Sengers syndrome - Disorder Mechanisms

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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.

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References

4

DOI:10.1002/iub.2767

Adenine nucleotide carrier protein dysfunction in human disease

No top-level findings curated for this source.

DOI:10.1007/s11897-023-00592-3

Cardiac Involvement in Mitochondrial Disorders

No top-level findings curated for this source.

DOI:10.1016/j.ymgme.2012.11.282

Mitochondrial citrate synthase crystals: Novel finding in Sengers syndrome caused by acylglycerol kinase (AGK) mutations

No top-level findings curated for this source.

DOI:10.1186/s40246-025-00723-y

Sengers syndrome caused by biallelic TIMM29 variants and RNAi silencing in Drosophila orthologue recapitulates the human phenotype

No top-level findings curated for this source.

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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.

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Phenotypes

6

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.

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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.

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Treatments

7

Coenzyme Q10 supplementation

Action: 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

Action: 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

Action: 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

Action: 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

Action: 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

Action: diuretic agent 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

Action: pharmacotherapy 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.

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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.

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Differential Diagnoses

3

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

Barth syndrome 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.

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Literature Summaries

2

Disorder ▸

Disorder

Name: Sengers syndrome
Category: Mendelian
Existing deep-research providers: falcon
Existing evidence reference count in YAML: 49

Key Pathophysiology Nodes

AGK loss of function disrupts lipid signaling
TIM22 complex assembly defect
Reduced TIM22-mediated import of inner-membrane carrier proteins
Impaired mitochondrial one-carbon metabolism
Disrupted mitochondrial phospholipid metabolism
Oxidative phosphorylation deficiency
Deep research literature mapping

Citation Inventory (for evidence mapping)

DOI:10.1002/iub.2767
DOI:10.1007/s10545-014-9759-7
DOI:10.1007/s11897-023-00592-3
DOI:10.1016/j.10.1007/s10545-014-9759-7
DOI:10.1016/j.ymgme.2012.11.282
DOI:10.1091/mbc.e20-06-0390
DOI:10.1186/s13052-022-01370-y
DOI:10.1186/s40246-025-00723-y
DOI:10.3389/fped.2021.639687
DOI:10.3390/ijms222413484

Falcon ▸

Disease Pathophysiology Research Report

Edison Scientific Literature 29 citations 2026-01-26T13:02:07.433949

Disease Pathophysiology Research Report

Target Disease - Disease Name: Sengers syndrome - MONDO ID: Not established in the sources cited below - Category: Mendelian

Pathophysiology description Sengers syndrome is an autosomal recessive mitochondrial disorder caused primarily by biallelic pathogenic variants in AGK (acylglycerol kinase), which encodes a mitochondrial lipid kinase that is also a metazoan subunit of the TIM22 carrier-translocase of the inner mitochondrial membrane. AGK deficiency perturbs mitochondrial lipid metabolism (conversion of diacylglycerol/monoacylglycerol to phosphatidic acid/lysophosphatidic acid) and compromises TIM22-dependent import/biogenesis of multi-pass inner-membrane proteins, notably SLC25 carrier proteins and, as more recently recognized, sideroflexins (SFXNs). These defects converge on impaired oxidative phosphorylation (OXPHOS), altered inner-membrane lipid milieu (with downstream effects on cardiolipin-dependent complex stability and ANT1 levels), and increased mitochondrial reactive oxygen species, producing a stereotyped tissue pattern of dysfunction in heart, skeletal muscle, and lens and systemic lactic acidosis. A small number of patients with a clinically indistinguishable severe phenotype have now been reported with biallelic variants in TIMM29 (Tim29), another TIM22 complex component, reinforcing TIM22 dysfunction as the core molecular lesion in Sengers syndrome. (siriwardena2013mitochondrialcitratesynthase pages 8-8, wortmann2015inbornerrorsof pages 5-6, barbosagouveia2021characterizationofa pages 5-6, jackson2021thetim22complex pages 1-2, shalata2025sengerssyndromecaused pages 1-2)

Key concepts and definitions with current understanding - Dual role of AGK: lipid kinase and TIM22 subunit. AGK catalyzes DAG/MAG phosphorylation to PA/LPA within the inner mitochondrial membrane and functions kinase-independently within the TIM22 complex required for carrier import; AGK loss reduces OXPHOS complex I and V activities and mitochondrial respiration (OCR and OCR:ECAR) in patient cells. (Barbosa‑Gouveia 2021, Int J Mol Sci; DOI:10.3390/ijms222413484; published Dec 2021; https://doi.org/10.3390/ijms222413484) (barbosagouveia2021characterizationofa pages 5-6, barbosagouveia2021characterizationofa pages 1-2) - TIM22 substrate spectrum: In addition to canonical SLC25 carriers (6 TMs), TIM22 mediates the import of non-canonical substrates, including the 5‑TM sideroflexins (SFXNs) and other atypical clients, linking AGK/TIM22 dysfunction to disrupted mitochondrial one‑carbon metabolism via SFXNs. (Jackson 2021, Mol Biol Cell; DOI:10.1091/mbc.E20-06-0390; published Mar 2021; https://doi.org/10.1091/mbc.e20-06-0390) (jackson2021thetim22complex pages 1-2) - ANT1 and inner-membrane lipidopathy: Historic clinical biochemistry shows reduced ANT1 (SLC25A4) in muscle and combined OXPHOS defects (often complexes I and V) in AGK deficiency, plausibly due to cardiolipin-dependent assembly/stability defects and carrier-import insufficiency. (Wortmann 2015, JIMD; DOI:10.1007/s10545-014-9759-7; published Jan 2015; https://doi.org/10.1007/s10545-014-9759-7) (wortmann2015inbornerrorsof pages 5-6) - Oxidative stress: AGK loss is associated with mitochondrial DAG accumulation, upregulated mitochondrial antioxidant defenses (e.g., SOD2, PRDX3), and mitochondrial ROS-mediated damage to [Fe–S] enzymes and OXPHOS complexes. (Siriwardena 2013, Mol Genet Metab; DOI:10.1016/j.ymgme.2012.11.282; published Jan 2013; https://doi.org/10.1016/j.ymgme.2012.11.282) (siriwardena2013mitochondrialcitratesynthase pages 8-8, siriwardena2013mitochondrialcitratesynthase pages 8-10)

Recent developments and latest research (priority on 2023–2024) - Mitochondrial carrier and ANT biology in disease: Contemporary reviews emphasize ANT/carrier dysfunction and protein‑import stress as themes in human disease. In this context, Sengers syndrome is linked to TIM22/AGK defects affecting carrier biogenesis. (Mishra 2023, IUBMB Life; DOI:10.1002/iub.2767; published Jul 2023; https://doi.org/10.1002/iub.2767) (wang2021casereporttwo pages 8-9) - Cardiac involvement in mitochondrial disorders: A 2023 cardiology review highlights Sengers syndrome as an AGK/TIM22-linked cardiomyopathy, underscoring the heart’s vulnerability to OXPHOS impairment. (Popoiu 2023, Curr Heart Fail Rep; DOI:10.1007/s11897-023-00592-3; published Feb 2023; https://doi.org/10.1007/s11897-023-00592-3) (wang2021casereporttwo pages 2-4) - Expansion of TIM22-linked genetic etiology (2025, relevant): Biallelic TIMM29 (Tim29) variants have been proposed to cause a severe Sengers-like phenotype (SS–TIMM29), with biochemical differences such as frequent marked hyperCKemia and reduced ANT1; a Drosophila model supports pathogenicity. This extends the mechanism from AGK alone to broader TIM22 complex dysfunction. (Shalata 2025, Human Genomics; DOI:10.1186/s40246-025-00723-y; published Feb 2025; https://doi.org/10.1186/s40246-025-00723-y) (shalata2025sengerssyndromecaused pages 1-2)

Current applications and real-world implementations - Diagnostics: Molecular confirmation relies on next-generation sequencing (exome/panels) targeting AGK (and, increasingly, TIM22/TIMM29). Muscle histopathology can show COX-negative/SDH‑positive fibers, lipid accumulation, and cristae loss on TEM; OXPHOS enzymology often reveals complex I and/or IV/V deficiencies. Metabolic workup frequently identifies lactic acidosis. (Wang 2021, Front Pediatr; DOI:10.3389/fped.2021.639687; published Jun 2021; https://doi.org/10.3389/fped.2021.639687) (wang2021casereporttwo pages 2-4) - Longitudinal management: Supportive multidisciplinary care includes early cataract surgery, standard heart failure therapies, and symptomatic metabolic management; long-term follow-up into adulthood has been documented in milder forms. (Panicucci 2022, Ital J Pediatr; DOI:10.1186/s13052-022-01370-y; published Oct 2022; https://doi.org/10.1186/s13052-022-01370-y) (panicucci2022longtermfollowup pages 6-6, panicucci2022longtermfollowup pages 2-4) - Functional cellular assays: Patient fibroblasts can demonstrate reduced oxygen consumption rate (OCR), decreased OCR:ECAR, and specific OXPHOS complex defects, supporting pathogenicity assessments for new variants. (Barbosa‑Gouveia 2021, Int J Mol Sci; DOI:10.3390/ijms222413484; https://doi.org/10.3390/ijms222413484) (barbosagouveia2021characterizationofa pages 5-6)

Expert opinions and analysis from authoritative sources - Mechanistic framing: Reviews and mechanistic studies converge on AGK/TIM22 dysfunction as the proximate cause of Sengers syndrome pathophysiology, integrating lipid kinase insufficiency (affecting PA/CL milieu) with carrier import failure (affecting SLC25 and SFXN families) to explain OXPHOS compromise and organ-selective vulnerability. (Wortmann 2015, JIMD; Siriwardena 2013, MGM; Jackson 2021, MBoC; Mishra 2023, IUBMB Life) (wortmann2015inbornerrorsof pages 5-6, siriwardena2013mitochondrialcitratesynthase pages 8-8, jackson2021thetim22complex pages 1-2, wang2021casereporttwo pages 8-9) - Cardiac pathobiology: Given the heart’s reliance on oxidative metabolism, AGK/TIM22 defects precipitate hypertrophic/dilated cardiomyopathy through ATP shortfall, altered carrier complement (e.g., ANT1), and membrane‑lipid derangements that impair complex stability. (Popoiu 2023, Curr Heart Fail Rep; Wortmann 2015, JIMD) (wang2021casereporttwo pages 2-4, wortmann2015inbornerrorsof pages 5-6)

Relevant statistics and data from recent studies - Proteomic remodeling in AGK/TIM22 dysfunction: Loss of AGK leads to broad down-regulation of inner-membrane carriers (SLC25 family) and SFXN proteins, with functional dependence on exogenous serine—implicating impaired mitochondrial one‑carbon metabolism. Though largely qualitative, this establishes substrate classes impacted. (Jackson 2021, Mol Biol Cell; https://doi.org/10.1091/mbc.e20-06-0390) (jackson2021thetim22complex pages 1-2) - Enzymology and bioenergetics: Reduced activity of complexes I and V and decreased OCR:ECAR ratio were documented in AGK‑mutant patient fibroblasts; earlier reports show combined complex I/IV deficiencies and ANT1 reduction in muscle. (Barbosa‑Gouveia 2021, Int J Mol Sci; Wortmann 2015, JIMD) (barbosagouveia2021characterizationofa pages 5-6, wortmann2015inbornerrorsof pages 5-6) - Clinical longitudinal data: A 20‑year follow‑up in two siblings with a benign form suggests slowly progressive HCM with preserved LVEF and no late gadolinium enhancement on MRI under standard care; systemic features included persistent lactic acidosis and ovarian agenesis in one case. (Panicucci 2022, Ital J Pediatr; https://doi.org/10.1186/s13052-022-01370-y) (panicucci2022longtermfollowup pages 6-6, panicucci2022longtermfollowup pages 2-4)

Core Pathophysiology Primary mechanisms
TIM22-dependent protein import defect: AGK, as a TIM22 subunit, supports biogenesis of multi-pass inner-membrane carriers (SLC25) and SFXNs; AGK loss reduces these substrates and perturbs mitochondrial one‑carbon metabolism, limiting respiratory capacity. (Jackson 2021; https://doi.org/10.1091/mbc.e20-06-0390) (jackson2021thetim22complex pages 1-2)
Lipid kinase insufficiency: Reduced PA/LPA synthesis disturbs inner-membrane lipid composition and cardiolipin-dependent OXPHOS complex stability and ANT1 function. (Wortmann 2015; https://doi.org/10.1007/s10545-014-9759-7; Siriwardena 2013; https://doi.org/10.1016/j.ymgme.2012.11.282) (wortmann2015inbornerrorsof pages 5-6, siriwardena2013mitochondrialcitratesynthase pages 8-8)
Oxidative stress axis: DAG accumulation and membrane disruption increase mitochondrial ROS, upregulating SOD2/PRDX3 and damaging OXPHOS components. (Siriwardena 2013; https://doi.org/10.1016/j.ymgme.2012.11.282) (siriwardena2013mitochondrialcitratesynthase pages 8-8) Dysregulated pathways
Mitochondrial carrier import (TIM22), cardiolipin-related OXPHOS assembly/function, mitochondrial one‑carbon metabolism via SFXNs, and redox homeostasis. (Jackson 2021; Wortmann 2015) (jackson2021thetim22complex pages 1-2, wortmann2015inbornerrorsof pages 5-6) Affected cellular processes
Carrier biogenesis, ADP/ATP exchange, electron transport (complex I/IV/V activity), mitochondrial respiration (OCR/ECAR), and cristae architecture. (Barbosa‑Gouveia 2021; Siriwardena 2013) (barbosagouveia2021characterizationofa pages 5-6, siriwardena2013mitochondrialcitratesynthase pages 8-8)
Key Molecular Players
Genes/Proteins: AGK (primary causal gene); TIM22 complex subunits (TIMM22, AGK; and in extended genetics, TIMM29/Tim29); ANT1/SLC25A4 as a vulnerable carrier; SFXN family as TIM22 substrates. (Wortmann 2015; Siriwardena 2013; Jackson 2021; Shalata 2025) (wortmann2015inbornerrorsof pages 5-6, siriwardena2013mitochondrialcitratesynthase pages 8-8, jackson2021thetim22complex pages 1-2, shalata2025sengerssyndromecaused pages 1-2)
Chemical entities: phosphatidic acid (PA), lysophosphatidic acid (LPA), diacylglycerol (DAG), lactate. (Siriwardena 2013; Barbosa‑Gouveia 2021; Wang 2021) (siriwardena2013mitochondrialcitratesynthase pages 8-8, barbosagouveia2021characterizationofa pages 5-6, wang2021casereporttwo pages 8-9)
Cell types: cardiomyocytes, skeletal myofibers, lens fiber cells. (Siriwardena 2013; Wortmann 2015) (siriwardena2013mitochondrialcitratesynthase pages 8-8, wortmann2015inbornerrorsof pages 5-6)
Anatomical locations: heart, skeletal muscle, ocular lens. (Wang 2021; Siriwardena 2013) (wang2021casereporttwo pages 2-4, siriwardena2013mitochondrialcitratesynthase pages 8-8)
Biological Processes (for GO annotation)
Mitochondrial protein import via TIM22 (carrier translocase–mediated insertion of multi-pass inner-membrane proteins; includes SLC25, SFXN). (Jackson 2021) (jackson2021thetim22complex pages 1-2)
Phosphatidic acid biosynthetic process and lipid metabolism impacting cardiolipin content and OXPHOS complex stability. (Siriwardena 2013; Wortmann 2015) (siriwardena2013mitochondrialcitratesynthase pages 8-8, wortmann2015inbornerrorsof pages 5-6)
Cellular response to oxidative stress and mitochondrial redox homeostasis. (Siriwardena 2013) (siriwardena2013mitochondrialcitratesynthase pages 8-8)
Mitochondrial one‑carbon metabolism perturbed via SFXN deficits. (Jackson 2021) (jackson2021thetim22complex pages 1-2)
Cellular Components
Inner mitochondrial membrane; TIM22 complex localized within IMM; mitochondrial matrix/cristae where ultrastructural changes and citrate synthase crystals may be observed. (Siriwardena 2013; Barbosa‑Gouveia 2021) (siriwardena2013mitochondrialcitratesynthase pages 8-8, barbosagouveia2021characterizationofa pages 5-6)
Disease Progression
Sequence of events: Biallelic AGK (or TIMM29) variants → reduced AGK protein and/or TIM22 complex function → decreased carrier import (SLC25, SFXN) + impaired PA/CL milieu → OXPHOS complex I/IV/V instability and ANT1 reduction → ATP shortfall, increased ROS, and cristae derangement → organ-level failure in high-energy tissues (HCM, myopathy), lens opacification, and systemic lactic acidosis. (Wortmann 2015; Jackson 2021; Siriwardena 2013) (wortmann2015inbornerrorsof pages 5-6, jackson2021thetim22complex pages 1-2, siriwardena2013mitochondrialcitratesynthase pages 8-8)
Clinical phases: Severe neonatal form with early heart failure and hyperlactatemia (often truncating genotypes) versus milder chronic forms with survival into adulthood; overlap and variability occur. (Barbosa‑Gouveia 2021; Panicucci 2022) (barbosagouveia2021characterizationofa pages 5-6, panicucci2022longtermfollowup pages 6-6)
Phenotypic Manifestations
Core clinical phenotypes: congenital bilateral cataracts; hypertrophic (occasionally dilated) cardiomyopathy; mitochondrial myopathy with hypotonia/weakness; persistent or episodic lactic acidosis. (Wang 2021; Siriwardena 2013; Panicucci 2022) (wang2021casereporttwo pages 2-4, siriwardena2013mitochondrialcitratesynthase pages 8-8, panicucci2022longtermfollowup pages 6-6)
Pathology correlations: COX-negative/SDH-strong fibers; lipid droplets in muscle; severe cristae loss; reduced complex I/IV/V activities; decreased OCR:ECAR in fibroblasts; reduced ANT1 in some muscle biopsies. (Siriwardena 2013; Wortmann 2015; Barbosa‑Gouveia 2021) (siriwardena2013mitochondrialcitratesynthase pages 8-8, wortmann2015inbornerrorsof pages 5-6, barbosagouveia2021characterizationofa pages 5-6)

Gene/protein annotations with ontology terms - AGK (HGNC; protein: acylglycerol kinase): mitochondrial lipid kinase and TIM22 subunit; loss causes Sengers syndrome. Processes: phosphatidic acid biosynthesis; mitochondrial carrier import via TIM22; OXPHOS assembly/function; response to oxidative stress. Components: inner mitochondrial membrane; TIM22 complex. (siriwardena2013mitochondrialcitratesynthase pages 8-8, barbosagouveia2021characterizationofa pages 5-6, wortmann2015inbornerrorsof pages 5-6, jackson2021thetim22complex pages 1-2) - TIM22 complex (includes TIMM22, AGK, Tim9/10/10b, TIMM29/Tim29): mediates insertion of multi-pass carriers (SLC25) and SFXNs; dysfunction underlies Sengers spectrum. (jackson2021thetim22complex pages 1-2, shalata2025sengerssyndromecaused pages 1-2) - ANT1/SLC25A4: mitochondrial ADP/ATP carrier impacted secondarily in AGK/TIM22 dysfunction. (wortmann2015inbornerrorsof pages 5-6)

Phenotype associations (HP terms) - Congenital cataract (HP:0000538) (siriwardena2013mitochondrialcitratesynthase pages 8-8, wang2021casereporttwo pages 2-4) - Hypertrophic cardiomyopathy (HP:0001639) (wang2021casereporttwo pages 2-4, panicucci2022longtermfollowup pages 6-6) - Lactic acidosis (HP:0002151) (barbosagouveia2021characterizationofa pages 5-6, panicucci2022longtermfollowup pages 6-6) - Mitochondrial myopathy (HP:0003016) (siriwardena2013mitochondrialcitratesynthase pages 8-8, wang2021casereporttwo pages 2-4)

Cell type involvement (CL terms) - Cardiomyocytes (CL:0000746) (wang2021casereporttwo pages 2-4) - Skeletal muscle fibers (CL:0000186) (siriwardena2013mitochondrialcitratesynthase pages 8-8) - Lens fiber cells (CL:0000653) (siriwardena2013mitochondrialcitratesynthase pages 8-8)

Anatomical locations (UBERON terms) - Heart (UBERON:0000948) (wang2021casereporttwo pages 2-4) - Skeletal muscle (UBERON:0001134) (siriwardena2013mitochondrialcitratesynthase pages 8-8) - Ocular lens (UBERON:0001105) (siriwardena2013mitochondrialcitratesynthase pages 8-8)

Chemical entities (CHEBI terms) - Phosphatidic acid (CHEBI:PA) (siriwardena2013mitochondrialcitratesynthase pages 8-8) - Lysophosphatidic acid (CHEBI:LPA) (siriwardena2013mitochondrialcitratesynthase pages 8-8) - Diacylglycerol (CHEBI:DAG) (siriwardena2013mitochondrialcitratesynthase pages 8-8) - Lactate (CHEBI:16526) (wang2021casereporttwo pages 2-4)

Evidence items and selected sources (URLs, publication dates) - Siriwardena et al., Mol Genet Metab 2013; DOI:10.1016/j.ymgme.2012.11.282; published Jan 2013; https://doi.org/10.1016/j.ymgme.2012.11.282 (siriwardena2013mitochondrialcitratesynthase pages 8-8, siriwardena2013mitochondrialcitratesynthase pages 8-10) - Wortmann et al., J Inherit Metab Dis 2015; DOI:10.1007/s10545-014-9759-7; published Jan 2015; https://doi.org/10.1007/s10545-014-9759-7 (wortmann2015inbornerrorsof pages 5-6) - Jackson et al., Mol Biol Cell 2021; DOI:10.1091/mbc.E20-06-0390; published Mar 2021; https://doi.org/10.1091/mbc.e20-06-0390 (jackson2021thetim22complex pages 1-2) - Barbosa‑Gouveia et al., Int J Mol Sci 2021; DOI:10.3390/ijms222413484; published Dec 2021; https://doi.org/10.3390/ijms222413484 (barbosagouveia2021characterizationofa pages 5-6, barbosagouveia2021characterizationofa pages 1-2) - Wang et al., Front Pediatr 2021; DOI:10.3389/fped.2021.639687; published Jun 2021; https://doi.org/10.3389/fped.2021.639687 (wang2021casereporttwo pages 8-9, wang2021casereporttwo pages 2-4) - Panicucci et al., Ital J Pediatr 2022; DOI:10.1186/s13052-022-01370-y; published Oct 2022; https://doi.org/10.1186/s13052-022-01370-y (panicucci2022longtermfollowup pages 6-6, panicucci2022longtermfollowup pages 2-4) - Mishra et al., IUBMB Life 2023; DOI:10.1002/iub.2767; published Jul 2023; https://doi.org/10.1002/iub.2767 (wang2021casereporttwo pages 8-9) - Popoiu et al., Curr Heart Fail Rep 2023; DOI:10.1007/s11897-023-00592-3; published Feb 2023; https://doi.org/10.1007/s11897-023-00592-3 (wang2021casereporttwo pages 2-4) - Shalata et al., Hum Genomics 2025; DOI:10.1186/s40246-025-00723-y; published Feb 2025; https://doi.org/10.1186/s40246-025-00723-y (shalata2025sengerssyndromecaused pages 1-2)

Embedded core annotations table | Category | Entity Name | Ontology/ID | Role/Description | Evidence (DOI/URL), Year | |---|---|---|---|---| | Genes / Proteins | AGK (acylglycerol kinase) | HGNC:AGK | Mitochondrial lipid kinase; structural subunit of TIM22 complex — required for PA/LPA production and TIM22-dependent carrier import | https://doi.org/10.3390/ijms222413484 (barbosagouveia2021characterizationofa pages 5-6), https://doi.org/10.1016/j.ymgme.2012.11.282 (siriwardena2013mitochondrialcitratesynthase pages 8-8), https://doi.org/10.1007/s10545-014-9759-7 (wortmann2015inbornerrorsof pages 5-6), 2021/2013/2015 | | Genes / Proteins | TIM22 complex (TIMM22 + subunits; AGK as TIM22 subunit) | Complex:TIM22 (includes TIMM22, TIMM29, AGK) | Inner-membrane carrier translocase that inserts multispanning carrier proteins (SLC25 family, SFXNs); loss impairs carrier biogenesis and downstream metabolism | Functional/TIM22 role noted in AGK studies: https://doi.org/10.3390/ijms222413484 (barbosagouveia2021characterizationofa pages 5-6), mechanistic TIM22 literature summarized in reviews (wortmann2015inbornerrorsof pages 5-6), 2021/2015 | | Genes / Proteins | SLC25A4 (ANT1, adenine nucleotide translocator 1) | HGNC:SLC25A4 | Mitochondrial ADP/ATP carrier; reported decreased/absent in some AGK-deficient patient muscle — links to impaired ADP/ATP exchange and OXPHOS dysfunction | https://doi.org/10.1007/s10545-014-9759-7 (wortmann2015inbornerrorsof pages 5-6), https://doi.org/10.1016/j.ymgme.2012.11.282 (siriwardena2013mitochondrialcitratesynthase pages 8-8), 2015/2013 | | Biological Process | Mitochondrial protein import via TIM22 | GO: mitochondrial carrier import (TIM22-related) | Insertion/biogenesis of multispanning inner-membrane carrier proteins (SLC25 family, SFXNs); AGK deficiency reduces TIM22 substrates and impairs metabolism (e.g., one-carbon) | Functional proteomics and TIM22 substrate loss in AGK deficiency: https://doi.org/10.3390/ijms222413484 (barbosagouveia2021characterizationofa pages 5-6), 2021 | | Biological Process | Phosphatidic acid (PA) biosynthesis / DAG -> PA conversion | GO: phosphatidic acid biosynthetic process | AGK phosphorylates DAG/MAG to produce PA/LPA in mitochondria; loss perturbs inner-membrane lipid composition and signaling | Lipid-kinase role described: https://doi.org/10.1016/j.ymgme.2012.11.282 (siriwardena2013mitochondrialcitratesynthase pages 8-8), https://doi.org/10.3390/ijms222413484 (barbosagouveia2021characterizationofa pages 5-6), 2013/2021 | | Biological Process | Cardiolipin-related OXPHOS assembly/function | GO: cardiolipin metabolic process / OXPHOS assembly | Altered PA/CL metabolism destabilizes respiratory-chain complexes (esp. complexes I and V) and ANT function, reducing ATP synthesis | Reviews and mechanistic reports: https://doi.org/10.1007/s10545-014-9759-7 (wortmann2015inbornerrorsof pages 5-6), https://doi.org/10.3390/ijms222413484 (barbosagouveia2021characterizationofa pages 5-6), 2015/2021 | | Biological Process | Reactive oxygen species (ROS) response / oxidative stress | GO: cellular response to oxidative stress | AGK loss → DAG accumulation, increased mitochondrial ROS, upregulation of SOD2/antioxidant responses and oxidative damage to OXPHOS components | Mitochondrial ROS and antioxidant changes: https://doi.org/10.1016/j.ymgme.2012.11.282 (siriwardena2013mitochondrialcitratesynthase pages 8-8), 2013 | | Cellular Component | Inner mitochondrial membrane (IMM) | GO:0005743 (inner mitochondrial membrane) | Location of AGK, TIM22 complex, carrier proteins and critical lipid milieu (PA/CL) required for OXPHOS and carrier import | AGK/TIM22 localizations and IMM dysfunction: https://doi.org/10.3390/ijms222413484 (barbosagouveia2021characterizationofa pages 5-6), https://doi.org/10.1016/j.ymgme.2012.11.282 (siriwardena2013mitochondrialcitratesynthase pages 8-8), 2021/2013 | | Cellular Component | TIM22 complex | Complex:TIM22 (IMM translocase) | Multisubunit carrier translocase that inserts multispanning proteins into IMM; AGK functions as an accessory/subunit for stability/function | TIM22–AGK relationship and substrate loss: https://doi.org/10.3390/ijms222413484 (barbosagouveia2021characterizationofa pages 5-6), 2021 | | Cellular Component | Mitochondrial matrix / cristae | UBERON:mitochondrial matrix / mitochondrial cristae | Cristae structure and matrix enzymes (e.g., citrate synthase) show ultrastructural/biochemical abnormalities (including citrate synthase crystals) in Sengers patients | Ultrastructure and citrate synthase crystals: https://doi.org/10.1016/j.ymgme.2012.11.282 (siriwardena2013mitochondrialcitratesynthase pages 8-8), 2013 | | Phenotype | Congenital cataract | HPO: Congenital cataract (HP:0000538) | Early bilateral lens opacities are a defining clinical feature (very high penetrance in AGK cases) linked to mitochondrial/lipid dysfunction in lens fibers | Multiple case series/reviews reporting high cataract frequency: https://doi.org/10.1016/j.ymgme.2012.11.282 (siriwardena2013mitochondrialcitratesynthase pages 8-8), https://doi.org/10.1016/j.ymgme.2012.11.282 (siriwardena2013mitochondrialcitratesynthase pages 8-10), 2013 | | Phenotype | Hypertrophic cardiomyopathy (HCM) / cardiomyopathy | HPO: Hypertrophic cardiomyopathy (HP:0001639) | Severe neonatal-onset HCM or dilated cardiomyopathy occurs commonly and is a major cause of early mortality; reflects high cardiac energy demand and OXPHOS failure | Clinical cohorts and case reports: https://doi.org/10.3389/fped.2021.639687 (wang2021casereporttwo pages 8-9), https://doi.org/10.1016/j.ymgme.2012.11.282 (siriwardena2013mitochondrialcitratesynthase pages 8-8), 2021/2013 | | Phenotype | Lactic acidosis / elevated lactate | HPO: Lactic acidosis (HP:0002151) | Impaired oxidative phosphorylation leads to increased anaerobic glycolysis and elevated blood/tissue lactate; variable severity from intermittent to marked neonatal lactic acidosis | Metabolic findings in patient fibroblasts / clinical reports: https://doi.org/10.3390/ijms222413484 (barbosagouveia2021characterizationofa pages 5-6), https://doi.org/10.3389/fped.2021.639687 (wang2021casereporttwo pages 8-9), 2021 | | Phenotype | Skeletal myopathy / mitochondrial myopathy | HPO: Mitochondrial myopathy (HP:0003016) | Hypotonia, weakness, exercise intolerance and muscle pathology (RRF-like changes, lipid droplets, abnormal mitochondria) reflect impaired muscle OXPHOS | Case reports and muscle pathology studies: https://doi.org/10.3389/fped.2021.639687 (wang2021casereporttwo pages 8-9), https://doi.org/10.1016/j.ymgme.2012.11.282 (siriwardena2013mitochondrialcitratesynthase pages 8-8), 2021/2013 | | Cell Type | Cardiomyocytes | CL: cardiomyocyte (CL:0000746) | High-energy cardiac myocytes show pronounced vulnerability to AGK/TIM22 dysfunction, resulting in cardiomyopathy and heart failure | Cardiac involvement reviews and cases: https://doi.org/10.1016/j.ymgme.2012.11.282 (siriwardena2013mitochondrialcitratesynthase pages 8-8), https://doi.org/10.1016/j.10.1007/s10545-014-9759-7 (wortmann2015inbornerrorsof pages 5-6), 2013/2015 | | Cell Type | Skeletal myofibers | CL: skeletal muscle fiber (CL:0000186) | Skeletal muscle fibers display mitochondrial structural defects, OXPHOS deficiency and clinical myopathy | Muscle biopsy and ultrastructure reports: https://doi.org/10.1016/j.ymgme.2012.11.282 (siriwardena2013mitochondrialcitratesynthase pages 8-8), https://doi.org/10.3389/fped.2021.639687 (wang2021casereporttwo pages 8-9), 2013/2021 | | Cell Type | Lens fiber cells | CL: lens fiber cell (CL:0000653) | Lens fibers rely on mitochondrial/lipid homeostasis during development; AGK-related lipid/protein import defects associated with congenital cataract | Cataract genetics and AGK frequency: https://doi.org/10.1016/j.ymgme.2012.11.282 (siriwardena2013mitochondrialcitratesynthase pages 8-8), 2013 | | Anatomical Location | Heart | UBERON:0000948 (heart) | Primary organ affected with early hypertrophic/dilated cardiomyopathy and heart failure in severe forms | Clinical case series and reviews: https://doi.org/10.3389/fped.2021.639687 (wang2021casereporttwo pages 8-9), https://doi.org/10.1007/s10545-014-9759-7 (wortmann2015inbornerrorsof pages 5-6), 2021/2015 | | Anatomical Location | Skeletal muscle | UBERON:0001134 (skeletal muscle) | Affected tissue with mitochondrial myopathy, exercise intolerance and histopathologic mitochondrial changes | Muscle pathology reports: https://doi.org/10.1016/j.ymgme.2012.11.282 (siriwardena2013mitochondrialcitratesynthase pages 8-8), 2013 | | Anatomical Location | Ocular lens | UBERON:0001105 (lens) | Early bilateral congenital cataracts are a hallmark, reflecting mitochondrial/lipid dysregulation in lens cells | Cataract-focused reviews and case reports: https://doi.org/10.1016/j.ymgme.2012.11.282 (siriwardena2013mitochondrialcitratesynthase pages 8-8), 2013 | | Chemical / Metabolite | Phosphatidic acid (PA) | CHEBI:PA (phosphatidic acid) | Product of AGK-mediated phosphorylation (DAG -> PA); PA is precursor for cardiolipin and critical for IMM lipid homeostasis | Lipid-kinase function and PA role: https://doi.org/10.3390/ijms222413484 (barbosagouveia2021characterizationofa pages 5-6), https://doi.org/10.1016/j.ymgme.2012.11.282 (siriwardena2013mitochondrialcitratesynthase pages 8-8), 2021/2013 | | Chemical / Metabolite | Lysophosphatidic acid (LPA) | CHEBI:LPA (lysophosphatidic acid) | AGK product (from MAG) and signaling lipid; perturbation implicated in IMM lipid imbalance | AGK substrate/product descriptions: https://doi.org/10.1016/j.ymgme.2012.11.282 (siriwardena2013mitochondrialcitratesynthase pages 8-8), 2013 | | Chemical / Metabolite | Diacylglycerol (DAG) | CHEBI:DAG (diacylglycerol) | AGK substrate; DAG accumulation in AGK deficiency may drive ROS signaling and PKD1 activation | DAG accumulation and ROS links: https://doi.org/10.1016/j.ymgme.2012.11.282 (siriwardena2013mitochondrialcitratesynthase pages 8-8), 2013 | | Chemical / Metabolite | Lactate | CHEBI:16526 (lactate) | Elevated systemic/tissue lactate due to impaired oxidative phosphorylation; used clinically as a metabolic marker | Clinical metabolic findings and lactic acidosis in reports: https://doi.org/10.3389/fped.2021.639687 (wang2021casereporttwo pages 8-9), https://doi.org/10.3390/ijms222413484 (barbosagouveia2021characterizationofa pages 5-6), 2021 |

Table: Concise ontology-aligned annotations for Sengers syndrome covering genes, processes, components, phenotypes, cells, organs and metabolites with primary evidence links to the collected literature (context IDs).

Notes on limitations - Cohort-level statistics remain sparse in the available 2023–2024 literature cited here; most data are mechanistic, case-based, or review-level. A 2023 mini‑review of AGK‑confirmed cases (Wu et al., Mol Genet Metab) was unobtainable in this search, limiting the ability to provide pooled phenotypic frequencies from 2023–2024. (jackson2021thetim22complex pages 1-2)

References

(siriwardena2013mitochondrialcitratesynthase pages 8-8): Komudi Siriwardena, Nevena MacKay, Valeriy Levandovskiy, Susan Blaser, Julian Raiman, Paul F. Kantor, Cameron Ackerley, Brian H. Robinson, Andreas Schulze, and Jessie M. Cameron. Mitochondrial citrate synthase crystals: novel finding in sengers syndrome caused by acylglycerol kinase (agk) mutations. Molecular genetics and metabolism, 108 1:40-50, Jan 2013. URL: https://doi.org/10.1016/j.ymgme.2012.11.282, doi:10.1016/j.ymgme.2012.11.282. This article has 46 citations and is from a peer-reviewed journal.
(wortmann2015inbornerrorsof pages 5-6): Saskia B. Wortmann, Marc Espeel, Ligia Almeida, Annette Reimer, Dennis Bosboom, Frank Roels, Arjan P.M. de Brouwer, and Ron A. Wevers. Inborn errors of metabolism in the biosynthesis and remodelling of phospholipids. Journal of Inherited Metabolic Disease, 38:99-110, Jan 2015. URL: https://doi.org/10.1007/s10545-014-9759-7, doi:10.1007/s10545-014-9759-7. This article has 64 citations and is from a peer-reviewed journal.
(barbosagouveia2021characterizationofa pages 5-6): Sofia Barbosa-Gouveia, Maria E. Vázquez-Mosquera, Emiliano Gonzalez-Vioque, Álvaro Hermida-Ameijeiras, Laura L. Valverde, Judith Armstrong-Moron, Maria del Carmen Fons-Estupiña, Liesbeth T. Wintjes, Antonia Kappen, Richard J. Rodenburg, and Maria L. Couce. Characterization of a novel splicing variant in acylglycerol kinase (agk) associated with fatal sengers syndrome. International Journal of Molecular Sciences, 22:13484, Dec 2021. URL: https://doi.org/10.3390/ijms222413484, doi:10.3390/ijms222413484. This article has 12 citations and is from a poor quality or predatory journal.
(jackson2021thetim22complex pages 1-2): Thomas D. Jackson, Daniella H. Hock, Kenji M. Fujihara, Catherine S. Palmer, Ann E. Frazier, Yau C. Low, Yilin Kang, Ching-Seng Ang, Nicholas J. Clemons, David R. Thorburn, David A. Stroud, and Diana Stojanovski. The tim22 complex mediates the import of sideroflexins and is required for efficient mitochondrial one-carbon metabolism. Molecular Biology of the Cell, 32:475-491, Mar 2021. URL: https://doi.org/10.1091/mbc.e20-06-0390, doi:10.1091/mbc.e20-06-0390. This article has 37 citations and is from a domain leading peer-reviewed journal.
(shalata2025sengerssyndromecaused pages 1-2): Adel Shalata, Ann Saada, Mohammed Mahroum, Yarin Hadid, Chaya Furman, Zaher Eldin Shalata, Robert J. Desnick, Avraham Lorber, Asaad Khoury, Adnan Higazi, Avraham Shaag, Varda Barash, Ronen Spiegel, Euvgeni Vlodavsky, Pierre Rustin, Shmuel Pietrokovski, Irena Manov, Dan Gieger, Galit Tal, Adi Salzberg, and Hanna Mandel. Sengers syndrome caused by biallelic timm29 variants and rnai silencing in drosophila orthologue recapitulates the human phenotype. Human Genomics, Feb 2025. URL: https://doi.org/10.1186/s40246-025-00723-y, doi:10.1186/s40246-025-00723-y. This article has 2 citations and is from a peer-reviewed journal.
(barbosagouveia2021characterizationofa pages 1-2): Sofia Barbosa-Gouveia, Maria E. Vázquez-Mosquera, Emiliano Gonzalez-Vioque, Álvaro Hermida-Ameijeiras, Laura L. Valverde, Judith Armstrong-Moron, Maria del Carmen Fons-Estupiña, Liesbeth T. Wintjes, Antonia Kappen, Richard J. Rodenburg, and Maria L. Couce. Characterization of a novel splicing variant in acylglycerol kinase (agk) associated with fatal sengers syndrome. International Journal of Molecular Sciences, 22:13484, Dec 2021. URL: https://doi.org/10.3390/ijms222413484, doi:10.3390/ijms222413484. This article has 12 citations and is from a poor quality or predatory journal.
(siriwardena2013mitochondrialcitratesynthase pages 8-10): Komudi Siriwardena, Nevena MacKay, Valeriy Levandovskiy, Susan Blaser, Julian Raiman, Paul F. Kantor, Cameron Ackerley, Brian H. Robinson, Andreas Schulze, and Jessie M. Cameron. Mitochondrial citrate synthase crystals: novel finding in sengers syndrome caused by acylglycerol kinase (agk) mutations. Molecular genetics and metabolism, 108 1:40-50, Jan 2013. URL: https://doi.org/10.1016/j.ymgme.2012.11.282, doi:10.1016/j.ymgme.2012.11.282. This article has 46 citations and is from a peer-reviewed journal.
(wang2021casereporttwo pages 8-9): Benzhen Wang, Zhanhui Du, Guangsong Shan, Chuanzhu Yan, Victor Wei Zhang, and Zipu Li. Case report: two chinese infants of sengers syndrome caused by mutations in agk gene. Frontiers in Pediatrics, Jun 2021. URL: https://doi.org/10.3389/fped.2021.639687, doi:10.3389/fped.2021.639687. This article has 10 citations and is from a poor quality or predatory journal.
(wang2021casereporttwo pages 2-4): Benzhen Wang, Zhanhui Du, Guangsong Shan, Chuanzhu Yan, Victor Wei Zhang, and Zipu Li. Case report: two chinese infants of sengers syndrome caused by mutations in agk gene. Frontiers in Pediatrics, Jun 2021. URL: https://doi.org/10.3389/fped.2021.639687, doi:10.3389/fped.2021.639687. This article has 10 citations and is from a poor quality or predatory journal.
(panicucci2022longtermfollowup pages 6-6): Chiara Panicucci, Maria Cristina Schiaffino, Claudia Nesti, Maria Derchi, Gianluca Trocchio, Mariasavina Severino, Nicola Stagnaro, Enrico Priolo, Federico Zara, Filippo M. Santorelli, and Claudio Bruno. Long term follow-up in two siblings with sengers syndrome: case report. Italian Journal of Pediatrics, Oct 2022. URL: https://doi.org/10.1186/s13052-022-01370-y, doi:10.1186/s13052-022-01370-y. This article has 3 citations and is from a peer-reviewed journal.
(panicucci2022longtermfollowup pages 2-4): Chiara Panicucci, Maria Cristina Schiaffino, Claudia Nesti, Maria Derchi, Gianluca Trocchio, Mariasavina Severino, Nicola Stagnaro, Enrico Priolo, Federico Zara, Filippo M. Santorelli, and Claudio Bruno. Long term follow-up in two siblings with sengers syndrome: case report. Italian Journal of Pediatrics, Oct 2022. URL: https://doi.org/10.1186/s13052-022-01370-y, doi:10.1186/s13052-022-01370-y. This article has 3 citations and is from a peer-reviewed journal.

{ }

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
    reference_title: "Case Report: Two Chinese Infants of Sengers Syndrome Caused by Mutations in AGK Gene."
    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:0032048
      label: cardiolipin 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
    reference_title: "Case Report: Two Chinese Infants of Sengers Syndrome Caused by Mutations in AGK Gene."
    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
    reference_title: "Case Report: Two Chinese Infants of Sengers Syndrome Caused by Mutations in AGK Gene."
    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
    reference_title: "Case Report: Two Chinese Infants of Sengers Syndrome Caused by Mutations in AGK Gene."
    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
    reference_title: "Case Report: Two Chinese Infants of Sengers Syndrome Caused by Mutations in AGK Gene."
    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
    reference_title: "Case Report: Two Chinese Infants of Sengers Syndrome Caused by Mutations in AGK Gene."
    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
    reference_title: "Case Report: Two Chinese Infants of Sengers Syndrome Caused by Mutations in AGK Gene."
    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
    reference_title: "Case Report: Two Chinese Infants of Sengers Syndrome Caused by Mutations in AGK Gene."
    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
    reference_title: "Case Report: Two Chinese Infants of Sengers Syndrome Caused by Mutations in AGK Gene."
    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
    reference_title: "Case Report: Two Chinese Infants of Sengers Syndrome Caused by Mutations in AGK Gene."
    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
    reference_title: "Case Report: Two Chinese Infants of Sengers Syndrome Caused by Mutations in AGK Gene."
    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
    reference_title: "Case Report: Two Chinese Infants of Sengers Syndrome Caused by Mutations in AGK Gene."
    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
    reference_title: "Case Report: Two Chinese Infants of Sengers Syndrome Caused by Mutations in AGK Gene."
    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
    reference_title: "Case Report: Two Chinese Infants of Sengers Syndrome Caused by Mutations in AGK Gene."
    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
    reference_title: "A neonate with a spongy failing heart - What could it be?"
    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
    reference_title: "Cardiac transplantation for hypertrophic cardiomyopathy associated with Sengers syndrome."
    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
    reference_title: "A neonate with a spongy failing heart - What could it be?"
    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
    reference_title: "A neonate with a spongy failing heart - What could it be?"
    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
    reference_title: "Case Report: Two Chinese Infants of Sengers Syndrome Caused by Mutations in AGK Gene."
    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
    reference_title: "A neonate with a spongy failing heart - What could it be?"
    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: []