FASTKD5-related COX deficiency (mitochondrial complex IV deficiency nuclear type 24, MC4DN24) is a rare autosomal recessive nuclear form of cytochrome c oxidase (COX, Complex IV) deficiency caused by biallelic variants in FASTKD5. Unlike most nuclear-type COX deficiencies — which arise from defective assembly factors, metallochaperones, or structural subunits — FASTKD5 encodes a mitochondrial protein essential for processing the polycistronic primary mitochondrial transcript at non-canonical cleavage sites, a step required for maturation of the mtDNA-encoded mRNAs. Loss of FASTKD5 impairs production of the mature COX1 mRNA, reducing translation of the core catalytic subunit COX1, which in turn stalls Complex IV assembly and lowers cytochrome c oxidase enzymatic activity. The disorder presents as early- to late-onset Leigh syndrome, a progressive neurodegenerative disease with lesions in the brainstem and basal ganglia, and the magnitude of the molecular deficiency correlates with clinical severity. It conforms to the conserved Complex IV biogenesis-failure mechanism, with the primary lesion situated at the mitochondrial mRNA-processing step upstream of COX1 translation and holoenzyme assembly.
Ask a research question about FASTKD5-Related COX Deficiency. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).
Do not include personal health information in your question. Questions and results are cached in your browser's local storage.
name: FASTKD5-Related COX Deficiency
category: Mendelian
creation_date: "2026-06-24T00:00:00Z"
synonyms:
- FASTKD5 deficiency
- Mitochondrial complex IV deficiency, nuclear type 24
- MC4DN24
- FASTKD5-related cytochrome c oxidase deficiency
- Leigh syndrome due to FASTKD5 deficiency
description: >
FASTKD5-related COX deficiency (mitochondrial complex IV deficiency nuclear
type 24, MC4DN24) is a rare autosomal recessive nuclear form of cytochrome c
oxidase (COX, Complex IV) deficiency caused by biallelic variants in FASTKD5.
Unlike most nuclear-type COX deficiencies — which arise from defective
assembly factors, metallochaperones, or structural subunits — FASTKD5 encodes
a mitochondrial protein essential for processing the polycistronic primary
mitochondrial transcript at non-canonical cleavage sites, a step required for
maturation of the mtDNA-encoded mRNAs. Loss of FASTKD5 impairs production of
the mature COX1 mRNA, reducing translation of the core catalytic subunit COX1,
which in turn stalls Complex IV assembly and lowers cytochrome c oxidase
enzymatic activity. The disorder presents as early- to late-onset Leigh
syndrome, a progressive neurodegenerative disease with lesions in the
brainstem and basal ganglia, and the magnitude of the molecular deficiency
correlates with clinical severity. It conforms to the conserved Complex IV
biogenesis-failure mechanism, with the primary lesion situated at the
mitochondrial mRNA-processing step upstream of COX1 translation and holoenzyme
assembly.
disease_term:
preferred_term: FASTKD5-related COX deficiency (MC4DN24)
term:
id: MONDO:0980755
label: mitochondrial complex IV deficiency, nuclear type 24
parents:
- Mitochondrial Disease
- Inborn Error of Metabolism
references:
- reference: PMID:40499538
title: "Bi-allelic mutations in FASTKD5 are associated with cytochrome c oxidase deficiency and early- to late-onset Leigh syndrome."
pathophysiology:
- name: FASTKD5 Loss and Defective Mitochondrial mRNA Processing
conforms_to: "complex_iv_assembly_deficiency#Complex IV Biogenesis Failure"
description: >
Biallelic FASTKD5 variants reduce the steady-state level of FASTKD5, a
mitochondrial protein essential for processing mRNAs at non-canonical
cleavage sites in the polycistronic primary mitochondrial transcript.
Defective processing impairs maturation of the mtDNA-encoded COX1 mRNA, so
translation of the core catalytic subunit COX1 falls and assembly of Complex
IV is impaired, producing an isolated Complex IV biogenesis failure. This
situates the lesion at the mitochondrial mRNA-processing step, upstream of
COX1 translation and holoenzyme assembly — distinct from the assembly-factor,
metallochaperone, and structural-subunit defects that underlie most other
nuclear-type COX deficiencies.
biological_processes:
- preferred_term: mitochondrial mRNA processing
term:
id: GO:0090615
label: mitochondrial mRNA processing
modifier: DECREASED
- preferred_term: mitochondrial respiratory chain complex IV assembly
term:
id: GO:0033617
label: mitochondrial respiratory chain complex IV assembly
modifier: DECREASED
evidence:
- reference: PMID:40499538
reference_title: "Bi-allelic mutations in FASTKD5 are associated with cytochrome c oxidase deficiency and early- to late-onset Leigh syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "compound heterozygous variants of unknown significance in FASTKD5, a gene that codes for a mitochondrial protein essential for processing mRNAs at non-canonical cleavage sites in the primary mitochondrial transcript, in three subjects with Leigh syndrome"
explanation: Identifies biallelic FASTKD5 variants in a mitochondrial mRNA-processing protein as the causal lesion.
- reference: PMID:40499538
reference_title: "Bi-allelic mutations in FASTKD5 are associated with cytochrome c oxidase deficiency and early- to late-onset Leigh syndrome."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "reduced steady-state levels of FASTKD5 protein by immunoblot, reduced translation of the cytochrome c oxidase subunit 1, impaired assembly of complex IV, and a consequent decrease in cytochrome c oxidase enzymatic activity"
explanation: Patient fibroblasts show that FASTKD5 loss reduces COX1 translation and impairs Complex IV assembly — the biogenesis-failure cascade.
downstream:
- target: Impaired Terminal Electron Transfer and ATP Synthesis
causal_link_type: DIRECT
description: Impaired Complex IV assembly yields a catalytically deficient holoenzyme.
- name: Impaired Terminal Electron Transfer and ATP Synthesis
conforms_to: "complex_iv_assembly_deficiency#Impaired Terminal Electron Transfer and ATP Synthesis"
description: >
The reduced amount of assembled Complex IV blocks electron transfer from
cytochrome c to molecular oxygen and the coupled proton pumping, lowering
oxidative ATP synthesis. In FASTKD5-deficient patient fibroblasts the
cytochrome c oxidase enzymatic activity is decreased, consistent with the
upstream assembly defect.
biological_processes:
- preferred_term: mitochondrial electron transport, cytochrome c to oxygen
term:
id: GO:0006123
label: mitochondrial electron transport, cytochrome c to oxygen
modifier: DECREASED
- preferred_term: ATP synthesis coupled electron transport
term:
id: GO:0042775
label: mitochondrial ATP synthesis coupled electron transport
modifier: DECREASED
evidence:
- reference: PMID:40499538
reference_title: "Bi-allelic mutations in FASTKD5 are associated with cytochrome c oxidase deficiency and early- to late-onset Leigh syndrome."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "impaired assembly of complex IV, and a consequent decrease in cytochrome c oxidase enzymatic activity"
explanation: The decreased COX enzymatic activity establishes the functional terminal-electron-transfer deficit downstream of impaired assembly.
downstream:
- target: High-Energy Tissue Dysfunction
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: The oxidative-phosphorylation deficit injures high-energy-demand tissue, here predominantly the brainstem and basal ganglia.
- name: High-Energy Tissue Dysfunction
conforms_to: "complex_iv_assembly_deficiency#High-Energy Tissue Dysfunction"
description: >
The bioenergetic deficit manifests in high-demand tissue. In FASTKD5-related
disease the dominant phenotype is Leigh syndrome — a progressive
neurodegenerative disease characterized by lesions in the brainstem and
basal ganglia — with an onset that ranges from early to late. The extent of
the molecular Complex IV deficiency correlates with the severity of the
clinical phenotype.
biological_processes:
- preferred_term: aerobic respiration
term:
id: GO:0009060
label: aerobic respiration
modifier: DECREASED
evidence:
- reference: PMID:40499538
reference_title: "Bi-allelic mutations in FASTKD5 are associated with cytochrome c oxidase deficiency and early- to late-onset Leigh syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "three subjects with Leigh syndrome, a progressive neurodegenerative disease characterized by lesions in the brainstem and basal ganglia"
explanation: The high-energy-tissue manifestation of the bioenergetic deficit is Leigh syndrome with brainstem and basal ganglia lesions.
- reference: PMID:40499538
reference_title: "Bi-allelic mutations in FASTKD5 are associated with cytochrome c oxidase deficiency and early- to late-onset Leigh syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The extent of these deficiencies appeared to correlate with the severity of the clinical phenotype"
explanation: Genotype-phenotype correlation linking the magnitude of the Complex IV deficit to clinical severity.
downstream:
- target: Leigh syndrome
causal_link_type: DIRECT
description: The bioenergetic deficit in the brainstem and basal ganglia manifests as Leigh syndrome.
- target: Abnormal brainstem morphology
causal_link_type: DIRECT
description: Neurodegeneration produces the characteristic brainstem lesions of Leigh syndrome.
- target: Abnormal basal ganglia morphology
causal_link_type: DIRECT
description: Neurodegeneration produces the characteristic basal ganglia lesions of Leigh syndrome.
phenotypes:
- name: Leigh syndrome
description: >
Leigh syndrome, a progressive neurodegenerative disease, is the dominant
presentation of FASTKD5-related Complex IV deficiency, with onset ranging
from early to late.
phenotype_term:
preferred_term: Leigh syndrome
term:
id: HP:0002180
label: Neurodegeneration
clinical_course: PROGRESSIVE
evidence:
- reference: PMID:40499538
reference_title: "Bi-allelic mutations in FASTKD5 are associated with cytochrome c oxidase deficiency and early- to late-onset Leigh syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "three subjects with Leigh syndrome, a progressive neurodegenerative disease characterized by lesions in the brainstem and basal ganglia"
explanation: All three reported subjects had Leigh syndrome, a progressive neurodegenerative disease.
- name: Abnormal brainstem morphology
description: >
Brainstem lesions, a defining neuroimaging feature of the Leigh syndrome
seen in FASTKD5 deficiency.
phenotype_term:
preferred_term: Brainstem lesions
term:
id: HP:0002363
label: Abnormal brainstem morphology
evidence:
- reference: PMID:40499538
reference_title: "Bi-allelic mutations in FASTKD5 are associated with cytochrome c oxidase deficiency and early- to late-onset Leigh syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "a progressive neurodegenerative disease characterized by lesions in the brainstem and basal ganglia"
explanation: Brainstem lesions are part of the defining Leigh syndrome neuropathology.
- name: Abnormal basal ganglia morphology
description: >
Basal ganglia lesions, a defining neuroimaging feature of the Leigh syndrome
seen in FASTKD5 deficiency.
phenotype_term:
preferred_term: Basal ganglia lesions
term:
id: HP:0002134
label: Abnormal basal ganglia morphology
evidence:
- reference: PMID:40499538
reference_title: "Bi-allelic mutations in FASTKD5 are associated with cytochrome c oxidase deficiency and early- to late-onset Leigh syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "a progressive neurodegenerative disease characterized by lesions in the brainstem and basal ganglia"
explanation: Basal ganglia lesions are part of the defining Leigh syndrome neuropathology.
biochemical:
- name: Reduced cytochrome c oxidase (Complex IV) enzyme activity
presence: DECREASED
context: >
Decreased cytochrome c oxidase enzymatic activity in patient fibroblasts is
the defining biochemical readout of FASTKD5-related Complex IV deficiency,
arising downstream of reduced COX1 translation and impaired holoenzyme
assembly. The magnitude of the deficit tracks with clinical severity. This
mirrors the COX-activity biochemical signature shared across the nuclear-type
Complex IV deficiencies (e.g. the sibling SURF1 entry).
evidence:
- reference: PMID:40499538
reference_title: "Bi-allelic mutations in FASTKD5 are associated with cytochrome c oxidase deficiency and early- to late-onset Leigh syndrome."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "a consequent decrease in cytochrome c oxidase enzymatic activity"
explanation: Patient fibroblasts show decreased COX (Complex IV) enzymatic activity, the defining biochemical feature of the disorder.
- reference: PMID:40499538
reference_title: "Bi-allelic mutations in FASTKD5 are associated with cytochrome c oxidase deficiency and early- to late-onset Leigh syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The extent of these deficiencies appeared to correlate with the severity of the clinical phenotype"
explanation: The magnitude of the biochemical Complex IV deficit correlates with clinical severity.
genetic:
- name: FASTKD5 pathogenic variants causing MC4DN24
gene_term:
preferred_term: FASTKD5
term:
id: hgnc:25790
label: FASTKD5
inheritance:
- name: Autosomal recessive
evidence:
- reference: PMID:40499538
reference_title: "Bi-allelic mutations in FASTKD5 are associated with cytochrome c oxidase deficiency and early- to late-onset Leigh syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "compound heterozygous variants of unknown significance in FASTKD5"
explanation: Compound heterozygous (biallelic) FASTKD5 variants establish autosomal recessive inheritance.
features: >
Biallelic FASTKD5 variants cause MC4DN24. Across three subjects the authors
identified three missense variants and two frameshift variants leading to a
premature stop codon. Two of the three missense mutations caused near
complete loss of function, while one was hypomorphic owing to impaired
protein stability. Re-expression of a wild-type FASTKD5 cDNA — but not the
missense cDNAs — rescued the molecular defects in patient fibroblasts,
confirming pathogenicity.
evidence:
- reference: PMID:40499538
reference_title: "Bi-allelic mutations in FASTKD5 are associated with cytochrome c oxidase deficiency and early- to late-onset Leigh syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "we identified three missense variants and two frameshift variants leading to a premature stop codon"
explanation: Describes the spectrum of pathogenic FASTKD5 alleles identified in the three subjects.
- reference: PMID:40499538
reference_title: "Bi-allelic mutations in FASTKD5 are associated with cytochrome c oxidase deficiency and early- to late-onset Leigh syndrome."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Two of the three identified missense mutations resulted in near complete loss of function, while one was hypomorphic, resulting from impaired protein stability"
explanation: Functional characterization of the missense alleles as loss-of-function or hypomorphic.
- reference: PMID:40499538
reference_title: "Bi-allelic mutations in FASTKD5 are associated with cytochrome c oxidase deficiency and early- to late-onset Leigh syndrome."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Expression of a wild-type FASTKD5 cDNA, but not cDNAs expressing the missense mutations, rescued all the molecular defects in the subjects' fibroblasts, demonstrating that the alleles are pathogenic"
explanation: Complementation rescue in patient fibroblasts confirms causality of the FASTKD5 variants.
treatments:
- name: Supportive and Metabolic Care
description: >
No curative therapy exists; management is supportive and multidisciplinary,
addressing the progressive neurological manifestations of Leigh syndrome.
treatment_term:
preferred_term: supportive care
term:
id: MAXO:0000950
label: supportive care