Carbohydrate Disorders Flashcards
Hereditary Fructose Intolerance
Gene: ALDOB
Aldolase B Deficiency
Apparent in infancy
– when fructose or sucrose added to the diet
– but some formulas contain fructose
* Frequent aversion to sweets
* Signs of symptoms are always observed while
on fructose and resolve off fructose
What are symptoms of acute fructose exposure?
- Symptoms of acute hypoglycemia post-fructose
ingestion (rarely presenting sign) - Vomiting
- Acute liver dysfunction (the most frequent)
- Jaundice
- Bleeding
- Hypoglycemia
- Acidosis
- Renal Fanconi syndrome
- Liver disease/failure
- Seizures, coma, death
Management for fructose exposure
- Elimination of fructose from diet (long lists)
- SUCROSE (table sugar) = glucose + FRUCTOSE
- Danger of IV infusions or oral meds in
emergency room/hospitals - Awareness and information is all that is
required for management - www.bu.edu/aldolase/HFI/treatment/
Fructose-1,6 biphosphatase
deficiency
Gene: FBP2
▪ Triggered by intercurrent illness, fasting, variably
by fructose/sucrose ingestion
▪ Two groups
▪ Newborn
▪ Later-onset
▪ Acute presentation
▪ Hepatomegaly
▪ Hypoglycemia
▪ Lactic acidosis
▪ Ketosis
Management for Fructose-1,6 biphosphatase
deficiency
▪ Avoidance of fasting prevent further episodes
▪ Tolerance to fasting increases with age
Galactose-1-Phosphate
Uridylyltransferase (GALT) Deficiency
Gene: GALT
- Symptoms triggered by lactose/galactose in diet
- Stop milk feeding IMMEDIATELY in an ill infant in
whom you are considering galactosemia
What are the common variants of GALT deficiency?
– p.N314D Duarte (still residual function)
– p.Q188R Classical European ancestry
– p.S135L African ancestry
– 5 kb del Ashkenazi Jewish ancestry
What are signs of GALT deficiency?
Brain damage, pseudotumor cerebri
Cataracts
Jaundice
Enlarged liver and liver failure
Kidney damage (renal Fanconi syndrome)
± Hemolysis
Gram negative sepsis
Premature ovarian insufficiency
Uridine Diphosphate Galactose
4′-Epimerase (GALE) Deficiency
Gene: GALE
- Symptoms
– Severe (rare): similar to GALT deficiency and allo
have psychomotor delays
– Milder variants
Galactokinase (GALK) Deficiency
Gene: GALK
- Cataracts only
- Though recent suggestion of complications
with poor dietary compliance — FTT,
microcephaly, ID, and hypercholesterolemia
Galactose Mutarotase (GALM)
Deficiency
Gene: GALM
- Cataracts only
- Recently described condition, no much
information about long- term outcomes
What is management for the galactosemias?
- Formula: soy or elemental
- Avoid milk and diary products
- Complete restriction of galactose no longer
recommended
What are the clinical presentations for glycogen storage disorders?
- Clinical presentation:
– Liver GSD
– Muscle GSD
– Liver + muscle GSD
– Neurological: Adult form polyglucosan body
disease, GBE1 gene
What are the patterns of inheritance for glycogen storage disorders (GSDs)?
GSD IXa
Gene: PHKA2
* X-linked inheritance
* alpha-2 subunit of hepatic phosphorylase kinase
GSD IXd
Gene: PHKA1
* X-linked inheritance
* alpha-1 subunit of hepatic phosphorylase kinase
How is a GSD diagnosed?
- Molecular testing
- Enzyme level low in blood
- Enzyme deficiency in liver or muscle biopsy (invasive)
GSD Type 0
- GYS2 (liver 0a) and GYS1 (muscle 0b) gene analysis
- Hypoglycemia
- No hepatomegaly
- Treatment: Dietary, regular meals with increased
protein to stimulate gluconeogenesis and complex carbohydrates to provide slow release glucose - Prognosis: Good with dietary control, significant hypoglycemia less frequent in older children and adults
GSD Type 1
- G6PC and SLC37A4 gene analysis
- GSD Ib also has neutropenia (frequent and severe infections)
- Liver adenomas with risk of malignant
transformation
What are clinical features/presentation for GSD Types 0 and 1?
- Hepatomegaly
- Normal liver function
- “Doll face”
- Truncal obesity
- Profound hypoglycemia
- Increased bleeding time
- (↓ Platelet aggregation)
- Growth delay
What is the management for GSD Types 0 and 1?
- Frequent feedings
- Restriction to complex carbohydrates
- Corn starch/glycosade
- Nutrient supplementation
- Allopurinol for hyperuricemia
- Bicarbonate or citrate
- G-CSF for neutropenia in type I non-a
- SGLT2 inhibitors (empagliflozin)
What is GSD Type 0 also called?
Glycogen Synthase
Pompe Disease (GSD II)
Gene: GAA
- Detected on NBS, low acid alpha-glucosidase enzyme level
- Caution pseudodeficiency alleles
- Lysosomal storage disease
- Myopathy»_space; motor delays, FTT, respiratory insuficiency
- Late onset vs infantile (cardiomyopathy and arrhythmias)
- Treatment with enzyme replacement therapy
(Also a lysosomal storage disorder - not covered much in this lecture)
What are clinical features of GSD III?
- Glycogen debranching enzyme (GDE) deficiency
- Hypoglycemia
- Hepatomegaly
- Rhabdomyolysis
- Cardiomyopathy
- Growth and developmental delays
- Treatment: High protein diet, frequent feedings
- Complications: Cirrhosis, liver cancer and distal myopathy
What are clinical features of GSD IV?
Hepatic glycogen phosphorylase deficiency
* Hypoglycemia
* Hepatomegaly
* Rhabdomyolysis
* Growth and developmental delays
* Treatment: Corn starch
* Prognosis: Good, rare liver adenomas, fibrosis and cardiomyopathy
What are clinical features, treatment, and prognosis of GSD V?
- Muscle glycogen phosphorylase deficiency
- Exercise intolerance
- Second wind phenomenon
- Rhabdomyolysis
- Treatment: Ingestion of glucose source prior to exercise and avoidance of strenuous effort during exercise
- Prognosis: Good
What are clinical features, treatment, and prognosis for GSD VI?
- Hepatic glycogen phosphorylase deficiency
- Hypoglycemia
- Hepatomegaly
- Growth and developmental delays
- Treatment: Corn starch
- Prognosis: Good, rare liver adenomas, fibrosis and cardiomyopathy
What are the clinical features, treatment, and prognosis for GSD VII?
- Muscle phosphofructokinase deficiency
- Exercise intolerance
- Hemolysis
- Rhabdomyolysis
- Treatment: Avoidance of strenuous effort during exercise
- Prognosis: Good
Phenotypes associated with enzyme deficiencies
See table
What is the mode of inheritance of Danon Disease?
X-Linked
(Also a lysosomal storage disorder)
What are the liver GSDs?
Liver GSDs
0a, Ia, Ib, III, IV, VI, IXa, IXb, IXc
Hypoglycemia, hepatomegaly
What are the muscle GSDs?
Muscle GSDs
0b, II, IIb, (III), IV, V, VII, IXd, X-
XV, PRKAG2, RBCK1
Exercise intolerance, muscle
pain, rhabdomyolsis,
cardiomyopathy
What are the neurologic GSDs?
Neurologic GSDs
GBE1, EPM2A, PRDM8
Polyglucosan bodies,
neurodegeneration
True or false: There is enzyme replacement therapy for GSDs
True, but only for Pompe Disease
Only clinical trials for gene therapy for Danon Disease
What is another name for GSD Type 1?
Von Gierke Disease
Mutations in what gene cause galactosemia?
GALT
What symptoms/features do we see in galactosemia?
Brain damage, cataracts, jaundice, enlarged liver, kidney damage
Untreated galactosemia can predispose to what infection?
E. Coli Sepsis
What biochemical testing is done for galactosemia?
GALT enzyme testing
Gal-1-p
Urine galactitol
Mutations in what gene cause Hereditary Fructose Intolerance?
ALDOB
What biochemical testing is done for hereditary fructose intolerance?
None - only molecular testing
(enzyme testing on biopsy is no longer done)
