Glycogen Storage Diseases and Inborn Errors of Galactose and Fructose Metabolism Flashcards
GSD I symptoms
*deficiency in glucose-6-phosphatase
- hepatomegaly, but normal liver function –> protruding abdomen
- “doll face”
- truncal obesity
- profound hypoglycemia after meal (contrary to FAO disorders)
- hyperlactacidemia
- hyperuricemia
- hyperlipidemia, primarily hypertriglyceridemia (suggests increased cardiovascular risk)
- increased bleeding time, perhaps due to decreased platelet aggregation
- growth retardation
GSD 1b symptoms
1/5 of patients with GSD1; have all symptoms of GSD 1 plus:
- neutropenia (low white blood cell count); neutrophil dysfuntion (impaired motility and migration)
- risk of frequent and severe infections that can affect upper and lower respiratory tract, the skin, the urinary tract
- protracted diarrhea, inflammatory bowel disease
GSD I Complications
- short stature
- gout
- osteoporosis
- nephropathy
- pulmonary hypertension
- liver adenomas with risk of malignant transformation
- polycystic ovaries
- necrotizing pancreatitis
Diagnosis of GSD I
- fasting profile
- enzyme assay
- molecular (genetics)
Characteristic fasting profile
Measure G6Pase activity + glycogen concentration in liver tissue
Enzyme assay
- measure released free phosphate
- measure protein concentration of liver homogenate
Molecular
- normal cell count–> G6PC = GSD 1A.
- neutropenia –> G6PT1 = GSD 1b
- if both genes show no mutation, back to start of specific assays in liver
GSD I conventional treatment
MAIN GOAL: do not let patient become hypoglycemic
- frequent feedings (avoid fasting mode)
- restruct complex carbs
- cornstarch supplement
- night-time nasogastric tube feedings
- nutrient supplementation
- ALLOPURINOL for hyperuricemia
- bicarbonate or citrate
- G-CSF for neutropenia
- ACE inhibitor
GSD I and liver transplantation
GSD Ia patients may have liver adenoma
- corrects metabolic abnormalities
- neutropenia persists in GSD I non-a
- reserved for patients with liver adenoma (+malignant growth)…but no good early markers
- not standard of care because there are effective dietary therapies
Short fasting in GSD I
glucose is decreasing more rapidly than in controls, lactate increases. In controls, lactate does not increase
Excess lactate –> metabolic acidosis
GSD III (Cori, Forbes) etiology
deficiency of glycogen debranching enzyme
GSD IIIa –> liver and muscle
GSD IIIb –> only liver
as opposed to GSD I, no fasting lactic acidemia, but they do have slight postprandial hyperlactatemia
GSD III (Cori, Forbes)
- symptoms
- findings
SYMPTOMS
- hepatomegaly
- protruding abdomen
- normal kidneys
- growth delay
- muscle weakness
FINDINGS
- hypoglycemia
- hyperlipidemia
- elevated creatine kinase (CK)
- peripheral neuropathy
- cardiomyopathy
Minimal fasting in GSD III
rapid, progressive hypoglycemia
rapid elevation of ketone bodies
no acidosis –> lactate plus ketones is low enough
Diagnosis of GSD III
suspected in infancy
- metabolic profile: look for ketotic hypoglycemia, normal lactate at short fast
- elevated CK
measure debranching enzyme in leukocytes, RBCs, fibroblasts
DNA investigation
- IIIb - exon 3
- IIIa - beyond exon 3
GSD III
- treatment
- complications
TREATMENT
- high protein diet (carbs will accumulate)
- frequent feedings if hypoglycemia
- supplement 3-OH butyrate
COMPLICATIONS
- liver cirrhosis
- liver cancer
- muscle hypotonia and wasting developing with age
GSD VI (Hers)
- deficient in what enzyme?
- genetics
Liver phosphorylase deficiency
Gene defect PYGL on chromosome 14, autosomal recessive
GSD VI (Hers) symptoms
isolated hepatomegaly
growth/motor development delay
mild fasting hypoglycemia and fasting ketosis
hyperlipidemia and elevated LFTs
GSD VI (Hers)
- diagnosis
- treatment
- prognosis
DIAGNOSIS
- enzyme assay: liver biopsy
- molecular diagnosis (PYGL) most common
TREATMENT
- avoid prolonged fasting and alcohol
PROGNOSIS: most symptoms resolve at puberty
GSD IXa etiology
X-linked; affects only males
liver phosphorylase B-kinase deficiency
PHKA2 on chr X
similar to, more common than GSD VI
GSD IXa symptoms
isolated hepatomegaly
growth/motor development delay
mild fasting hypoglycemia + ketosis
hyperlipidemia and elevated LFTs
muscle involvement
GSD IXa
- diagnosis
- treatment
- prognosis
DIAGNOSIS
- enzyme assay in RBC, might need tissue for isoenzymes
TREATMENT
- dietary; bedtime snack
PROGNOSIS
- Benign, most symptoms resolve during puberty (ie hepatomegaly and failure to grow resolves)
GSD 0
- deficiency of what?
- genetics
deficiency of either:
- liver glycogen synthase (GYS2)
- muscle glycogen synthase (GYS1) (expressed in muscle AND liver)
GYS1 and 2: 70% homologous, located on diff chromosomes
frequently not diagnosed because it mimics functional ketotic hypoglycemia
GSD 0 symptoms
fasting-induced ketotic hypoglycemia with normal lactate
drowsiness, fatigue
convulsions
no hepatomegaly
often: postprandial hyperglycemia and hyperlactacidemia with glycosuria
GSD 0
- diagnosis
- treatment
- prognosis
DIAGNOSIS
- molecular genetic analysis of GYS2
- Enzyme assay requires liver biopsy
TREATMENT
- dietary
PROGNOSIS: good, but females at risk of hypoglycemia during pregnancy
GSD V (McArdle)
- deficiency in what?
- genetics
myophosphorylase deficiency
PYGM gene on chromosome 12q13
GSD V (McArdle) symptoms
child-onset exercise intolerance
brief exertion may cause muscle cramps, myoglobinuria, hyperuricemia, mild CPK elevation
GSD V (McArdle)
- diagnosis
- treatment
- prognosis
DIAGNOSIS
- bicycle/treadmill test to detect increased uric acid and ammonia
- if treadmill test is abnormal, enzyme assay
TREATMENT
- avoid strenuous exercise
- protein-rich diet, glucose, fructose
good prognosis
GSD VII (Tarui) etiology
muscle phosphofructokinase deficiency
PFKM gene on chrom 11
prevalent in Japanese and Ashkenazim
GSD VII (Tarui) symptoms
child-onset exercise intolerance
brief exertion may cause muscle cramps, myoglobinuria, hyperuricemia, mild CPK elevation
compensated hemolysis
GSD VII (Tarui)
- diagnosis
- treatment
- prognosis
DIAGNOSIS
- bicycle/treadmill test to detect increased uric acid and ammonia
- if treadmill test is abnormal, enzyme assay
TREATMENT
- avoid strenuous exercise
PROGNOSIS: good
AMPK deficiency: gene and inheritance
PRKAG2 on chr 7
AD, full penetrance
AMPK deficiency: symptoms
onset typically late adolescence
cardiac symptoms including hypertrophy, familial hypertrophic cardiomyopathy with WPW syndrome
AMPK deficiency:
- diagnosis
- treatment
- differential diagnoses
DIAGNOSIS:
- ECG
- heart biopsy
- molecular genetics
TREATMENT
- pacemaker/defibrillator
- heart transplant
DDx: Pompe, Danon, Fabry
Lafora Disease etiology
mutations in Laforin-malin complex, which brings glycogen synthase from neurons to proteosome for glycogen breakdown
- accumulation of branched chain glycogen
- triggers neuronal apoptosis
EPM2A encodes laforin
EPM2B encodes malin
Lafora Disease symptoms
adolescent onset of myoclonic epilepsy and absence seizures
progressing to dementia with visual loss, apraxia, and aphasia
ultimately leads to vegetative state
Lafora disease:
- diagnosis
- treatment
- prognosis
DIAGNOSIS
- skin biopsy to detect Lafora bodies
- mutation analysis to confirm
TREATMENT: none
Poor prognosis, death within decade of disease onset
