established, we can define some of their desired characteristics. First, cellular phenotypes have to relate to the biological pathways identified by genetics. Second, although there are many risk genes in disparate biological pathways, at some level, phenotypes should converge onto a much smaller grouping. Third, phenotypes need to be quantifiable. Finally, to be useful for drug development cellular phenotypes should be reversed by pharmacological treatment, although not necessarily by drugs in current use. > Although human iPSC-based approaches underrepresent the complexity of the human central nervous system, cellular phenotypes are likely to lie more proximal to molecular disease mechanisms than phenotypes seen at the level of a tissue or organism, 55 and thus may bypass compensatory homeostatic (2) Gene expression profiles of SCZ human iPSC neurons identified altered expression of many components of the cyclic AMP and WNT signaling pathways. > (3

[20] Transcriptional profiling of Hutchinson-Gilford progeria patients identifies primary target pathways of progerin

  • Authors: Sandra Vidak, Sohyoung Kim, Tom Misteli
  • Year: 2026
  • Venue: Nucleus
  • URL: https://www.semanticscholar.org/paper/4bd99b0875508364d8672b6da5a50d024d485a53
  • DOI: 10.1080/19491034.2025.2611484
  • PMID: 41489464
  • PMCID: 12773485
  • Summary: To probe the clinical relevance of previously implicated cellular pathways and to address the extent of gene expression heterogeneity between patients, transcriptomic analysis of a comprehensive set of HGPS patients finds misexpression of several cellular pathways, including multiple signaling pathways, the UPR and mesodermal cell fate specification.
  • Evidence snippets:
  • Snippet 1 (score: 0.379) > Oxidative stress represents another key pathogenic mechanism in HGPS, as impaired NRF2 activity or increased reactive oxygen species (ROS) levels are sufficient to recapitulate HGPSassociated phenotypes [17,32,60]. Collectively, these findings underscore the multifactorial nature of HGPS pathogenesis, implicating interconnected signaling cascades involved in inflammation, oxidative stress, proteostasis, and vascular remodeling. Reassuringly, our findings indicate that many of the major pathways that have been described to contribute to HGPS phenotypes in mouse and cellular disease models are also misregulated in progeria patients, and targeting these pathways may provide therapeutic avenues to mitigate disease severity and improve outcomes in HGPS. > Although individuals with HGPS typically exhibit a characteristic set of clinical features, such as craniofacial abnormalities, growth retardation, and cardiovascular complications, there is notable variability in the age of onset, severity, and progression of symptoms between patients [7,9]. At the cellular level, HGPS is associated with several hallmark abnormalities, including nuclear envelope defects, decreased expression of several nuclear proteins and epigenetic marks, mitochondrial dysfunction, and increased cellular senescence [1,11,30,31,61]. These cellular phenotypes also exhibit considerable variation between patients, possibly contributing to differences in clinical outcomes. Our results indicate that even though some degree of transcriptional heterogeneity between the individual patients exists, the majority of patients exhibit misregulation of a set of shared pathways, suggesting that these pathways are universal driver mechanisms in HGPS. Further work is needed to understand the molecular and genetic factors that underlie inter-individual variability in disease expression and progression. > A limitation of pathway analysis of HGPS patient samples is to distinguish the pathways which are directly targeted by the disease-causing progerin protein and the emergence of adaptive secondary response pathways during progression of the disease in patients during their lifetime. The same caveat applies to the use of cell-based models used in the study of HGPS disease mechanisms.

Notes

  • This provider combines search_papers_by_relevance with snippet_search.
  • No synthesis or second-stage model call is performed.