Complex I Deficiency Module

Metabolism Module complex_i_deficiency 21 disorders Pathograph 4

A conserved mechanism module representing isolated mitochondrial complex I (NADH:ubiquinone oxidoreductase) deficiency, the most common cause of mitochondrial disease in childhood. Complex I is the largest respiratory-chain complex, and two mechanistically distinct lesions converge on the same functional failure: loss of a structural subunit or an assembly factor prevents the holoenzyme from being *built* (the MC1DN series), while loss of a chaperone that exchanges oxidatively damaged subunits prevents an assembled holoenzyme from being *repaired* (DNAJC30/arLHON). Either way the cell cannot oxidize NADH and transfer electrons to ubiquinone, collapsing proton pumping and oxidative ATP synthesis, forcing anaerobic glycolysis (lactic acidosis) and producing energy failure in high-demand tissues - brain and basal ganglia (Leigh syndrome), retinal ganglion cells and optic nerve (optic atrophy/LHON), heart, and skeletal muscle. The module captures the gene-agnostic core shared across the many nuclear and mtDNA causes; conforming entries substitute the specific gene, the affected biogenesis or repair sub-step, and the organ tropism. Key conformance target: `complex_i_deficiency#Impaired NADH:Ubiquinone Oxidoreduction and ATP Synthesis`. Deliberately complementary to `complex_iv_assembly_deficiency` (the same chain one complex downstream, at cytochrome c oxidase) and to `mitochondrial_dysfunction` (the aging-hallmark module, which covers age-associated bioenergetic decline rather than a monogenic respiratory-chain lesion).

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Pathophysiology Nodes

4 shared nodes are defined in this module.

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Cell Types

No cell types are annotated for this module.

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Biological Processes

mitochondrial respiratory chain complex I assembly GO:0032981 ↓ DECREASED mitochondrial electron transport, NADH to ubiquinone GO:0006120 ↓ DECREASED mitochondrial ATP synthesis coupled electron transport GO:0042775 ↓ DECREASED lactate biosynthetic process GO:0019249 ↑ INCREASED aerobic respiration GO:0009060 ↓ DECREASED

Notes

This is a mechanism module, not a specific disease. Disorder entries reference individual nodes via conforms_to (e.g. "complex_i_deficiency#Impaired NADH:Ubiquinone Oxidoreduction and ATP Synthesis"). Scope decision - assembly AND repair. The trigger node is deliberately scoped wider than its complex IV sibling, which is named for assembly alone. DNAJC30/arLHON is explicitly NOT an assembly defect: the Leber-like_Hereditary_Optic_Neuropathy_Autosomal_Recessive_1 entry states that DNAJC30 "services complex I after it has been built" and that the disease is one "of impaired repair rather than of impaired construction". Naming this module `complex_i_assembly_deficiency` would therefore have excluded it, even though MONDO places it under MONDO:0100223. The two branches are kept as one trigger node because they converge on a single rate-limiting step - a catalytically incompetent complex I - which is the module bar. Sub-step substitutions: core/accessory structural subunits (NDUFS1-8, NDUFV1-2, NDUFA/NDUFB families, NDUFC2); assembly factors (NDUFAF1-8, TIMMDC1, FOXRED1, NUBPL, ACAD9); subunit-exchange repair (DNAJC30); mtDNA-encoded subunits (MT-ND1-6). Tissue substitutions: basal ganglia/brainstem and Leigh syndrome (NDUFS4, NDUFAF4, NDUFC2); retinal ganglion cell and optic nerve (DNAJC30, NDUFA12, NDUFS2); heart (NDUFB7, ACAD9); skeletal muscle. MONDO anchoring: complex I carries the full three-term set that complex IV lacks - MONDO:0100133 (pan-form) over MONDO:0100223 (nuclear type) and MONDO:0100134 (mitochondrial type). This is recorded in the complex_iv_assembly_deficiency module notes (verified 2026-08-01, issue #3544). Curation guardrail - do NOT create a "Complex I Deficiency" Disease entry for this module. Whether the nuclear MC1DN number series should be collapsed, covered by a Grouping mapped to MONDO:0100223, or kept per-number is an OPEN nosology question under discussion in issue #9864, where the ruling is explicitly reserved for a human curator. This module takes no position on it: it factors out the shared mechanism and moves no entity boundary. A "Mitochondrial Complex I Deficiency" Grouping over this module, mirroring "Mitochondrial Complex IV Deficiency", is the natural follow-up once #9864 is settled.

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Used By Disorder Entries

Leber-like Hereditary Optic Neuropathy, Autosomal Recessive 1 via DNAJC30 Loss of Function → Complex I Biogenesis or Repair Failure , Reduced Complex I-Dependent Respiration and ATP Output → Impaired NADH:Ubiquinone Oxidoreduction and ATP Synthesis , Subacute Necrotizing Encephalopathy of Basal Ganglia and Brainstem → High-Energy Tissue Dysfunction

Mitochondrial Complex I Deficiency Nuclear Type 19 via FOXRED1 Assembly Chaperone Loss of Function → Complex I Biogenesis or Repair Failure , Isolated Complex I Deficiency → Impaired NADH:Ubiquinone Oxidoreduction and ATP Synthesis , Lactate Accumulation → Lactic Acidosis and Metabolic Decompensation , Neuronal Energy Failure and Grey Matter Degeneration → High-Energy Tissue Dysfunction

Mitochondrial Complex I Deficiency Nuclear Type 21 via NUBPL Loss of Function → Complex I Biogenesis or Repair Failure , Mitochondrial Complex I Deficiency → Impaired NADH:Ubiquinone Oxidoreduction and ATP Synthesis , Cerebellar and Deep White Matter Degeneration → High-Energy Tissue Dysfunction

Mitochondrial Complex I Deficiency Nuclear Type 23 via NDUFA12 Loss of Function → Complex I Biogenesis or Repair Failure , Reduced NADH Dehydrogenase Activity → Impaired NADH:Ubiquinone Oxidoreduction and ATP Synthesis , Basal Ganglia Vulnerability → High-Energy Tissue Dysfunction

Mitochondrial Complex I Deficiency Nuclear Type 3 via NDUFS7 Loss of Function → Complex I Biogenesis or Repair Failure , Defective NADH-to-Ubiquinone Electron Transfer → Impaired NADH:Ubiquinone Oxidoreduction and ATP Synthesis , Basal Ganglia and Brainstem Vulnerability → High-Energy Tissue Dysfunction

Mitochondrial Complex I Deficiency Nuclear Type 31 via TIMMDC1 Poison-Exon Inclusion → Complex I Biogenesis or Repair Failure , Isolated Complex I Deficiency → Impaired NADH:Ubiquinone Oxidoreduction and ATP Synthesis , Central and Peripheral Neurodegeneration → High-Energy Tissue Dysfunction

Mitochondrial Complex I Deficiency, Nuclear Type 1 via Biallelic NDUFS4 Loss-of-Function Variant → Complex I Biogenesis or Repair Failure , Isolated Complex I Deficiency → Impaired NADH:Ubiquinone Oxidoreduction and ATP Synthesis , Symmetric Necrotizing Brainstem and Basal Ganglia Lesions → High-Energy Tissue Dysfunction

Mitochondrial Complex I Deficiency, Nuclear Type 11 via NDUFAF1 Loss of Function → Complex I Biogenesis or Repair Failure , Neural Bioenergetic Failure → High-Energy Tissue Dysfunction

Mitochondrial Complex I Deficiency, Nuclear Type 12 via NDUFA1 Loss of Function → Complex I Biogenesis or Repair Failure , Impaired NADH-Ubiquinone Oxidoreduction and OXPHOS Deficit → Impaired NADH:Ubiquinone Oxidoreduction and ATP Synthesis , Mitochondrial Encephalomyopathy → High-Energy Tissue Dysfunction

Mitochondrial Complex I Deficiency, Nuclear Type 13 via Biallelic NDUFA2 Variant → Complex I Biogenesis or Repair Failure , Bioenergetic Failure in Brain and Heart → High-Energy Tissue Dysfunction

Mitochondrial Complex I Deficiency, Nuclear Type 14 via Biallelic NDUFA11 Splice-Site Variant → Complex I Biogenesis or Repair Failure , Isolated Complex I Deficiency → Impaired NADH:Ubiquinone Oxidoreduction and ATP Synthesis , Cytosolic Redox Shift and Lactate Accumulation → Lactic Acidosis and Metabolic Decompensation , Energy Deficit in Heart and Brain → High-Energy Tissue Dysfunction

Mitochondrial Complex I Deficiency, Nuclear Type 15 via Biallelic NDUFAF4 Variant → Complex I Biogenesis or Repair Failure , Neonatal and Infantile Encephalopathy with Lactic Acidosis → High-Energy Tissue Dysfunction

Mitochondrial Complex I Deficiency, Nuclear Type 2 via NDUFS8 Loss of Function → Complex I Biogenesis or Repair Failure , Impaired NADH-Ubiquinone Oxidoreduction and OXPHOS Deficit → Impaired NADH:Ubiquinone Oxidoreduction and ATP Synthesis , Leigh Syndrome and Mitochondrial Encephalomyopathy → High-Energy Tissue Dysfunction

Mitochondrial Complex I Deficiency, Nuclear Type 24 via NDUFB9 Variant → Complex I Biogenesis or Repair Failure

Mitochondrial Complex I Deficiency, Nuclear Type 26 via Biallelic NDUFA9 Missense Variants → Complex I Biogenesis or Repair Failure , Isolated Complex I Deficiency → Impaired NADH:Ubiquinone Oxidoreduction and ATP Synthesis , Striatal and Brainstem Energy Failure → High-Energy Tissue Dysfunction

Mitochondrial Complex I Deficiency, Nuclear Type 32 via Biallelic NDUFB8 Loss-of-Function Variants → Complex I Biogenesis or Repair Failure , Impaired NADH-Linked Oxidative Phosphorylation → Impaired NADH:Ubiquinone Oxidoreduction and ATP Synthesis , Cytosolic Redox Shift and Lactate Overproduction → Lactic Acidosis and Metabolic Decompensation , Bioenergetic Failure of Basal Ganglia and Brainstem Neurons → High-Energy Tissue Dysfunction

Mitochondrial Complex I Deficiency, Nuclear Type 33 via Biallelic NDUFA6 Variant → Complex I Biogenesis or Repair Failure , Impaired Mitochondrial Respiration → Impaired NADH:Ubiquinone Oxidoreduction and ATP Synthesis , Lactate Accumulation and Metabolic Acidosis → Lactic Acidosis and Metabolic Decompensation , White Matter and Deep Grey Matter Injury → High-Energy Tissue Dysfunction

Mitochondrial Complex I Deficiency, Nuclear Type 34 via Biallelic NDUFAF8 Variant → Complex I Biogenesis or Repair Failure , Retinal Ganglion Cell and Optic Nerve Degeneration → High-Energy Tissue Dysfunction

Mitochondrial Complex I Deficiency, Nuclear Type 36 via Biallelic NDUFC2 Variant → Complex I Biogenesis or Repair Failure , Impaired Mitochondrial Respiration → Impaired NADH:Ubiquinone Oxidoreduction and ATP Synthesis , Lactate and Pyruvate Accumulation → Lactic Acidosis and Metabolic Decompensation , Basal Ganglia, Thalamic and Brainstem Injury → High-Energy Tissue Dysfunction

Mitochondrial Complex I Deficiency, Nuclear Type 39 via Biallelic Intronic NDUFB7 Variant → Complex I Biogenesis or Repair Failure , Isolated Complex I Enzyme Deficiency → Impaired NADH:Ubiquinone Oxidoreduction and ATP Synthesis , Bioenergetic Failure in High-Demand Tissues → High-Energy Tissue Dysfunction

Mitochondrial Complex I Deficiency, Nuclear Type 6 via NDUFS2 Loss of Function → Complex I Biogenesis or Repair Failure , Isolated Complex I Deficiency and Bioenergetic Failure → Impaired NADH:Ubiquinone Oxidoreduction and ATP Synthesis , Lactic Acidosis and Multisystem Metabolic Decompensation → Lactic Acidosis and Metabolic Decompensation , Progressive Encephalopathy of the Leigh Syndrome Spectrum → High-Energy Tissue Dysfunction

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Pathograph

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Pathophysiology

Complex I Biogenesis or Repair Failure

trigger

Pathogenic variants in a complex I structural subunit, an assembly factor, or a subunit-exchange chaperone prevent a catalytically competent NADH:ubiquinone oxidoreductase from being assembled or, once assembled, from being maintained. Complex I comprises 44 subunits and requires at least 14 assembly factors, so a large and genetically heterogeneous set of genes converges on this step. Conforming entries substitute either the biogenesis branch (the MC1DN series) or the repair branch (DNAJC30).

mitochondrial respiratory chain complex I assembly GO:0032981 ↓ DECREASED

Used by disorders

Leber-like Hereditary Optic Neuropathy, Autosomal Recessive 1 as DNAJC30 Loss of Function

Mitochondrial Complex I Deficiency Nuclear Type 19 as FOXRED1 Assembly Chaperone Loss of Function

Mitochondrial Complex I Deficiency Nuclear Type 21 as NUBPL Loss of Function

Mitochondrial Complex I Deficiency Nuclear Type 23 as NDUFA12 Loss of Function

Mitochondrial Complex I Deficiency Nuclear Type 3 as NDUFS7 Loss of Function

Mitochondrial Complex I Deficiency Nuclear Type 31 as TIMMDC1 Poison-Exon Inclusion

Mitochondrial Complex I Deficiency, Nuclear Type 1 as Biallelic NDUFS4 Loss-of-Function Variant

Mitochondrial Complex I Deficiency, Nuclear Type 11 as NDUFAF1 Loss of Function

Mitochondrial Complex I Deficiency, Nuclear Type 12 as NDUFA1 Loss of Function

Mitochondrial Complex I Deficiency, Nuclear Type 13 as Biallelic NDUFA2 Variant

Mitochondrial Complex I Deficiency, Nuclear Type 14 as Biallelic NDUFA11 Splice-Site Variant

Mitochondrial Complex I Deficiency, Nuclear Type 15 as Biallelic NDUFAF4 Variant

Mitochondrial Complex I Deficiency, Nuclear Type 2 as NDUFS8 Loss of Function

Mitochondrial Complex I Deficiency, Nuclear Type 24 as NDUFB9 Variant

Mitochondrial Complex I Deficiency, Nuclear Type 26 as Biallelic NDUFA9 Missense Variants

Mitochondrial Complex I Deficiency, Nuclear Type 32 as Biallelic NDUFB8 Loss-of-Function Variants

Mitochondrial Complex I Deficiency, Nuclear Type 33 as Biallelic NDUFA6 Variant

Mitochondrial Complex I Deficiency, Nuclear Type 34 as Biallelic NDUFAF8 Variant

Mitochondrial Complex I Deficiency, Nuclear Type 36 as Biallelic NDUFC2 Variant

Mitochondrial Complex I Deficiency, Nuclear Type 39 as Biallelic Intronic NDUFB7 Variant

Mitochondrial Complex I Deficiency, Nuclear Type 6 as NDUFS2 Loss of Function

Downstream

Impaired NADH:Ubiquinone Oxidoreduction and ATP Synthesis Without a competent holoenzyme, electron entry into the respiratory chain at complex I cannot proceed.

Show evidence (3 references)

PMID:32969598 SUPPORT BACKGROUND Other

"complex I comprises 44 different subunits with at least 14 assembly factors required for its biosynthesis"

Establishes the scale of the biogenesis machinery whose failure defines this node.

PMID:22200994 SUPPORT Human Clinical

"Causative mutations were detected in 16 genes, 15 of which had previously been associated with complex I deficiency: three mitochondrial DNA genes encoding complex I subunits, two mitochondrial tRNA genes and nuclear DNA genes encoding six complex I subunits and four assembly factors."

Documents the genetic heterogeneity - subunits and assembly factors across both genomes - converging on this biogenesis-failure step.

PMID:33465056 SUPPORT In Vitro

"DNAJC30 is a chaperone protein needed for the efficient exchange of complex I subunits exposed to reactive oxygen species and integral to a mitochondrial complex I repair mechanism"

Establishes the repair branch of this node - subunit exchange in an already-assembled complex I, mechanistically distinct from an assembly defect.

Impaired NADH:Ubiquinone Oxidoreduction and ATP Synthesis

central effector

Loss of functional complex I blocks oxidation of NADH and transfer of electrons to ubiquinone, and abolishes the associated proton pumping across the inner mitochondrial membrane, reducing the proton-motive force and oxidative ATP synthesis. This is the rate-limiting step every conforming disorder funnels through, whatever the upstream lesion.

mitochondrial electron transport, NADH to ubiquinone GO:0006120 ↓ DECREASED mitochondrial ATP synthesis coupled electron transport GO:0042775 ↓ DECREASED

Used by disorders

Leber-like Hereditary Optic Neuropathy, Autosomal Recessive 1 as Reduced Complex I-Dependent Respiration and ATP Output

Mitochondrial Complex I Deficiency Nuclear Type 19 as Isolated Complex I Deficiency

Mitochondrial Complex I Deficiency Nuclear Type 21 as Mitochondrial Complex I Deficiency

Mitochondrial Complex I Deficiency Nuclear Type 23 as Reduced NADH Dehydrogenase Activity

Mitochondrial Complex I Deficiency Nuclear Type 3 as Defective NADH-to-Ubiquinone Electron Transfer

Mitochondrial Complex I Deficiency Nuclear Type 31 as Isolated Complex I Deficiency

Mitochondrial Complex I Deficiency, Nuclear Type 1 as Isolated Complex I Deficiency

Mitochondrial Complex I Deficiency, Nuclear Type 12 as Impaired NADH-Ubiquinone Oxidoreduction and OXPHOS Deficit

Mitochondrial Complex I Deficiency, Nuclear Type 14 as Isolated Complex I Deficiency

Mitochondrial Complex I Deficiency, Nuclear Type 2 as Impaired NADH-Ubiquinone Oxidoreduction and OXPHOS Deficit

Mitochondrial Complex I Deficiency, Nuclear Type 26 as Isolated Complex I Deficiency

Mitochondrial Complex I Deficiency, Nuclear Type 32 as Impaired NADH-Linked Oxidative Phosphorylation

Mitochondrial Complex I Deficiency, Nuclear Type 33 as Impaired Mitochondrial Respiration

Mitochondrial Complex I Deficiency, Nuclear Type 36 as Impaired Mitochondrial Respiration

Mitochondrial Complex I Deficiency, Nuclear Type 39 as Isolated Complex I Enzyme Deficiency

Mitochondrial Complex I Deficiency, Nuclear Type 6 as Isolated Complex I Deficiency and Bioenergetic Failure

Downstream

Lactic Acidosis and Metabolic Decompensation Failure of oxidative ATP synthesis forces a shift to anaerobic glycolysis.
High-Energy Tissue Dysfunction The bioenergetic deficit is most damaging in tissues with high oxidative demand.

Show evidence (2 references)

PMID:33502047 SUPPORT In Vitro

"The detected variant resulted in a significant reduction of the NDUFB7 protein and reduced complex I activity."

Links a subunit lesion directly to measured loss of complex I catalytic activity, the function this node represents.

PMID:33465056 SUPPORT In Vitro

"we measured reduced turnover of specific complex I N-module subunits and a resultant impairment of complex I function"

Shows the repair branch converging on the same loss of complex I function as the assembly branch.

Lactic Acidosis and Metabolic Decompensation

consequence

The shift to anaerobic glycolysis increases pyruvate-to-lactate conversion, elevating lactate in blood and cerebrospinal fluid; metabolic stressors can precipitate acute decompensation.

lactate biosynthetic process GO:0019249 ↑ INCREASED

Used by disorders

Mitochondrial Complex I Deficiency Nuclear Type 19 as Lactate Accumulation

Mitochondrial Complex I Deficiency, Nuclear Type 14 as Cytosolic Redox Shift and Lactate Accumulation

Mitochondrial Complex I Deficiency, Nuclear Type 32 as Cytosolic Redox Shift and Lactate Overproduction

Mitochondrial Complex I Deficiency, Nuclear Type 33 as Lactate Accumulation and Metabolic Acidosis

Mitochondrial Complex I Deficiency, Nuclear Type 36 as Lactate and Pyruvate Accumulation

Mitochondrial Complex I Deficiency, Nuclear Type 6 as Lactic Acidosis and Multisystem Metabolic Decompensation

Show evidence (2 references)

PMID:32969598 SUPPORT Human Clinical

"key diagnostic findings are developmental regression, elevated lactate and characteristic neuroimaging abnormalities"

Documents elevated lactate as a core diagnostic finding in complex I-deficient Leigh syndrome.

PMID:33502047 SUPPORT Human Clinical

"postpartum hypertrophic cardiomyopathy, lactic acidosis, encephalopathy, and a severe complex I defect with fatal outcome"

A worked case linking a complex I defect to lactic acidosis and metabolic decompensation.

High-Energy Tissue Dysfunction

consequence

Energy failure manifests in high-demand tissues, producing the organ-specific phenotypes of complex I deficiency: subacute necrotizing encephalomyelopathy of the basal ganglia and brainstem (Leigh syndrome), retinal ganglion cell loss and optic atrophy (including arLHON), cardiomyopathy, and myopathy. Conforming entries substitute the dominant tissue and its cell types.

aerobic respiration GO:0009060 ↓ DECREASED

Used by disorders

Leber-like Hereditary Optic Neuropathy, Autosomal Recessive 1 as Subacute Necrotizing Encephalopathy of Basal Ganglia and Brainstem

Mitochondrial Complex I Deficiency Nuclear Type 19 as Neuronal Energy Failure and Grey Matter Degeneration

Mitochondrial Complex I Deficiency Nuclear Type 21 as Cerebellar and Deep White Matter Degeneration

Mitochondrial Complex I Deficiency Nuclear Type 23 as Basal Ganglia Vulnerability

Mitochondrial Complex I Deficiency Nuclear Type 3 as Basal Ganglia and Brainstem Vulnerability

Mitochondrial Complex I Deficiency Nuclear Type 31 as Central and Peripheral Neurodegeneration

Mitochondrial Complex I Deficiency, Nuclear Type 1 as Symmetric Necrotizing Brainstem and Basal Ganglia Lesions

Mitochondrial Complex I Deficiency, Nuclear Type 11 as Neural Bioenergetic Failure

Mitochondrial Complex I Deficiency, Nuclear Type 12 as Mitochondrial Encephalomyopathy

Mitochondrial Complex I Deficiency, Nuclear Type 13 as Bioenergetic Failure in Brain and Heart

Mitochondrial Complex I Deficiency, Nuclear Type 14 as Energy Deficit in Heart and Brain

Mitochondrial Complex I Deficiency, Nuclear Type 15 as Neonatal and Infantile Encephalopathy with Lactic Acidosis

Mitochondrial Complex I Deficiency, Nuclear Type 2 as Leigh Syndrome and Mitochondrial Encephalomyopathy

Mitochondrial Complex I Deficiency, Nuclear Type 26 as Striatal and Brainstem Energy Failure

Mitochondrial Complex I Deficiency, Nuclear Type 32 as Bioenergetic Failure of Basal Ganglia and Brainstem Neurons

Mitochondrial Complex I Deficiency, Nuclear Type 33 as White Matter and Deep Grey Matter Injury

Mitochondrial Complex I Deficiency, Nuclear Type 34 as Retinal Ganglion Cell and Optic Nerve Degeneration

Mitochondrial Complex I Deficiency, Nuclear Type 36 as Basal Ganglia, Thalamic and Brainstem Injury

Mitochondrial Complex I Deficiency, Nuclear Type 39 as Bioenergetic Failure in High-Demand Tissues

Mitochondrial Complex I Deficiency, Nuclear Type 6 as Progressive Encephalopathy of the Leigh Syndrome Spectrum

Show evidence (2 references)

PMID:32969598 SUPPORT Human Clinical

"Leigh syndrome is a progressive neurodegenerative disorder, most commonly observed in paediatric mitochondrial disease, and is often associated with pathogenic variants in complex I structural subunits or assembly factors resulting in isolated respiratory chain complex I deficiency."

Establishes the brain/basal-ganglia tropism (Leigh syndrome) as the dominant high-energy-tissue outcome of complex I deficiency.

PMID:22200994 SUPPORT Human Clinical

"Mitochondrial complex I deficiency is the most common cause of mitochondrial disease in childhood."

Supports the clinical weight of this module's terminal node in paediatric mitochondrial disease.