Glycogen Storage Disease Flashcards
Glycogen Storage Diseases:
- Group of 14 disorders of glycogen metabolism.
-Liver involvement in types 1a, 1b, 3, 4, 6, and 9.
- Hypoglycemia/ hyperlactatemia: 1a, 1b, 3.
-Fibrosis/cirrhosis: 3, 4, 6, 9.
- Hepatomegaly: all
GSD Type 1a. Von Gierke’s Disease
- Deficiency of G-6 phosphatase (liver and kidney).
- 1 in 100,000 liver births, AR. G6PC on 17q21.
- Clinical presentation: 3-6 months of age, hepatomegaly (not spleen), hypoglycemia (seizures), poor growth, doll-like facies.
GSD1a Von Gierke’s Disease pathophys
- G6-P cannot be converted to glucose, instead converted to lactic acid or glycogen.
- Present with hypoglycemia upon short time of fasting, elevated blood lactate, acidosis.
- Glycogen stored in liver and - kidney: organomegaly.
- Uric acid product increases: gout
- TG and cholesterol increased.
Platelet dysfunction 2/2 dyslipidemia.
Von Gierke’s disease: GSD1a tx
- keep blood glucose normal all the time: treat with uncooked corn starch, continuous nocturnal GT feeds.
Frequent meals with complex CHO, avoid simple sugars. supplement vitamins. - uric acid: allopurinol
-hyperlipidemia: treat with MCT oil, statins, liver transplant. - short stature improves with good metabolic control: avoid growth hormone (can stimulate growth of adenomas).
- Osteoporosis: check vitamin D and DXA scans.
- Renal disease: US annually, renal panel, microalbuminuria: state ACEi if abnormal. Treat HTN.
Von Gierke’s Disease GSD1a Liver disease.
- Can develop Hepatic Adenomas and HCC.
- AFP yearly, Liver US Q12-24 months.
- Avoid estrogen containing oral contraceptives.
- Pulm HTN: ECHO Q3 years starting at age 10.
- Liver transplant: for poor metabolic control, increasing adenomas, HCC, or liver failure (rare).
GSD 1b: (Think Von Gierke’s +neutropenia)
Similar clinical presentation and treatment as GSD1a (Von Gierke’s) with the addition of Neutropenia.
- mutations in SLC37A4, G6-P Er translocate.
- All clinical manifestations of GSD1a + neutropenia (recurrent infections), peri oral and perianal lesions and Crohn’s-like IBD, GT cellulitis.
- Add G-CSF: raises neutrophil count, risk of bone failure
GSD Type III (Cori disease): Glycogen Debrancher Deficiency
- Inability to hydrolyze branch points in glycogen.
- AR. mutations in AGL gene.
- Liver and muscle/cardiac specific isoforms.
-GSD 3a: liver and muscle: majority.
-GSD 3b: Liver only ~15%. - GSD 3c and 3d: rare.
GSD 3 (Cori Disease) Presentation
Clinical presentation: hypoglycemia, elevated AST/ALT. Inconsistent elevation of TG/cholesterol, lactate, uric acid.
- Liver histology: mosaic appearance, fibrosis, normal glycogen on EM.
-Muscle: elevated CPK.
- AGL DNA mutation.
GSD 3 (Cori’s Disease) Management
- Hypoglycemia: usually easier to manage than GSD1. High protein diet.
- Liver transplantation is rarely needed, indicated for metabolic control and cirrhosis. Does NOT improve muscle disease.
- Muscle clinic and cardiology follow up.
GSD 4: Andersen Disease: Deficiency of Glycogen Branching Enzyme
`- Results in abnormal glycogen structure. AR, enzyme expressed in liver, muscle, heart, other tissues.
- Hepatic phenotype: early infancy: cirrhosis, HepatoSplenomegaly, FTT, PHT, terminal liver failure and hypoglycemia.
GSD 4 Andersen Disease Diagnosis
- Liver/muscle biopsy: excess glycogen (PAS+-diastatase resistant fibrillar glycogen on EM).
Fibrosis and Cirrhosis early in course. - DNA: GBE1 mutations. Prenatal diagnosis is possible.
GSD4 Andersen Disease Treatment
- No specific tx. Manage chronic liver failure. Liver transplant successful: improved liver status.
GSD type 6/9 (HERS) are related: Patients present with asymptomatic hepatomegaly.
Type 6: Deficiency of Liver phosphorylase b (milder form of GSD usually). Mutations in PYGL. X-linked and recessive forms. Muscle not affected.
Type 9: mutations in PHKA2 phosphorylase b kinase. Also expressed in heart and muscle.
Present with asymptomatic hepatomegaly and growth retardation, mild hypoglycemia/hyperlipidemia.
Dx: DNA mutation testing.
Management: no specific treatment. If hypoglycemic, treat with corn starch.
Patients usually outgrowth this disease, hepatomegaly improves with age.
- screen for adenomas and HCC (annual US).
Hereditary Tyrosinemia
AR. 1 in 100,000 liver births.More common in Quebec.
- FAH gene mutations. No clear genotype-phenotype correlation.
- Pathway: Phenylalanine is converted through Tyrosine finally into Fumarate and acetoacetate.
-When broken: mutation in FAH: causes build up of precursors: build up of 4 phenylactate, eventually converted to succinylacetone, leads to neurological symptoms.
Hereditary Tyrosinemia treatment
- NTBC which prevents toxic components from accumulating.
Hereditary Tyrosinemia presentation
- Hepatic: neonatal cholestasis, neonatal liver failure, cirrhosis.
- hepatocellular carcinoma (37% after 2 years old). Not predicted by AFP.
- Renal tubular dysfunction: rickets, aminoaciduraia, hypophosphatemia, CRF.
- Neurologic crisis: up to 50% of pts: painful paresthesias, autonomic signs, progressive weakness and paralysis, death.
Hereditary Tyrosinemia Diagnosis
- suspect in all infants with cholestasis, cirrhosis, liver failure, rickets, coagulopathy, neurologic crisis.
Labs: increased urine or blood succinylacetone (also elevated AFP). Decreased FAH (blood spot). - Genetic testing: common alleles.
- Plasma tyrosine raised in many conditions: not specific.
Hereditary Tyrosinemia Histology
- Cholestasis
- Giant cell transformation (infant)
- Macrovesicular steatosis
- Pseudoacinar formation
- Iron deposition
- Periportal fibrosis to micro nodular cirrhosis
- Hepatocyte dysplasia
- Hepatocellular carcinoma
Hereditary Tyrosinemia treatment
- Dietary restriction of phenylalanine and tyrosine
-NTBC: maintain absence of urine and blood SA and plasma NTBC levels >50 and normal AFP. - patients still need to be monitored with liver US to ensure no liver nodules are developing.
hereditary tyrosinemia treatment: NTBC
NTBC:
-improves liver function
- prevents renal dysfunction and neurologic crises
- improves growth and development
- prevents cirrhosis, appears to prevent HCC if started very early in infancy.
Hereditary tyrosinemia liver transplant
only if patient has established cirrhosis not responding to NTBC, hepatic nodules, rising AFP, or if prior to age 2-3 years of age if not treated with NTBC from early infancy.
