Metabolic Disease
Carbohydrate Disorders
Galactosemia
- Biochemical Pathway
Galactose + ATP, 1 Galactose-1-P 2 UDP Galactose + Glucose 1-P 3 UDP Glucose + Galactose-1-P 4 Glucose-1-P
- Involved enzymes and their consequences if deficient or absent
1- galactokinase – some problems, not as fatal as 2
2- Galactose-1-P uridyl transferase – Fatal
3- UDP Galactose-4-epimerase – rare; no consequences
4- Hexose-1-P uridyl transferase
- Incidence: 1/30,000-60,000 (whites)
- Symptoms
1) vomiting and diarrhea
2) liver disease with jaundice; hepatomegaly
3) cataracts
4) MR, FTT, death
- State screen in TX since 1979 – 1/65000
- Diagnosis: elevated galactose in serum
- Treatment: diet restriction from galactose
- Bad problem: Cannot eliminate all galactose from diet and the body endogenously produces galactose
- Galactose toxicities
1) brain
2) ovaries (all females have ovarian failure evident even at 10 days postnatal)
- Genetic Variants
1) Duarte variant:
- (50% activity)
- 25% activity overall;
- More common in pop than classic
- Better prognosis
- Can take off diet at 18-24 months and challenge – usually normal at this time
2) Classic
3) More than 100% activity?
4) Negro variant – 0% activity in RBC, 10% activity in liver and intestine
- Types of enzyme deficiencies and their effects
1) Transferase deficiency – hepatomegaly and cataracts; susceptible to E.coli. sepsis
2) Galactokinase deficiency – cataracts, kidney problems, usually DO NOT have problem with liver
3) Epimerase deficiency – “non-disease” because there are no symptoms
Fructose Disorders
- rare
- Symptoms: poor feeding, vomiting, liver and renal damage
- Diagnosis: enzyme assay
- Treatment: frequent feed and avoid fructose
- Biochemical Pathway
Fructose: 1 Fructose-1-P 2 DHA-P 2 Fructose-1,6-bis-P 3 Fructose-6-P
Enzymes and their associated disease/symptoms:
1- Fructose Kinase fructosuria (benign)
2- Aldolase B (Main player) hereditary fructose intolerance – chromosome 9q -
Hypoglycemia, vomiting, child refuses fructose
3- Fructose-1,6-bis-phosphatase apnea, hypoglycemia, ketosis, acidosis, vomiting,
tolerance comes with age
Glycogen Storage Diseases
- incidence – 1/100000
- Glycogen stores
1) Liver – source of glucose when fasting
2) Muscle – quick release of glucose to support activity
- Symptoms of glycogen storage diseases
1) Liver type: hypoglycemia, lactic acidosis, hepatomegaly, short stature
2) Muscle type: muscle pain, weakness, cramps, myoglobinuria, (Hypotonia and cardiomegaly seen in Pompe’s)
- Enzymes in the LIVER
1) Glucose-6-phosphatase – used to convert glucose to glucose-6-P
2) Phosphorylase
3) branching enzyme
4) Debranching enzyme
5) Phosphofructokinase
Liver Glycogen Storage Diseases – Hypoglycemia
Type Ia: von Gierke Disease – Glucose-6-phosphatase deficiency
- MOST COMMON FORM
- Autosomal recessive
- Glucose-6-phosphatase deficiency
- Symptoms:
1) hepatomegaly
2) hypoglycemia
3) short stature, hepatic adenoma, delayed maturity, cherub cheeks
Type Ib – Glucose-6-Phosphatase microsomal translocase deficiency
- do not restrict simple sugars
Type III – debrancher enzyme deficiency
- results in inability to release glucose
- Symptoms
1) hypoglycemia
2) hepatomegaly
3) mild muscle weakness, short stature, elevated liver enzymes
Type VI
- heterogenous group of diseases caused by a deficiency of the liver phosphorylase system
- x-linked
- much milder form
TREATMENT OF HEPATIC-HYPOGLYCEMIC FORMS of GSD
- frequent feeds
- avoid simple sugars (sucrose and lactose)
- RAW CORNSTARCH for slow release of glucose
Muscle forms of Glycogen Storage Diseases
- rarer than Hepatic forms
- usually go undiagnosed
Type V: McArdle’s disease – muscle phosphorylase deficiency
- increased CPK
- Symptoms:
1) muscle pain
2) cramps
Type VII – muscle phosphofructokinase deficiency
Type II – Pompe’s Lysosomal Storage Disease
- actually a lysosomal storage disease than a glycogen storage disease
- defect in lysosomal alpha-glucosidase
- presents with enlarged heart and tongue
TREATMENT OF MUSCLE FORMS OF GSD
- give simple sugars prior to exercise
Lysosomal Storage Diseases
General
- macromolecules cannot be degraded and they accululate in organelles
- results in tissue and organ distortion, tissue injury, and organomegaly
- rare
- infantile, juvenile, and adult forms
- diagnose by enzyme assay
- no known treatment for most
Pompe’s Disease
- 1/100000
- defect in lysosomal alpha-glucosidase
- enlarged heart and tongue
- enzyme replacement therapy just out on the market.
Tay-Sachs Disease
- 1/30 Ashkenazi Jews is a carrier
- Hexomaninindase A deficiency
- Fatal neurodegenerative disease with macrocephaly, loss of motor skills, increased startle reaction, and a macular cherry red spot
- Juvenile onset form presents with dementia and ataxia and death by 10-15 years
- Sandhoff Disease is nearly identical but without HSM and bony dysplasias.
Krabbe’s Disease
- Beta-galactosidase deficiency
- Symptoms similar to Tay-Sach
1) cherry red spot on retina
2) neurologic deterioration
3) death by age of 2
- lab: elevated CSF protein
- diagnosis: enzyme assay
- no treatment
- 1/100000-200000
Fabry Disease
- X-linked recessive
- Alpha-galactosidase deficiency
- Symptoms
1) neuropathy: pain and paresthesias in the extremities
2) angiokeratomas on skin and mucus membranes
3) cloudy corneas
4) decreased sweating
5) renal and heart failure possible
- Treatment: Diphenylhydantoin for neuropathy relief, enzyme replacement, dialysis, transplant
Metachromatic Leukodystrophy
- classic white matter disease
- 1/100000
- NO SEIZURES (seen in gray matter disease)
- Elevated CSF protein and decreased nerve conduction
- Arylsulfatase deficiency
- No treatment
Gaucher’s Disease
- Beta-glucosidase deficiency
- 1/50000; increased incidence in Ashkenazi Jews
- MOST COMMON LYSOSOAML STORAGE DISORDER
- Three types
1) Type I – non-neuropathic
Ø Ashkenazi Jews
Ø Painless spleenomegaly, decreased platelets, anemia, leukopenia, bone involvement
2) Type II – acute infantile
Ø severe brain disorder
Ø die by age 2
3) Type III – juvenile, subacute, Norbottian form
Ø similar to type II but with later onset
- Diagonsis: Lipid Storage Cells in BONE MARROW
- Treatment: enzyme replacement, complete or partial spleenectomy
- Type I may not need treatment.
Mucolipidosis
Mucolipidosis II: I-cell disease
- deficiency in transport
- defect in post-translational processing of multiple lysosomal enzymes due to decreased enzyme level
- early death
- Symptoms
1) dysostosis multiplex
2) MR
3) Hepatomegaly
4) Cardiomegaly
5) Hernias
6) Corneal clouding
7) Claw hand
- Treatment: none
Mucolipidosis III: pseudo-Hurler polydystrophy
- rare
- can live into 60s
- phenotype = Hurler’s
Tags: Duarte variant, Epimerase deficiency, Fabry Disease, Fructose Disorders, Galactokinase deficiency, Galactosemia, Gaucher's Disease, Glycogen stores, Hepatomegaly, Hypoglycemia, Jaundice, Krabbe's Disease, Metachromatic leukodystrophy, Mucolipidosis, Phosphatase microsomal translocase deficiency, Pompe's Disease, Tay-Sachs disease, Transferase deficiency, von Gierke Disease
