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Inheritance

1

Autosomal recessive HP:0000007

GSD III follows autosomal recessive inheritance. The AGL gene is located on chromosome 1p21.2. Carrier frequency varies by population, with notably higher prevalence in certain ethnic groups including Faroese, North African Jewish, and Inuit communities.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:20301788 SUPPORT Human Clinical

"GSD III is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an AGL pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected with GSD III, a 50% chance of being an asymptomatic carrier, and a 25% chance of..."

GeneReviews confirms autosomal recessive inheritance of GSD III with standard Mendelian ratios for carrier parents.

PMID:11949933 SUPPORT Human Clinical

"Deficiency of the glycogen debranching enzyme (gene, AGL) causes glycogen storage disease type III (GSD-III), an autosomal recessive disease affecting glycogen metabolism."

Confirms autosomal recessive inheritance and AGL gene involvement.

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Subtypes

2

GSD IIIa

~85%

The most common subtype, accounting for approximately 85% of GSD III cases. Involves both liver and muscle (skeletal and cardiac). Characterized by hepatomegaly and hypoglycemia in childhood with progressive myopathy and cardiomyopathy developing over time.

Show evidence (1 reference)

PMID:20301788 SUPPORT Human Clinical

"GSD IIIa is the most common subtype, present in about 85% of affected individuals; it manifests with liver and muscle involvement."

GeneReviews confirms GSD IIIa as the predominant subtype with liver and muscle involvement.

GSD IIIb

~15%

Accounts for approximately 15% of GSD III cases. Affects liver only without muscle involvement. Exon 3 mutations in AGL are specifically associated with this subtype.

Show evidence (2 references)

PMID:20301788 SUPPORT Human Clinical

"GSD IIIb, with liver involvement only, comprises about 15% of all affected individuals."

GeneReviews confirms GSD IIIb as the liver-only subtype comprising approximately 15% of cases.

PMID:11949933 SUPPORT Human Clinical

"exon 3 mutations (17delAG and Q6X) are specifically associated with GSD-IIIb"

Molecular characterization identifies specific genotype-phenotype correlation for the GSD IIIb subtype.

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Pathophysiology

3

Glycogen debranching enzyme deficiency

Deficiency of the glycogen debranching enzyme (AGL) impairs the complete degradation of glycogen. The enzyme normally has two catalytic activities: oligo-1,4-1,4-glucantransferase (transferase) and amylo-1,6-glucosidase (glucosidase). Without this enzyme, glycogen breakdown halts at the branch points, leading to accumulation of limit dextrin (abnormally short-branched glycogen) in hepatocytes, skeletal myocytes, and cardiomyocytes.

Hepatocyte link Skeletal muscle cell link Cardiac muscle cell link

Glycogen catabolic process link ↓ DECREASED Glucose metabolic process link ↓ DECREASED

4-alpha-glucanotransferase activity link ↓ DECREASED amylo-alpha-1,6-glucosidase activity link ↓ DECREASED

Downstream

Hepatic glycogen accumulation and fibrosis Loss of AGL debranching activity leaves incompletely degraded glycogen in hepatocytes, driving hepatic storage injury and fibrosis risk.

Skeletal and cardiac myopathy In GSD IIIa, the same debranching block affects skeletal and cardiac muscle, causing progressive glycogen storage myopathy and cardiomyopathy.

Fasting hypoglycemia Impaired hepatic glycogen mobilization limits fasting glucose release and clinically manifests as ketotic fasting hypoglycemia.

Low blood glucose Impaired hepatic glycogen mobilization lowers blood glucose during fasting.

Failure to thrive Recurrent early-life fasting hypoglycemia and hepatic metabolic disease contribute to poor growth.

Show evidence (3 references)

PMID:11949933 SUPPORT Human Clinical

"Most GSD-III patients have AGL deficiency in both the liver and muscle (type IIIa), but some have it in the liver but not muscle (type IIIb)."

Confirms AGL deficiency causes GSD III with tissue-specific subtypes.

PMID:27106217 SUPPORT Human Clinical

"Glycogen storage disease type III (GSDIII) is a rare disorder of glycogenolysis due to AGL gene mutations, causing glycogen debranching enzyme deficiency and storage of limited dextrin."

Large international cohort study confirms AGL mutations cause debranching enzyme deficiency and limit dextrin accumulation.

PMID:33368379 SUPPORT Human Clinical

"Glycogen storage disorder type III (GSDIII) is a rare inborn error of metabolism due to loss of glycogen debranching enzyme activity, causing inability to fully mobilize glycogen stores and its consequent accumulation in various tissues, notably liver, cardiac and skeletal muscle."

Review confirms the pathophysiology of debranching enzyme loss causing glycogen accumulation in liver, cardiac, and skeletal muscle.

Hepatic glycogen accumulation and fibrosis

Progressive accumulation of limit dextrin in hepatocytes causes hepatomegaly and hepatic dysfunction. Over time, the glycogen storage leads to hepatocyte injury, inflammation, fibrosis, and potentially cirrhosis. Hepatocellular adenomas and carcinoma can develop as long-term complications. Liver fibrosis can begin early in life; aminotransferases may paradoxically normalize with age as fibrosis progresses.

Hepatocyte link

Glycogen metabolic process link Carbohydrate metabolic process link

Downstream

Hepatomegaly Hepatic limit-dextrin and glycogen storage enlarges the liver.

Elevated circulating hepatic transaminase concentration Hepatocyte storage injury elevates circulating aminotransferases early in disease.

Elevated cholesterol Hepatic metabolic dysfunction in GSD III is reflected by elevated cholesterol early in life.

Elevated triglycerides Hepatic metabolic dysfunction in GSD III is reflected by elevated triglycerides early in life.

Elevated glucose tetrasaccharide Glucose tetrasaccharide is a glycogen-storage biomarker elevated early in GSD III.

Hepatic fibrosis Chronic hepatic glycogen storage injury can progress to fibrosis, cirrhosis, and related complications.

Show evidence (3 references)

PMID:31263214 SUPPORT Human Clinical

"Liver fibrosis can occur at an early age, and may explain the decrease in aminotransferases and Glc4 with age."

Demonstrates that liver fibrosis occurs early in GSD III and that normalization of aminotransferases with age does not indicate hepatic improvement.

PMID:27106217 SUPPORT Human Clinical

"Chronic complications involved the liver (hepatic cirrhosis, adenoma(s), and/or hepatocellular carcinoma in 11 %)"

Large cohort study documents hepatic cirrhosis and HCC as chronic complications of GSD III.

PMID:34820282 SUPPORT Human Clinical

"hepatomegaly and cirrhosis were the most common radiological findings; and 28% developed decompensated liver disease and portal hypertension, the latter being more prevalent in older patients."

Retrospective study of adults shows high rate of liver disease progression including cirrhosis and portal hypertension.

Skeletal and cardiac myopathy

In GSD IIIa, glycogen accumulation in skeletal and cardiac muscle leads to progressive myopathy and cardiomyopathy. Muscle involvement may be minimal in childhood but typically worsens with age. The myopathy is slowly progressive and can lead to significant disability. Cardiac involvement manifests primarily as left ventricular hypertrophy, which may progress to cardiomyopathy.

Skeletal muscle cell link Cardiac muscle cell link

Glycogen catabolic process link ↓ DECREASED

Downstream

Myopathy Skeletal muscle glycogen storage causes progressive weakness and exercise intolerance in GSD IIIa.

Hypertrophic cardiomyopathy Cardiac muscle glycogen storage commonly manifests as left ventricular hypertrophy and cardiomyopathy.

Elevated circulating creatine kinase concentration Skeletal muscle involvement is reflected biochemically by persistently elevated creatine kinase.

Serum creatine kinase Skeletal muscle involvement is reflected biochemically by persistently elevated serum creatine kinase.

Show evidence (3 references)

PMID:20301788 SUPPORT Human Clinical

"Most individuals develop cardiac involvement with cardiac hypertrophy and/or cardiomyopathy. Skeletal myopathy manifesting as weakness may be evident in childhood and slowly progresses, typically becoming prominent in the third to fourth decade."

GeneReviews describes the progressive nature of cardiac and skeletal muscle involvement in GSD III.

PMID:27106217 SUPPORT Human Clinical

"heart (cardiac involvement and cardiomyopathy, in 58 % and 15 %, respectively, generally presenting in early childhood), and muscle (pain in 34 %)."

Large international cohort quantifies cardiac involvement at 58% and cardiomyopathy at 15% in GSD III patients.

PMID:34820282 SUPPORT Human Clinical

"muscle weakness was a major feature, noted in 89% of the GSD IIIa cohort, a third of whom depended on a wheelchair or an assistive walking device."

Adult cohort study shows high prevalence and severity of muscle weakness in GSD IIIa, with significant functional disability.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

9

Cardiovascular 1

Hypertrophic cardiomyopathy HP_0040282 Hypertrophic cardiomyopathy (HP:0001639)

Show evidence (2 references)

PMID:34820282 SUPPORT Human Clinical

"Asymptomatic left ventricular hypertrophy (LVH) was the most common cardiac manifestation, present in 43%. Symptomatic cardiomyopathy and reduced ejection fraction was evident in 10%."

Adult cohort study quantifies LVH at 43% and symptomatic cardiomyopathy at 10%.

PMID:27106217 SUPPORT Human Clinical

"heart (cardiac involvement and cardiomyopathy, in 58 % and 15 %, respectively, generally presenting in early childhood)"

International study reports cardiac involvement in 58% and cardiomyopathy in 15% of GSD III patients.

Digestive 2

Hepatomegaly HP_0040281 Hepatomegaly (HP:0002240)

Show evidence (1 reference)

PMID:27106217 SUPPORT Human Clinical

"GSDIII patients first presented before the age of 1.5 years, hepatomegaly was the most common presenting clinical sign."

Large international cohort confirms hepatomegaly as the most common presenting sign of GSD III, appearing before 1.5 years of age.

Hepatic fibrosis HP_0040282 Hepatic fibrosis (HP:0001395)

Show evidence (2 references)

PMID:31263214 SUPPORT Human Clinical

"Liver fibrosis can occur at an early age, and may explain the decrease in aminotransferases and Glc4 with age."

Study demonstrates early onset of liver fibrosis in GSD III and its paradoxical relationship to normalizing aminotransferases.

PMID:34820282 SUPPORT Human Clinical

"28% developed decompensated liver disease and portal hypertension"

Adult cohort shows significant progression to decompensated liver disease.

Metabolism 4

Fasting hypoglycemia HP_0040281 Fasting hypoglycemia (HP:0003162)

Show evidence (2 references)

PMID:20301788 SUPPORT Human Clinical

"In infancy and early childhood, liver involvement presents as hepatomegaly and failure to thrive, with fasting ketotic hypoglycemia, hyperlipidemia, and elevated hepatic transaminases."

GeneReviews describes fasting ketotic hypoglycemia as a key feature of GSD III in infancy and early childhood.

PMID:38196773 SUPPORT Human Clinical

"Hypoglycemia was frequently reported in both adults and children, with more than half reporting hospitalizations due to hypoglycemia."

Patient burden study confirms high prevalence of hypoglycemia requiring hospitalization.

Hyperlipidemia HP_0040282 Hyperlipidemia (HP:0003077)

Show evidence (1 reference)

PMID:20301788 SUPPORT Human Clinical

"fasting ketotic hypoglycemia, hyperlipidemia, and elevated hepatic transaminases."

GeneReviews lists hyperlipidemia as a key metabolic feature in GSD III.

Elevated circulating creatine kinase concentration HP_0040282 Elevated circulating creatine kinase concentration (HP:0003236)

Show evidence (1 reference)

PMID:31263214 SUPPORT Human Clinical

"Creatine phosphokinase was also elevated with no significant correlation with age (p = 0.4)."

Study shows CK is persistently elevated in GSD III patients regardless of age.

Elevated circulating hepatic transaminase concentration HP_0040281 Elevated circulating hepatic transaminase concentration (HP:0002910)

Show evidence (1 reference)

PMID:31263214 SUPPORT Human Clinical

"Markers of liver injury (aminotransferases), dysfunction (cholesterol, triglycerides), and glycogen storage (glucose tetrasaccharide, Glc4) were elevated at an early age, and decreased significantly thereafter"

Demonstrates elevated aminotransferases in early GSD III that paradoxically decrease with age.

Musculoskeletal 1

Myopathy HP_0040282 Myopathy (HP:0003198)

Show evidence (2 references)

PMID:34820282 SUPPORT Human Clinical

"In the GSD IIIa group, muscle weakness was a major feature, noted in 89% of the GSD IIIa cohort, a third of whom depended on a wheelchair or an assistive walking device."

Retrospective study of adults quantifies muscle weakness at 89% prevalence in GSD IIIa with significant functional impact.

PMID:38196773 SUPPORT Human Clinical

"Adults most often reported muscle weakness as a top interfering symptom and the most important goal of a potential therapy."

Patient burden study identifies muscle weakness as the most impactful symptom from the patient perspective.

Growth 1

Failure to thrive HP_0040282 Failure to thrive (HP:0001508)

Show evidence (1 reference)

PMID:20301788 SUPPORT Human Clinical

"In infancy and early childhood, liver involvement presents as hepatomegaly and failure to thrive"

GeneReviews identifies failure to thrive as a key early presentation.

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Genetic Associations

1

AGL (Pathogenic Variants)

Show evidence (1 reference)

CGGV:assertion_a7b762bc-a12f-4194-91b9-764784248cc7-2023-02-24T170000.000Z SUPPORT Other

ClinGen classifies the AGL-glycogen storage disease III gene-disease relationship as definitive with autosomal recessive inheritance.

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Treatments

3

Dietary management

Action: dietary intervention MAXO:0000088

Frequent meals and cornstarch supplementation to prevent hypoglycemia. High-protein diet (3 g/kg) is recommended to provide amino acid substrate for gluconeogenesis and to support muscle integrity. Uncooked cornstarch provides a slow-release glucose source. Modified Atkins or ketogenic diets may improve cardiac and skeletal muscle function by reducing glycogen storage.

Mechanism Target:

BYPASSES Glycogen debranching enzyme deficiency — Frequent feeds and uncooked cornstarch provide exogenous slow-release carbohydrate to maintain euglycemia around the impaired glycogenolysis block.

Show evidence (1 reference)

PMID:20301788 SUPPORT Human Clinical

"Dietary management tailored to the individual patient remains the primary therapy. Frequent feeds (every 3-4 hours) are needed to maintain euglycemia in infancy."

GeneReviews supports dietary management as the primary therapy for maintaining euglycemia despite the upstream debranching defect.

MODULATES Hepatic glycogen accumulation and fibrosis — Cornstarch-based metabolic control reduces hypoglycemia and serum aminotransferases, mitigating the hepatic injury branch.

Show evidence (1 reference)

PMID:2403059 SUPPORT Human Clinical

"Cornstarch therapy was associated with maintenance of normoglycemia, increased growth velocity, and decreased serum aminotransferase concentrations in all patients."

Clinical cornstarch therapy evidence supports dietary modulation of glycemic control, growth, and liver injury markers.

MODULATES Skeletal and cardiac myopathy — High-fat, high-protein, low-carbohydrate dietary strategies have case-level evidence for improving the cardiomyopathy branch in GSD III.

Show evidence (1 reference)

PMID:25308556 SUPPORT Human Clinical

"A diet rich in fats as well as proteins and poor in carbohydrates could be a beneficial therapeutic choice for GSD III with cardiomyopathy."

Reported sibling cases support dietary modulation of cardiac muscle involvement in GSD III.

Show evidence (3 references)

PMID:20301788 SUPPORT Human Clinical

"Dietary management tailored to the individual patient remains the primary therapy. Frequent feeds (every 3-4 hours) are needed to maintain euglycemia in infancy."

GeneReviews establishes dietary management as the primary therapy with specific recommendations for meal frequency.

PMID:2403059 SUPPORT Human Clinical

"Cornstarch therapy was associated with maintenance of normoglycemia, increased growth velocity, and decreased serum aminotransferase concentrations in all patients."

Clinical study demonstrates efficacy of cornstarch therapy in GSD III for glycemic control, growth, and liver function.

PMID:25308556 SUPPORT Human Clinical

"A diet rich in fats as well as proteins and poor in carbohydrates could be a beneficial therapeutic choice for GSD III with cardiomyopathy."

Case report of two siblings shows high-fat low-carbohydrate diet improves cardiomyopathy in GSD IIIa.

Liver transplantation

Action: organ transplantation MAXO:0010039

Liver transplantation may be considered for patients with severe hepatic fibrosis, cirrhosis, or hepatocellular carcinoma. It corrects the hepatic metabolic defect but does not address myopathy and may exacerbate muscle disease.

Show evidence (1 reference)

PMID:20301788 SUPPORT Human Clinical

"Liver transplantation is reserved for those with severe hepatic cirrhosis, liver dysfunction, and/or hepatocellular carcinoma. Liver transplantation may exacerbate myopathy and cardiomyopathy."

GeneReviews describes liver transplantation indications and the important caveat that it may worsen muscle disease.

Genetic counseling

Action: genetic counseling MAXO:0000079

Genetic counseling for affected families regarding autosomal recessive inheritance, carrier testing, and reproductive options. Once pathogenic variants are identified, prenatal and preimplantation genetic testing are possible.

Show evidence (1 reference)

PMID:20301788 SUPPORT Human Clinical

"Once the AGL pathogenic variants have been identified in an affected family member, carrier testing for at-risk family members and prenatal and preimplantation genetic testing for a pregnancy at increased risk are possible."

GeneReviews outlines genetic counseling recommendations for GSD III families.

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Biochemical Markers

5

Low blood glucose (DECREASED)

Context: Fasting blood glucose can fall because impaired hepatic debranching limits glycogen-derived glucose release during fasting.

Pathograph Readouts

Readout Of Glycogen debranching enzyme deficiency Negative Diagnostic

Lower blood glucose reports impaired hepatic glycogen mobilization during fasting.

Readout Of Fasting hypoglycemia Negative Monitoring

Blood glucose monitoring tracks the fasting hypoglycemia branch.

Show evidence (1 reference)

PMID:20301788 SUPPORT Human Clinical

"In infancy and early childhood, liver involvement presents as hepatomegaly and failure to thrive, with fasting ketotic hypoglycemia, hyperlipidemia, and elevated hepatic transaminases."

GeneReviews supports fasting hypoglycemia as a blood-glucose abnormality in GSD III.

Elevated cholesterol (INCREASED)

Context: Elevated cholesterol is a liver-dysfunction marker in pediatric GSD III and can improve with better metabolic control.

Pathograph Readouts

Readout Of Hepatic glycogen accumulation and fibrosis Positive Monitoring

Higher cholesterol tracks hepatic metabolic dysfunction in GSD III.

Show evidence (1 reference)

PMID:31263214 SUPPORT Human Clinical

"Markers of liver injury (aminotransferases), dysfunction (cholesterol, triglycerides), and glycogen storage (glucose tetrasaccharide, Glc4) were elevated at an early age, and decreased significantly thereafter"

Supports elevated cholesterol as a hepatic dysfunction marker in GSD III.

Elevated triglycerides (INCREASED)

Context: Elevated triglycerides are part of the hepatic metabolic dysfunction profile in early GSD III.

Pathograph Readouts

Readout Of Hepatic glycogen accumulation and fibrosis Positive Monitoring

Higher triglycerides track hepatic metabolic dysfunction in GSD III.

Show evidence (1 reference)

PMID:31263214 SUPPORT Human Clinical

"Markers of liver injury (aminotransferases), dysfunction (cholesterol, triglycerides), and glycogen storage (glucose tetrasaccharide, Glc4) were elevated at an early age, and decreased significantly thereafter"

Supports elevated triglycerides as a hepatic dysfunction marker in GSD III.

Elevated glucose tetrasaccharide (INCREASED)

Context: Glucose tetrasaccharide (Glc4) is elevated as a glycogen-storage marker in pediatric GSD III and tends to decline with age.

Pathograph Readouts

Readout Of Hepatic glycogen accumulation and fibrosis Positive Monitoring

Higher Glc4 reports glycogen storage burden in the hepatic branch.

Show evidence (1 reference)

PMID:31263214 SUPPORT Human Clinical

"Markers of liver injury (aminotransferases), dysfunction (cholesterol, triglycerides), and glycogen storage (glucose tetrasaccharide, Glc4) were elevated at an early age, and decreased significantly thereafter"

Supports elevated glucose tetrasaccharide as a glycogen-storage marker in pediatric GSD III.

Serum creatine kinase (INCREASED)

Context: Elevated serum creatine kinase reflects skeletal muscle involvement in GSD III and may remain elevated across childhood.

Pathograph Readouts

Readout Of Skeletal and cardiac myopathy Positive Monitoring

Higher serum creatine kinase reports the myopathy branch of GSD III.

Show evidence (1 reference)

PMID:31263214 SUPPORT Human Clinical

"Creatine phosphokinase was also elevated with no significant correlation with age (p = 0.4)."

Supports elevated serum creatine kinase as a muscle-involvement readout.

{ }

Source YAML

click to show

name: Cori Forbes Disease
creation_date: '2026-03-08T00:00:00Z'
updated_date: '2026-05-20T02:37:34Z'
category: Mendelian
description: >
  Cori Forbes Disease (Glycogen Storage Disease Type III, GSD III) is an autosomal
  recessive disorder of glycogen metabolism caused by deficiency of the glycogen
  debranching enzyme (amylo-1,6-glucosidase, 4-alpha-glucanotransferase) encoded
  by the AGL gene. The enzyme deficiency leads to accumulation of abnormally structured
  glycogen (limit dextrin) in liver, skeletal muscle, and cardiac muscle. The disease
  presents primarily with hepatomegaly, fasting hypoglycemia, hyperlipidemia, and
  growth retardation in childhood. Myopathy and cardiomyopathy become increasingly
  prominent with age. GSD IIIa (approximately 85% of cases) affects both liver and
  muscle, while GSD IIIb affects liver only. Hepatic fibrosis and cirrhosis may
  develop in adulthood, and hepatocellular carcinoma is a recognized complication.
disease_term:
  preferred_term: glycogen storage disease III
  term:
    id: MONDO:0009291
    label: glycogen storage disease III
parents:
- Glycogen Storage Disease
prevalence:
- population: Global and founder populations
  percentage: 1 in 100,000 globally; 1 in 5,400 in North African Jews; 1 in 3,100-3,600 in the Faroe Islands
  notes: >-
    Glycogen storage disease type III is rare in the general population but
    shows major founder enrichment in certain populations, especially North
    African Jewish and Faroese groups.
  evidence:
  - reference: PMID:9412782
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The overall incidence of the disease is about 1:100,000 life births in the USA; however, it is unusually frequent among North African Jews in Israel (prevalence 1:5,400, carrier prevalence 1:35)."
    explanation: This population study provides both the general-population incidence estimate and the founder-population prevalence estimate for North African Jews.
  - reference: PMID:11378828
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "From the fact that we are currently aware of a total of 14 GSD IIIA cases in the Faroese population of 45 000, the observed prevalence is 1 : 3100."
    explanation: This founder-population study documents exceptionally high prevalence of GSD IIIA in the Faroe Islands.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >
    GSD III follows autosomal recessive inheritance. The AGL gene is located on
    chromosome 1p21.2. Carrier frequency varies by population, with notably higher
    prevalence in certain ethnic groups including Faroese, North African Jewish,
    and Inuit communities.
  evidence:
  - reference: PMID:20301788
    reference_title: "Glycogen Storage Disease Type III."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "GSD III is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an AGL pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected with GSD III, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial AGL pathogenic variants."
    explanation: GeneReviews confirms autosomal recessive inheritance of GSD III with standard Mendelian ratios for carrier parents.
  - reference: PMID:11949933
    reference_title: "Molecular characterization of glycogen storage disease type III."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Deficiency of the glycogen debranching enzyme (gene, AGL) causes glycogen storage disease type III (GSD-III), an autosomal recessive disease affecting glycogen metabolism."
    explanation: Confirms autosomal recessive inheritance and AGL gene involvement.
has_subtypes:
- name: GSD IIIa
  description: >
    The most common subtype, accounting for approximately 85% of GSD III cases.
    Involves both liver and muscle (skeletal and cardiac). Characterized by
    hepatomegaly and hypoglycemia in childhood with progressive myopathy and
    cardiomyopathy developing over time.
  subtype_frequency: "~85%"
  evidence:
  - reference: PMID:20301788
    reference_title: "Glycogen Storage Disease Type III."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "GSD IIIa is the most common subtype, present in about 85% of affected individuals; it manifests with liver and muscle involvement."
    explanation: GeneReviews confirms GSD IIIa as the predominant subtype with liver and muscle involvement.
- name: GSD IIIb
  description: >
    Accounts for approximately 15% of GSD III cases. Affects liver only without
    muscle involvement. Exon 3 mutations in AGL are specifically associated with
    this subtype.
  subtype_frequency: "~15%"
  evidence:
  - reference: PMID:20301788
    reference_title: "Glycogen Storage Disease Type III."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "GSD IIIb, with liver involvement only, comprises about 15% of all affected individuals."
    explanation: GeneReviews confirms GSD IIIb as the liver-only subtype comprising approximately 15% of cases.
  - reference: PMID:11949933
    reference_title: "Molecular characterization of glycogen storage disease type III."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "exon 3 mutations (17delAG and Q6X) are specifically associated with GSD-IIIb"
    explanation: Molecular characterization identifies specific genotype-phenotype correlation for the GSD IIIb subtype.
pathophysiology:
- name: Glycogen debranching enzyme deficiency
  description: >
    Deficiency of the glycogen debranching enzyme (AGL) impairs the complete
    degradation of glycogen. The enzyme normally has two catalytic activities:
    oligo-1,4-1,4-glucantransferase (transferase) and amylo-1,6-glucosidase
    (glucosidase). Without this enzyme, glycogen breakdown halts at the branch
    points, leading to accumulation of limit dextrin (abnormally short-branched
    glycogen) in hepatocytes, skeletal myocytes, and cardiomyocytes.
  gene:
    preferred_term: AGL
    description: Amylo-1,6-glucosidase, 4-alpha-glucanotransferase; the glycogen debranching enzyme with dual transferase and glucosidase activities.
    modifier: DECREASED
    term:
      id: hgnc:321
      label: AGL
  evidence:
  - reference: PMID:11949933
    reference_title: "Molecular characterization of glycogen storage disease type III."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most GSD-III patients have AGL deficiency in both the liver and muscle (type IIIa), but some have it in the liver but not muscle (type IIIb)."
    explanation: Confirms AGL deficiency causes GSD III with tissue-specific subtypes.
  - reference: PMID:27106217
    reference_title: "Glycogen storage disease type III: diagnosis, genotype, management, clinical course and outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Glycogen storage disease type III (GSDIII) is a rare disorder of glycogenolysis due to AGL gene mutations, causing glycogen debranching enzyme deficiency and storage of limited dextrin."
    explanation: Large international cohort study confirms AGL mutations cause debranching enzyme deficiency and limit dextrin accumulation.
  - reference: PMID:33368379
    reference_title: "Narrative review of glycogen storage disorder type III with a focus on neuromuscular, cardiac and therapeutic aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Glycogen storage disorder type III (GSDIII) is a rare inborn error of metabolism due to loss of glycogen debranching enzyme activity, causing inability to fully mobilize glycogen stores and its consequent accumulation in various tissues, notably liver, cardiac and skeletal muscle."
    explanation: Review confirms the pathophysiology of debranching enzyme loss causing glycogen accumulation in liver, cardiac, and skeletal muscle.
  cell_types:
  - preferred_term: Hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  - preferred_term: Skeletal muscle cell
    term:
      id: CL:0000188
      label: cell of skeletal muscle
  - preferred_term: Cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  molecular_functions:
  - preferred_term: 4-alpha-glucanotransferase activity
    modifier: DECREASED
    term:
      id: GO:0004134
      label: 4-alpha-glucanotransferase activity
  - preferred_term: amylo-alpha-1,6-glucosidase activity
    modifier: DECREASED
    term:
      id: GO:0004135
      label: amylo-alpha-1,6-glucosidase activity
  biological_processes:
  - preferred_term: Glycogen catabolic process
    modifier: DECREASED
    term:
      id: GO:0005980
      label: glycogen catabolic process
  - preferred_term: Glucose metabolic process
    modifier: DECREASED
    term:
      id: GO:0006006
      label: glucose metabolic process
  chemical_entities:
  - preferred_term: glycogen
    modifier: INCREASED
    term:
      id: CHEBI:28087
      label: glycogen
  - preferred_term: glucose
    modifier: DECREASED
    term:
      id: CHEBI:17234
      label: glucose
  downstream:
  - target: Hepatic glycogen accumulation and fibrosis
    description: Loss of AGL debranching activity leaves incompletely degraded glycogen in hepatocytes, driving hepatic storage injury and fibrosis risk.
    causal_link_type: DIRECT
  - target: Skeletal and cardiac myopathy
    description: In GSD IIIa, the same debranching block affects skeletal and cardiac muscle, causing progressive glycogen storage myopathy and cardiomyopathy.
    causal_link_type: DIRECT
  - target: Fasting hypoglycemia
    description: Impaired hepatic glycogen mobilization limits fasting glucose release and clinically manifests as ketotic fasting hypoglycemia.
    causal_link_type: DIRECT
  - target: Low blood glucose
    description: Impaired hepatic glycogen mobilization lowers blood glucose during fasting.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301788
      reference_title: "Glycogen Storage Disease Type III."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In infancy and early childhood, liver involvement presents as hepatomegaly and failure to thrive, with fasting ketotic hypoglycemia, hyperlipidemia, and elevated hepatic transaminases."
      explanation: GeneReviews supports fasting hypoglycemia as the blood-glucose readout of impaired hepatic glycogen mobilization in GSD III.
  - target: Failure to thrive
    description: Recurrent early-life fasting hypoglycemia and hepatic metabolic disease contribute to poor growth.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Fasting hypoglycemia
- name: Hepatic glycogen accumulation and fibrosis
  description: >
    Progressive accumulation of limit dextrin in hepatocytes causes hepatomegaly
    and hepatic dysfunction. Over time, the glycogen storage leads to hepatocyte
    injury, inflammation, fibrosis, and potentially cirrhosis. Hepatocellular
    adenomas and carcinoma can develop as long-term complications. Liver fibrosis
    can begin early in life; aminotransferases may paradoxically normalize with
    age as fibrosis progresses.
  evidence:
  - reference: PMID:31263214
    reference_title: "Liver fibrosis during clinical ascertainment of glycogen storage disease type III: a need for improved and systematic monitoring."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Liver fibrosis can occur at an early age, and may explain the decrease in aminotransferases and Glc4 with age."
    explanation: Demonstrates that liver fibrosis occurs early in GSD III and that normalization of aminotransferases with age does not indicate hepatic improvement.
  - reference: PMID:27106217
    reference_title: "Glycogen storage disease type III: diagnosis, genotype, management, clinical course and outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Chronic complications involved the liver (hepatic cirrhosis, adenoma(s), and/or hepatocellular carcinoma in 11 %)"
    explanation: Large cohort study documents hepatic cirrhosis and HCC as chronic complications of GSD III.
  - reference: PMID:34820282
    reference_title: "A retrospective longitudinal study and comprehensive review of adult patients with glycogen storage disease type III."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hepatomegaly and cirrhosis were the most common radiological findings; and 28% developed decompensated liver disease and portal hypertension, the latter being more prevalent in older patients."
    explanation: Retrospective study of adults shows high rate of liver disease progression including cirrhosis and portal hypertension.
  cell_types:
  - preferred_term: Hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  biological_processes:
  - preferred_term: Glycogen metabolic process
    term:
      id: GO:0005977
      label: glycogen metabolic process
  - preferred_term: Carbohydrate metabolic process
    term:
      id: GO:0005975
      label: carbohydrate metabolic process
  chemical_entities:
  - preferred_term: glycogen
    modifier: INCREASED
    term:
      id: CHEBI:28087
      label: glycogen
  downstream:
  - target: Hepatomegaly
    description: Hepatic limit-dextrin and glycogen storage enlarges the liver.
    causal_link_type: DIRECT
  - target: Elevated circulating hepatic transaminase concentration
    description: Hepatocyte storage injury elevates circulating aminotransferases early in disease.
    causal_link_type: DIRECT
  - target: Elevated cholesterol
    description: Hepatic metabolic dysfunction in GSD III is reflected by elevated cholesterol early in life.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:31263214
      reference_title: "Liver fibrosis during clinical ascertainment of glycogen storage disease type III: a need for improved and systematic monitoring."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Markers of liver injury (aminotransferases), dysfunction (cholesterol, triglycerides), and glycogen storage (glucose tetrasaccharide, Glc4) were elevated at an early age, and decreased significantly thereafter"
      explanation: The liver natural-history study supports elevated cholesterol as a hepatic dysfunction marker in pediatric GSD III.
  - target: Elevated triglycerides
    description: Hepatic metabolic dysfunction in GSD III is reflected by elevated triglycerides early in life.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:31263214
      reference_title: "Liver fibrosis during clinical ascertainment of glycogen storage disease type III: a need for improved and systematic monitoring."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Markers of liver injury (aminotransferases), dysfunction (cholesterol, triglycerides), and glycogen storage (glucose tetrasaccharide, Glc4) were elevated at an early age, and decreased significantly thereafter"
      explanation: The liver natural-history study supports elevated triglycerides as a hepatic dysfunction marker in pediatric GSD III.
  - target: Elevated glucose tetrasaccharide
    description: Glucose tetrasaccharide is a glycogen-storage biomarker elevated early in GSD III.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:31263214
      reference_title: "Liver fibrosis during clinical ascertainment of glycogen storage disease type III: a need for improved and systematic monitoring."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Markers of liver injury (aminotransferases), dysfunction (cholesterol, triglycerides), and glycogen storage (glucose tetrasaccharide, Glc4) were elevated at an early age, and decreased significantly thereafter"
      explanation: The liver natural-history study identifies Glc4 as an elevated glycogen-storage marker in pediatric GSD III.
  - target: Hepatic fibrosis
    description: Chronic hepatic glycogen storage injury can progress to fibrosis, cirrhosis, and related complications.
    causal_link_type: DIRECT
- name: Skeletal and cardiac myopathy
  description: >
    In GSD IIIa, glycogen accumulation in skeletal and cardiac muscle leads to
    progressive myopathy and cardiomyopathy. Muscle involvement may be minimal
    in childhood but typically worsens with age. The myopathy is slowly progressive
    and can lead to significant disability. Cardiac involvement manifests primarily
    as left ventricular hypertrophy, which may progress to cardiomyopathy.
  evidence:
  - reference: PMID:20301788
    reference_title: "Glycogen Storage Disease Type III."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most individuals develop cardiac involvement with cardiac hypertrophy and/or cardiomyopathy. Skeletal myopathy manifesting as weakness may be evident in childhood and slowly progresses, typically becoming prominent in the third to fourth decade."
    explanation: GeneReviews describes the progressive nature of cardiac and skeletal muscle involvement in GSD III.
  - reference: PMID:27106217
    reference_title: "Glycogen storage disease type III: diagnosis, genotype, management, clinical course and outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "heart (cardiac involvement and cardiomyopathy, in 58 % and 15 %, respectively, generally presenting in early childhood), and muscle (pain in 34 %)."
    explanation: Large international cohort quantifies cardiac involvement at 58% and cardiomyopathy at 15% in GSD III patients.
  - reference: PMID:34820282
    reference_title: "A retrospective longitudinal study and comprehensive review of adult patients with glycogen storage disease type III."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "muscle weakness was a major feature, noted in 89% of the GSD IIIa cohort, a third of whom depended on a wheelchair or an assistive walking device."
    explanation: Adult cohort study shows high prevalence and severity of muscle weakness in GSD IIIa, with significant functional disability.
  cell_types:
  - preferred_term: Skeletal muscle cell
    term:
      id: CL:0000188
      label: cell of skeletal muscle
  - preferred_term: Cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: Glycogen catabolic process
    modifier: DECREASED
    term:
      id: GO:0005980
      label: glycogen catabolic process
  chemical_entities:
  - preferred_term: glycogen
    modifier: INCREASED
    term:
      id: CHEBI:28087
      label: glycogen
  downstream:
  - target: Myopathy
    description: Skeletal muscle glycogen storage causes progressive weakness and exercise intolerance in GSD IIIa.
    causal_link_type: DIRECT
  - target: Hypertrophic cardiomyopathy
    description: Cardiac muscle glycogen storage commonly manifests as left ventricular hypertrophy and cardiomyopathy.
    causal_link_type: DIRECT
  - target: Elevated circulating creatine kinase concentration
    description: Skeletal muscle involvement is reflected biochemically by persistently elevated creatine kinase.
    causal_link_type: DIRECT
  - target: Serum creatine kinase
    description: Skeletal muscle involvement is reflected biochemically by persistently elevated serum creatine kinase.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:31263214
      reference_title: "Liver fibrosis during clinical ascertainment of glycogen storage disease type III: a need for improved and systematic monitoring."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Creatine phosphokinase was also elevated with no significant correlation with age (p = 0.4)."
      explanation: Pediatric GSD III natural-history data support elevated creatine kinase as a muscle-involvement readout.
phenotypes:
- name: Hepatomegaly
  description: >
    Enlargement of the liver due to glycogen accumulation, present from infancy.
    Typically most prominent in childhood and may decrease with age. Hepatomegaly
    is the most common presenting sign.
  frequency: HP_0040281
  phenotype_term:
    preferred_term: Hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly
  evidence:
  - reference: PMID:27106217
    reference_title: "Glycogen storage disease type III: diagnosis, genotype, management, clinical course and outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "GSDIII patients first presented before the age of 1.5 years, hepatomegaly was the most common presenting clinical sign."
    explanation: Large international cohort confirms hepatomegaly as the most common presenting sign of GSD III, appearing before 1.5 years of age.
- name: Fasting hypoglycemia
  description: >
    Ketotic hypoglycemia during fasting due to impaired glycogenolysis. Less severe
    than in GSD I because gluconeogenesis is intact. More than half of patients
    report hospitalizations due to hypoglycemia.
  frequency: HP_0040281
  phenotype_term:
    preferred_term: Fasting hypoglycemia
    term:
      id: HP:0003162
      label: Fasting hypoglycemia
  evidence:
  - reference: PMID:20301788
    reference_title: "Glycogen Storage Disease Type III."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In infancy and early childhood, liver involvement presents as hepatomegaly and failure to thrive, with fasting ketotic hypoglycemia, hyperlipidemia, and elevated hepatic transaminases."
    explanation: GeneReviews describes fasting ketotic hypoglycemia as a key feature of GSD III in infancy and early childhood.
  - reference: PMID:38196773
    reference_title: "Glycogen storage disease type III: a mixed-methods study to assess the burden of disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hypoglycemia was frequently reported in both adults and children, with more than half reporting hospitalizations due to hypoglycemia."
    explanation: Patient burden study confirms high prevalence of hypoglycemia requiring hospitalization.
- name: Hyperlipidemia
  description: >
    Elevated blood lipids, including elevated triglycerides and cholesterol.
  frequency: HP_0040282
  phenotype_term:
    preferred_term: Hyperlipidemia
    term:
      id: HP:0003077
      label: Hyperlipidemia
  evidence:
  - reference: PMID:20301788
    reference_title: "Glycogen Storage Disease Type III."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "fasting ketotic hypoglycemia, hyperlipidemia, and elevated hepatic transaminases."
    explanation: GeneReviews lists hyperlipidemia as a key metabolic feature in GSD III.
- name: Myopathy
  description: >
    Progressive skeletal myopathy in GSD IIIa, manifesting as proximal muscle
    weakness and exercise intolerance. Distal myopathy may also develop. Muscle
    weakness is the major cause of morbidity in adult GSD IIIa patients.
  frequency: HP_0040282
  phenotype_term:
    preferred_term: Myopathy
    term:
      id: HP:0003198
      label: Myopathy
  evidence:
  - reference: PMID:34820282
    reference_title: "A retrospective longitudinal study and comprehensive review of adult patients with glycogen storage disease type III."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the GSD IIIa group, muscle weakness was a major feature, noted in 89% of the GSD IIIa cohort, a third of whom depended on a wheelchair or an assistive walking device."
    explanation: Retrospective study of adults quantifies muscle weakness at 89% prevalence in GSD IIIa with significant functional impact.
  - reference: PMID:38196773
    reference_title: "Glycogen storage disease type III: a mixed-methods study to assess the burden of disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Adults most often reported muscle weakness as a top interfering symptom and the most important goal of a potential therapy."
    explanation: Patient burden study identifies muscle weakness as the most impactful symptom from the patient perspective.
- name: Hypertrophic cardiomyopathy
  description: >
    Left ventricular hypertrophy is common in GSD IIIa patients and may be
    present from childhood. Asymptomatic LVH is the most common cardiac
    manifestation. Symptomatic cardiomyopathy with reduced ejection fraction
    occurs in approximately 10-15% of patients.
  frequency: HP_0040282
  phenotype_term:
    preferred_term: Hypertrophic cardiomyopathy
    term:
      id: HP:0001639
      label: Hypertrophic cardiomyopathy
  evidence:
  - reference: PMID:34820282
    reference_title: "A retrospective longitudinal study and comprehensive review of adult patients with glycogen storage disease type III."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Asymptomatic left ventricular hypertrophy (LVH) was the most common cardiac manifestation, present in 43%. Symptomatic cardiomyopathy and reduced ejection fraction was evident in 10%."
    explanation: Adult cohort study quantifies LVH at 43% and symptomatic cardiomyopathy at 10%.
  - reference: PMID:27106217
    reference_title: "Glycogen storage disease type III: diagnosis, genotype, management, clinical course and outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "heart (cardiac involvement and cardiomyopathy, in 58 % and 15 %, respectively, generally presenting in early childhood)"
    explanation: International study reports cardiac involvement in 58% and cardiomyopathy in 15% of GSD III patients.
- name: Elevated circulating creatine kinase concentration
  description: >
    Elevated CK levels reflecting skeletal muscle involvement, frequently found
    in GSD IIIa patients. CK is significantly associated with disease burden.
  frequency: HP_0040282
  phenotype_term:
    preferred_term: Elevated circulating creatine kinase concentration
    term:
      id: HP:0003236
      label: Elevated circulating creatine kinase concentration
  evidence:
  - reference: PMID:31263214
    reference_title: "Liver fibrosis during clinical ascertainment of glycogen storage disease type III: a need for improved and systematic monitoring."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Creatine phosphokinase was also elevated with no significant correlation with age (p = 0.4)."
    explanation: Study shows CK is persistently elevated in GSD III patients regardless of age.
- name: Hepatic fibrosis
  description: >
    Progressive hepatic fibrosis develops in many patients, potentially leading
    to cirrhosis in adulthood. Fibrosis can be present from infancy and may be
    severe even in young children.
  frequency: HP_0040282
  phenotype_term:
    preferred_term: Hepatic fibrosis
    term:
      id: HP:0001395
      label: Hepatic fibrosis
  evidence:
  - reference: PMID:31263214
    reference_title: "Liver fibrosis during clinical ascertainment of glycogen storage disease type III: a need for improved and systematic monitoring."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Liver fibrosis can occur at an early age, and may explain the decrease in aminotransferases and Glc4 with age."
    explanation: Study demonstrates early onset of liver fibrosis in GSD III and its paradoxical relationship to normalizing aminotransferases.
  - reference: PMID:34820282
    reference_title: "A retrospective longitudinal study and comprehensive review of adult patients with glycogen storage disease type III."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "28% developed decompensated liver disease and portal hypertension"
    explanation: Adult cohort shows significant progression to decompensated liver disease.
- name: Failure to thrive
  description: >
    Growth retardation and short stature, particularly in childhood, due to
    metabolic derangements and recurrent hypoglycemia.
  frequency: HP_0040282
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:20301788
    reference_title: "Glycogen Storage Disease Type III."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In infancy and early childhood, liver involvement presents as hepatomegaly and failure to thrive"
    explanation: GeneReviews identifies failure to thrive as a key early presentation.
- name: Elevated circulating hepatic transaminase concentration
  description: >
    Elevated liver transaminases (AST and ALT) reflecting hepatocyte injury
    from glycogen accumulation. Tend to normalize with age as fibrosis progresses.
  frequency: HP_0040281
  phenotype_term:
    preferred_term: Elevated circulating hepatic transaminase concentration
    term:
      id: HP:0002910
      label: Elevated circulating hepatic transaminase concentration
  evidence:
  - reference: PMID:31263214
    reference_title: "Liver fibrosis during clinical ascertainment of glycogen storage disease type III: a need for improved and systematic monitoring."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Markers of liver injury (aminotransferases), dysfunction (cholesterol, triglycerides), and glycogen storage (glucose tetrasaccharide, Glc4) were elevated at an early age, and decreased significantly thereafter"
    explanation: Demonstrates elevated aminotransferases in early GSD III that paradoxically decrease with age.
biochemical:
- name: Low blood glucose
  presence: DECREASED
  context: >
    Fasting blood glucose can fall because impaired hepatic debranching limits
    glycogen-derived glucose release during fasting.
  biomarker_term:
    preferred_term: glucose
    term:
      id: CHEBI:17234
      label: glucose
  readouts:
  - target: Glycogen debranching enzyme deficiency
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Lower blood glucose reports impaired hepatic glycogen mobilization during fasting.
  - target: Fasting hypoglycemia
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: MONITORING
    interpretation: Blood glucose monitoring tracks the fasting hypoglycemia branch.
  evidence:
  - reference: PMID:20301788
    reference_title: "Glycogen Storage Disease Type III."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In infancy and early childhood, liver involvement presents as hepatomegaly and failure to thrive, with fasting ketotic hypoglycemia, hyperlipidemia, and elevated hepatic transaminases."
    explanation: GeneReviews supports fasting hypoglycemia as a blood-glucose abnormality in GSD III.
- name: Elevated cholesterol
  presence: INCREASED
  context: >
    Elevated cholesterol is a liver-dysfunction marker in pediatric GSD III and
    can improve with better metabolic control.
  biomarker_term:
    preferred_term: cholesterol
    term:
      id: CHEBI:16113
      label: cholesterol
  readouts:
  - target: Hepatic glycogen accumulation and fibrosis
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: MONITORING
    interpretation: Higher cholesterol tracks hepatic metabolic dysfunction in GSD III.
  evidence:
  - reference: PMID:31263214
    reference_title: "Liver fibrosis during clinical ascertainment of glycogen storage disease type III: a need for improved and systematic monitoring."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Markers of liver injury (aminotransferases), dysfunction (cholesterol, triglycerides), and glycogen storage (glucose tetrasaccharide, Glc4) were elevated at an early age, and decreased significantly thereafter"
    explanation: Supports elevated cholesterol as a hepatic dysfunction marker in GSD III.
- name: Elevated triglycerides
  presence: INCREASED
  context: >
    Elevated triglycerides are part of the hepatic metabolic dysfunction profile
    in early GSD III.
  biomarker_term:
    preferred_term: triglyceride
    term:
      id: CHEBI:17855
      label: triglyceride
  readouts:
  - target: Hepatic glycogen accumulation and fibrosis
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: MONITORING
    interpretation: Higher triglycerides track hepatic metabolic dysfunction in GSD III.
  evidence:
  - reference: PMID:31263214
    reference_title: "Liver fibrosis during clinical ascertainment of glycogen storage disease type III: a need for improved and systematic monitoring."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Markers of liver injury (aminotransferases), dysfunction (cholesterol, triglycerides), and glycogen storage (glucose tetrasaccharide, Glc4) were elevated at an early age, and decreased significantly thereafter"
    explanation: Supports elevated triglycerides as a hepatic dysfunction marker in GSD III.
- name: Elevated glucose tetrasaccharide
  presence: INCREASED
  context: >
    Glucose tetrasaccharide (Glc4) is elevated as a glycogen-storage marker in
    pediatric GSD III and tends to decline with age.
  readouts:
  - target: Hepatic glycogen accumulation and fibrosis
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: MONITORING
    interpretation: Higher Glc4 reports glycogen storage burden in the hepatic branch.
  evidence:
  - reference: PMID:31263214
    reference_title: "Liver fibrosis during clinical ascertainment of glycogen storage disease type III: a need for improved and systematic monitoring."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Markers of liver injury (aminotransferases), dysfunction (cholesterol, triglycerides), and glycogen storage (glucose tetrasaccharide, Glc4) were elevated at an early age, and decreased significantly thereafter"
    explanation: Supports elevated glucose tetrasaccharide as a glycogen-storage marker in pediatric GSD III.
- name: Serum creatine kinase
  presence: INCREASED
  context: >
    Elevated serum creatine kinase reflects skeletal muscle involvement in GSD
    III and may remain elevated across childhood.
  readouts:
  - target: Skeletal and cardiac myopathy
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: MONITORING
    interpretation: Higher serum creatine kinase reports the myopathy branch of GSD III.
  evidence:
  - reference: PMID:31263214
    reference_title: "Liver fibrosis during clinical ascertainment of glycogen storage disease type III: a need for improved and systematic monitoring."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Creatine phosphokinase was also elevated with no significant correlation with age (p = 0.4)."
    explanation: Supports elevated serum creatine kinase as a muscle-involvement readout.
genetic:
- name: AGL
  gene_term:
    preferred_term: AGL
    term:
      id: hgnc:321
      label: AGL
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_a7b762bc-a12f-4194-91b9-764784248cc7-2023-02-24T170000.000Z
    reference_title: "AGL / glycogen storage disease III (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "AGL | HGNC:321 | glycogen storage disease III | MONDO:0009291 | AR | Definitive"
    explanation: ClinGen classifies the AGL-glycogen storage disease III gene-disease relationship as definitive with autosomal recessive inheritance.
treatments:
- name: Dietary management
  description: >
    Frequent meals and cornstarch supplementation to prevent hypoglycemia.
    High-protein diet (3 g/kg) is recommended to provide amino acid substrate for
    gluconeogenesis and to support muscle integrity. Uncooked cornstarch
    provides a slow-release glucose source. Modified Atkins or ketogenic diets
    may improve cardiac and skeletal muscle function by reducing glycogen storage.
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: MAXO:0000088
      label: dietary intervention
  target_mechanisms:
  - target: Glycogen debranching enzyme deficiency
    treatment_effect: BYPASSES
    description: Frequent feeds and uncooked cornstarch provide exogenous slow-release carbohydrate to maintain euglycemia around the impaired glycogenolysis block.
    evidence:
    - reference: PMID:20301788
      reference_title: "Glycogen Storage Disease Type III."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Dietary management tailored to the individual patient remains the primary therapy. Frequent feeds (every 3-4 hours) are needed to maintain euglycemia in infancy."
      explanation: GeneReviews supports dietary management as the primary therapy for maintaining euglycemia despite the upstream debranching defect.
  - target: Hepatic glycogen accumulation and fibrosis
    treatment_effect: MODULATES
    description: Cornstarch-based metabolic control reduces hypoglycemia and serum aminotransferases, mitigating the hepatic injury branch.
    evidence:
    - reference: PMID:2403059
      reference_title: "Efficacy of cornstarch therapy in type III glycogen-storage disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Cornstarch therapy was associated with maintenance of normoglycemia, increased growth velocity, and decreased serum aminotransferase concentrations in all patients."
      explanation: Clinical cornstarch therapy evidence supports dietary modulation of glycemic control, growth, and liver injury markers.
  - target: Skeletal and cardiac myopathy
    treatment_effect: MODULATES
    description: High-fat, high-protein, low-carbohydrate dietary strategies have case-level evidence for improving the cardiomyopathy branch in GSD III.
    evidence:
    - reference: PMID:25308556
      reference_title: "Improvement of Cardiomyopathy After High-Fat Diet in Two Siblings with Glycogen Storage Disease Type III."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "A diet rich in fats as well as proteins and poor in carbohydrates could be a beneficial therapeutic choice for GSD III with cardiomyopathy."
      explanation: Reported sibling cases support dietary modulation of cardiac muscle involvement in GSD III.
  evidence:
  - reference: PMID:20301788
    reference_title: "Glycogen Storage Disease Type III."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dietary management tailored to the individual patient remains the primary therapy. Frequent feeds (every 3-4 hours) are needed to maintain euglycemia in infancy."
    explanation: GeneReviews establishes dietary management as the primary therapy with specific recommendations for meal frequency.
  - reference: PMID:2403059
    reference_title: "Efficacy of cornstarch therapy in type III glycogen-storage disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cornstarch therapy was associated with maintenance of normoglycemia, increased growth velocity, and decreased serum aminotransferase concentrations in all patients."
    explanation: Clinical study demonstrates efficacy of cornstarch therapy in GSD III for glycemic control, growth, and liver function.
  - reference: PMID:25308556
    reference_title: "Improvement of Cardiomyopathy After High-Fat Diet in Two Siblings with Glycogen Storage Disease Type III."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A diet rich in fats as well as proteins and poor in carbohydrates could be a beneficial therapeutic choice for GSD III with cardiomyopathy."
    explanation: Case report of two siblings shows high-fat low-carbohydrate diet improves cardiomyopathy in GSD IIIa.
- name: Liver transplantation
  description: >
    Liver transplantation may be considered for patients with severe hepatic
    fibrosis, cirrhosis, or hepatocellular carcinoma. It corrects the hepatic
    metabolic defect but does not address myopathy and may exacerbate muscle disease.
  treatment_term:
    preferred_term: organ transplantation
    term:
      id: MAXO:0010039
      label: organ transplantation
  evidence:
  - reference: PMID:20301788
    reference_title: "Glycogen Storage Disease Type III."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Liver transplantation is reserved for those with severe hepatic cirrhosis, liver dysfunction, and/or hepatocellular carcinoma. Liver transplantation may exacerbate myopathy and cardiomyopathy."
    explanation: GeneReviews describes liver transplantation indications and the important caveat that it may worsen muscle disease.
- name: Genetic counseling
  description: >
    Genetic counseling for affected families regarding autosomal recessive
    inheritance, carrier testing, and reproductive options. Once pathogenic variants
    are identified, prenatal and preimplantation genetic testing are possible.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: MAXO:0000079
      label: genetic counseling
  evidence:
  - reference: PMID:20301788
    reference_title: "Glycogen Storage Disease Type III."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Once the AGL pathogenic variants have been identified in an affected family member, carrier testing for at-risk family members and prenatal and preimplantation genetic testing for a pregnancy at increased risk are possible."
    explanation: GeneReviews outlines genetic counseling recommendations for GSD III families.
references:
- reference: PMID:20301788
  title: "Glycogen Storage Disease Type III."
  tags:
  - GeneReviews
  findings: []

📚

References & Deep Research

References

1

PMID:20301788

Glycogen Storage Disease Type III.

No top-level findings curated for this source.

Deep Research

1

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Disease Pathophysiology Research Template

Edison Scientific Literature 24 citations 2026-03-08T18:52:21.406272

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Pathophysiology Research Template

Target Disease

Disease Name: Cori Forbes Disease
MONDO ID: (if available)
Category: Mendelian

Research Objectives

Please provide a comprehensive research report on the pathophysiology of Cori Forbes Disease. Focus on the molecular and cellular mechanisms underlying disease progression.

Required Information

1. Core Pathophysiology

What are the primary pathophysiological mechanisms?
What molecular pathways are dysregulated?
What cellular processes are affected?

2. Key Molecular Players

Genes/Proteins: Which genes are causally involved or implicated?
Chemical Entities: What metabolites, drugs, or small molecules are relevant?
Cell Types: Which cell types are primarily affected?
Anatomical Locations: Which tissues/organs are involved?

3. Biological Processes (for GO annotation)

What biological processes (GO terms) are disrupted?
Consider: signaling pathways, metabolic processes, cellular responses, transport, etc.

4. Cellular Components

Where in the cell do key processes occur?
Consider: organelles, membrane compartments, extracellular space, etc.

5. Disease Progression

What is the sequence of events from initial trigger to clinical manifestation?
Are there distinct stages or phases?

6. Phenotypic Manifestations

What are the key clinical phenotypes?
How do they relate to the underlying mechanisms?

Citation Requirements

Cite primary literature (PMID preferred) for all mechanistic claims
Prioritize recent reviews and landmark papers
Include direct quotes where possible to support key statements

Output Format

Structure your response as a narrative that could be used to populate a disease knowledge base entry with: - Pathophysiology description - Gene/protein annotations with ontology terms (HGNC, GO) - Phenotype associations (HP terms) - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Evidence items with PMIDs

Research Report: Cori–Forbes Disease (Glycogen Storage Disease Type III, GSD III)

1) Key concepts, definitions, and current understanding (pathophysiology core)

Disease definition / genetics. Cori–Forbes disease is glycogen storage disease type III (GSD III), an autosomal recessive Mendelian disorder caused by biallelic pathogenic variants in AGL (HGNC:317), which encodes the glycogen debranching enzyme (GDE; amylo-α-1,6-glucosidase / 4-α-glucanotransferase). Clinical guidelines describe the consequence as “structurally abnormal glycogen” with “defective glucose release from glycogen in the liver and sometimes in the muscles, whereas gluconeogenesis is normal.” (wicker2023frenchrecommendationsfor pages 1-2)

Biochemical lesion in glycogenolysis. GDE is required to complete glycogen breakdown because glycogen phosphorylase cannot remove glucose residues close to branch points. A recent mechanistic study summarizes that GDE deficiency causes accumulation of phosphorylase-limit dextrin (PLD), i.e., the abnormal, incompletely degraded glycogen species: “Phosphorylase-limit dextrin (PLD)… [is] the type of glycogen which accumulates in GSDIII.” (mishra2024theautophagicactivator pages 2-3)

Primary tissue distribution and why multiple organs are affected. Glycogen stores are most abundant in liver and muscle; accordingly, GSD III affects these tissues, and (for IIIa) also heart, producing a multisystem metabolic myopathy/hepatopathy (mishra2024theautophagicactivator pages 1-2, hannah2023glycogenstoragediseases pages 1-3).

2) Molecular pathways and cellular processes dysregulated

A. Glycogen metabolism dysregulation (core pathway). - Blocked glycogen debranching step → persistence of branched limit dextrins (PLD) in cytosol → cellular glycogen overload (mishra2024theautophagicactivator pages 2-3, wicker2023frenchrecommendationsfor pages 1-2).

B. Autophagy–lysosome system involvement (glycogen clearance / organelle stress). - In a GSD III mouse model and patient fibroblasts, an autophagy-activating small molecule (GHF-201) improved key cellular phenotypes, including lysosomal abnormalities: in patient fibroblasts “GHF-201 restored mitochondrial membrane polarization and corrected lysosomal swelling.” (mishra2024theautophagicactivator pages 1-2) - These data support a model in which impaired or insufficient glycogen handling intersects with lysosomal/autophagic pathways and cellular stress responses (mishra2024theautophagicactivator pages 1-2).

C. Mitochondrial dysfunction and oxidative stress. - A 2024 review focused on GSDs notes that in GSD III patients there are mitochondrial abnormalities including “reduced activities of mitochondrial respiratory chain complexes, increased oxidative stress, and altered mitochondrial morphology,” which may contribute to “muscle weakness, cardiomyopathy, and hepatic dysfunction.” (mishra2024mitochondrialdysfunctionin pages 2-4) - The GHF-201 study’s rescue of mitochondrial membrane polarization provides experimental support that mitochondrial dysfunction is a modifiable component of cellular pathology in GSD III (mishra2024theautophagicactivator pages 1-2).

D. Fibrosis and structural remodeling (liver and heart). - The 2023 Nature Reviews Disease Primers paper and French PNDS guidance both highlight fibrosis/cirrhosis risk (hannah2023glycogenstoragediseases pages 1-3, wicker2023frenchrecommendationsfor pages 1-2). The French recommendations include surveillance for fibrosis/cirrhosis using imaging, and note that MR elastography “may be better to detect fibrosis” though data are limited (wicker2023frenchrecommendationsfor pages 6-8). - Cardiac remodeling in GSD IIIa includes hypertrophic cardiomyopathy and fibrosis detectable by CMR (late enhancement, T1 mapping/ECV) per PNDS recommendations (wicker2023frenchrecommendationsfor pages 5-6).

3) Key molecular players and entities

Genes/Proteins

AGL / GDE (amylo-α-1,6-glucosidase/4-α-glucanotransferase): causal gene/protein; deficiency leads to PLD accumulation (wicker2023frenchrecommendationsfor pages 1-2, mishra2024theautophagicactivator pages 2-3).

Chemical entities / metabolites / relevant small molecules

Glycogen (PLD/limit dextrin): primary accumulated substrate form in GSD III (mishra2024theautophagicactivator pages 2-3).
GHF-201: experimental “autophagic activator” that improved metabolic, structural, lysosomal, and mitochondrial phenotypes in preclinical models (mishra2024theautophagicactivator pages 1-2, mishra2024theautophagicactivator pages 2-3).
UX053: investigational AGL mRNA therapeutic (“1,6-glucosidase 4-alpha-glucanotransferase Messenger Ribonucleic Acid (AGL mRNA)”) tested in a Phase 1/2 study (terminated) (NCT04990388 chunk 2, NCT04990388 chunk 1).

Cell types (CL-aligned)

Hepatocytes (CL:0000182): hepatic glycogen overload → hepatomegaly, transaminase elevation; fibrosis risk (wicker2023frenchrecommendationsfor pages 1-2, hannah2023glycogenstoragediseases pages 1-3).
Skeletal muscle cells / myofibers (e.g., CL:0000515 skeletal muscle cell): “massive glycogen accumulation” in muscle biopsy with PAS-positive vacuoles (wicker2023frenchrecommendationsfor pages 6-8).
Cardiomyocytes (CL:0000746) and cardiac conduction system cells: hypertrophic cardiomyopathy, arrhythmia risk; conduction system involvement described in recent cardiac review (wicker2023frenchrecommendationsfor pages 5-6, pinos2026cardiovascularinvolvementin pages 17-21).

Anatomical locations (UBERON-aligned)

Liver (UBERON:0002107): hepatomegaly → fibrosis/cirrhosis/HCC risk (wicker2023frenchrecommendationsfor pages 1-2, hannah2023glycogenstoragediseases pages 1-3).
Skeletal muscle tissue (UBERON:0001134): progressive myopathy, weakness (hannah2023glycogenstoragediseases pages 1-3, wicker2023frenchrecommendationsfor pages 5-6).
Heart (UBERON:0000948) including myocardium and conduction system: LVH/HCM, fibrosis, arrhythmias (hannah2023glycogenstoragediseases pages 1-3, wicker2023frenchrecommendationsfor pages 5-6, pinos2026cardiovascularinvolvementin pages 17-21).

4) Disease progression: sequence of events

A commonly described sequence is: 1. Inherited AGL deficiency → impaired debranching step of glycogenolysis → PLD accumulation (mishra2024theautophagicactivator pages 2-3, wicker2023frenchrecommendationsfor pages 1-2). 2. Early hepatic/metabolic presentation: GSDIII “usually starts as a liver disorder characterized by hepatomegaly, hypoglycemia, hyperlipidemia, and hyperketonemia” (mishra2024theautophagicactivator pages 2-3). 3. Over time, extrahepatic progression: “leading to liver disorder followed by fatal myopathy” in model-organism framing (mishra2024theautophagicactivator pages 1-2), with clinical recognition that muscle involvement can progress with age (wicker2023frenchrecommendationsfor pages 5-6). 4. Long-term complications: hepatic fibrosis/cirrhosis and tumors can occur (hannah2023glycogenstoragediseases pages 1-3, wicker2023frenchrecommendationsfor pages 1-2), and cardiac disease (LVH/HCM, arrhythmias) may emerge or progress, requiring structured surveillance (wicker2023frenchrecommendationsfor pages 5-6).

5) Phenotypic manifestations (clinical phenotypes) linked to mechanism

From guideline and review sources: - Hypoglycemia (ketotic): “short fasting hypoglycaemia (less than 4 to 5 h) with no hyperlactataemia” (wicker2023frenchrecommendationsfor pages 1-2). - Hepatomegaly, elevated transaminases (wicker2023frenchrecommendationsfor pages 1-2, hannah2023glycogenstoragediseases media 16fd5731). - Myopathy / weakness: GSD IIIa includes myopathy and weakness; muscle biopsy shows “massive glycogen accumulation… with large vacuoles of muscle fibres” (wicker2023frenchrecommendationsfor pages 6-8, hannah2023glycogenstoragediseases media 16fd5731). - Cardiac manifestations: “Hypertrophic cardiomyopathy can occur in the first years of life” (wicker2023frenchrecommendationsfor pages 1-2) and later LVH/HCM with arrhythmias risk (hannah2023glycogenstoragediseases pages 1-3, wicker2023frenchrecommendationsfor pages 5-6).

6) Recent developments and latest research (prioritize 2023–2024)

A. Autophagy-targeting small molecule therapy (preclinical, 2024). - In Agl−/− mice and patient fibroblasts, the autophagy activator GHF-201 improved locomotor function and metabolic biomarkers and corrected key cellular defects. Importantly, in patient fibroblasts “GHF-201 restored mitochondrial membrane polarization and corrected lysosomal swelling,” supporting a mechanistic link between glycogen overload and organelle stress that may be therapeutically targetable (mishra2024theautophagicactivator pages 1-2). - The same work reiterates epidemiology and natural history framing and notes that currently “patients are only managed by dietary restrictions” (mishra2024theautophagicactivator pages 2-3).

B. AAV gene therapy engineering breakthrough (JCI, 2024). - A major technical barrier for single-vector rAAV gene therapy in GSD III is the ~4.6 kb GDE cDNA size. A 2024 JCI study reports a truncated “mini-GDE” (ΔNter2-GDE) enabling single rAAV delivery; the vector “allowed significant glycogen reduction in heart and muscle… as well as normalization of histology features and restoration of muscle strength” in Agl−/− mice and also corrected pathology in a rat model and human cellular models (gardin2024afunctionalminigde pages 1-2).

C. Gene therapy landscape synthesis (JIMD review, 2024). - A 2024 review summarizes multiple strategies for GSD III, including dual-AAV split vectors and heterologous bacterial debranching enzymes, emphasizing immune/toxicity challenges and organ targeting. It notes that liver-targeted strategies can reverse hepatic fibrosis in models, while muscle/cardiac correction requires different delivery considerations (koeberl2024genetherapyfor pages 11-13).

D. Updated clinical management recommendations (PNDS France, 2023). - The 2023 French recommendations provide detailed surveillance frameworks for liver and heart, including the role of cardiac MRI for fibrosis detection (late enhancement, T1 mapping/ECV) and Holter monitoring cadence in patients with HCM (wicker2023frenchrecommendationsfor pages 5-6).

7) Current applications and real-world implementations

Standard-of-care dietary management. PNDS guidance states: “The treatment mainly relies on dietary measures” and specifically that “preserving gluconeogenesis requires an increased protein intake.” (wicker2023frenchrecommendationsfor pages 1-2)

Cardiac-focused dietary strategy (expert analysis). A recent Nature Reviews Cardiology synthesis (2026) argues that traditional frequent feeding/cornstarch to prevent hypoglycemia may worsen cardiac glycogen burden, and highlights expert-consensus macronutrient guidance and reported improvements in case series with high-protein/low-complex-carbohydrate regimens (pinos2026cardiovascularinvolvementin pages 17-21). (Note: This is authoritative but outside 2023–2024.)

Surveillance implementations. - Cardiac surveillance: LVH prevalence reported as 27–86%, ECG abnormalities in >80% of children/adults, and CMR is recommended to assess fibrosis (wicker2023frenchrecommendationsfor pages 5-6). - Hepatic surveillance: abdominal ultrasound and contrast-enhanced MRI are used to monitor hepatomegaly, adenomas, fibrosis/cirrhosis (wicker2023frenchrecommendationsfor pages 5-6, wicker2023frenchrecommendationsfor pages 6-8).

Real-world research infrastructure. The French national registry (NCT06616545) is designed to define natural history and sensitive outcomes over ~10 years, capturing metabolic, neurological, cardiac, and biological data in ~150 patients (NCT06616545 chunk 1).

8) Expert opinions / authoritative sources (selected)

Nature Reviews Disease Primers (2023) provides authoritative synthesis of GSDs including GSD III and highlights phenotypic variability and risks of hepatic fibrosis/cirrhosis, arrhythmias, and cardiomyopathy (hannah2023glycogenstoragediseases pages 1-3) with a tabulated clinical summary for GSD III (hannah2023glycogenstoragediseases media 16fd5731).
French PNDS recommendations (2023) provide an expert-consensus clinical pathway emphasizing structured monitoring of cardiac and hepatic complications and functional assessments for neuromuscular disease (wicker2023frenchrecommendationsfor pages 5-6, wicker2023frenchrecommendationsfor pages 6-8).

9) Relevant statistics and data from recent sources

Incidence: 2023 PNDS reports incidence ~“1 in 100 000” (wicker2023frenchrecommendationsfor pages 1-2). A 2024 mechanistic study similarly states incidence “(incidence of 1:100,000)” (mishra2024theautophagicactivator pages 2-3).
Cardiac involvement metrics: PNDS reports LVH prevalence 27–86% and ECG abnormalities >80% (wicker2023frenchrecommendationsfor pages 5-6). A 2024 gene-therapy paper notes that “most adult patients display left-ventricle hypertrophy though only ~15% have overt cardiomyopathy” (gardin2024afunctionalminigde pages 1-2).

10) Clinical trials and translational pipeline (selected, with URLs/dates)

UX053 (AGL mRNA) Phase 1/2 trial (NCT04990388), Ultragenyx. Started 2021-10-18, completed 2023-03-20, TERMINATED (“Sponsor decision not related to safety concerns”). UX053 is an “mRNA-based biologic” given by IV infusion; key endpoint includes TEAEs and detailed PK (Cmax, Tmax, AUC). (NCT04990388 chunk 1, NCT04990388 chunk 2) URL: https://clinicaltrials.gov/study/NCT04990388
Biomarkers & manifestations study (NCT04574830) (COMPLETED; completion 2022-06-30). Primary objective: “evaluate potential biomarkers of GSD III”; primary outcome: urine Hex4 mean and variance. (NCT04574830 chunk 1) URL: https://clinicaltrials.gov/study/NCT04574830
Hypoglycemia incidence & function survey (NCT05196165) (TERMINATED). Primary objective: “evaluate the incidence of hypoglycemia”; outcome: “Number of Hypoglycemic Events During the 26-week Observation Period”; “No investigational product (IP) will be administered.” (NCT05196165 chunk 1) URL: https://clinicaltrials.gov/study/NCT05196165
French GSD III Observatory registry (NCT06616545) (RECRUITING). Captures natural history; primary endpoint includes “Fasting period”; secondary includes “6MWT distance.” (NCT06616545 chunk 1) URL: https://clinicaltrials.gov/study/NCT06616545
Pediatric liver fibrosis assessment by elastography (NCT07303140) (RECRUITING). Primary outcome: “Liver elastography values” with fibrosis staging F0–F4; start 2024-10-18. (NCT07303140 chunk 1) URL: https://clinicaltrials.gov/study/NCT07303140

Knowledge-base style structured annotations

Pathophysiology description (narrative)

Cori–Forbes disease (GSD III) is an autosomal recessive disorder caused by AGL/GDE deficiency that blocks complete glycogenolysis at branch points, producing cytosolic accumulation of phosphorylase-limit dextrin (PLD), a structurally abnormal glycogen. The resulting glycogen overload in hepatocytes, skeletal myofibers, and cardiomyocytes leads to fasting intolerance and hepatic injury in early life, with progression to skeletal myopathy and possible cardiac hypertrophy/arrhythmias. Secondary cellular dysfunction includes autophagy–lysosome involvement (lysosomal swelling) and mitochondrial dysfunction (respiratory chain impairment, oxidative stress, impaired membrane polarization), which are being explored as therapeutic targets. Progressive hepatic fibrosis/cirrhosis and cardiac fibrosis may occur, motivating systematic surveillance. (mishra2024theautophagicactivator pages 2-3, wicker2023frenchrecommendationsfor pages 1-2, hannah2023glycogenstoragediseases pages 1-3, wicker2023frenchrecommendationsfor pages 5-6, mishra2024theautophagicactivator pages 1-2)

Gene/protein annotations (HGNC) and related processes

AGL (HGNC:317) – causal gene; encodes glycogen debranching enzyme with glucosyltransferase and amylo-1,6-glucosidase activities (wicker2023frenchrecommendationsfor pages 1-2, mishra2024theautophagicactivator pages 2-3).

GO Biological Processes (examples for annotation)

(These are ontology-aligned labels suitable for curation; evidence is cited for the disrupted biology, not for the GO term IDs themselves.) - Glycogen catabolic process (blocked by GDE deficiency; PLD accumulation) (mishra2024theautophagicactivator pages 2-3, wicker2023frenchrecommendationsfor pages 1-2) - Carbohydrate metabolic process / glucose homeostasis (fasting hypoglycemia; impaired glycogen-derived glucose release with intact gluconeogenesis) (wicker2023frenchrecommendationsfor pages 1-2) - Autophagy / lysosome organization (lysosomal swelling corrected by autophagy activator) (mishra2024theautophagicactivator pages 1-2) - Mitochondrial electron transport / oxidative phosphorylation (reduced respiratory chain activities; oxidative stress) (mishra2024mitochondrialdysfunctionin pages 2-4) - Fibrosis / extracellular matrix organization (liver; myocardium) (clinical fibrosis surveillance and risk) (hannah2023glycogenstoragediseases pages 1-3, wicker2023frenchrecommendationsfor pages 5-6)

Cellular Components (examples)

Cytosol (glycogen/PLD storage; cytosolic accumulation emphasized vs lysosomal storage in other GSDs) (mishra2024theautophagicactivator pages 2-3)
Lysosome (lysosomal swelling; autophagy-lysosome axis) (mishra2024theautophagicactivator pages 1-2)
Mitochondrion (membrane polarization; respiratory chain defects) (mishra2024theautophagicactivator pages 1-2, mishra2024mitochondrialdysfunctionin pages 2-4)

Phenotype associations (HP-aligned labels; examples)

Hepatomegaly (wicker2023frenchrecommendationsfor pages 1-2, hannah2023glycogenstoragediseases media 16fd5731)
Hypoglycemia (ketotic) (wicker2023frenchrecommendationsfor pages 1-2)
Hyperlipidemia / hyperketonemia (mishra2024theautophagicactivator pages 2-3)
Elevated transaminases (wicker2023frenchrecommendationsfor pages 1-2)
Myopathy / muscle weakness (hannah2023glycogenstoragediseases pages 1-3, wicker2023frenchrecommendationsfor pages 6-8)
Hypertrophic cardiomyopathy / left ventricular hypertrophy (wicker2023frenchrecommendationsfor pages 1-2, wicker2023frenchrecommendationsfor pages 5-6)
Arrhythmia risk (hannah2023glycogenstoragediseases pages 1-3, wicker2023frenchrecommendationsfor pages 5-6)

Cell type involvement (CL-aligned; examples)

Hepatocyte (CL:0000182) (wicker2023frenchrecommendationsfor pages 1-2)
Skeletal muscle cell / myofiber (CL:0000515) (wicker2023frenchrecommendationsfor pages 6-8)
Cardiomyocyte (CL:0000746) (wicker2023frenchrecommendationsfor pages 5-6)

Anatomical locations (UBERON-aligned; examples)

Liver (UBERON:0002107) (wicker2023frenchrecommendationsfor pages 1-2)
Skeletal muscle (UBERON:0001134) (wicker2023frenchrecommendationsfor pages 6-8)
Heart / myocardium (UBERON:0000948) (wicker2023frenchrecommendationsfor pages 5-6)

Chemical entities (CHEBI-aligned; examples)

Glycogen (accumulated as PLD) (mishra2024theautophagicactivator pages 2-3)

Summary artifacts

Pathophysiological Domain	Core Defect & Cellular Dysregulation	Affected Tissues & Cell Types	Representative Clinical Phenotypes	Key Evidence & Citations
Primary Biochemical Defect	Enzyme Deficiency: Biallelic AGL variants cause Glycogen Debranching Enzyme (GDE) deficiency. Accumulation: Incomplete glycogenolysis leads to cytosolic accumulation of Phosphorylase-Limit Dextrin (PLD), a structurally abnormal glycogen with short outer branches.	Systemic Expression: • Liver (Hepatocytes) • Skeletal Muscle (Myofibers) • Heart (Cardiomyocytes)	• Metabolic: Fasting hypoglycemia (ketotic), hyperlipidemia, hyperketonemia. • Growth: Short stature, failure to thrive in infancy.	Biomolecules 2024 (mishra2024theautophagicactivator pages 2-3, mishra2024mitochondrialdysfunctionin pages 2-4, mishra2024theautophagicactivator pages 1-2) J Clin Invest 2024 (gardin2024afunctionalminigde pages 1-2) Eur J Med Res 2023 (wicker2023frenchrecommendationsfor pages 1-2)
Secondary Cellular Dysfunction	Mitochondrial Impairment: Reduced respiratory chain complex activity, altered morphology, and increased oxidative stress (ROS). Autophagy Block: Impaired autophagic flux and lysosomal swelling contribute to cellular toxicity.	• Fibroblasts • Myocytes • Hepatocytes	• Functional: Exercise intolerance, muscle fatigue. • Progression: Contribution to long-term muscle atrophy and metabolic inflexibility.	Biomolecules 2024 (mishra2024theautophagicactivator pages 2-3, mishra2024mitochondrialdysfunctionin pages 1-2) Cell Prolif 2024 (mishra2024theautophagicactivator pages 1-2)
Hepatic Pathophysiology	Structural Damage: Massive glycogen deposition causes hepatocyte ballooning and injury. Fibrogenesis: Progression from inflammation to bridging fibrosis, cirrhosis, and potential tumorigenesis (adenoma/HCC).	• Liver Parenchyma	• Hepatic: Hepatomegaly (often improves with age), elevated transaminases (AST/ALT), hepatic fibrosis, hepatocellular adenoma/carcinoma risk.	Nat Rev Dis Primers 2023 (hannah2023glycogenstoragediseases pages 1-3) Eur J Med Res 2023 (wicker2023frenchrecommendationsfor pages 1-2) J Clin Invest 2024 (gardin2024afunctionalminigde pages 1-2)
Cardiac & Muscular Pathology	Myopathy: Vacuolar myopathy with myofibrillar disruption. Cardiomyopathy: Cytosolic PLD accumulation, cardiomyocyte vacuolation, and replacement fibrosis (scarring). Remodeling: Massive hypertrophy (LVH) and conduction system deposition.	• Skeletal Muscle • Myocardium • Conduction System (SA/AV nodes)	• Muscular: Proximal/distal weakness, muscle wasting, elevated CK. • Cardiac: Hypertrophic cardiomyopathy (HCM), left ventricular hypertrophy, arrhythmias, heart failure.	Nat Rev Cardiol 2026 (pinos2026cardiovascularinvolvementin pages 17-21) Eur J Med Res 2023 (wicker2023frenchrecommendationsfor pages 5-6, wicker2023frenchrecommendationsfor pages 6-8) Biomolecules 2024 (mishra2024theautophagicactivator pages 2-3)

Table: A summary of the molecular defects, downstream cellular dysfunctions, and resulting clinical phenotypes in GSD III, mapping specific mechanisms to affected tissues and recent literature evidence.

Modality / Intervention	Mechanism / Rationale	Development Stage / Status	Key Endpoints / Measures	Selected Recent Citations
Dietary therapy: high-protein intake, uncooked cornstarch	Maintain euglycemia between feeds; preserve gluconeogenesis; limit hepatic glycogen re-accumulation; high-protein/low-carbohydrate may benefit cardiac hypertrophy	Standard of care (guidelines)	Fasting tolerance, glucose stability, growth; liver enzymes; lipid profile; symptom control	(wicker2023frenchrecommendationsfor pages 1-2, hannah2023glycogenstoragediseases pages 1-3, pinos2026cardiovascularinvolvementin pages 17-21, gardin2024afunctionalminigde pages 1-2)
Multimodal monitoring – liver (ultrasound, MRI ± contrast, MR elastography)	Detect hepatomegaly, adenomas, fibrosis progression; non-invasive fibrosis staging	Recommended in guidelines; prospective pediatric elastography study recruiting	Liver stiffness (F0–F4), adenoma detection/size, hepatomegaly trend	(wicker2023frenchrecommendationsfor pages 5-6, wicker2023frenchrecommendationsfor pages 6-8, NCT07303140 chunk 1)
Multimodal monitoring – cardiac (ECG, echocardiography, CMR with LGE/T1, Holter; NT-proBNP)	Detect LVH/HCM, fibrosis, conduction disease/arrhythmias; guide surveillance	Recommended in guidelines; case/series and reviews support HCM/fibrosis detection	LV mass, wall thickness, LGE/fibrosis, arrhythmias (Holter), NT-proBNP	(wicker2023frenchrecommendationsfor pages 5-6, pinos2026cardiovascularinvolvementin pages 17-21, hannah2023glycogenstoragediseases pages 1-3)
Small-molecule autophagy activation (GHF-201)	Enhance autophagic flux/lysosomal function; reduce cytosolic PLD; improve mitochondrial membrane potential	Preclinical: Agl−/− mice; patient fibroblasts	Locomotion (open field/rotarod), glycogen reduction (muscle/liver), lysosomal swelling, mitochondrial polarization	(mishra2024theautophagicactivator pages 2-3, mishra2024theautophagicactivator pages 1-2)
Gene therapy – single AAV mini-GDE (ΔNter2-GDE)	Truncated GDE transgene enables single-vector delivery; restores debranching	Preclinical: Agl−/− mouse/rat; human myotubes	Glycogen reduction (heart/muscle), normalized histology, muscle strength restoration	(gardin2024afunctionalminigde pages 1-2)
Gene therapy – AAV pullulanase (heterologous debranching enzyme)	Bacterial pullulanase substitutes GDE activity; liver/muscle targeting	Preclinical (mice), multiple promoters/vectors evaluated	Glycogen reduction (liver/muscle), reversal of hepatic fibrosis, improved muscle function	(koeberl2024genetherapyfor pages 11-13)
Gene therapy – dual AAV split hGDE	Overcome AGL cDNA size limits via dual vectors	Preclinical; high-dose requirements and immunogenicity noted	Restoration of hGDE activity in liver/muscle; safety/CTL response considerations	(koeberl2024genetherapyfor pages 11-13)
mRNA therapy – UX053 (NCT04990388)	IV AGL mRNA (with ATX95 excipient) to transiently restore GDE	Phase 1/2; TERMINATED (sponsor decision, not safety)	Safety/tolerability (TEAEs), PK (Cmax, Tmax, AUC, t½, CL, Vss)	(NCT04990388 chunk 1, NCT04990388 chunk 2)
Biomarker study – Hexose tetrasaccharide (Hex4) (NCT04574830)	Evaluate urinary Hex4 as exploratory biomarker of glycogen burden	Observational; COMPLETED	Urine Hex4 mean/variance over ~35 days	(NCT04574830 chunk 1)
Hypoglycemia survey – incidence and function (NCT05196165)	Real-world hypoglycemia rate and functional status under standard care	Observational; TERMINATED	Number of hypoglycemic events (26 weeks); motor/strength batteries (e.g., 6MWT)	(NCT05196165 chunk 1)
National registry – French GSD III Observatory (NCT06616545)	Natural history, outcomes, prognostic factors; standard-of-care capture	Registry; RECRUITING (150 target)	Fasting duration, 6MWT distance; metabolic, cardiac, neuromuscular outcomes	(NCT06616545 chunk 1)
Pediatric liver elastography – fibrosis assessment (NCT07303140)	Non-invasive staging to reduce need for biopsy in pediatric GSD III	Observational; RECRUITING	Liver elastography stiffness (F0–F4), longitudinal trends	(NCT07303140 chunk 1)

Table: Structured summary of current clinical management, monitoring, and emerging therapeutic strategies for GSD III, alongside active/completed studies and registries. It consolidates modalities, mechanisms, development stages, endpoints, and citations to guide evidence-based practice and research planning.

Notes on evidence completeness

This report prioritizes 2023–2024 peer-reviewed sources and guidelines for mechanistic and translational claims. Some detailed quantitative natural-history estimates (e.g., precise fibrosis stage distributions by age, genotype–phenotype penetrance across cohorts) were not available in the retrieved text segments and would require additional targeted cohort papers beyond the current evidence set.

References

(wicker2023frenchrecommendationsfor pages 1-2): Camille Wicker, Aline Cano, Valérie Decostre, Roseline Froissart, François Maillot, Ariane Perry, François Petit, Catherine Voillot, Karim Wahbi, Joëlle Wenz, Pascal Laforêt, and Philippe Labrune. French recommendations for the management of glycogen storage disease type iii. European Journal of Medical Research, Jul 2023. URL: https://doi.org/10.1186/s40001-023-01212-5, doi:10.1186/s40001-023-01212-5. This article has 14 citations and is from a peer-reviewed journal.
(mishra2024theautophagicactivator pages 2-3): Kumudesh Mishra, Sahar Sweetat, Saja Baraghithy, Uri Sprecher, Monzer Marisat, Sultan Bastu, Hava Glickstein, Joseph Tam, Hanna Rosenmann, Miguel Weil, Edoardo Malfatti, and Or Kakhlon. The autophagic activator ghf-201 can alleviate pathology in a mouse model and in patient fibroblasts of type iii glycogenosis. Biomolecules, 14:893, Jul 2024. URL: https://doi.org/10.3390/biom14080893, doi:10.3390/biom14080893. This article has 4 citations.
(mishra2024theautophagicactivator pages 1-2): Kumudesh Mishra, Sahar Sweetat, Saja Baraghithy, Uri Sprecher, Monzer Marisat, Sultan Bastu, Hava Glickstein, Joseph Tam, Hanna Rosenmann, Miguel Weil, Edoardo Malfatti, and Or Kakhlon. The autophagic activator ghf-201 can alleviate pathology in a mouse model and in patient fibroblasts of type iii glycogenosis. Biomolecules, 14:893, Jul 2024. URL: https://doi.org/10.3390/biom14080893, doi:10.3390/biom14080893. This article has 4 citations.
(hannah2023glycogenstoragediseases pages 1-3): William B. Hannah, Terry G. J. Derks, Mitchell L. Drumm, Sarah C. Grünert, Priya S. Kishnani, and John Vissing. Glycogen storage diseases. Nature Reviews Disease Primers, 9:1-23, Sep 2023. URL: https://doi.org/10.1038/s41572-023-00456-z, doi:10.1038/s41572-023-00456-z. This article has 102 citations.
(mishra2024mitochondrialdysfunctionin pages 2-4): Kumudesh Mishra and Or Kakhlon. Mitochondrial dysfunction in glycogen storage disorders (gsds). Biomolecules, 14:1096, Sep 2024. URL: https://doi.org/10.3390/biom14091096, doi:10.3390/biom14091096. This article has 9 citations.
(wicker2023frenchrecommendationsfor pages 6-8): Camille Wicker, Aline Cano, Valérie Decostre, Roseline Froissart, François Maillot, Ariane Perry, François Petit, Catherine Voillot, Karim Wahbi, Joëlle Wenz, Pascal Laforêt, and Philippe Labrune. French recommendations for the management of glycogen storage disease type iii. European Journal of Medical Research, Jul 2023. URL: https://doi.org/10.1186/s40001-023-01212-5, doi:10.1186/s40001-023-01212-5. This article has 14 citations and is from a peer-reviewed journal.
(wicker2023frenchrecommendationsfor pages 5-6): Camille Wicker, Aline Cano, Valérie Decostre, Roseline Froissart, François Maillot, Ariane Perry, François Petit, Catherine Voillot, Karim Wahbi, Joëlle Wenz, Pascal Laforêt, and Philippe Labrune. French recommendations for the management of glycogen storage disease type iii. European Journal of Medical Research, Jul 2023. URL: https://doi.org/10.1186/s40001-023-01212-5, doi:10.1186/s40001-023-01212-5. This article has 14 citations and is from a peer-reviewed journal.
(NCT04990388 chunk 2): Safety, Tolerability, and Pharmacokinetics of UX053 in Patients With Glycogen Storage Disease Type III (GSD III). Ultragenyx Pharmaceutical Inc. 2021. ClinicalTrials.gov Identifier: NCT04990388
(NCT04990388 chunk 1): Safety, Tolerability, and Pharmacokinetics of UX053 in Patients With Glycogen Storage Disease Type III (GSD III). Ultragenyx Pharmaceutical Inc. 2021. ClinicalTrials.gov Identifier: NCT04990388
(pinos2026cardiovascularinvolvementin pages 17-21): Tomàs Pinós, Richard M. Cubbon, Alfredo Santalla, Carmen Fiuza-Luces, Alejandro Santos-Lozano, Miguel A. Martín, Joaquín Arenas, Joachim Nielsen, Niels Ørtenblad, and Alejandro Lucia. Cardiovascular involvement in glycogen storage diseases. Nature reviews. Cardiology, Jun 2026. URL: https://doi.org/10.1038/s41569-025-01171-w, doi:10.1038/s41569-025-01171-w. This article has 2 citations.
(hannah2023glycogenstoragediseases media 16fd5731): William B. Hannah, Terry G. J. Derks, Mitchell L. Drumm, Sarah C. Grünert, Priya S. Kishnani, and John Vissing. Glycogen storage diseases. Nature Reviews Disease Primers, 9:1-23, Sep 2023. URL: https://doi.org/10.1038/s41572-023-00456-z, doi:10.1038/s41572-023-00456-z. This article has 102 citations.
(gardin2024afunctionalminigde pages 1-2): Antoine Gardin, Jérémy Rouillon, Valle Montalvo-Romeral, Lucille Rossiaud, Patrice Vidal, Romain Launay, Mallaury Vie, Youssef Krimi Benchekroun, Jérémie Cosette, Bérangère Bertin, Tiziana La Bella, Guillaume Dubreuil, Justine Nozi, Louisa Jauze, Romain Fragnoud, Nathalie Daniele, Laetitia Van Wittenberghe, Jérémy Esque, Isabelle André, Xavier Nissan, Lucile Hoch, and Giuseppe Ronzitti. A functional mini-gde transgene corrects impairment in models of glycogen storage disease type iii. Journal of Clinical Investigation, Jan 2024. URL: https://doi.org/10.1172/jci172018, doi:10.1172/jci172018. This article has 19 citations and is from a highest quality peer-reviewed journal.
(koeberl2024genetherapyfor pages 11-13): Dwight D. Koeberl, Rebecca L. Koch, Jeong‐A. Lim, Elizabeth D. Brooks, Benjamin D. Arnson, Baodong Sun, and Priya S. Kishnani. Gene therapy for glycogen storage diseases. Journal of Inherited Metabolic Disease, 47:93-118, Jul 2024. URL: https://doi.org/10.1002/jimd.12654, doi:10.1002/jimd.12654. This article has 28 citations and is from a peer-reviewed journal.
(NCT06616545 chunk 1): French Observatory for Patients with Type 3 Glycogenosis. Institut de Myologie, France. 2013. ClinicalTrials.gov Identifier: NCT06616545
(NCT04574830 chunk 1): Study to Evaluate Biomarkers and Clinical Manifestations in Individuals With Glycogen Storage Disease Type III (GSD III). Ultragenyx Pharmaceutical Inc. 2020. ClinicalTrials.gov Identifier: NCT04574830
(NCT05196165 chunk 1): Clinical Survey Study to Assess Physical Function and the Incidence of Hypoglycemia in Participants With Glycogen Storage Disease Type III. Ultragenyx Pharmaceutical Inc. 2022. ClinicalTrials.gov Identifier: NCT05196165
(NCT07303140 chunk 1): Non-invasive Assessment of Liver Fibrosis in a French Cohort of Pediatric Patients With Type III Glycogen Storage Disease: Current State and Perspectives. University Hospital, Strasbourg, France. 2024. ClinicalTrials.gov Identifier: NCT07303140
(mishra2024mitochondrialdysfunctionin pages 1-2): Kumudesh Mishra and Or Kakhlon. Mitochondrial dysfunction in glycogen storage disorders (gsds). Biomolecules, 14:1096, Sep 2024. URL: https://doi.org/10.3390/biom14091096, doi:10.3390/biom14091096. This article has 9 citations.

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OpenScientist Report

Inheritance

Subtypes

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Treatments

Biochemical Markers

Source YAML

References & Deep Research

References

Deep Research

Disease Pathophysiology Research Template

Target Disease

Research Objectives

Required Information

1. Core Pathophysiology

2. Key Molecular Players

3. Biological Processes (for GO annotation)

4. Cellular Components

5. Disease Progression

6. Phenotypic Manifestations

Citation Requirements

Output Format

Research Report: Cori–Forbes Disease (Glycogen Storage Disease Type III, GSD III)

1) Key concepts, definitions, and current understanding (pathophysiology core)

2) Molecular pathways and cellular processes dysregulated

3) Key molecular players and entities

Genes/Proteins

Chemical entities / metabolites / relevant small molecules

Cell types (CL-aligned)

Anatomical locations (UBERON-aligned)

4) Disease progression: sequence of events

5) Phenotypic manifestations (clinical phenotypes) linked to mechanism

6) Recent developments and latest research (prioritize 2023–2024)

7) Current applications and real-world implementations

8) Expert opinions / authoritative sources (selected)

9) Relevant statistics and data from recent sources

10) Clinical trials and translational pipeline (selected, with URLs/dates)

Knowledge-base style structured annotations

Pathophysiology description (narrative)

Gene/protein annotations (HGNC) and related processes

GO Biological Processes (examples for annotation)

Cellular Components (examples)

Phenotype associations (HP-aligned labels; examples)

Cell type involvement (CL-aligned; examples)

Anatomical locations (UBERON-aligned; examples)

Chemical entities (CHEBI-aligned; examples)

Summary artifacts

Notes on evidence completeness