Glycogen Storage Disease and Galactosemia

Define gluconeogenesis.

the formation of glucose from non-carbohydrates (ex: protein and fat)

What are the gluconeogenesis substrates?

lactate, alanine, glycerol

Define glycogenolysis.

The breakdown of glycogen into glucose (glycogen metabolism)

Define glycolysis.

the breakdown of glucose

What is glycogen?

the stored form of glucose in virtually all cells

In which organs is glucose most abundant?

muscle tissue and liver

Describe glycogen metabolism in the liver.

-glucose is taken from blood after a meal and stored as glycogen

-glucose is released from glycogen stores into the blood for other organs to use when the glucose levels start to fall (exercise, fasting)

Describe glycogen metabolism in the muscle.

glycogen in muslce cells is used for short-term, high energy consumptions (generation of ATP for muscle contraction)

What is glucose-6-phosphate?

non-specific phosphohydrolase that is associated with the membrane of the ER

True or False: G-6-P does not require a transporter to enter the active site within the lumen of the ER.

FALSE: G-6-P transporter is needed to move this molecule into the lumen

What is the role of glucose-6-phosphate?

-glucose precursor

-glycogen breaks down into G-6-P which is broken in to glucose

What causes Glycogen Storage Disease 1a?

glucose-6-phosphate deficiency

What causes Glycogen Storage Disease 1b?

glucose-6-phosphate translocase deficiency

List symptoms of GSD 1 (a & b)

-hepatomegaly

-normal liver function

-:doll face (taut skin and plump cheeks)

-truncal obesity due to massive hepatomegaly

-muscle wasting

-profound hypoglycemia

-hyperlactacidemia (lactate), hyperuricemia (uric acid), hyperlipidemia

-increased bleeding time

-stunted growth (due to chronic acidosis)

List specific features of GSD 1b.

-neutropenia (low neutrophils) --> chronic infection (impacting upper and lower respiratory tract, skin, urinary tract) , inflammatory bowel disease, protracted diarrhea

-neutrophil dysfunction caused by impaired motility and migration

-deep abscesses in the brain

-peri-oral and peri-anal infections (peri = around)

Describe complications of GSD 1 and what symptom may cause them.

- short stature and osteoporosis caused by chronic acidosis

-gout caused by hyperuricemia

-nephropathy

-pulmonary hypertension

-liver adenomas

-polycystic ovaries

-necrotizing pancreatitis

About how much of GSD I is GSD 1b?

about 1 in 5 GSD 1 cases

How is GSD 1 diagnosed?

-molecular genetic testing of G6PC and SLC37A4

-less commonly now, Glucose-6-phosphatase activity and glycogen concentration in fresh liver tissue

What lab findings might indicate GSD1 ?

-elevated triglycerides, lactic acid, uric acid, and cholesterol

-normal CK (rule out GSD 3)

-neutropenia (GSD 1b)

How is GSD 1 conventionally treated?

-frequent small servings of carbohydrates and uncooked cornstarch supplementation (may need continuous night-time NG tube feeding)

-calcium, vitamin D, iron supplementation

-ACE inhibitor for hypertension and to treat kidneys

-GCSF (Human granulocyte colony stimulating factor) can be used in 1b patients with frequent infections

What is Glycosade and what are the benefits? What condition is it used for?

-GSD 1 treatment

-high amylopectin corn starch made of complex, branched carbs that is slower releasing than regular cornstarch

-fasting interval can increase Fromm 4 to 6 hours, providing better sleep and better quality of life

Liver transplants for GSD 1 patients are typically reserved for those with ______.

adenoma and clear evidence of malignant transformation

What is the cause of GSD III?

glycogen debranching enzyme (GDE) deficiency

What are the symptoms of GSD III?

-hepatomegaly, +/- splenomegaly

-protruding abdomen

-growth delay

-muscle weakness

What are common clinical findings of GSD III?

-hypoglycemia

-ketosis

-mild lactate elevation after eating

-hyperlipidemia

-elevated CK

-peripheral neuropathy

-cardiomyopathy

How is GSD III treated?

-high protein diet

-frequent feedings as in GSD I if hypoglycemia is present

-3-OH butyrate supplementation

What are complications of GSD III?

-liver cirrhosis, liver cancer, muscle hypotonia and wasting with progressing age

What lab findings might indicate GSD III?

-ketotic hypoglycemia with normal lactate at short fast

-post prandial hyperlactatemia

How is GSD III diagnosed?

-metabolic profile

-GDE activity in leucocytes, RBCs

-molecular genetic testing

What causes GSD V (McArdle)?

myophosphorylase deficiency due to variant in PYGM on chromosome 12q13

What are the symptoms of GSD V?

-adult onset exercise intolerance

-muscle cramps

-myoglobinuria

-hyperuricemia

-mild CPK elevation at rest

How is GSD V treated?

-avoid strenuous exercise

-protein rich diet, glucose, fructose

How is GSD V diagnosed?

molecular genetic testing

When should a metabolic cause be suspected in patients with liver disease?

-hypoglycemia

-acidosis +/- anion gap

-hyperlactatemia

-hyperuricemia, hypophosphatemia

-urinary reducing substances

-manifestations of renal dysfunction

What causes GALT deficiency?

non working galactose-1-phosphate uridyltransferase

What are the neonatal clinical presentations of GALT deficiency?

-hyperbilirubinemia

-liver dysfunction (enlarge liver, liver failure)

-cataracts

-sepsis

-pseudotumor cerebri (bulging fontanelle --> caused by build up of pressure, soft spot bulges out)

-kidney damage (renal falcon syndrome)

How is GALT deficiency treated?

-lactose restriction (starting with no breastmilk)

-calcium supplementation

-monitoring Gal-1-P levels and urine galactitol

-ophthamology evaluation

What testing can be done to diagnose GALT deficiency?

-slit lamp test (diffuse cataracts)

-urinalysis

-RBC Gal-1-P

-GALT enzyme activity

-NBS

-molecular genetic testing

What is the most common GALT genotype in caucasians?

Q188R (classic)

What is the GALT Duarte genotype?

N314D

What GALT genotype is more common in African American populations?

S135L

List complications of GALT deficiency.

-neonatal liver disease and risk of sepsis

-cataracts

-ovarian dysfunction

-varying neurological outcomes (difficulties with speech, spatial orientation and visual perception, motor difficulties, leukodystrophy in adults)

Describe the basics of galactosemia dietary restrictions and management.

-exclude lactose milk in infant formula, avoid lactose and dairy products

-galactose in fruits and vegetables may not be easily avoided

-non dairy protein sources like soy (contain galactose)

-calcium supplementation and multivitamins

How is the phenotype of the Duarte variant different from that of classic galactosemia?

-about 25% GALT activity in RBCs

-Gal-1-P, galactitol normalize with age with or without treatment

True or False: If suspicious of galactosemia, it is okay to continue milk intake until confirmatory testing is returned.

FALSE: if suspicious of galactosemia, STOP milk intake immediately