Glycogen storage disease type II diagnostic study of choice

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anmol Pitliya, M.B.B.S. M.D.[2]

Overview

Acid α-glucosidase (GAA) activity in fibroblast of a dried blood sample is the gold standard test for the diagnosis of glycogen storage disease type 2. Decreased activity of GAA in fibroblasts a dried blood sample is confirmatory of glycogen storage disease type 2.

Diagnostic Study of Choice

Gold standard

• Acid α-glucosidase (GAA) activity in fibroblast of a dried blood sample is the gold standard test for the diagnosis of glycogen storage disease type 2.
• The following result of acid α-glucosidase (GAA) activity in fibroblast of a dried blood sample is confirmatory of glycogen storage disease type 2:
  • Decreased activity of GAA in fibroblasts

Diagnostic algorithms

Algorithms for diagnostic approach of glycogen storage disease type 2

Diagnostic algorithm for Infantile onset glyogen storage disease type II
COMMON PRESENTING SYMPTOMS	CARDIOVASCULAR Cardiomegaly; Congestive heart failure; Arrhythmias such as supraventricular tachycardia; Cardiac arrest during surgery.   PULMONARY Frequent infections; Respiratory distress/ insufficiency.   NEUROLOGICAL Hypotonia; Developmental delay; Gross motor delay; Loss of early motor milestones.   GASTROINTESTINAL Failure to thrive; Feeding difficulties.
PERTINENT PATIENT FINDNGS	CARDIOVASCULAR Murmur, gallop, pulsatile precordium, excessive sweating (cardiac related); Cardiomegaly; Cardiomyopathy; (hypertrophic +/- LVOTO) progressing to dilated cardiomyopathy.   PULMONARY Progressive respiratory involvement, nasal flaring; Use of accessory muscles, IC and SC retractions, decreased breath sounds in LLL; Coarse breath sounds.   NEUROLOGICAL Delayed motor milestones Hypotonia, head lag, floppy baby with ability to "slip through", frog leg position, hypertrophy of gastrocnemius muscle.   GASTROINTESTINAL Macroglossia, open mouth, low facial tone, decreased gag reflex, failure to thrive, poor suck and swallow, difficulty feeding with pooling of oral secretions; hepatomegaly.
INITIAL CLINICAL FINDINGS AND INVESTIGATIONS	If GAA present, follow- up with confirmatory testing, if strong clinical suspicion.       CLINICAL STUDIES Chest X-ray- Cardiomegaly; EKG - huge R wave, short PR interval and broad QRS complex; Echocardiography - cardiomyopathy Electrophysiology (EMG/NCS) - myopathy.   LABORATORY (BLOOD OR URINE) Elevated CK, AST, ALT, LDH (in blood) Glc4 (in urine); GAA activity in dried blood spots. lymphocytes, or leukocytes with blocking antibodies to neutral maltase; Mutation testing in familial mutation known                                   If GAA absent, obtain confirmatory studies for definitive diagnosis.
CONFIRMATOY STUDIES	DNA GAA mutation testing   ENZYMOLOGY GAA activity testing in fibroblasts or muscle (the gold standard). Caution with muscle biopsy is needed sue to anesthesia risk.   HISTOLOGY/ HISTOCHEMISTRY Increased lysosomal glycogen Vacuolated cells
Adapted from GENETICS IN MEDICINE

ABBREVIATIONS: LVOTO - left ventricular outlet tract obstruction; IC - intercostal; SC - subcostal; LLL - left lower lung; EMG - Electromyography; NCS - Nerve conduction study; GAA - acid-alpha glucosidase; CK - creatine kinase; AST - aspartate aminotransferase; ALT - alanine aminotransferase

Diagnostic algorithm for Late onset (>1 year) glyogen storage disease type II
COMMON PRESENTING SYMPTOMS	PULMONARY Frequent infections; Respiratory insufficiency/distress; Sleep apnea; Somnolence Morning headaches.   MUSCULOSKELETAL Limb girdle weakness Back pain; Exercise tolerance; Rigid spine syndrome.   GASTROINTESTINAL Feeding and swallowing difficulties; Poor weight gain.
PERTINENT PATIENT FINDNGS	RESPIRATORY Respiratory insufficiency; orthopnea, sleep apnea; exertional dyspnea; Weak cough.   MUSCULOSKELETAL Progressive proximal limb-girdle muscle weakness (lower extremities. upper extremities; gain abnormalities; exercise intolerance; lordosis/scoliosis; hypotonia; lower back pain; Gower's sign.   GASTROINTESTINAL Difficulty maintaining normal weight; Difficulty chewing or jaw muscle fatigue; Decreased gag reflex; hepatomegaly.   CARDIOVASCULAR Infrequent cardiomegaly (juveniles).
INITIAL CLINICAL FINDINGS AND INVESTIGATIONS	If GAA present, follow- up with confirmatory testing, if strong clinical suspicion.       CLINICAL STUDIES Lung function testing lying and sitting; Muscle strength testing; Electrophysiology (EMG/NCS) - myopathy; Muscle biopsy - histology and histochemistry.   LABORATORY (BLOOD OR URINE) Elevated CK, AST, ALT, LDH (in blood) Glc4 (in urine); GAA activity in dried blood spots, lymphocytes, or leukocytes with blocking antibodies to neutral maltase; Mutation testing in familial mutation known                                   If GAA absent, obtain confirmatory studies for definitive diagnosis.
CONFIRMATOY STUDIES	DNA GAA mutation testing   ENZYMOLOGY GAA activity testing in fibroblasts or muscle (the gold standard); ClinicaL coorelation with test result is required.   HISTOLOGY/ HISTOCHEMISTRY (dependent on the site of biopsy) Increased lysosomal glycogen; Vacuolated cells
Adapted from GENETICS IN MEDICINE

ABBREVIATIONS: EMG - Electromyogtaphy; NCS - Nerve conduction study; GAA - acid-alpha glucosidase; CK - creatine kinase; AST - aspartate aminotransferase; ALT - alanine aminotransferase