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Sengers syndrome

Mendelian MONDO:0008922
0
Mappings
0
Definitions
1
Inheritance
6
Pathophysiology
0
Histopathology
6
Phenotypes
1
Genes
7
Treatments
0
Subtypes
3
Differentials
0
Datasets
0
Trials
👪

Inheritance

1
Autosomal Recessive
Sengers syndrome is inherited in an autosomal recessive pattern, typically due to biallelic AGK variants (homozygous or compound heterozygous) with unaffected carrier parents.
Show evidence (2 references)
DOI:10.3389/fped.2021.639687 SUPPORT
"Sengers syndrome (OMIM #212350) is a rare autosomal recessive disorder due to mutations in acylglycerol kinase (AGK) gene."
This explicitly states autosomal recessive inheritance due to AGK variants.
PMID:34164355 SUPPORT
"Genetic testing of a boy revealed a homozygous pathogenic variant for Sengers syndrome in AGK (c.1131+2T>C) which was classified as likely pathogenic according to the ACMG guideline"
Identification of a homozygous AGK variant supports autosomal recessive inheritance.
⚙

Pathophysiology

6
AGK loss of function disrupts lipid signaling
Loss of functional AGK impairs lipid signaling activity attributed to mitochondrial acylglycerol kinase.
phosphatidic acid metabolic process link ↕ DYSREGULATED
Show evidence (1 reference)
DOI:10.3390/ijms222413484 SUPPORT
"AGK, a mitochondrial acylglycerol kinase, is not only involved in lipid signaling but is also a component of the TIM22 complex in the inner mitochondrial membrane, which mediates the import of a subset of membrane proteins."
This establishes AGK's role in lipid signaling that is lost with AGK deficiency.
TIM22 complex assembly defect
Disrupted TIM22 complex assembly at the mitochondrial inner membrane impairs the carrier protein import machinery.
mitochondrial inner membrane link
Show evidence (1 reference)
DOI:10.3390/ijms222413484 SUPPORT
"AGK, a mitochondrial acylglycerol kinase, is not only involved in lipid signaling but is also a component of the TIM22 complex in the inner mitochondrial membrane, which mediates the import of a subset of membrane proteins."
This supports a TIM22 assembly defect at the mitochondrial inner membrane in AGK deficiency.
Reduced TIM22-mediated import of inner-membrane carrier proteins
Disruption of the TIM22 complex reduces import of multi-pass carrier proteins and sideroflexins into the inner mitochondrial membrane.
protein insertion into mitochondrial inner membrane link ↓ DECREASED
Show evidence (1 reference)
DOI:10.1091/mbc.e20-06-0390 SUPPORT
"Proteomic profiling of Sengers patient fibroblasts and AGK knockout models identifies remodeling of the mitochondrial proteome, including mitochondrial one-carbon metabolism enzymes, inner membrane serine transporters, sideroflexins, and Complex I subunits and assembly factors."
This supports reduced import/abundance of inner-membrane carriers and sideroflexins in AGK deficiency.
Impaired mitochondrial one-carbon metabolism
Reduced abundance of sideroflexins and one-carbon enzymes disrupts mitochondrial one-carbon metabolism.
one-carbon metabolic process link ↕ DYSREGULATED
Show evidence (1 reference)
DOI:10.1091/mbc.e20-06-0390 SUPPORT
"Proteomic profiling of Sengers patient fibroblasts and AGK knockout models identifies remodeling of the mitochondrial proteome, including mitochondrial one-carbon metabolism enzymes, inner membrane serine transporters, sideroflexins, and Complex I subunits and assembly factors."
This links AGK/TIM22 dysfunction to loss of carrier and sideroflexin import with effects on one-carbon metabolism.
Disrupted mitochondrial phospholipid metabolism
AGK loss alters phospholipid metabolism in mitochondrial membranes, contributing to disease pathogenesis.
phospholipid metabolic process link ↕ DYSREGULATED
Show evidence (1 reference)
DOI:10.3390/ijms222413484 SUPPORT
"AGK mutations can alter both phospholipid metabolism and mitochondrial protein biogenesis, contributing to the pathogenesis of Sengers syndrome."
This statement links AGK mutations to altered phospholipid metabolism in Sengers syndrome.
Oxidative phosphorylation deficiency
Impaired respiratory chain function with reduced complex I and V activity and decreased oxygen consumption in patient cells.
oxidative phosphorylation link ↓ DECREASED
Show evidence (1 reference)
DOI:10.3390/ijms222413484 SUPPORT
"Decreases in the oxygen consumption rate (OCR) and the OCR:ECAR (extracellular acidification rate) ratio in the patient’s fibroblasts indicated reduced electron flow through the respiratory chain, and spectrophotometry revealed decreased activity of OXPHOS complexes I and V."
This provides direct evidence of impaired oxidative phosphorylation and reduced complex I and V activity.
●

Phenotypes

6
Cardiovascular(2) Eye(1) Genitourinary(1) Metabolism(1) Musculoskeletal(1)
Cardiovascular 2
Hypertrophic cardiomyopathy VERY_FREQUENT Hypertrophic cardiomyopathy (HP:0001639)
Show evidence (2 references)
DOI:10.3389/fped.2021.639687 SUPPORT
"Both infants had typical clinical features characterized by hypertrophic cardiomyopathy, bilateral cataracts, myopathy, and lactic acidosis, and heart failure was the most severe manifestation."
This case report documents hypertrophic cardiomyopathy as a core feature of Sengers syndrome.
DOI:10.1186/s13052-022-01370-y SUPPORT
"Sengers syndrome is characterized by congenital cataract, hypertrophic cardiomyopathy, mitochondrial myopathy, and lactic acidosis associated with mutations in AGK gene."
This longitudinal case report reiterates hypertrophic cardiomyopathy as a defining feature.
Congestive heart failure FREQUENT Congestive heart failure (HP:0001635)
Show evidence (2 references)
DOI:10.3389/fped.2021.639687 SUPPORT
"Both infants had typical clinical features characterized by hypertrophic cardiomyopathy, bilateral cataracts, myopathy, and lactic acidosis, and heart failure was the most severe manifestation."
Heart failure is reported as the most severe clinical manifestation in these cases.
PMID:34164355 SUPPORT
"NT-proBNP reached 6,076 pg/ml (reference ranges <125 pg/ml) reflecting the state of the heart failure."
This case report documents biochemical evidence of heart failure in a Sengers syndrome patient.
Eye 1
Developmental cataract VERY_FREQUENT Developmental cataract (HP:0000519)
Show evidence (2 references)
DOI:10.3389/fped.2021.639687 SUPPORT
"Both infants had typical clinical features characterized by hypertrophic cardiomyopathy, bilateral cataracts, myopathy, and lactic acidosis, and heart failure was the most severe manifestation."
This identifies bilateral cataracts as a defining phenotype in Sengers syndrome.
DOI:10.1186/s13052-022-01370-y SUPPORT
"Sengers syndrome is characterized by congenital cataract, hypertrophic cardiomyopathy, mitochondrial myopathy, and lactic acidosis associated with mutations in AGK gene."
This report highlights congenital cataract as a core feature.
Genitourinary 1
Aplasia of the ovary VERY_RARE Aplasia of the ovary (HP:0010463)
Show evidence (1 reference)
DOI:10.1186/s13052-022-01370-y SUPPORT
"Here we provide a 20-year follow-up in two siblings with a benign form of Sengers syndrome, expanding the phenotypical spectrum of the disease by reporting a condition of ovarian agenesis."
This report documents ovarian agenesis, consistent with ovarian aplasia.
Metabolism 1
Lactic acidosis VERY_FREQUENT Lactic acidosis (HP:0003128)
Show evidence (2 references)
DOI:10.3389/fped.2021.639687 SUPPORT
"Both infants had typical clinical features characterized by hypertrophic cardiomyopathy, bilateral cataracts, myopathy, and lactic acidosis, and heart failure was the most severe manifestation."
This report documents lactic acidosis as a characteristic feature of Sengers syndrome.
DOI:10.1186/s13052-022-01370-y SUPPORT
"Sengers syndrome is characterized by congenital cataract, hypertrophic cardiomyopathy, mitochondrial myopathy, and lactic acidosis associated with mutations in AGK gene."
This longitudinal case report includes lactic acidosis as a defining feature.
Musculoskeletal 1
Myopathy VERY_FREQUENT Myopathy (HP:0003198)
Show evidence (2 references)
DOI:10.3389/fped.2021.639687 SUPPORT
"Both infants had typical clinical features characterized by hypertrophic cardiomyopathy, bilateral cataracts, myopathy, and lactic acidosis, and heart failure was the most severe manifestation."
This case report includes myopathy among core Sengers syndrome features.
DOI:10.1186/s13052-022-01370-y SUPPORT
"Sengers syndrome is characterized by congenital cataract, hypertrophic cardiomyopathy, mitochondrial myopathy, and lactic acidosis associated with mutations in AGK gene."
This report specifies mitochondrial myopathy as a defining feature.
🧬

Genetic Associations

1
AGK (Causative)
Show evidence (2 references)
DOI:10.3389/fped.2021.639687 SUPPORT
"Sengers syndrome (OMIM #212350) is a rare autosomal recessive disorder due to mutations in acylglycerol kinase (AGK) gene."
This statement identifies AGK mutations as the cause of Sengers syndrome with autosomal recessive inheritance.
PMID:34164355 SUPPORT
"After genetic analysis, a novel homozygous (c.1131+2T>C) variant of AGK gene was identified in the proband."
This case report provides direct genetic evidence of a pathogenic AGK variant in Sengers syndrome.
💊

Treatments

7
Coenzyme Q10 supplementation MAXO:0010012
Coenzyme Q10 used as part of mitochondrial supportive therapy.
Show evidence (2 references)
PMID:34164355 SUPPORT
"Supplementation with coenzyme Q10, carnitine, B-vitamins, and biotin (called mitochondrial cocktail) was given daily, associated with angiotensin converting enzyme (ACE) inhibitors for cardiomyopathy management."
This case report lists coenzyme Q10 as part of a mitochondrial cocktail for Sengers syndrome.
PMID:34164355 SUPPORT
"Levocarnitine (100 mg/kg daily), coenzyme Q10 (1 mg/kg daily), and vitamin B complex (vitamin B1 20 mg/day and riboflavin 10 mg/day) were administered to improve metabolic status;"
This provides dosing detail confirming coenzyme Q10 use in Sengers syndrome.
Carnitine supplementation MAXO:0010006
L-carnitine provided as part of mitochondrial supportive therapy.
Show evidence (2 references)
PMID:34164355 SUPPORT
"Supplementation with coenzyme Q10, carnitine, B-vitamins, and biotin (called mitochondrial cocktail) was given daily, associated with angiotensin converting enzyme (ACE) inhibitors for cardiomyopathy management."
This case report lists carnitine within the mitochondrial cocktail for Sengers syndrome.
PMID:34164355 SUPPORT
"Levocarnitine (100 mg/kg daily), coenzyme Q10 (1 mg/kg daily), and vitamin B complex (vitamin B1 20 mg/day and riboflavin 10 mg/day) were administered to improve metabolic status;"
This provides dosing detail confirming levocarnitine use in Sengers syndrome.
B vitamin supplementation MAXO:0000761
Vitamin B complex supplementation as part of supportive therapy.
Show evidence (2 references)
PMID:34164355 SUPPORT
"Supplementation with coenzyme Q10, carnitine, B-vitamins, and biotin (called mitochondrial cocktail) was given daily, associated with angiotensin converting enzyme (ACE) inhibitors for cardiomyopathy management."
This case report lists B-vitamins within the mitochondrial cocktail for Sengers syndrome.
PMID:34164355 SUPPORT
"Levocarnitine (100 mg/kg daily), coenzyme Q10 (1 mg/kg daily), and vitamin B complex (vitamin B1 20 mg/day and riboflavin 10 mg/day) were administered to improve metabolic status;"
This provides dosing detail confirming vitamin B complex use in Sengers syndrome.
ACE inhibitor therapy MAXO:0000652
ACE inhibitor therapy used for heart failure management.
Show evidence (3 references)
PMID:34164355 SUPPORT
"Supplementation with coenzyme Q10, carnitine, B-vitamins, and biotin (called mitochondrial cocktail) was given daily, associated with angiotensin converting enzyme (ACE) inhibitors for cardiomyopathy management."
This case report notes ACE inhibitor use alongside mitochondrial cocktail therapy.
PMID:34164355 SUPPORT
"The patient received milrinone, diuretics (furosemide and spironolactone), and captopril to improve heart function."
This provides direct evidence of ACE inhibitor (captopril) therapy in Sengers syndrome.
PMID:38933059 SUPPORT
"Baby was on regular follow-up and was thriving well on diuretics, sacubitril-valsartan and weekly levosimendan infusions."
This neonatal case reports ongoing pharmacologic heart failure management including a neprilysin inhibitor/ARB regimen.
Cardiac transplantation MAXO:0010032
Heart transplantation for severe cardiomyopathy in Sengers syndrome.
Show evidence (2 references)
PMID:8526648 SUPPORT
"This report describes cardiac transplantation for the treatment of the cardiomyopathy associated with Sengers' syndrome."
This case report documents cardiac transplantation as a treatment for Sengers-associated cardiomyopathy.
PMID:38933059 SUPPORT
"At 8 months of age, cardiac transplantation was successfully done and baby has been doing well post-transplantation."
This neonatal case report describes successful cardiac transplantation in Sengers syndrome.
Diuretic therapy MAXO:0000165
Diuretics used for heart failure management in Sengers syndrome.
Show evidence (2 references)
PMID:38933059 SUPPORT
"Baby was on regular follow-up and was thriving well on diuretics, sacubitril-valsartan and weekly levosimendan infusions."
This case report documents ongoing diuretic therapy as part of heart failure management.
PMID:34164355 SUPPORT
"The patient received milrinone, diuretics (furosemide and spironolactone), and captopril to improve heart function."
This provides direct evidence of diuretic use in Sengers syndrome.
Levosimendan infusion MAXO:0000058
Levosimendan infusions used for heart failure support.
Show evidence (1 reference)
PMID:38933059 SUPPORT
"Baby was on regular follow-up and was thriving well on diuretics, sacubitril-valsartan and weekly levosimendan infusions."
This neonatal case report describes levosimendan infusions in Sengers syndrome.
🔬

Biochemical Markers

3
Lactate (Elevated)
Context: Lactic acidosis in Sengers syndrome
Show evidence (2 references)
DOI:10.3389/fped.2021.639687 SUPPORT
"Both infants had typical clinical features characterized by hypertrophic cardiomyopathy, bilateral cataracts, myopathy, and lactic acidosis, and heart failure was the most severe manifestation."
This report documents lactic acidosis as a core biochemical abnormality.
PMID:34164355 SUPPORT
"However, the serum lactic acid increased significantly, reaching 14.99 mmol/L, so appropriate limitation of physical activities is recommended in daily life."
This case report provides quantitative evidence of markedly elevated serum lactic acid.
N-terminal pro-brain natriuretic peptide (NT-proBNP) (Elevated)
Context: Cardiac stress marker in Sengers syndrome with heart failure
Show evidence (1 reference)
PMID:34164355 SUPPORT
"N-terminal pro-brain natriuretic peptide (NT-proBNP) reached 6,076 pg/ml (reference ranges <125 pg/ml) reflecting the state of the heart failure."
This provides biochemical evidence of elevated NT-proBNP in a Sengers syndrome patient with heart failure.
3-hydroxybutyrate (Elevated)
Context: Urinary organic acid analysis in Sengers syndrome
Show evidence (1 reference)
PMID:34164355 SUPPORT
"Urinary organic acid analysis showed increased amounts of 3-hydroxybutyrate (25.5 mmol/L, normal <9.0 mmol/L)"
This report documents elevated 3-hydroxybutyrate on urinary organic acid analysis.
🔀

Differential Diagnoses

3

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

Barth syndrome Not Yet Curated MONDO:0010543
Overlapping Features X-linked mitochondrial disorder with cardiomyopathy and metabolic features that can overlap with Sengers syndrome.
Distinguishing Features
  • X-linked inheritance and neutropenia are typical for Barth syndrome.
  • Cardiolipin remodeling defects due to TAZ variants distinguish it from AGK-related Sengers syndrome.
Show evidence (1 reference)
DOI:10.1007/s10545-014-9759-7 SUPPORT
"Sengers syndrome (due to mutations in AGK), MEGDEL syndrome (or SERAC defect, SERAC1), Barth syndrome (or TAZ defect, TAZ)"
This review lists Barth syndrome alongside Sengers syndrome among phospholipid metabolism disorders.
3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome Not Yet Curated MONDO:0013875
Overlapping Features SERAC1-related mitochondrial disorder (MEGDEL syndrome) with multisystem involvement and overlapping metabolic features.
Distinguishing Features
  • Prominent deafness and Leigh-like neurodegeneration are typical.
  • SERAC1-related disease has a different genetic cause than AGK-related Sengers syndrome.
Show evidence (1 reference)
DOI:10.1007/s10545-014-9759-7 SUPPORT
"Sengers syndrome (due to mutations in AGK), MEGDEL syndrome (or SERAC defect, SERAC1), Barth syndrome (or TAZ defect, TAZ)"
This review lists MEGDEL syndrome as a related phospholipid metabolism disorder to consider in the differential.
Adenine nucleotide translocator 1 (ANT1) deficiency
Overlapping Features Reduced ANT1 protein and activity can present with overlapping mitochondrial cardiomyopathy and myopathy features.
Distinguishing Features
  • ANT1 protein content and transport activity are markedly reduced in muscle, yet sequence and linkage analyses may exclude ANT1 as the primary genetic cause.
Show evidence (2 references)
DOI:10.1002/ana.10214 SUPPORT
"In immunoblot analysis, the protein content of the mitochondrial adenine nucleotide translocator 1 (ANT1) was found to be strongly reduced in the muscle tissues of two unrelated patients with Sengers syndrome."
The abstract documents reduced ANT1 protein in muscle, a key differential consideration.
DOI:10.1002/ana.10214 SUPPORT
"Sequence analysis and linkage analysis showed that ANT1 was not the primary genetic cause of Sengers syndrome."
This supports distinguishing ANT1 deficiency from primary AGK-related Sengers syndrome.
{ }

Source YAML

click to show 
name: Sengers syndrome
creation_date: '2026-01-27T00:22:49Z'
updated_date: '2026-02-17T21:53:14Z'
category: Mendelian
parents: []
disease_term:
  preferred_term: Sengers syndrome
  term:
    id: MONDO:0008922
    label: Sengers syndrome
prevalence:
- population: Reported cases
  percentage: Rare
  evidence:
  - reference: DOI:10.3389/fped.2021.639687
    supports: SUPPORT
    snippet: "Sengers syndrome (OMIM #212350) is a rare autosomal recessive disorder
      due to mutations in acylglycerol kinase (AGK) gene."
    explanation: This case report describes Sengers syndrome as a rare disorder.
epidemiology:
- name: Limited number of reported long-term survivors
  description: >
    Published reports note that only a small number of cases have been followed
    into the second decade, highlighting the rarity of long-term survival data.
  notes: Evidence is based on case-report literature rather than population
    estimates.
  evidence:
  - reference: DOI:10.1186/s13052-022-01370-y
    supports: SUPPORT
    snippet: "Thus far few reported cases have survived the second decade at their
      latest examination, and no natural history data are available for the disease."
    explanation: This statement indicates the scarcity of long-term follow-up
      and limited reported cases.
inheritance:
- name: Autosomal Recessive
  description: >
    Sengers syndrome is inherited in an autosomal recessive pattern, typically
    due to biallelic AGK variants (homozygous or compound heterozygous) with
    unaffected carrier parents.
  evidence:
  - reference: DOI:10.3389/fped.2021.639687
    supports: SUPPORT
    snippet: "Sengers syndrome (OMIM #212350) is a rare autosomal recessive disorder
      due to mutations in acylglycerol kinase (AGK) gene."
    explanation: This explicitly states autosomal recessive inheritance due to
      AGK variants.
  - reference: PMID:34164355
    supports: SUPPORT
    snippet: "Genetic testing of a boy revealed a homozygous pathogenic variant for
      Sengers syndrome in AGK (c.1131+2T>C) which was classified as likely pathogenic
      according to the ACMG guideline"
    explanation: Identification of a homozygous AGK variant supports autosomal
      recessive inheritance.
pathophysiology:
- name: AGK loss of function disrupts lipid signaling
  description: >
    Loss of functional AGK impairs lipid signaling activity attributed to
    mitochondrial acylglycerol kinase.
  biological_processes:
  - preferred_term: phosphatidic acid metabolic process
    term:
      id: GO:0046473
      label: phosphatidic acid metabolic process
    modifier: DYSREGULATED
  evidence:
  - reference: DOI:10.3390/ijms222413484
    supports: SUPPORT
    snippet: "AGK, a mitochondrial acylglycerol kinase, is not only involved in lipid
      signaling but is also a component of the TIM22 complex in the inner mitochondrial
      membrane, which mediates the import of a subset of membrane proteins."
    explanation: This establishes AGK's role in lipid signaling that is lost
      with AGK deficiency.
- name: TIM22 complex assembly defect
  description: >
    Disrupted TIM22 complex assembly at the mitochondrial inner membrane
    impairs the carrier protein import machinery.
  cellular_components:
  - preferred_term: mitochondrial inner membrane
    term:
      id: GO:0005743
      label: mitochondrial inner membrane
  evidence:
  - reference: DOI:10.3390/ijms222413484
    supports: SUPPORT
    snippet: "AGK, a mitochondrial acylglycerol kinase, is not only involved in lipid
      signaling but is also a component of the TIM22 complex in the inner mitochondrial
      membrane, which mediates the import of a subset of membrane proteins."
    explanation: This supports a TIM22 assembly defect at the mitochondrial
      inner membrane in AGK deficiency.
- name: Reduced TIM22-mediated import of inner-membrane carrier proteins
  description: >
    Disruption of the TIM22 complex reduces import of multi-pass carrier
    proteins and sideroflexins into the inner mitochondrial membrane.
  biological_processes:
  - preferred_term: protein insertion into mitochondrial inner membrane
    term:
      id: GO:0045039
      label: protein insertion into mitochondrial inner membrane
    modifier: DECREASED
  evidence:
  - reference: DOI:10.1091/mbc.e20-06-0390
    supports: SUPPORT
    snippet: "Proteomic profiling of Sengers patient fibroblasts and AGK knockout
      models identifies remodeling of the mitochondrial proteome, including mitochondrial
      one-carbon metabolism enzymes, inner membrane serine transporters, sideroflexins,
      and Complex I subunits and assembly factors."
    explanation: This supports reduced import/abundance of inner-membrane
      carriers and sideroflexins in AGK deficiency.
- name: Impaired mitochondrial one-carbon metabolism
  description: >
    Reduced abundance of sideroflexins and one-carbon enzymes disrupts
    mitochondrial one-carbon metabolism.
  biological_processes:
  - preferred_term: one-carbon metabolic process
    term:
      id: GO:0006730
      label: one-carbon metabolic process
    modifier: DYSREGULATED
  evidence:
  - reference: DOI:10.1091/mbc.e20-06-0390
    supports: SUPPORT
    snippet: "Proteomic profiling of Sengers patient fibroblasts and AGK knockout
      models identifies remodeling of the mitochondrial proteome, including mitochondrial
      one-carbon metabolism enzymes, inner membrane serine transporters, sideroflexins,
      and Complex I subunits and assembly factors."
    explanation: This links AGK/TIM22 dysfunction to loss of carrier and
      sideroflexin import with effects on one-carbon metabolism.
- name: Disrupted mitochondrial phospholipid metabolism
  description: >
    AGK loss alters phospholipid metabolism in mitochondrial membranes,
    contributing to disease pathogenesis.
  biological_processes:
  - preferred_term: phospholipid metabolic process
    term:
      id: GO:0006644
      label: phospholipid metabolic process
    modifier: DYSREGULATED
  evidence:
  - reference: DOI:10.3390/ijms222413484
    supports: SUPPORT
    snippet: "AGK mutations can alter both phospholipid metabolism and mitochondrial
      protein biogenesis, contributing to the pathogenesis of Sengers syndrome."
    explanation: This statement links AGK mutations to altered phospholipid
      metabolism in Sengers syndrome.
- name: Oxidative phosphorylation deficiency
  description: >
    Impaired respiratory chain function with reduced complex I and V activity
    and decreased oxygen consumption in patient cells.
  biological_processes:
  - preferred_term: oxidative phosphorylation
    term:
      id: GO:0006119
      label: oxidative phosphorylation
    modifier: DECREASED
  evidence:
  - reference: DOI:10.3390/ijms222413484
    supports: SUPPORT
    snippet: "Decreases in the oxygen consumption rate (OCR) and the OCR:ECAR (extracellular
      acidification rate) ratio in the patient’s fibroblasts indicated reduced electron
      flow through the respiratory chain, and spectrophotometry revealed decreased
      activity of OXPHOS complexes I and V."
    explanation: This provides direct evidence of impaired oxidative
      phosphorylation and reduced complex I and V activity.
phenotypes:
- name: Hypertrophic cardiomyopathy
  category: Cardiovascular
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Hypertrophic cardiomyopathy
    term:
      id: HP:0001639
      label: Hypertrophic cardiomyopathy
  evidence:
  - reference: DOI:10.3389/fped.2021.639687
    supports: SUPPORT
    snippet: "Both infants had typical clinical features characterized by hypertrophic
      cardiomyopathy, bilateral cataracts, myopathy, and lactic acidosis, and heart
      failure was the most severe manifestation."
    explanation: This case report documents hypertrophic cardiomyopathy as a
      core feature of Sengers syndrome.
  - reference: DOI:10.1186/s13052-022-01370-y
    supports: SUPPORT
    snippet: "Sengers syndrome is characterized by congenital cataract, hypertrophic
      cardiomyopathy, mitochondrial myopathy, and lactic acidosis associated with
      mutations in AGK gene."
    explanation: This longitudinal case report reiterates hypertrophic
      cardiomyopathy as a defining feature.
- name: Developmental cataract
  category: Ophthalmologic
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Developmental cataract
    term:
      id: HP:0000519
      label: Developmental cataract
  evidence:
  - reference: DOI:10.3389/fped.2021.639687
    supports: SUPPORT
    snippet: "Both infants had typical clinical features characterized by hypertrophic
      cardiomyopathy, bilateral cataracts, myopathy, and lactic acidosis, and heart
      failure was the most severe manifestation."
    explanation: This identifies bilateral cataracts as a defining phenotype in
      Sengers syndrome.
  - reference: DOI:10.1186/s13052-022-01370-y
    supports: SUPPORT
    snippet: "Sengers syndrome is characterized by congenital cataract, hypertrophic
      cardiomyopathy, mitochondrial myopathy, and lactic acidosis associated with
      mutations in AGK gene."
    explanation: This report highlights congenital cataract as a core feature.
- name: Myopathy
  category: Neuromuscular
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Myopathy
    term:
      id: HP:0003198
      label: Myopathy
  evidence:
  - reference: DOI:10.3389/fped.2021.639687
    supports: SUPPORT
    snippet: "Both infants had typical clinical features characterized by hypertrophic
      cardiomyopathy, bilateral cataracts, myopathy, and lactic acidosis, and heart
      failure was the most severe manifestation."
    explanation: This case report includes myopathy among core Sengers syndrome
      features.
  - reference: DOI:10.1186/s13052-022-01370-y
    supports: SUPPORT
    snippet: "Sengers syndrome is characterized by congenital cataract, hypertrophic
      cardiomyopathy, mitochondrial myopathy, and lactic acidosis associated with
      mutations in AGK gene."
    explanation: This report specifies mitochondrial myopathy as a defining
      feature.
- name: Lactic acidosis
  category: Metabolic
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Lactic acidosis
    term:
      id: HP:0003128
      label: Lactic acidosis
  evidence:
  - reference: DOI:10.3389/fped.2021.639687
    supports: SUPPORT
    snippet: "Both infants had typical clinical features characterized by hypertrophic
      cardiomyopathy, bilateral cataracts, myopathy, and lactic acidosis, and heart
      failure was the most severe manifestation."
    explanation: This report documents lactic acidosis as a characteristic
      feature of Sengers syndrome.
  - reference: DOI:10.1186/s13052-022-01370-y
    supports: SUPPORT
    snippet: "Sengers syndrome is characterized by congenital cataract, hypertrophic
      cardiomyopathy, mitochondrial myopathy, and lactic acidosis associated with
      mutations in AGK gene."
    explanation: This longitudinal case report includes lactic acidosis as a
      defining feature.
- name: Congestive heart failure
  category: Cardiovascular
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  evidence:
  - reference: DOI:10.3389/fped.2021.639687
    supports: SUPPORT
    snippet: "Both infants had typical clinical features characterized by hypertrophic
      cardiomyopathy, bilateral cataracts, myopathy, and lactic acidosis, and heart
      failure was the most severe manifestation."
    explanation: Heart failure is reported as the most severe clinical
      manifestation in these cases.
  - reference: PMID:34164355
    supports: SUPPORT
    snippet: "NT-proBNP reached 6,076 pg/ml (reference ranges <125 pg/ml) reflecting
      the state of the heart failure."
    explanation: This case report documents biochemical evidence of heart
      failure in a Sengers syndrome patient.
- name: Aplasia of the ovary
  category: Genitourinary
  frequency: VERY_RARE
  phenotype_term:
    preferred_term: Aplasia of the ovary
    term:
      id: HP:0010463
      label: Aplasia of the ovary
  evidence:
  - reference: DOI:10.1186/s13052-022-01370-y
    supports: SUPPORT
    snippet: "Here we provide a 20-year follow-up in two siblings with a benign form
      of Sengers syndrome, expanding the phenotypical spectrum of the disease by reporting
      a condition of ovarian agenesis."
    explanation: This report documents ovarian agenesis, consistent with ovarian
      aplasia.
genetic:
- name: AGK
  association: Causative
  notes: Autosomal recessive; HGNC:21869
  evidence:
  - reference: DOI:10.3389/fped.2021.639687
    supports: SUPPORT
    snippet: "Sengers syndrome (OMIM #212350) is a rare autosomal recessive disorder
      due to mutations in acylglycerol kinase (AGK) gene."
    explanation: This statement identifies AGK mutations as the cause of Sengers
      syndrome with autosomal recessive inheritance.
  - reference: PMID:34164355
    supports: SUPPORT
    snippet: "After genetic analysis, a novel homozygous (c.1131+2T>C) variant of
      AGK gene was identified in the proband."
    explanation: This case report provides direct genetic evidence of a
      pathogenic AGK variant in Sengers syndrome.
environmental: []
biochemical:
- name: Lactate
  presence: Elevated
  context: Lactic acidosis in Sengers syndrome
  biomarker_term:
    preferred_term: lactate
    term:
      id: CHEBI:24996
      label: lactate
  evidence:
  - reference: DOI:10.3389/fped.2021.639687
    supports: SUPPORT
    snippet: "Both infants had typical clinical features characterized by hypertrophic
      cardiomyopathy, bilateral cataracts, myopathy, and lactic acidosis, and heart
      failure was the most severe manifestation."
    explanation: This report documents lactic acidosis as a core biochemical
      abnormality.
  - reference: PMID:34164355
    supports: SUPPORT
    snippet: "However, the serum lactic acid increased significantly, reaching 14.99
      mmol/L, so appropriate limitation of physical activities is recommended in daily
      life."
    explanation: This case report provides quantitative evidence of markedly
      elevated serum lactic acid.
- name: N-terminal pro-brain natriuretic peptide (NT-proBNP)
  presence: Elevated
  context: Cardiac stress marker in Sengers syndrome with heart failure
  evidence:
  - reference: PMID:34164355
    supports: SUPPORT
    snippet: "N-terminal pro-brain natriuretic peptide (NT-proBNP) reached 6,076 pg/ml
      (reference ranges <125 pg/ml) reflecting the state of the heart failure."
    explanation: This provides biochemical evidence of elevated NT-proBNP in a
      Sengers syndrome patient with heart failure.
- name: 3-hydroxybutyrate
  presence: Elevated
  context: Urinary organic acid analysis in Sengers syndrome
  biomarker_term:
    preferred_term: 3-hydroxybutyrate
    term:
      id: CHEBI:37054
      label: 3-hydroxybutyrate
  evidence:
  - reference: PMID:34164355
    supports: SUPPORT
    snippet: "Urinary organic acid analysis showed increased amounts of 3-hydroxybutyrate
      (25.5 mmol/L, normal <9.0 mmol/L)"
    explanation: This report documents elevated 3-hydroxybutyrate on urinary
      organic acid analysis.
treatments:
- name: Coenzyme Q10 supplementation
  description: Coenzyme Q10 used as part of mitochondrial supportive therapy.
  evidence:
  - reference: PMID:34164355
    supports: SUPPORT
    snippet: "Supplementation with coenzyme Q10, carnitine, B-vitamins, and biotin
      (called mitochondrial cocktail) was given daily, associated with angiotensin
      converting enzyme (ACE) inhibitors for cardiomyopathy management."
    explanation: This case report lists coenzyme Q10 as part of a mitochondrial
      cocktail for Sengers syndrome.
  - reference: PMID:34164355
    supports: SUPPORT
    snippet: "Levocarnitine (100 mg/kg daily), coenzyme Q10 (1 mg/kg daily), and vitamin
      B complex (vitamin B1 20 mg/day and riboflavin 10 mg/day) were administered
      to improve metabolic status;"
    explanation: This provides dosing detail confirming coenzyme Q10 use in
      Sengers syndrome.
  treatment_term:
    preferred_term: coenzyme Q10 supplementation
    term:
      id: MAXO:0010012
      label: coenzyme Q10 supplementation
    qualifiers:
    - predicate:
        preferred_term: therapeutic agent
        term:
          id: NCIT:C2259
          label: Therapeutic Agent
      value:
        preferred_term: coenzyme Q10
        term:
          id: NCIT:C916
          label: Coenzyme Q10
- name: Carnitine supplementation
  description: L-carnitine provided as part of mitochondrial supportive therapy.
  evidence:
  - reference: PMID:34164355
    supports: SUPPORT
    snippet: "Supplementation with coenzyme Q10, carnitine, B-vitamins, and biotin
      (called mitochondrial cocktail) was given daily, associated with angiotensin
      converting enzyme (ACE) inhibitors for cardiomyopathy management."
    explanation: This case report lists carnitine within the mitochondrial
      cocktail for Sengers syndrome.
  - reference: PMID:34164355
    supports: SUPPORT
    snippet: "Levocarnitine (100 mg/kg daily), coenzyme Q10 (1 mg/kg daily), and vitamin
      B complex (vitamin B1 20 mg/day and riboflavin 10 mg/day) were administered
      to improve metabolic status;"
    explanation: This provides dosing detail confirming levocarnitine use in
      Sengers syndrome.
  treatment_term:
    preferred_term: carnitine supplementation
    term:
      id: MAXO:0010006
      label: carnitine supplementation
    qualifiers:
    - predicate:
        preferred_term: therapeutic agent
        term:
          id: NCIT:C2259
          label: Therapeutic Agent
      value:
        preferred_term: levocarnitine
        term:
          id: NCIT:C26657
          label: Levocarnitine
- name: B vitamin supplementation
  description: Vitamin B complex supplementation as part of supportive therapy.
  evidence:
  - reference: PMID:34164355
    supports: SUPPORT
    snippet: "Supplementation with coenzyme Q10, carnitine, B-vitamins, and biotin
      (called mitochondrial cocktail) was given daily, associated with angiotensin
      converting enzyme (ACE) inhibitors for cardiomyopathy management."
    explanation: This case report lists B-vitamins within the mitochondrial
      cocktail for Sengers syndrome.
  - reference: PMID:34164355
    supports: SUPPORT
    snippet: "Levocarnitine (100 mg/kg daily), coenzyme Q10 (1 mg/kg daily), and vitamin
      B complex (vitamin B1 20 mg/day and riboflavin 10 mg/day) were administered
      to improve metabolic status;"
    explanation: This provides dosing detail confirming vitamin B complex use in
      Sengers syndrome.
  treatment_term:
    preferred_term: B vitamin supplementation
    term:
      id: MAXO:0000761
      label: B vitamin supplementation
    qualifiers:
    - predicate:
        preferred_term: therapeutic agent
        term:
          id: NCIT:C2259
          label: Therapeutic Agent
      value:
        preferred_term: thiamine
        term:
          id: NCIT:C874
          label: Thiamine
    - predicate:
        preferred_term: therapeutic agent
        term:
          id: NCIT:C2259
          label: Therapeutic Agent
      value:
        preferred_term: riboflavin
        term:
          id: NCIT:C808
          label: Riboflavin
- name: ACE inhibitor therapy
  description: ACE inhibitor therapy used for heart failure management.
  evidence:
  - reference: PMID:34164355
    supports: SUPPORT
    snippet: "Supplementation with coenzyme Q10, carnitine, B-vitamins, and biotin
      (called mitochondrial cocktail) was given daily, associated with angiotensin
      converting enzyme (ACE) inhibitors for cardiomyopathy management."
    explanation: This case report notes ACE inhibitor use alongside
      mitochondrial cocktail therapy.
  - reference: PMID:34164355
    supports: SUPPORT
    snippet: "The patient received milrinone, diuretics (furosemide and spironolactone),
      and captopril to improve heart function."
    explanation: This provides direct evidence of ACE inhibitor (captopril)
      therapy in Sengers syndrome.
  - reference: PMID:38933059
    supports: SUPPORT
    snippet: "Baby was on regular follow-up and was thriving well on diuretics, sacubitril-valsartan
      and weekly levosimendan infusions."
    explanation: This neonatal case reports ongoing pharmacologic heart failure
      management including a neprilysin inhibitor/ARB regimen.
  treatment_term:
    preferred_term: ACE inhibitor therapy
    term:
      id: MAXO:0000652
      label: ACE inhibitor therapy
    qualifiers:
    - predicate:
        preferred_term: therapeutic agent
        term:
          id: NCIT:C2259
          label: Therapeutic Agent
      value:
        preferred_term: captopril
        term:
          id: NCIT:C340
          label: Captopril
- name: Cardiac transplantation
  description: Heart transplantation for severe cardiomyopathy in Sengers
    syndrome.
  evidence:
  - reference: PMID:8526648
    supports: SUPPORT
    snippet: "This report describes cardiac transplantation for the treatment of the
      cardiomyopathy associated with Sengers' syndrome."
    explanation: This case report documents cardiac transplantation as a
      treatment for Sengers-associated cardiomyopathy.
  - reference: PMID:38933059
    supports: SUPPORT
    snippet: "At 8 months of age, cardiac transplantation was successfully done and
      baby has been doing well post-transplantation."
    explanation: This neonatal case report describes successful cardiac
      transplantation in Sengers syndrome.
  treatment_term:
    preferred_term: cardiac transplantation
    term:
      id: MAXO:0010032
      label: cardiac transplantation
- name: Diuretic therapy
  description: Diuretics used for heart failure management in Sengers syndrome.
  evidence:
  - reference: PMID:38933059
    supports: SUPPORT
    snippet: "Baby was on regular follow-up and was thriving well on diuretics, sacubitril-valsartan
      and weekly levosimendan infusions."
    explanation: This case report documents ongoing diuretic therapy as part of
      heart failure management.
  - reference: PMID:34164355
    supports: SUPPORT
    snippet: "The patient received milrinone, diuretics (furosemide and spironolactone),
      and captopril to improve heart function."
    explanation: This provides direct evidence of diuretic use in Sengers
      syndrome.
  treatment_term:
    preferred_term: diuretic agent therapy
    term:
      id: MAXO:0000165
      label: diuretic agent therapy
    qualifiers:
    - predicate:
        preferred_term: therapeutic agent
        term:
          id: NCIT:C2259
          label: Therapeutic Agent
      value:
        preferred_term: furosemide
        term:
          id: NCIT:C515
          label: Furosemide
    - predicate:
        preferred_term: therapeutic agent
        term:
          id: NCIT:C2259
          label: Therapeutic Agent
      value:
        preferred_term: spironolactone
        term:
          id: NCIT:C840
          label: Spironolactone
- name: Levosimendan infusion
  description: Levosimendan infusions used for heart failure support.
  evidence:
  - reference: PMID:38933059
    supports: SUPPORT
    snippet: "Baby was on regular follow-up and was thriving well on diuretics, sacubitril-valsartan
      and weekly levosimendan infusions."
    explanation: This neonatal case report describes levosimendan infusions in
      Sengers syndrome.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
    qualifiers:
    - predicate:
        preferred_term: therapeutic agent
        term:
          id: NCIT:C2259
          label: Therapeutic Agent
      value:
        preferred_term: levosimendan
        term:
          id: NCIT:C174653
          label: Levosimendan
datasets: []
differential_diagnoses:
- name: Barth syndrome
  disease_term:
    preferred_term: Barth syndrome
    term:
      id: MONDO:0010543
      label: Barth syndrome
  description: >
    X-linked mitochondrial disorder with cardiomyopathy and metabolic features
    that can overlap with Sengers syndrome.
  distinguishing_features:
  - X-linked inheritance and neutropenia are typical for Barth syndrome.
  - Cardiolipin remodeling defects due to TAZ variants distinguish it from
    AGK-related Sengers syndrome.
  evidence:
  - reference: DOI:10.1007/s10545-014-9759-7
    supports: SUPPORT
    snippet: "Sengers syndrome (due to mutations in AGK), MEGDEL syndrome (or SERAC
      defect, SERAC1), Barth syndrome (or TAZ defect, TAZ)"
    explanation: This review lists Barth syndrome alongside Sengers syndrome
      among phospholipid metabolism disorders.
- name: 3-methylglutaconic aciduria with deafness, encephalopathy, and
    Leigh-like syndrome
  disease_term:
    preferred_term: 3-methylglutaconic aciduria with deafness, encephalopathy,
      and Leigh-like syndrome
    term:
      id: MONDO:0013875
      label: 3-methylglutaconic aciduria with deafness, encephalopathy, and
        Leigh-like syndrome
  description: >
    SERAC1-related mitochondrial disorder (MEGDEL syndrome) with multisystem
    involvement and overlapping metabolic features.
  distinguishing_features:
  - Prominent deafness and Leigh-like neurodegeneration are typical.
  - SERAC1-related disease has a different genetic cause than AGK-related
    Sengers syndrome.
  evidence:
  - reference: DOI:10.1007/s10545-014-9759-7
    supports: SUPPORT
    snippet: "Sengers syndrome (due to mutations in AGK), MEGDEL syndrome (or SERAC
      defect, SERAC1), Barth syndrome (or TAZ defect, TAZ)"
    explanation: This review lists MEGDEL syndrome as a related phospholipid
      metabolism disorder to consider in the differential.
- name: Adenine nucleotide translocator 1 (ANT1) deficiency
  description: Reduced ANT1 protein and activity can present with overlapping
    mitochondrial cardiomyopathy and myopathy features.
  distinguishing_features:
  - ANT1 protein content and transport activity are markedly reduced in muscle,
    yet sequence and linkage analyses may exclude ANT1 as the primary genetic
    cause.
  evidence:
  - reference: DOI:10.1002/ana.10214
    supports: SUPPORT
    snippet: "In immunoblot analysis, the protein content of the mitochondrial adenine
      nucleotide translocator 1 (ANT1) was found to be strongly reduced in the muscle
      tissues of two unrelated patients with Sengers syndrome."
    explanation: The abstract documents reduced ANT1 protein in muscle, a key
      differential consideration.
  - reference: DOI:10.1002/ana.10214
    supports: SUPPORT
    snippet: "Sequence analysis and linkage analysis showed that ANT1 was not the
      primary genetic cause of Sengers syndrome."
    explanation: This supports distinguishing ANT1 deficiency from primary
      AGK-related Sengers syndrome.
references:
- reference: DOI:10.1002/iub.2767
  title: Adenine nucleotide carrier protein dysfunction in human disease
  findings: []
- reference: DOI:10.1007/s11897-023-00592-3
  title: Cardiac Involvement in Mitochondrial Disorders
  findings: []
- reference: DOI:10.1016/j.ymgme.2012.11.282
  title: 'Mitochondrial citrate synthase crystals: Novel finding in Sengers syndrome
    caused by acylglycerol kinase (AGK) mutations'
  findings: []
- reference: DOI:10.1186/s40246-025-00723-y
  title: Sengers syndrome caused by biallelic TIMM29 variants and RNAi silencing
    in Drosophila orthologue recapitulates the human phenotype
  findings: []