ACAD9 deficiency is an autosomal recessive mitochondrial disorder caused by biallelic pathogenic variants in ACAD9. ACAD9 has two mutually exclusive molecular states: an FAD-containing long-chain acyl-CoA dehydrogenase state and an ECSIT-bound mitochondrial complex I assembly (MCIA) state. Impaired complex I assembly is the defining biochemical defect, while loss of tissue-dependent fatty-acid-oxidation activity may modify disease severity without producing the classic VLCAD-deficiency phenotype. Cardiomyopathy, muscle weakness, exercise intolerance, and lactic acidosis predominate; neurologic and other organ involvement is variable. Most recognized patients present in the first year of life, although later presentations occur. Riboflavin often improves complex I activity in patient fibroblasts and observational clinical responses are reported, but nonresponse is common and neither a causal survival benefit nor the molecular treatment mechanism has been established in a controlled trial.
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Conditions with similar clinical presentations that must be differentiated from ACAD9 Deficiency:
name: ACAD9 Deficiency
creation_date: '2026-07-02T00:00:00Z'
category: Mendelian
synonyms:
- Acyl-CoA dehydrogenase 9 deficiency
- ACAD9-related mitochondrial complex I deficiency
- Mitochondrial complex I deficiency, nuclear type 20
description: >
ACAD9 deficiency is an autosomal recessive mitochondrial disorder caused by
biallelic pathogenic variants in ACAD9. ACAD9 has two mutually exclusive
molecular states: an FAD-containing long-chain acyl-CoA dehydrogenase state
and an ECSIT-bound mitochondrial complex I assembly (MCIA) state. Impaired
complex I assembly is the defining biochemical defect, while loss of
tissue-dependent fatty-acid-oxidation activity may modify disease severity
without producing the classic VLCAD-deficiency phenotype. Cardiomyopathy,
muscle weakness, exercise intolerance, and lactic acidosis predominate;
neurologic and other organ involvement is variable. Most recognized patients
present in the first year of life, although later presentations occur.
Riboflavin often improves complex I activity in patient fibroblasts and
observational clinical responses are reported, but nonresponse is common and
neither a causal survival benefit nor the molecular treatment mechanism has
been established in a controlled trial.
disease_term:
preferred_term: acyl-CoA dehydrogenase 9 deficiency
term:
id: MONDO:0012624
label: acyl-CoA dehydrogenase 9 deficiency
parents:
- Mitochondrial Disease
- Inborn Error of Metabolism
references:
- reference: PMID:20816094
title: "Acyl-CoA dehydrogenase 9 is required for the biogenesis of oxidative phosphorylation complex I."
- reference: PMID:20929961
title: "Riboflavin-responsive oxidative phosphorylation complex I deficiency caused by defective ACAD9: new function for an old gene."
- reference: PMID:21057504
title: "Exome sequencing identifies ACAD9 mutations as a cause of complex I deficiency."
- reference: PMID:25721401
title: "Complex I assembly function and fatty acid oxidation enzyme activity of ACAD9 both contribute to disease severity in ACAD9 deficiency."
- reference: PMID:26669660
title: "High incidence and variable clinical outcome of cardiac hypertrophy due to ACAD9 mutations in childhood."
- reference: PMID:30025539
title: "Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: is riboflavin supplementation effective?"
- reference: PMID:33465056
title: "Impaired complex I repair causes recessive Leber's hereditary optic neuropathy."
- reference: PMID:38086790
title: "The assembly of the Mitochondrial Complex I Assembly complex uncovers a redox pathway coordination."
- reference: PMID:38797357
title: "ACAD9 treatment with bezafibrate and nicotinamide riboside temporarily stabilizes cardiomyopathy and lactic acidosis."
- reference: PMID:42046426
title: "Effectiveness of Riboflavin in Inherited Metabolic Diseases: A Systematic Review."
tracked_issues:
- url: https://github.com/monarch-initiative/dismech/issues/6618
title: "ACAD9 deficiency: define riboflavin efficacy, regimen, and response predictors"
tracked_issue_role: curation_followup
tracked_issue_status: OPEN
notes: >-
Expert follow-up for prospective efficacy, dose and timing, response
predictors, the FAD-release mechanism, and treatment of riboflavin
nonresponders.
prevalence:
- population: Worldwide
measure_type: UNKNOWN
prevalence_class: NOT_YET_DOCUMENTED
notes: >-
Observed population prevalence has not been established. A 2018 study used
population allele frequencies to model approximately 59 affected births per
year in Europe, but that projection is not an observed prevalence or
incidence measurement.
evidence:
- reference: PMID:30025539
reference_title: "Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: is riboflavin supplementation effective?"
supports: SUPPORT
evidence_source: COMPUTATIONAL
snippet: >-
we estimated that approximately 59 children with ACAD9 deficiency will be
born each year in Europe
explanation: >-
This allele-frequency model provides a burden projection but not an
observed population occurrence rate, so prevalence remains undocumented.
inheritance:
- name: Autosomal recessive inheritance
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
penetrance: UNKNOWN
expressivity: VARIABLE
evidence:
- reference: PMID:30025539
reference_title: "Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: is riboflavin supplementation effective?"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Disease causing biallelic variants in ACAD9 have been reported in
individuals presenting with lactic acidosis and cardiomyopathy.
explanation: >-
The 70-patient review establishes biallelic ACAD9 variation as the cause;
penetrance has not been quantified.
- reference: PMID:30025539
reference_title: "Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: is riboflavin supplementation effective?"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Age of onset, severity of symptoms and progression are variable.
explanation: >-
Directly supports variable expressivity across affected individuals.
progression:
- phase: Early-onset severe disease
age_range: Presentation in the first year of life
notes: >-
Most reported patients presented in the first year. In the retrospective
cohort, approximately half of this early-onset subgroup did not survive the
first two years; the estimate is sensitive to ascertainment and treatment.
evidence:
- reference: PMID:30025539
reference_title: "Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: is riboflavin supplementation effective?"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Most of the patients presented in the first year of life. For this
subgroup the survival was poor (50% not surviving the first 2 years)
comparing to patients with a later presentation (more than 90% surviving
10 years).
explanation: >-
The retrospective cohort documents poor survival in the early-onset
subgroup and a strong age-of-onset survival gradient.
- phase: Later-onset attenuated disease
age_range: After the first year of life
notes: >-
Later presentation is associated with substantially better survival, but
muscle, cardiac, and neurologic manifestations may still evolve over time.
evidence:
- reference: PMID:30025539
reference_title: "Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: is riboflavin supplementation effective?"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
For this subgroup the survival was poor (50% not surviving the first 2
years) comparing to patients with a later presentation (more than 90%
surviving 10 years).
explanation: >-
Cohort survival was markedly better among patients presenting after the
first year of life.
- reference: PMID:26669660
reference_title: "High incidence and variable clinical outcome of cardiac hypertrophy due to ACAD9 mutations in childhood."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
the surviving patients later developed delayed-onset neurologic or
muscular symptoms, namely cognitive impairment, seizures, muscle weakness
and exercise intolerance.
explanation: >-
A selected childhood series shows that later neurologic and muscular
manifestations can emerge in survivors.
pathophysiology:
- name: Impaired ACAD9 complex I assembly-factor function
description: >
ACAD9 binds NDUFAF1 and ECSIT within the mitochondrial complex I assembly
complex. ECSIT binding opens the ACAD9 FAD-binding loop, releases FAD, and
switches ACAD9 from its acyl-CoA dehydrogenase state into a complex I
assembly-factor state. Disease-causing ACAD9 variants impair this assembly
function.
genes:
- preferred_term: ACAD9
term:
id: hgnc:21497
label: ACAD9
biological_processes:
- preferred_term: mitochondrial respiratory chain complex I assembly
term:
id: GO:0032981
label: mitochondrial respiratory chain complex I assembly
modifier: DECREASED
cellular_components:
- preferred_term: mitochondrial inner membrane
term:
id: GO:0005743
label: mitochondrial inner membrane
evidence:
- reference: PMID:20816094
reference_title: "Acyl-CoA dehydrogenase 9 is required for the biogenesis of oxidative phosphorylation complex I."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
ACAD9 binds complex I assembly factors NDUFAF1 and Ecsit and is
specifically required for the assembly of complex I.
explanation: >-
Cell-based work establishes ACAD9 as a complex I assembly factor binding
NDUFAF1 and ECSIT.
- reference: PMID:38086790
reference_title: "The assembly of the Mitochondrial Complex I Assembly complex uncovers a redox pathway coordination."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
ECSIT binding induces a major conformational change in the FAD-binding
loop of ACAD9, releasing the FAD cofactor and converting ACAD9 from a
fatty acid β-oxidation (FAO) enzyme to a CI assembly factor.
explanation: >-
Structural and biochemical work defines the FAD-releasing molecular
switch between the two mutually exclusive ACAD9 states.
downstream:
- target: Mitochondrial complex I deficiency
description: >
Loss of ACAD9 assembly-factor function prevents proper assembly of
respiratory chain complex I, producing isolated complex I deficiency.
causal_link_type: DIRECT
evidence:
- reference: PMID:20816094
reference_title: "Acyl-CoA dehydrogenase 9 is required for the biogenesis of oxidative phosphorylation complex I."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Furthermore, ACAD9 mutations result in complex I deficiency and not in
disturbed long-chain fatty acid oxidation.
explanation: >-
Cell-based work directly links ACAD9 dysfunction to impaired complex I
assembly; it did not detect a classic long-chain FAO defect in the cells
tested.
- reference: PMID:21057504
reference_title: "Exome sequencing identifies ACAD9 mutations as a cause of complex I deficiency."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
We demonstrated the pathogenic role of the ACAD9 variants by the
correction of the complex I defect on expression of the wildtype ACAD9
protein in fibroblasts derived from affected individuals.
explanation: >-
Complementation rescue in patient fibroblasts causally links ACAD9
variants to the complex I defect.
- name: Tissue-dependent long-chain fatty-acid-oxidation impairment
description: >
In cells that express ACAD9 strongly, its FAD-dependent long-chain acyl-CoA
dehydrogenase activity contributes to fatty-acid-oxidation capacity. This
function is distinct from the ECSIT-bound assembly state and may modify
clinical severity even though ACAD9 deficiency does not usually present as
a classic long-chain fatty-acid-oxidation disorder.
genes:
- preferred_term: ACAD9
term:
id: hgnc:21497
label: ACAD9
molecular_functions:
- preferred_term: acyl-CoA dehydrogenase activity
term:
id: GO:0003995
label: acyl-CoA dehydrogenase activity
modifier: DECREASED
evidence:
- reference: PMID:25721401
reference_title: "Complex I assembly function and fatty acid oxidation enzyme activity of ACAD9 both contribute to disease severity in ACAD9 deficiency."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
ACAD9 knockout in HEK293 cells affected long-chain fatty acid oxidation
along with Cl, both of which were rescued by wild type ACAD9.
explanation: >-
Knockout and rescue establish a tissue-expression-dependent contribution
of ACAD9 to long-chain fatty-acid oxidation.
- reference: PMID:25721401
reference_title: "Complex I assembly function and fatty acid oxidation enzyme activity of ACAD9 both contribute to disease severity in ACAD9 deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We showed that there was a significant inverse correlation between
residual enzyme ACAD activity and phenotypic severity of ACAD9-deficient
patients.
explanation: >-
Functional study of 16 variants from 24 patients supports ACAD activity as
a severity modifier rather than the sole disease mechanism.
- name: Mitochondrial complex I deficiency
description: >
Impaired assembly of respiratory chain complex I (NADH:ubiquinone
oxidoreductase) produces isolated complex I deficiency. This is demonstrable
biochemically in patient skeletal muscle and fibroblasts.
cellular_components:
- preferred_term: mitochondrial inner membrane
term:
id: GO:0005743
label: mitochondrial inner membrane
biological_processes:
- preferred_term: oxidative phosphorylation
term:
id: GO:0006119
label: oxidative phosphorylation
modifier: DECREASED
evidence:
- reference: PMID:20929961
reference_title: "Riboflavin-responsive oxidative phosphorylation complex I deficiency caused by defective ACAD9: new function for an old gene."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In muscle, subsarcolemmal mitochondrial proliferation and a severe
complex I deficiency were observed.
explanation: >-
Patient skeletal muscle shows severe complex I deficiency with
mitochondrial proliferation.
downstream:
- target: Reduced electron transport and oxidative phosphorylation
description: >
Complex I deficiency impairs electron transport and oxidative
phosphorylation.
causal_link_type: DIRECT
evidence:
- reference: PMID:20816094
reference_title: "Acyl-CoA dehydrogenase 9 is required for the biogenesis of oxidative phosphorylation complex I."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Contrary to its previously proposed involvement in fatty acid
oxidation, we describe a role for ACAD9 in oxidative phosphorylation.
explanation: >-
Places the ACAD9-dependent complex I defect within oxidative
phosphorylation.
- name: Reduced electron transport and oxidative phosphorylation
description: >
Reduced complex I function impairs NADH-to-ubiquinone electron transport and
oxidative phosphorylation, limiting mitochondrial ATP production.
biological_processes:
- preferred_term: mitochondrial electron transport, NADH to ubiquinone
term:
id: GO:0006120
label: mitochondrial electron transport, NADH to ubiquinone
modifier: DECREASED
- preferred_term: oxidative phosphorylation
term:
id: GO:0006119
label: oxidative phosphorylation
modifier: DECREASED
evidence:
- reference: PMID:30025539
reference_title: "Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: is riboflavin supplementation effective?"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Disease causing biallelic variants in ACAD9 have been reported in
individuals presenting with lactic acidosis and cardiomyopathy.
explanation: >-
Clinical co-occurrence is consistent with bioenergetic failure but does
not experimentally resolve each downstream tissue mechanism.
downstream:
- target: ATP deficit and compensatory lactate production
description: >
Impaired oxidative phosphorylation lowers ATP availability and increases
reliance on glycolysis, contributing to lactate accumulation.
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
intermediate_mechanisms:
- Reduced electron transport limits proton-motive-force generation and ATP synthesis.
- Increased glycolytic flux regenerates cytosolic ATP and produces lactate.
evidence:
- reference: PMID:30025539
reference_title: "Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: is riboflavin supplementation effective?"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Disease causing biallelic variants in ACAD9 have been reported in
individuals presenting with lactic acidosis and cardiomyopathy.
explanation: >-
The clinical association supports, but does not by itself prove, the
proposed ATP-deficit and lactate-producing intermediate.
- name: ATP deficit and compensatory lactate production
description: >
Reduced oxidative ATP production particularly stresses heart, skeletal
muscle, brain, and renal tissue. Compensatory glycolytic metabolism can
raise circulating lactate; the precise tissue intermediates leading to each
clinical manifestation remain incompletely resolved.
biological_processes:
- preferred_term: aerobic respiration
term:
id: GO:0009060
label: aerobic respiration
modifier: DECREASED
chemical_entities:
- preferred_term: lactate
term:
id: CHEBI:24996
label: lactate
modifier: INCREASED
evidence:
- reference: PMID:30025539
reference_title: "Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: is riboflavin supplementation effective?"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Disease causing biallelic variants in ACAD9 have been reported in
individuals presenting with lactic acidosis and cardiomyopathy.
explanation: >-
Human disease co-occurrence supports the bioenergetic model while leaving
the organ-specific intermediates partly inferential.
downstream:
- target: Cardiomyopathy
description: >
Cardiac energy failure is consistent with cardiomyopathy, most often a
hypertrophic phenotype, in ACAD9 deficiency.
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
intermediate_mechanisms:
- Cardiomyocyte energy failure from complex I deficiency drives hypertrophic remodeling.
evidence:
- reference: PMID:26669660
reference_title: "High incidence and variable clinical outcome of cardiac hypertrophy due to ACAD9 mutations in childhood."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Acyl-CoA dehydrogenase family, member 9 (ACAD9) mutation is a frequent,
usually fatal cause of early-onset cardiac hypertrophy and mitochondrial
respiratory chain complex I deficiency in early childhood.
explanation: >-
Human co-occurrence supports the link but does not isolate the complete
cardiomyocyte remodeling mechanism.
- target: Lactic acidosis
description: >
Increased reliance on glycolysis can raise lactate and produce lactic
acidosis.
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
intermediate_mechanisms:
- Impaired respiratory-chain NADH oxidation shifts cellular redox balance and increases pyruvate-to-lactate conversion.
- Systemic lactate concentration also depends on tissue production and hepatic and renal clearance.
evidence:
- reference: PMID:20929961
reference_title: "Riboflavin-responsive oxidative phosphorylation complex I deficiency caused by defective ACAD9: new function for an old gene."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In a consanguineous family, patients presented easy fatigability,
exercise intolerance and lactic acidosis in blood from early childhood.
explanation: >-
Clinical co-occurrence supports lactic acidosis as a downstream
manifestation without quantifying its specificity.
- target: Exercise intolerance
description: >
Skeletal muscle cannot meet oxidative energy demand during exertion,
producing exercise intolerance and easy fatigability.
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
intermediate_mechanisms:
- Skeletal-muscle ATP deficit limits sustained contractile work during exertion.
evidence:
- reference: PMID:20929961
reference_title: "Riboflavin-responsive oxidative phosphorylation complex I deficiency caused by defective ACAD9: new function for an old gene."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In a consanguineous family, patients presented easy fatigability,
exercise intolerance and lactic acidosis in blood from early childhood.
explanation: >-
Documents exercise intolerance but does not experimentally resolve the
full causal path from complex I dysfunction.
- target: Muscle weakness
description: >
Chronic muscle energy failure from complex I deficiency causes muscular
weakness, one of the most common findings.
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
intermediate_mechanisms:
- Skeletal muscle ATP deficit from complex I deficiency impairs contractile function.
evidence:
- reference: PMID:30025539
reference_title: "Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: is riboflavin supplementation effective?"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The most common clinical findings were cardiomyopathy (85%), muscular
weakness (75%) and exercise intolerance (72%).
explanation: >-
Human cohort quantifies muscular weakness; the energy-failure
intermediate remains mechanistically inferred.
- target: Cognitive impairment
description: >
Brain bioenergetic stress may contribute to cognitive impairment in some
survivors.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:26669660
reference_title: "High incidence and variable clinical outcome of cardiac hypertrophy due to ACAD9 mutations in childhood."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
the surviving patients later developed delayed-onset neurologic or
muscular symptoms, namely cognitive impairment, seizures, muscle
weakness and exercise intolerance.
explanation: >-
Documents cognitive impairment among delayed manifestations but does
not establish a tissue-specific mechanism.
- target: Developmental delay
description: >
Developmental delay, usually mild in the large cohort, may reflect
neurodevelopmental consequences of mitochondrial bioenergetic dysfunction.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:30025539
reference_title: "Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: is riboflavin supplementation effective?"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Mild developmental delay (clinical impression) 23 51 45
explanation: >-
Mild developmental delay was recorded in 23/51 (45%) assessed patients,
but the causal neurodevelopmental intermediates were not tested.
- target: Seizure
description: >
Seizures can occur with delayed neurologic involvement; the intervening
neuronal mechanism is unresolved.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:26669660
reference_title: "High incidence and variable clinical outcome of cardiac hypertrophy due to ACAD9 mutations in childhood."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
the surviving patients later developed delayed-onset neurologic or
muscular symptoms, namely cognitive impairment, seizures, muscle
weakness and exercise intolerance.
explanation: >-
Documents seizures as a case-series manifestation without resolving the
causal intermediates.
- target: Optic atrophy
description: >
Optic atrophy has been reported in a selected series, although it was
absent from the larger 70-patient cohort.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:26669660
reference_title: "High incidence and variable clinical outcome of cardiac hypertrophy due to ACAD9 mutations in childhood."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Other organ involvement included proximal tubulopathy, renal failure,
secondary ovarian failure and optic atrophy.
explanation: >-
Provides case-series support for rare optic involvement; larger-cohort
counterevidence is retained on the phenotype entry.
- target: Renal tubular dysfunction
description: >
Proximal tubulopathy is a reported rare organ manifestation, with the
tissue-specific mechanism unresolved.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:26669660
reference_title: "High incidence and variable clinical outcome of cardiac hypertrophy due to ACAD9 mutations in childhood."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Other organ involvement included proximal tubulopathy, renal failure,
secondary ovarian failure and optic atrophy.
explanation: >-
Documents proximal tubulopathy in a selected case series without
resolving the causal intermediates.
phenotypes:
- name: Cardiomyopathy
frequency: VERY_FREQUENT
category: Cardiovascular
description: >
Cardiomyopathy occurred during the course in 56/66 (85%) patients with
available data. Hypertrophic cardiomyopathy predominates, but the 85%
estimate is for the broader cardiomyopathy category and must not be
interpreted as an HCM-specific frequency.
phenotype_term:
preferred_term: Cardiomyopathy
term:
id: HP:0001638
label: Cardiomyopathy
evidence:
- reference: PMID:26669660
reference_title: "High incidence and variable clinical outcome of cardiac hypertrophy due to ACAD9 mutations in childhood."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Acyl-CoA dehydrogenase family, member 9 (ACAD9) mutation is a frequent,
usually fatal cause of early-onset cardiac hypertrophy and mitochondrial
respiratory chain complex I deficiency in early childhood.
explanation: >-
Identifies early cardiac hypertrophy as an important, sometimes fatal
presentation without supplying a population-wide HCM frequency.
- reference: PMID:30025539
reference_title: "Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: is riboflavin supplementation effective?"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The most common clinical findings were cardiomyopathy (85%), muscular
weakness (75%) and exercise intolerance (72%).
explanation: >-
The cohort table records broad cardiomyopathy during the disease course in
56/66 assessed patients (85%).
- name: Exercise intolerance
frequency: FREQUENT
category: Musculoskeletal
description: >
Exercise intolerance was recorded during the course in 34/47 (72%) patients
with available data. It is consistent with failure to meet skeletal-muscle
oxidative energy demand and may improve with riboflavin in some responsive
patients.
phenotype_term:
preferred_term: Exercise intolerance
term:
id: HP:0003546
label: Exercise intolerance
evidence:
- reference: PMID:30025539
reference_title: "Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: is riboflavin supplementation effective?"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The most common clinical findings were cardiomyopathy (85%), muscular
weakness (75%) and exercise intolerance (72%).
explanation: >-
The cohort table records exercise intolerance during the disease course in
34/47 assessed patients (72%).
- reference: PMID:20929961
reference_title: "Riboflavin-responsive oxidative phosphorylation complex I deficiency caused by defective ACAD9: new function for an old gene."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Exercise intolerance and complex I activity was improved by a supplement
of riboflavin at high dosage.
explanation: >-
Documents exercise intolerance and its improvement with riboflavin.
- name: Lactic acidosis
category: Metabolic
description: >
Lactic acidosis is consistent with increased glycolytic lactate production
when complex I-dependent oxidative phosphorylation is impaired. It supports
mitochondrial dysfunction but is not specific to ACAD9 deficiency.
phenotype_term:
preferred_term: Lactic acidosis
term:
id: HP:0003128
label: Lactic acidosis
evidence:
- reference: PMID:20929961
reference_title: "Riboflavin-responsive oxidative phosphorylation complex I deficiency caused by defective ACAD9: new function for an old gene."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In a consanguineous family, patients presented easy fatigability,
exercise intolerance and lactic acidosis in blood from early childhood.
explanation: >-
Documents lactic acidosis from early childhood in ACAD9 deficiency.
- reference: PMID:30025539
reference_title: "Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: is riboflavin supplementation effective?"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Disease causing biallelic variants in ACAD9 have been reported in
individuals presenting with lactic acidosis and cardiomyopathy.
explanation: >-
Names lactic acidosis as a cardinal presenting feature.
- name: Muscle weakness
frequency: FREQUENT
category: Musculoskeletal
description: >
Muscular weakness was recorded during the course in 37/49 (75%) patients
with available data and is consistent with chronic skeletal-muscle energy
failure from complex I deficiency.
phenotype_term:
preferred_term: Muscle weakness
term:
id: HP:0001324
label: Muscle weakness
evidence:
- reference: PMID:30025539
reference_title: "Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: is riboflavin supplementation effective?"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The most common clinical findings were cardiomyopathy (85%), muscular
weakness (75%) and exercise intolerance (72%).
explanation: >-
The cohort table records muscular weakness during the disease course in
37/49 assessed patients (75%).
- name: Cognitive impairment
category: Neurologic
description: >
Cognitive impairment is among the delayed-onset neurologic features that can
emerge in survivors of early-onset ACAD9 disease.
phenotype_term:
preferred_term: Cognitive impairment
term:
id: HP:0100543
label: Cognitive impairment
evidence:
- reference: PMID:26669660
reference_title: "High incidence and variable clinical outcome of cardiac hypertrophy due to ACAD9 mutations in childhood."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
the surviving patients later developed delayed-onset neurologic or
muscular symptoms, namely cognitive impairment, seizures, muscle weakness
and exercise intolerance.
explanation: >-
Lists cognitive impairment among delayed-onset neurologic symptoms.
- name: Developmental delay
frequency: FREQUENT
category: Neurologic
description: >
Developmental delay was commonly reported and was usually mild; mild delay
was recorded in 23/51 (45%) assessed patients, while severe impairment was
much less prominent in the cohort.
phenotype_term:
preferred_term: Neurodevelopmental delay
term:
id: HP:0012758
label: Neurodevelopmental delay
evidence:
- reference: PMID:30025539
reference_title: "Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: is riboflavin supplementation effective?"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Mild developmental delay (clinical impression) 23 51 45
explanation: >-
The cohort table records mild developmental delay in 23/51 (45%) assessed
patients.
- name: Seizure
category: Neurologic
description: >
Seizures occur as part of the delayed-onset neurologic involvement in some
ACAD9-deficient survivors.
phenotype_term:
preferred_term: Seizure
term:
id: HP:0001250
label: Seizure
evidence:
- reference: PMID:26669660
reference_title: "High incidence and variable clinical outcome of cardiac hypertrophy due to ACAD9 mutations in childhood."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
the surviving patients later developed delayed-onset neurologic or
muscular symptoms, namely cognitive impairment, seizures, muscle weakness
and exercise intolerance.
explanation: >-
Lists seizures among delayed-onset neurologic symptoms.
- name: Optic atrophy
category: Ophthalmologic
description: >
Optic atrophy has been reported in a selected childhood series, but the
combined optic-atrophy/retinitis-pigmentosa field was 0/70 in the larger
cohort; it should therefore be considered exceptional or uncertain rather
than a routine feature.
phenotype_term:
preferred_term: Optic atrophy
term:
id: HP:0000648
label: Optic atrophy
evidence:
- reference: PMID:26669660
reference_title: "High incidence and variable clinical outcome of cardiac hypertrophy due to ACAD9 mutations in childhood."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Other organ involvement included proximal tubulopathy, renal failure,
secondary ovarian failure and optic atrophy.
explanation: >-
Provides case-series support for optic atrophy.
- reference: PMID:30025539
reference_title: "Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: is riboflavin supplementation effective?"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Optic atrophy, retinits pigmentosa 0 70 0
explanation: >-
Neither optic atrophy nor retinitis pigmentosa was recorded in the larger
cohort; this limits frequency inference but does not refute rare cases.
- name: Renal tubular dysfunction
category: Renal
description: >
Proximal renal tubulopathy is reported among the multiorgan involvement in
ACAD9 deficiency.
phenotype_term:
preferred_term: Renal tubular dysfunction
term:
id: HP:0000124
label: Renal tubular dysfunction
evidence:
- reference: PMID:26669660
reference_title: "High incidence and variable clinical outcome of cardiac hypertrophy due to ACAD9 mutations in childhood."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Other organ involvement included proximal tubulopathy, renal failure,
secondary ovarian failure and optic atrophy.
explanation: >-
Lists proximal tubulopathy among additional organ involvement.
biochemical:
- name: Circulating lactate
presence: INCREASED
context: >
Elevated blood lactate or lactic acidosis is a nonspecific supportive
readout of impaired oxidative metabolism.
biomarker_term:
preferred_term: lactate
term:
id: CHEBI:24996
label: lactate
readouts:
- target: ATP deficit and compensatory lactate production
relationship: READOUT_OF
direction: POSITIVE
endpoint_context: DIAGNOSTIC
interpretation: >-
Increased lactate is consistent with compensatory glycolytic metabolism
but is not diagnostic of ACAD9 deficiency by itself.
evidence:
- reference: PMID:20929961
reference_title: "Riboflavin-responsive oxidative phosphorylation complex I deficiency caused by defective ACAD9: new function for an old gene."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In a consanguineous family, patients presented easy fatigability,
exercise intolerance and lactic acidosis in blood from early childhood.
explanation: >-
Blood lactic acidosis is consistent with the modeled metabolic shift but
the family-level observation does not establish specificity.
evidence:
- reference: PMID:30025539
reference_title: "Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: is riboflavin supplementation effective?"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Disease causing biallelic variants in ACAD9 have been reported in
individuals presenting with lactic acidosis and cardiomyopathy.
explanation: >-
Identifies lactic acidosis as a presenting biochemical feature without
establishing diagnostic sensitivity or specificity.
- name: Respiratory-chain complex I activity
presence: DECREASED
context: >
Isolated complex I deficiency in skeletal muscle or patient fibroblasts is
the defining biochemical abnormality. Tissue and cell-line results vary;
near-normal activity in a tested sample does not exclude molecularly
confirmed ACAD9 deficiency.
readouts:
- target: Mitochondrial complex I deficiency
relationship: READOUT_OF
direction: NEGATIVE
endpoint_context: DIAGNOSTIC
interpretation: >-
Reduced complex I activity supports the biochemical diagnosis, while a
normal result in one tissue or cell line is not an exclusion criterion.
evidence:
- reference: PMID:20929961
reference_title: "Riboflavin-responsive oxidative phosphorylation complex I deficiency caused by defective ACAD9: new function for an old gene."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In muscle, subsarcolemmal mitochondrial proliferation and a severe
complex I deficiency were observed.
explanation: >-
Patient muscle demonstrated severe complex I deficiency.
evidence:
- reference: PMID:30025539
reference_title: "Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: is riboflavin supplementation effective?"
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Complex I-dependent respiration was found to be significantly decreased
in 13 of 17 evaluated patient cell lines.
explanation: >-
Most tested fibroblast lines showed decreased complex I respiration, but
the incomplete proportion demonstrates that the assay is not universally
sensitive.
diagnosis:
- name: ACAD9 molecular genetic testing
description: >
Molecular confirmation requires biallelic pathogenic or likely pathogenic
ACAD9 variants. In patients with a compatible mitochondrial cardiomyopathy
or myopathy, sequencing should not be deferred solely because
respiratory-chain testing in one tissue is normal.
diagnosis_term:
preferred_term: molecular genetic testing
term:
id: NCIT:C19770
label: Molecular Analysis
results: Biallelic pathogenic or likely pathogenic ACAD9 variants
evidence:
- reference: PMID:21057504
reference_title: "Exome sequencing identifies ACAD9 mutations as a cause of complex I deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
led us to identify compound heterozygous mutations in ACAD9, which
encodes a poorly understood member of the mitochondrial acyl-CoA
dehydrogenase protein family.
explanation: >-
Exome sequencing identified biallelic ACAD9 variants in affected patients.
- reference: PMID:26669660
reference_title: "High incidence and variable clinical outcome of cardiac hypertrophy due to ACAD9 mutations in childhood."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We retrospectively studied a series of 20 unrelated children with cardiac
hypertrophy and isolated complex I deficiency and identified compound
heterozygosity for missense, splice site or frame shift ACAD9 variants in
8/20 patients (40%).
explanation: >-
The 40% figure is a molecular diagnostic yield in a narrowly selected
subgroup, not a population prevalence estimate.
- name: Respiratory-chain complex I activity testing
description: >
Enzymatic or respiratory testing in skeletal muscle or patient fibroblasts
can demonstrate an isolated complex I defect and support pathogenicity.
Some molecularly affected fibroblast lines have normal or only mildly
reduced activity, so a normal result does not exclude ACAD9 deficiency.
diagnosis_term:
preferred_term: diagnostic procedure
term:
id: NCIT:C18020
label: Diagnostic Procedure
results: Reduced isolated complex I activity or respiration
evidence:
- reference: PMID:20929961
reference_title: "Riboflavin-responsive oxidative phosphorylation complex I deficiency caused by defective ACAD9: new function for an old gene."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In muscle, subsarcolemmal mitochondrial proliferation and a severe
complex I deficiency were observed.
explanation: >-
Skeletal-muscle testing demonstrated the characteristic isolated complex
I defect.
- reference: PMID:30025539
reference_title: "Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: is riboflavin supplementation effective?"
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Complex I-dependent respiration was found to be significantly decreased
in 13 of 17 evaluated patient cell lines.
explanation: >-
Most, but not all, tested patient fibroblast lines showed decreased
complex I-dependent respiration.
- name: Blood lactate measurement
description: >
Elevated lactate can support suspicion of mitochondrial energy failure but
is neither sensitive nor specific enough to confirm ACAD9 deficiency.
diagnosis_term:
preferred_term: diagnostic procedure
term:
id: NCIT:C18020
label: Diagnostic Procedure
results: Elevated lactate or lactic acidosis
evidence:
- reference: PMID:20929961
reference_title: "Riboflavin-responsive oxidative phosphorylation complex I deficiency caused by defective ACAD9: new function for an old gene."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In a consanguineous family, patients presented easy fatigability,
exercise intolerance and lactic acidosis in blood from early childhood.
explanation: >-
Family-level evidence supports lactate as a clue but not as a specific
confirmatory test.
differential_diagnoses:
- name: Other mitochondrial complex I deficiencies
description: >
Nuclear and mitochondrial-DNA complex I disorders can produce the same
combination of cardiomyopathy, myopathy, lactic acidosis, neurologic
involvement, and isolated complex I deficiency.
distinguishing_features:
- Molecular identification of biallelic ACAD9 variants establishes ACAD9 deficiency.
- ACAD9 deficiency often has a prominent cardiomyopathic/myopathic phenotype and may show riboflavin responsiveness, but neither feature is diagnostic alone.
evidence:
- reference: PMID:21057504
reference_title: "Exome sequencing identifies ACAD9 mutations as a cause of complex I deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
An isolated defect of respiratory chain complex I activity is a frequent
biochemical abnormality in mitochondrial disorders.
explanation: >-
The nonspecificity of isolated complex I deficiency necessitates molecular
differentiation from other mitochondrial etiologies.
- name: Very long-chain acyl-CoA dehydrogenase deficiency
disease_term:
preferred_term: very long chain acyl-CoA dehydrogenase deficiency
term:
id: MONDO:0008723
label: very long chain acyl-CoA dehydrogenase deficiency
description: >
VLCAD deficiency overlaps through acyl-CoA-dehydrogenase-family membership,
cardiomyopathy, and muscle disease. ACAD9 also has tissue-dependent
long-chain FAO activity, so the distinction should be based on the full
clinical, biochemical, and molecular pattern rather than protein-family
membership.
distinguishing_features:
- Hypoglycemia, rhabdomyolysis, and liver failure are typical of VLCAD deficiency but infrequent in ACAD9 deficiency.
- ACAD9 deficiency is defined by biallelic ACAD9 variants and a complex I assembly defect rather than the classic VLCAD biochemical phenotype.
evidence:
- reference: PMID:30025539
reference_title: "Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: is riboflavin supplementation effective?"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Although both ACAD9 and VLCAD deficiency can present with cardiomyopathy,
the clinical pheno- type is otherwise distinct, with hypoglycemia,
rhabdo- myolysis and liver failure, typically seen in VLCAD.
explanation: >-
The cohort review states the principal clinical distinctions from VLCAD
deficiency while newer work preserves the tissue-dependent FAO nuance.
treatments:
- name: Riboflavin (Vitamin B2) Supplementation
description: >
Riboflavin is a commonly attempted empiric treatment. Complex I
activity improved in 9/15 patient fibroblast lines, whereas 6/15 did not
respond. Physicians reported clinical benefit in 20/31 retrospectively
described patients and no effect in 11/31; a 2026 systematic review
classified 22/29 reported patients as responsive. These overlapping,
nonrandomized reports support a possible benefit but do not establish a
causal survival effect, optimal regimen, or reliable response predictor.
action_category: THERAPEUTIC
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: B vitamin supplementation
term:
id: NCIT:C15425
label: Nutritional Supplementation
therapeutic_agent:
- preferred_term: riboflavin
term:
id: CHEBI:17015
label: riboflavin
target_mechanisms:
- target: Mitochondrial complex I deficiency
treatment_effect: MODULATES
description: >
Riboflavin increased complex I activity in a subset of patient fibroblast
lines. Improved folding or stability of some mutant ACAD9 species has been
proposed as the upstream explanation, but the direct mechanism remains
unresolved and ECSIT normally releases FAD when ACAD9 enters its assembly
state.
evidence:
- reference: PMID:30025539
reference_title: "Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: is riboflavin supplementation effective?"
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Riboflavin supplementation led to a significant im- provement of complex
I activity in nine out of 15 patient cell lines and had no effect in the
remaining six cell lines.
explanation: >-
Patient-fibroblast rescue is reproducible in a subset but does not prove
the proposed FAD/folding mechanism or universal responsiveness.
- reference: PMID:30025539
reference_title: "Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: is riboflavin supplementation effective?"
supports: SUPPORT
evidence_source: OTHER
snippet: >-
previous studies suggested that riboflavin increases the mitochondrial
FAD concentration thereby supporting FAD binding and consecutively
improving ACAD9 folding and stability, thus promoting complex I assembly
explanation: >-
The authors explicitly present ACAD9 stabilization as a prior-study
suggestion rather than a demonstrated treatment mechanism.
- reference: PMID:38086790
reference_title: "The assembly of the Mitochondrial Complex I Assembly complex uncovers a redox pathway coordination."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
ECSIT binding induces a major conformational change in the FAD-binding
loop of ACAD9, releasing the FAD cofactor and converting ACAD9 from a
fatty acid β-oxidation (FAO) enzyme to a CI assembly factor.
explanation: >-
The normal FAD-release step in assembly-state conversion complicates a
simple model in which sustained FAD binding directly rescues MCIA
function.
evidence:
- reference: PMID:30025539
reference_title: "Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: is riboflavin supplementation effective?"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
For 20 patients (20/31 = 65%) physicians reported a beneficial effect, for
11 (35%) no effect.
explanation: >-
Retrospective physician reports show frequent response alongside a
substantial nonresponder group.
- reference: PMID:30025539
reference_title: "Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: is riboflavin supplementation effective?"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
This might indicate that our analysis is prone to survivor treatment
selection bias. Detailed data about the starting point of riboflavin
treatment, the dosage etc. in more patients are needed.
explanation: >-
The study's own limitations prevent interpreting the early-onset survival
association as controlled evidence of efficacy.
- reference: PMID:42046426
reference_title: "Effectiveness of Riboflavin in Inherited Metabolic Diseases: A Systematic Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
ACAD 9 (n = 29, 75.9% responsive)
explanation: >-
The 2026 systematic review summarizes reported response, but the ACAD9
evidence derives from small, nonrandomized and partly overlapping reports.
- reference: PMID:42046426
reference_title: "Effectiveness of Riboflavin in Inherited Metabolic Diseases: A Systematic Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Adverse effects were infrequent and mild.
explanation: >-
The systematic review found generally mild adverse effects across the
included inherited metabolic diseases, without an ACAD9-specific safety
denominator.
- reference: PMID:20929961
reference_title: "Riboflavin-responsive oxidative phosphorylation complex I deficiency caused by defective ACAD9: new function for an old gene."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Exercise intolerance and complex I activity was improved by a supplement
of riboflavin at high dosage.
explanation: >-
Documents family-level clinical and biochemical responsiveness without
establishing general effectiveness.
- name: Bezafibrate plus nicotinamide riboside (experimental)
description: >
One riboflavin-unresponsive infant with life-threatening cardiomyopathy and
lactic acidosis temporarily improved and stabilized after high-dose
bezafibrate plus nicotinamide riboside, but later died of cardiac failure
with infection at 10.5 months. This is experimental, single-patient evidence
and does not establish efficacy or a standard regimen.
action_category: THERAPEUTIC
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: bezafibrate
term:
id: CHEBI:47612
label: bezafibrate
- preferred_term: nicotinamide riboside
term:
id: CHEBI:15927
label: N-ribosylnicotinamide
target_phenotypes:
- preferred_term: Cardiomyopathy
term:
id: HP:0001638
label: Cardiomyopathy
- preferred_term: Lactic acidosis
term:
id: HP:0003128
label: Lactic acidosis
evidence:
- reference: PMID:38797357
reference_title: "ACAD9 treatment with bezafibrate and nicotinamide riboside temporarily stabilizes cardiomyopathy and lactic acidosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Treatment with high dose bezafibrate and nicotinamide riboside resulted in
marked clinical improvement including reduced lactate and NT-pro-brain
type natriuretic peptide levels, with stabilized echocardiographic
measures. After a long stable period, the child succumbed from cardiac
failure with infection at 10.5 months.
explanation: >-
A single case supports temporary stabilization while the fatal outcome and
absence of a comparator preclude an efficacy conclusion.
genetic:
- name: ACAD9 gene variants
association: Biallelic pathogenic variants cause ACAD9 deficiency
relationship_type: CAUSATIVE
variant_origin: GERMLINE
gene_term:
preferred_term: ACAD9
term:
id: hgnc:21497
label: ACAD9
inheritance:
- name: Autosomal recessive inheritance
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
penetrance: UNKNOWN
expressivity: VARIABLE
evidence:
- reference: PMID:21057504
reference_title: "Exome sequencing identifies ACAD9 mutations as a cause of complex I deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
led us to identify compound heterozygous mutations in ACAD9, which
encodes a poorly understood member of the mitochondrial acyl-CoA
dehydrogenase protein family.
explanation: >-
Compound heterozygous ACAD9 mutations in affected individuals indicate
biallelic (recessive) disease.
- reference: PMID:30025539
reference_title: "Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: is riboflavin supplementation effective?"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Age of onset, severity of symptoms and progression are variable.
explanation: >-
Directly supports variable expressivity among affected individuals.
features: >
ACAD9 deficiency results from biallelic pathogenic variants in ACAD9.
Causal variants are distributed throughout the gene with no clear
genotype-phenotype correlation. No patient in the 70-patient cohort carried
two clear loss-of-function alleles; complete loss may be incompatible with
life, but the observation is not proof of embryonic lethality in humans.
evidence:
- reference: PMID:21057504
reference_title: "Exome sequencing identifies ACAD9 mutations as a cause of complex I deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
led us to identify compound heterozygous mutations in ACAD9, which
encodes a poorly understood member of the mitochondrial acyl-CoA
dehydrogenase protein family.
explanation: >-
Human molecular data establish biallelic ACAD9 variants as causative.
- reference: PMID:30025539
reference_title: "Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: is riboflavin supplementation effective?"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
No patients harbored biallelic loss of function mutations, indicating that
this combination is unlikely to be compatible with life.
explanation: >-
Absence of biallelic clear loss-of-function genotypes supports, but does
not prove, incompatibility of complete loss with human viability.
- reference: PMID:30025539
reference_title: "Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: is riboflavin supplementation effective?"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The mutations of the 70 patients from 50 families with ACAD9 deficiency
were located across the coding se- quence of the gene, with no founder
mutations identified.
explanation: >-
The large cohort supports a distributed variant spectrum rather than a
single recurrent founder allele.
- reference: PMID:30025539
reference_title: "Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: is riboflavin supplementation effective?"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
No genotype- phenotype correlation for mutations could be identified based
on specific regions of the gene or functional do- mains of the protein.
explanation: >-
The cohort did not identify a clear genotype-phenotype correlation.
discussions:
- discussion_id: gap_acad9_riboflavin_response_mechanism
prompt: >-
Which patients with ACAD9 deficiency benefit from riboflavin, what dose and
treatment timing are optimal, and how does response arise when ECSIT-driven
conversion of ACAD9 into its complex I assembly state normally releases the
FAD cofactor?
kind: KNOWLEDGE_GAP
status: OPEN
attaches_to:
- pathophysiology#Impaired ACAD9 complex I assembly-factor function
- pathophysiology#Tissue-dependent long-chain fatty-acid-oxidation impairment
- treatments#Riboflavin (Vitamin B2) Supplementation
rationale: >-
Riboflavin improves complex I activity in only 9/15 tested fibroblast lines,
and retrospective reports include substantial clinical nonresponse and an
acknowledged survivor-treatment-selection bias. The recent structural model
also shows FAD release, rather than retention, when ECSIT commits ACAD9 to
the assembly state. Prospective response criteria and a variant-aware
mechanism are needed before observational survival differences can be
interpreted causally or a regimen can be optimized.
evidence:
- reference: PMID:30025539
reference_title: "Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: is riboflavin supplementation effective?"
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Riboflavin supplementation led to a significant im- provement of complex I
activity in nine out of 15 patient cell lines and had no effect in the
remaining six cell lines.
explanation: >-
Establishes cellular response heterogeneity.
- reference: PMID:30025539
reference_title: "Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: is riboflavin supplementation effective?"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
This might indicate that our analysis is prone to survivor treatment
selection bias. Detailed data about the starting point of riboflavin
treatment, the dosage etc. in more patients are needed.
explanation: >-
Identifies the principal limitation of the reported survival association.
- reference: PMID:38086790
reference_title: "The assembly of the Mitochondrial Complex I Assembly complex uncovers a redox pathway coordination."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
ECSIT binding induces a major conformational change in the FAD-binding
loop of ACAD9, releasing the FAD cofactor and converting ACAD9 from a
fatty acid β-oxidation (FAO) enzyme to a CI assembly factor.
explanation: >-
Defines the structural observation that a therapeutic mechanism must
reconcile.
- reference: PMID:42046426
reference_title: "Effectiveness of Riboflavin in Inherited Metabolic Diseases: A Systematic Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
ACAD 9 (n = 29, 75.9% responsive)
explanation: >-
Summarizes reported responsiveness while leaving trial-level efficacy and
response predictors unresolved.
datasets:
- accession: pride:PXD021386
title: "Complexome profiling of mitochondrial protein complexes from patients with mutations in either DNAJC30 or ACAD9 compared to an age and gender matched control"
description: "Complexome proteomics that includes an ACAD9-mutant patient as a comparator relevant to mitochondrial complex I assembly research."
data_type: PROTEOMICS
publication: PMID:33465056
notes: "Organism: human. PRIDE/ProteomeXchange. The linked publication is primarily a DNAJC30/LHON study; the ACAD9-mutant sample is a comparator and should not be treated as an ACAD9 clinical cohort."