GLYCOGEN STORAGE DISEASE ROTO ROBO INTERNAL MEDICINE
INTRODUCTIONThese are group of inherited inborn errors of metabolism due to deficiency or dysfunction of enzymes related to glycogen metabolism.Usually manifestations are confined to liver and muscle but some cause more generalized pathology and affect tissues such as the kidney, heart and bowel.
GLYCOGENGlycogen is the storage polysaccharide and is sometimes called animal starch.It is highly branched structure with chains of 12–14 α-D-glucopyranose residues.Most of the glucose residues in glycogen are linked by α-1-4-glycosidic bonds.Branches at about every 4th to 10th residue are created by α-1,6-glycosidic bonds.The chains are arranged in concentric layers.
GLYCOGEN STORAGE DISORDERS (GSD)• Glycogen storage disease is a generic term to describe group of inherited disorders characterized by deposition of an abnormal type or quantity of glycogen in tissues, or failure to mobilize glycogen.• GSD were categorized numerically in the order in which enzymatic defects were identified.• They are also classified by the organs involved & clinical manifestations.• Overall incidence is estimated at 1 / 20,000 live births.• Inheritance patterns - Autosomal recessive (I, II, III, IV, V, VII, some IX). - X-linked (some IX, VI)
LIVER GLYCOGEN STORAGE DISEASEIa / Von Gierke Glucose-6-phosphatase Common, Severe hypoglycemia, hepatic adenomas & ca, renal failureIb Glucose-6-phosphate ~10% of type I translocaseIIIa / cori or forbes Liver & muscle debranching Common, mild hypoglycemia, hepatic enzyme adenoma & carcinomaIIIb Liver debranching enzyme ~15% of type IIIVI /Hers Liver phosphorylase Rare , often benignIX Liver phosphorylase kinase Common, x-linked,0 Glycogen synthase Decreased glycogen storeXI / Fanconi-Bickel Glucose transporter-2 Rare ,consanguinity in 70%DISORDER WITH LIVER CIRRHOSISIV / Andersen Branching enzyme One of rarer glycogenoses
GLYCOGEN STORAGE DISEASE CAUSING SKELETALMYOPATHY AND / OR CARDIOMYOPATHYII / Pompe Lysosomal acid Common, undetectable, or a-glucosidase very low level of enzyme activity on infantile formCardiac phosphorylase kinase deficiency Severe cardiomyopathy & early heart failure, Very rare
TYPE I, VON GIERKES DISEASE Itis the most common GSDAffected enzyme: glucose-6-phosphataseAffected tissue: Liver, kidney and intestinal mucosaTwo subtypes-1. Type I a- glucose-6-phosphatase enzyme is defective2. Type I b- glucose-6-phosphatase translocase is defective
Clinical features: Neonatal period - Hypoglycemia & lactic acidosisHepatomegaly by 3-4 months of ageEasy bruising & epistaxis d/t prolonged bleedingtime.Kidneys - enlarged, but normal spleen & heart sizeHyperuricemia and hyperlipidemia.Type I b - neutropenia with reccurrent infection, oral & mucosal ulceration.
Long term complications Puberty delayed Gout becomes symptomatic by puberty. Increased bleeding during menstrual cycles- life threatening menorrhagia 2nd & 3rd decade - hepatic adenoma > haemorrhage > malignant. Renal - proteinuria, Hypertension, stones, altered creatinine, complete failure.
TYPE II, POMPES DISEASE Affected enzyme- α-1,4-glucosidase (acid maltase)Clinical feature: Clinical spectrum is continuous &broad, with presentation in infants, children and adults.1. Infantile Form Infant normal at birth, develop generalised muscle weakness with feeding difficulties, Hepatomegaly, cardiomegaly, CHF due to HCMP death before 1 yr of age2. Juvenile form Delayed motor milestones & difficulty in walking Swallowing difficulties , proximal Ms weakness & respiratory Ms involvement & death before end of 2nd
3. Adult form Slowly progressive myopathy without overt cardiac involvement. Onset between 2nd & 7th decade Dominated by progressive muscle weakness with truncal involvement. Pelvic girdle, paraspinal Ms & diaphragm are seriously affected.
TYPE III, CORI OR FORBES DISEASEAffected enzyme: Glycogen debranching enzymeAffected tissues: Liver and muscleSubtypes: 1. type III a - Both liver & muscle involved 2. type III b – Only liver involved (15%)Clinical features: Hepatomegaly, hypoglycemia, short stature, variable skeletal myopathy and cardiomyopathy. Hyperlipidemia, elevated liver transaminases. Hepatomegaly improves with age. Liver cirrhosis & hepatocellular carcinoma may occur in late adulthood.
TYPE IV, ANDERSENS DISEASE, AMYLOPECTINOSISAffected enzyme: Glycogen branching enzymeAffected tissues: LiverClinical features: – Hepatomegaly, failure to thrive, cirrhosis, splenomegaly, jaundice, hypotonia, waddling gait, lumbar lordosis.Treatment: Liver transplant.Prognosis: Mostly death within 4 yr of age due to cirrhosis and portal hypertension.
TYPE V, MCARDLES DISEASE Affected enzyme: Muscle phosphorylase deficiency Affected tissue: Muscle Clinical features Symptoms develop in adulthood with exercise intolerance & muscle cramps Two types of activity – 1 .Brief exercise of great intensity 2. Less intensity but sustained activity 35% report permanent pain that seriously affects sleep & other activities. Half of pt report burgundry-coloured urine after exercise, resulting from myoglobinuria 20 to rhabdomyolysis, which later can lead to renal failure.
TYPE VI, HERS DISEASE Affected enzyme: Liver phosphorylase Affected tissues: Liver, rare cardiac form Clinical features: Most common variant is X-linked Hepatomegaly, hypoglycemia, growth retardation, hyperlipidemia.Treatment: Cardiac transplantation for rare cardiac formPrognosis: Usually normal life span.
TYPE VII, TARUI DISEASE Affected enzyme: Phosphofructokinase(PFK)Affected tissue: MuscleClinical features:Exercise intolerance, muscle cramping, exertional myopathy, compensated haemolysis & myoglobinuria.Note : Symptoms can be similar to McArdlesGlycogen Storage Disease but more severe.
TYPE IX, GLYCOGEN STORAGE DISEASE Affected enzyme: liver phosphorylase kinase deficiency Different subtypes – Gene/subunit involved, Tissue affected, Mode of inheritance Clinical features Child 1-5 yr age – growth retardation, hepatomegaly Cholesterol, triglycerides & liver enzymes mildly elevated. Fasting ketosis, mild hypoglycemia. Most adult reach normal final Ht & practically asymptomatic Prognosis is good, hepatomegaly & abnormal blood chemistries return to normal with age.
TYPE 0, LEWIS DISEASEAffected enzyme: Hepatic glycogen synthase.Affected tissues: Liver.Clinical features Seizures can occur. Fatigue and muscle cramps after exertion. Mild growth retardation in some cases.
INVESTIGATION Blood tests: – Blood glucose: hypoglycemia is likely – Liver function tests: monitoring for hepatic failure – Anion gap calculation: may indicate lactic acidaemia – Urate – Creatinine clearance Urine tests: Myoglobinuria after exercise found in 50% of people with McArdles disease.
INVESTIGATION ImagingUSG abdomen - hepatomegalyEchocardiography - to look for cardiac involvement in certain types of GSD BiopsyOf liver.Muscle or other tissues gives definitive diagnosis.
DIAGNOSIS Clinical presentation Abnormal biochemical parameters Liver & muscle biopsy for enzyme deficient. Gene based mutation analysis.prenatal diagnosis: chorionic villus sampling andamniocentesis can be used to determine enzyme activity in a fetus.
TREATMENT Supportive treatment maintaining normal blood sugar level Supplementation of multivitamins, calcium & vit DAllopurinol - raised uric acid. ACE-inhibitors - microalbuminuria. Statin - hyperlipidemia Diet therapy : high-protein, low-carbohydrate diet Physiotherapy and occupational therapy may be required
TREATMENT Enzyme replacement therapy – Pompe disease Alglucosidase alfa (Myozyme) recombinant human acid alpha - glucosidase at 20 mg/kg every 2 weeks Genetic counsellingGene therapy remains a potentially effective treatment for the future.