Glycogen storage disorders investigations

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Glycogen Storage Disorders — Investigations

Glycogen metabolism pathway showing key enzymes

Pathway of glycogen synthesis and glycogenolysis. Enzyme defects at each step define the different GSD types.

Overview

Glycogen storage diseases (GSDs) are ≥12 inherited disorders of glycogen metabolism. Collectively they occur in ~1:10,000–25,000 births. Because liver and skeletal muscle have the highest glycogen turnover, these are the tissues most affected. Investigation follows a tiered approach: biochemical screening → metabolic provocation tests → enzyme assay → molecular genetics.

First-Line Biochemical Investigations (All Types)

Test	Significance
Fasting plasma glucose	Hypoglycemia is hallmark of hepatic GSDs (GSD I, III, VI, IX); blood glucose 20–50 mg/dL tolerated without symptoms because ketones/lactate serve as alternative CNS fuel
Serum lactate	Markedly elevated in GSD I (↑↑↑); normal or mildly elevated in GSD III; absent lactic acidosis helps distinguish GSD III from GSD I
Uric acid	Hyperuricemia in GSD I (lactate competitively inhibits renal tubular urate secretion + increased uric acid synthesis)
Triglycerides / lipid profile	Hypertriglyceridaemia in GSD I (↑↑↑ lipolysis due to low glucose); also elevated in GSD III
Liver transaminases (ALT/AST)	Markedly elevated in GSD III (and GSD IV); helps differentiate from GSD I (where transaminases are normal/mildly raised)
Creatine kinase (CK)	Elevated at rest in GSD III (myopathic form), V (McArdle), and VII (Tarui); key marker of muscle involvement
Insulin / glucagon ratio	Low insulin and raised glucagon during hypoglycemia
Ketones	Ketonaemia/ketonuria during hypoglycaemia — present in GSD III/VI/IX; absent or low in GSD I

Provocation / Dynamic Tests

Glucagon stimulation test

Administer glucagon (0.02–0.03 mg/kg IV/IM); measure glucose at 0, 15, 30, 45, 60 min
Normal: glucose rises ≥30 mg/dL
GSD I: no rise in blood glucose; lactate rises markedly
GSD III, VI, IX: blunted or absent rise after prolonged fasting, but partial response post-prandially (distinguishes from GSD I)

Galactose tolerance test (oral or IV)

Galactose → glucose-1-phosphate → glucose-6-phosphate → glucose (via glucose-6-phosphatase)
GSD I: failure of blood glucose to rise after galactose administration is diagnostic (glucose-6-phosphatase cannot complete the final step); lactate rises instead
Still used to confirm GSD I before enzyme assay

Epinephrine tolerance test (historical)

IM epinephrine: normal response = blood glucose rises 35–45 mg/dL within 40–60 min
GSD I: no glucose rise; GSD III: no rise after fasting, partial rise after carbohydrate feeding
Rarely used today; replaced by molecular testing

Ischaemic forearm exercise test (McArdle / GSD V & VII)

Patient squeezes hand dynamometer 30× under tourniquet (ischaemic conditions)
Blood sampled for lactate and ammonia before and 1, 2, 3, 5, 10 min after
Normal: both lactate and ammonia rise (2–5× baseline lactate)
GSD V (McArdle) / GSD VII (Tarui): ammonia rises normally, but lactate fails to rise (blocked glycolysis in muscle)
Caution: the non-ischaemic (aerobic) version is safer and preferred now

Enzyme Assays (Tissue-Specific)

The specific diagnosis is confirmed by demonstrating the enzyme defect in relevant tissue:

GSD Type	Enzyme Deficiency	Diagnostic Tissue
I (von Gierke)	Glucose-6-phosphatase	Liver biopsy (intact vs. disrupted microsomes differentiates Ia from Ib)
II (Pompe)	Acid α-glucosidase (GAA)	Dried blood spot (DBS) for newborn screening; confirmed by leukocytes, muscle, or fibroblasts
III (Cori/Forbes)	Glycogen debranching enzyme (amylo-1,6-glucosidase)	Liver + muscle biopsy; erythrocytes (occasionally)
IV (Andersen)	Branching enzyme	Leukocytes, cultured fibroblasts, liver/muscle biopsy
V (McArdle)	Muscle phosphorylase	Muscle biopsy (histochemistry + enzymatic)
VI (Hers)	Liver phosphorylase	Liver biopsy; RBCs or WBCs
VII (Tarui)	Muscle phosphofructokinase	Muscle biopsy; erythrocytes (also show partial enzyme deficiency → haemolysis)
IX	Phosphorylase kinase	RBCs/WBCs (for X-linked form); liver/muscle biopsy

Molecular Genetic Testing

Now the primary recommended method of diagnosis (Goldman-Cecil):

Gene-targeted testing: single-gene sequencing or multigene panel (clinically preferred first-line where genotype is strongly suspected)
Comprehensive testing: whole-exome sequencing (WES) or whole-genome sequencing (WGS) when panel testing is non-diagnostic
Common mutations are population-specific (e.g. GSD Ia: p.Arg83Cys in Caucasian/Jewish; c.648G→T splicing in Japanese; GSD Ib: c.1042_1043delCT in Caucasian)
Used for prenatal diagnosis and carrier detection

Tissue Biopsy

Biopsy Finding	Significance
Liver biopsy — light microscopy with PAS/diastase	Massive glycogen accumulation (PAS+, diastase-sensitive); fat accumulation in GSD I; fibrosis/cirrhosis in GSD III and IV
Liver biopsy — electron microscopy	Monoparticulate glycogen (GSD I, III, VI) vs. abnormal polyglucosan/amylopectin-like material (GSD IV)
Muscle biopsy — ATPase, phosphorylase histochemistry	Absent phosphorylase staining in GSD V; sub-sarcolemmal vacuoles in GSD II (lysosomal glycogen)
Muscle biopsy — EM	Lysosomal glycogen accumulation characteristic of GSD II (Pompe)

Imaging

Modality	Findings
Ultrasound abdomen	Hepatomegaly (bright, echogenic liver); renomegaly in GSD I; splenomegaly in GSD III/IV
MRI liver	Increased glycogen content; distinguishes steatosis (GSD I) from fibrosis
Echocardiography	Hypertrophic cardiomyopathy in GSD II (Pompe) — critical for management; also GSD III
ECG	Short PR interval and massive QRS voltages in infantile Pompe; conduction defects in GSD III
Skeletal X-ray/bone densitometry	Osteoporosis in GSD I (long-term)

Newborn Screening (GSD II — Pompe)

Dried blood spot (DBS) acid α-glucosidase (GAA) enzyme activity assay — several countries include GSD II in neonatal screening
Confirmed by GAA gene sequencing ± lymphocyte/fibroblast enzyme assay
Rationale: enzyme replacement therapy (ERT) with alglucosidase alfa is most effective when started before symptom onset

Type-Specific Investigation Highlights

GSD I (von Gierke) — Key Lab Fingerprint

Hypoglycaemia + lactic acidosis + hyperuricaemia + hypertriglyceridaemia + hepatomegaly
No glucose response to glucagon or galactose
Confirm: liver biopsy → G6Pase assay (intact microsomes: Ia; + disrupted microsomes required: Ib); G6PC1 / SLC37A4 sequencing

GSD II (Pompe) — Key Lab Fingerprint

Infantile: cardiomegaly, hypotonia, elevated CK, very high GAA deficiency on DBS
Late-onset: progressive proximal myopathy, respiratory failure, CK elevated, normal/mild CK in some
Confirm: DBS GAA activity → GAA gene sequencing; muscle biopsy shows lysosomal glycogen

GSD III (Cori/Forbes) — Distinguishing from GSD I

Elevated transaminases (GSD I has normal AST/ALT), elevated CK (muscle involvement in IIIa)
Hyperglycaemic response to galactose (unlike GSD I)
Lower uric acid and lactate than GSD I
Confirm: debranching enzyme (AGL) assay in erythrocytes or liver/muscle; AGL gene sequencing

GSD IV (Andersen) — Key Findings

Hepatosplenomegaly → cirrhosis → liver failure
Abnormal glycogen (amylopectin-like) on biopsy (PAS+, poorly diastase-digestible)
Confirm: branching enzyme (GBE1) assay in leukocytes/fibroblasts; GBE1 sequencing

GSD V (McArdle) — Key Lab Fingerprint

Elevated resting CK; myoglobinuria after exercise
Ischaemic forearm test: ammonia rises, lactate fails to rise
"Second-wind" phenomenon
Confirm: absent phosphorylase on muscle biopsy histochemistry; PYGM sequencing

GSD VII (Tarui) — Key Lab Fingerprint

Like GSD V but also haemolytic anaemia (RBCs share the PFK defect)
Hyperbilirubinaemia + reticulocytosis + pigmenturia
Glucose does not relieve symptoms (unlike GSD V)
Confirm: PFK assay in RBCs + muscle biopsy; PFKM sequencing

Summary Algorithm

Suspected GSD
     │
     ├── Hepatic features (hepatomegaly, hypoglycaemia)
     │         ├── + Lactic acidosis + ↑↑ uric acid + ↑↑ TG → GSD I → galactose test → liver biopsy/G6PC gene
     │         ├── + ↑ transaminases + ↑ CK ± cardiomyopathy → GSD III → AGL enzyme/gene
     │         ├── + Cirrhosis/liver failure → GSD IV → GBE enzyme/gene
     │         └── Mild, asymptomatic hepatomegaly → GSD VI / IX → phosphorylase/kinase assay
     │
     └── Muscle features (exercise intolerance, cramps, rhabdomyolysis)
               ├── + Cardiomyopathy + hypotonia (infant) → GSD II → DBS GAA assay
               ├── + Forearm test: ↑↑ NH₃, flat lactate + "second wind" → GSD V → PYGM gene
               └── + Haemolytic anaemia + flat lactate forearm test → GSD VII → PFK assay

Sources:

Tietz Textbook of Laboratory Medicine, 7th Edition — Table 35.1, GSD types I–VII
Henry's Clinical Diagnosis and Management by Laboratory Methods — Tables 17.6 & 17.7
Goldman-Cecil Medicine (International Edition) — Chapter 191 (Kishnani)
Sleisenger & Fordtran's GI and Liver Disease — Chapter 77

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