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Med Gen Section 2 > Glycogen Storage Diseases and Inborn Errors of Galactose and Fructose > Flashcards

Glycogen Storage Diseases and Inborn Errors of Galactose and Fructose Flashcards

1
Q

What defects of liver glycogenesis present with preponderant hypoglycemia?

A 
Type III (liver debranching enzyme deficiency)
Type Ia and Ib (glucose-6-Pase system)
Type O (liver glycogen synthase deficiency)
Glut 2/ Fanconi-Bickel syndrome (liver glucose transporter deficiency)
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2
Q

What defects of liver glycogenesis present with isolated hepatomegally or liver disease?

A 
Type VI/IXa (phosphorylase/phosphorylase kinase system)
Type IV (liver branching enzyme)
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3
Q

What defects of muscle and heart glycogenesis present with exercise intolerance?

A

Type V/ McArdle disease (muscle phosphorylase deficiency)
Type VII/ Hemolytic Anemia (phosphofructokinase deficiency)
other more rare types that we will not discuss (Types X-XIII)

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4
Q

What defects of muscle and heart glycogenesis present with myopathy/cardiomyopathy?

A

Type II/ Pompe (lysosomal acid maltase deficiency)
Type 0 (muscle glycogen synthase deficiency)
Type III
Type IV

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5
Q

When does myopathy/caridomyopathy present in defects in muscle and heart glycogenesis?

A

can be found in utero
mostly present early in life with failure to thrive
Type III presents mostly in adults with pre-existing hepatic signs

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6
Q

What defects of muscle and heart glycogenesis present with adult cardiomyopahty and WPW?

A

AMP activated protein kinase deficiency (AMPK)

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7
Q

What symptoms are associated with GSD I?

A 
HLD, hypoglycemia, hyperuricemia
"doll face" and short stature
hepatomegally (normal liver function)
decreased platelet aggregation (increased bleeding time)
growth retardation and failure to thrive
truncal obesity
hyperlactacidemia (acidosis)
gout
osteoporosis
nephropathy
liver adenomas (can become malignant)
polycystic ovaries
necrotizing pancreatitis
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8
Q

What makes GSD Ib different from GSD Ia?

A

presence of neutropenia with increased infections (severe)

severe GI symptoms (including diarrhea and IBD)

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9
Q

How is GSD I diagnosed?

A

measurements of G-6-Pase activity and glycogen concentration in fresh liver tissue
enzyme activity
molecular assay (standard of care)
enzyme assay (rarely)

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10
Q

How can GSD I be treated?

A

frequent feedings
restrict carbs (give complex carbs like corn starch)
allopurinol to decrease gout risk (due to hyperuricemia)
citrate/bicarb to normalize pH and prevent bone degradation
G-CSF for neutropenia (Type Ib)
ACE inhibitors for HTN
liver transplant is curative (neutropenia persists in GSDIb)

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11
Q

What is GSD III?

A

Cori, Forbes
deficiency of debranching enzyme
GSDIIIa –> liver and muscle
GADIIIb –> just liver

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12
Q

What symptoms are associated with GSDIII?

A

hypoglycemia, HLD, hepatomegally, short stature

liver cirrhosis, liver cancer, distal myopathy

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13
Q

How can GSD III be diagnosed?

A

suspected in infancy

increased creatine kinase, metabolic assay, glycogen debranching enzyme, DNA investigation in leukocytes

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14
Q

How is GSD III treated?

A

high protein diet
frequent feedings
3-OH butyrate

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15
Q

What is GSD VI?

A

Hers
liver phosphorylase deficiency
good prognosis- hepatomegally improves with age and disappears around puberty
diagnosed by enzyme assay in liver biopsy specimen or by molecular diagnosis

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16
Q

What is GSD IXa?

A 
liver phosphorylase B-kinase deficiency (gene PHKA2 on chromosome Xp22 or 5 other rare autosomal loci)
benign prognosis (catch-up growth curve and decreased hepatomegally with treatment)
diagnosed by enzyme assay
treat with dietary restrictions
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17
Q

What is GSD 0?

A

etiology is tissue specific: GYS1 (liver glycogen synthase) expressed ubiquitously, GYS2 (muscle glycogen synthase) expressed only in the liver
glucose metabolism is fine but can’t make much glycogen due to deficiency of a glycogen due to deficiency of glycogen synthase enzyme (liver and muscle)
diagnosed by molecular genetic analysis of GYS2 and enzyme assay requires liver biopsy
treat with frequent snacking

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18
Q

What are the symptoms of GSD 0?

A

fasting-induced ketotic hypoglycemia
small
normal liver and serum analytes

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19
Q

What is GSD V?

A

McArdle disease
myophosphorylase deficiency caused by PYGM gene on chromosome 12q13
most common

20
Q

What is GSD VII?

A

Tauri
phosphofructokinase deficiency caused by PFKM gene on chromosome 11q13
distinguished from V by presence of hemolytic anemia
rare (<1%)

21
Q

What is AMPK deficiency?

A

due to PRKAG2 on chromosome 7q36 (AD)
diagnosed on heart biopsy, ECG, and molecular genetics
may require defibrulator or heart transplant when extreme

22
Q

What is GSD II?

A

Pompe disease
lysosomal acid maltase deficiency
see Pompe lecture for more detail

23
Q

What is Lafora disease?

A

accumulation of branched chain glycogen (Lafora bodies) –> neuronal apoptosis (mechanism unknown)
caused by EPM2A gene (coding for laforin) and EPM2B gene (coding for malin)
no treatments known

24
Q

What are the symptoms of Lafora?

A

adolescent onset of myoclonic epilepsy and absence seizures
progressing to dementia with vision loss, apraxia, and aphasia
ultimately leads to vegetative state
death within a decade of disease onset

25
Q

How is Lafora diagnosed?

A 
skin biopsy (checks for Lafora bodies)
mutation analysis to confirm
26
Q

Name the galactosemias.

A 
Galactokinase deficiency (GALK)
Galactose uridyl transferase deficiency (GALT)
Uridine diphosphate galactose 4'-epimerase deficiency (GALE)
27
Q

Name the diseases of inborn errors of fructose metabolism.

A 
fructokinase deficiency (essential fructosuria)
hereditary fructose intolerance (aldolase B deficiency)
fructose-1,6-bisphosphatase deficiency
28
Q

What are common, overarching symptoms of galactosemias?

A

cataracts (due to galactose–> galactol buildup in lense)

ID (due to galactose –> galactol buildup in brain)

29
Q

How can you differentiate cataracts caused by galactosemias from other kinds of neonatal cararacts?

A

cataracts due to galactosemias are diffuse while those from other etiolgies like TORCH are more dense
these differences can be seen using a slit lamp exam

30
Q

What are the symptoms of neonatal GALT deficiency?

A 
brain damage
pseudotumor cerebri
hematomegally (increased bili with jaundice, liver failure, hemolysis)
kidney damage (renal Fanconi syndrome)
Gram negative sepsis (~10% of patients)
31
Q

How is neonatal GALT deficiency treated?

A

symptoms are triggered by lactose/galactose in diet so you should always stop milk feeding first and then seek a diagnosis if it is suspected

32
Q

What should be done when a child comes up positive for GALT deficiency on NBS?

A

within 48 hours must be in ED for treatment (normally no symptoms yet)
due to increased risk of false positives/negatives recommend follow-up with quantitative RBC gal-1-P, quantitative GALT enzyme activity, and DNA mutation analysis

33
Q

What genotypes are associated with GALT?

A 
Q188R (classical --> severe phenotype)
N314D (Duarte variant allele --> less severe phenotype)
K285N (variant allele; less common)
S135L (classical in African Americans)
5kb deletion (variant in AJ populations)
34
Q

What are lactose DEPENDENT outcomes of untreated GALT deficiency?

A 
neonatal liver disease
neuro outcomes varied (even with treatment due to endogenous lactate production)
increased risk of neonatal sepsis
cataracts
renal proximal tubule dysfunction
35
Q

What are lactose INDEPENDENT outcomes of untreated GALT deficiency?

A

cirrhosis
lenticular strategies
ovarian dysfunction (regardless of treatment)
verbal dyspraxia (regardless of treatment)
ID

36
Q

What are neurological outcomes of GALT?

A 
decreased concentration
difficulties with spatial orientation and visual perception
speech difficulties (common)
motor difficulties (less common)
leukodystrophy in adults
37
Q

How is GALT deficiency treated?

A 
dietary restrictions (work with nutritionist to ensure diet that avoids milk containing galactose, awareness of galactose in fruits/vegetables)
monitoring (liver function, bone density, gal-1-P levels)
supplement (calcium, non-dairy protein sources, multivitamins)
check all drugs and supplements (check regularly with manufacturer to ensure no lactose is used as an additive; especially important in oral contraceptives)
38
Q

What is DIG?

A

Duarte-Galactosemia
biochemical manifestations (RBC 25% GALT activity, neonatal elevated RBC gal-1-P, galactitol)
genotype is predictive of severity (always test)
treated with lactose restriction
Gal-1-P, galactitol normalizes with age (regardless of treatment)

39
Q

What is galactokinase deficiency?

A

found on NBS
biochemical analysis shows glycosuria, high galactose and urine galactitol, low normal gal-1-P
monitored with blood galactose and urine galactitol
presents with only cataracts
treat with elimination of lactose from diet
frequency is population dependent (Increased in Roma Gypsies)

40
Q

Describe galactose-4-epimerase deficiency?

A 
mild variants are easily managed
severe variants (though rare) present with psychomotor retardation and are difficult to manage
biochemical analysis shows glycosuria; high glalactose, gal-1-P, and urine galactitol; and normal GALT activity
41
Q

What are the symptoms of acute fructose exposure in patients with inborn errors of fructose metabolism?

A

acute hypoglycemia (rare)
emesis
acute liver dysfunction (most frequent) with jaundice, bleeding, acidosis, and liver disease/failure
seizures, coma, death
frequent aversion to sweets (lack of cavities)

42
Q

What are the symptoms of chronic fructose exposure in patients with inborn errors of fructose metabolism?

A 
poor feeding and growth/ failure to thrive
neurological symptoms
emesis/diarrhea
jaundice and hepatomegally
edema and ascites
tremor/jerking
irritability/ incessant crying
apathy/listlessness
drowsiness
abdominal distension
43
Q

What acute blood findings suggest an of inborn error of fructose metabolism?

A

increased lactate and uric acid
decreased glucose, Potassium, Bicarb, phosphorous
liver dysfunction
prolonged prothrombin (PT) and partial thromboplastin time (PTT)

44
Q

What acute urine finding suggest an inborn error of fructose metabolism?

A

increased bicarb, glucose, phosphorous, and aminoaciduria

increased fructose and protein

45
Q

What is HFI?

A

Hereditary Fructose Intolerance
deficiency of Aldolase B on chromosome 9q22.3
many mutations found on NBS but diagnosed primarily through molecular testing
treat with elimination of fructose from diet with strict compliance (careful with IV fluids and oral medications)

46
Q

Describe Fructose-1,6-Bisphosphatase deficiency?

A 
neonatal onset (severe with ketolactic acidosis) or later onset (mild with hypoglycemia and hypoketonemia or severe with lactic acidosis and hypoclycemia adn ketosis 4+)
acute attacks (hypoglycemia, lactic acidosis, ketosis, hepatomegally secondary to transient triglyceride accumulation) can be caused by incurrent illness, fasting, and variably by fructose/sucrose ingestion
treat with avoidance of fasting (tolerance for fast increases with age)
molecular testing for fasting hypoglycemia and lactic acidosis when suspected (fasting tests will increase lactate and decrease glucose)
enzyme measurements in liver should be checked if mutation cannot be found

Med Gen Section 2 (13 decks)

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