Pathbio 2 Non Lysozomal Enzyme Defects

Front 1

Galactosemia

Back 1

Lactose -> glucose + galactose
Galactose-1-phosphate uridyltransferase deficiency (classic galactosemia)

Clinical features:
 symptoms appear few days after milk ingestion
 vomiting
 failure to thrive
 Diarrhea, liver dysfunction
 Accumulation causes damage to liver, CNS and
other body systems
 renal failure
 Hepatomegaly and cirrhosis
 cataracts
 Brain damage
 Increased frequency of E.coli septicemia

Diagnosis by:
Newborn screening

Front 2

Glycogen Storage Disease
(General)

Back 2

Inherited disorders that affect glycogen metabolism
Most cells store some amount of glycogen & muscle & Liver are key players in glycogen metabolism

Classification based on pathophysiology -> hepative, myopathic, miscellaneous
Liver: glycogen is mainly used to maintain normal blood glucose during fasting
Muscle: glycogen provides substrates for generation of ATP through glycolysis for muscle contraction with formation of
lactate
Hepatic type defects
- storage of glycogen in liver
- reduced blood glucose
Myopathic type defects
- storage of glycogen in muscle
- muscle weakness

Clinical features:
GSD should be considered in any child presenting with
 Hepatomegaly
 Hypoglycemia
 Growth failure
 Excessive fat in the face and buttocks (doll-like appearance)
 Mild serum transaminase elevations

Front 3

Von Gierke Disease
(Type 1)
Glycogen Storage Disease

Back 3

Defect: glucose-6-phosphatase

Hepatic form: hepatomegaly & hypoglycemia

Clinical features:
 Hepatomegaly ->adenomas -> carcinoma
 Renomegaly
 Short stature
 Excessive fat in the face and buttocks (doll-like appearance), marked lipidemiaeruptive xanthomas
 hypoglycemia
Microscopically:
 Liver: uniform distribution of glycogen within
hepatocytes with distension
 muscle normal
 diffuse fibrosis and remaining
hepatocytes contain cytoplasmic accumulations of chunky, hyaline or vacuolated material
 PAS positive diastase resistant material

Front 4

McArdle Disease
(Type V)
Glycogen Storage Disease

Back 4

Deficiency of muscle phosphorylase

Myopathic form: glycogen storage in muscles

Clinical features:
• Muscle weakness, painful cramps after
exercise without increased lactate levels
• prolonged exercise may result in muscle
fiber necrosis, myoglobinuria, and acute
renal failure microscopically: glycogen accumulated in skeletal muscle

Front 5

Pompe Disease
(Type II)

Glycogen Storage Disease

Back 5

Lysosomal enzyme acid maltase (alpha-1-4-glucosidase)

Generalized glycogenosis


Clinical features:
clinical presentation: infantile (classic)
- Muscle weakness
- Heart involvement-> progressive heart failure
- Hepatomegaly
- Enlarged tongue
- Death in early life (1-2 years)
microscopically: glycogen deposits in myocardium and skeletal muscle, liver etc.

Front 6

Anderson Disease
(Type IV)

Glycogen Storage Disease

Back 6

Brancher enzyme (amylo1,4,6 transglucosidase)

Amylopectinosis

Clinical featuers:
 More generalized disease
 Hepatomegaly and FTT present in the 1st
year, progressive portal fibrosis -> cirrhosis -> death
 Cardiomyopathy
 Muscle atrophy

Front 7

Phenylketonuria

Back 7

- Disorder of AA metabolism
 Classic PKU results from a deficiency of
phenylalanine hydroxylase (PAH) (98%)
 2% result from abnormalities in
synthesis or recycling of BH4

Minor pathway-> toxic to brain

Clinical featuers:
 Mental retardation
 Fair hair and blue eyes
 Musty body odor
 eczema

Diagnosis by:
 Laboratory testing
-Newborn screening
-Urinary excretion of minor pathways of phenylalanine metabolism (phenylpyruvic acid, phenyllactic acid,
phenylacetic acid…)
-Serum phenylalanine levels
 Management
-Infant strict dietary restriction
-Child > 10 may be able to tolerate normal diet
-Pregnancy: may need dietary restriction
 Pathologic findings
-Both gray and white matter changes with demyelination
and gliosis in the white matter

Front 8

Cystic Fibrosis

Back 8

Impaired membrane transport of chloride
 abnormal content of secretions
 Recessive
 Mutations result in little or no functional CFTR
 Most common genotype F508 (70%)

Defect in CFTR
 Lungs
 Intestines
 Pancreas
 Sweat glands
 Reproductive tract

Clinical features:
 Lungs-> bronchial secretions are thick->
obstruction -> infections
 Pancreas-> thick secretions block ducts->
backup of pancreatic enzymes->
autodigestion-> fibrosis-> loss of pancreatic
parenchyma
 intestines-> lead to blockage-> in utero atresia
 Vas deferens-> blockage ->sterility

Front 9

Marfan Syndrome

Back 9

- Defect in FBN1 gene coding fibrillin-1 located on chromosome 15q21
- Autosomal Dominant
- Mutant fibrillin-1 disrupts the assembly of normal microfibrils

2 forms fibrillin-1 and fibrillin-2 coded on 2 different chromosomes
 major component of microfibrils in the extracellular matrix
 abundant in aorta, ligaments and ciliary zonules supporting lens

Clinical features:
 cardiovascular:
-Dilated ascending aorta, aneurysms, dissection due to cystic medionecrosis
-mitral valve prolapse
 skeletal abnormalities
-Tall stature
-Abnormal joint mobility
-Scoliosis, pectus excavatum
- arachnodactyly
 Ocular abnormalities
-ectopia lentis
-myopia

Front 10

Neurofibromatosis Type I (NF-1)

Back 10

- frequency 1/3000
- autosomal dominant
penetrance 100%, expressivity is variable
- NF-1 gene 17q11.2 ---> neurofibromin (down regulates p21 and RAS)

Clinical features:
NIH diagnostic criteria (need 2 or >):
1) 6 or > pigmented skin lesions “café au lait
spots” ( > 90% of patients)
2) freckling in the axillary or inguinal regions
3) pigmented iris hamartomas( > 94% of patients)
4) 2 or > neurofibromas of any type, or 1
plexiform neurofibroma
5) optic glioma
6) 1st degree relative with NF1
Other
wide range of associated anomalies :30% skeletal abnormalities (scoliosis), 2-4 x risk of developing other tumors

Front 11

Neurofibromatosis Type II (NF-2)

Back 11

Autosomal dominant : defect of NF-2 gene coding for a protein merlin located on chromosome 22 at 22.12

Clinical features:
 Presents 2nd and 3rd decades
 ~ 100% penetrance by age 60
 Bilateral acoustic schwannomas
 Multiple meningiomas
 Ependymomas of spinal cord