1. Inherited Hyperlipidemias: types, manifestations, specific changes in serum lipids.
See Robbins 6th
edition, pgs. 150-153, Figs. 6-8,9,10.
General Description autosomal dominant defect in LDL receptor
Relatively frequent: 1/500 heterozygote
Results in early onset atherosclerosis and xanthomas (esp. on extensor hand, Achilles’ tendon); early MI for homozygote
Serum changes plasma LDL doubles; plasma cholesterol ~350; higher in homozygotes
Classes of mutations
- Class I null allele: non-functioning receptor
relatively uncommon
- Class II defect in Golgi trafficking; receptor accumulates in ER
relatively common
- Class III defect in LDL-binding domain
- Class IV defect in localization to coated pits; normal LDL binding but no internalization
- Class V defect in endosome function; LDL can bind and be internalized but cannot dissociate from receptor
2. Glycogen and lysosomal storage diseases.
See Robbins 6th,
pg. 160-61, Fig. 6-17, Table 6-6 for glycogen diseases.
See Robbins 6th,
pg. 153-160, Table 6-5 for lysosomal storage diseases.
Glycogen Storage Diseases Result in accumulation of glycogen
There are a total of 12 diseases
Type I Defect in glucose-6-phosphatase
Von Gierke’s Disease
Results in severe fasting hypoglycemia; normal glycogen accumulates in liver
Type II Defect in α-1,4-glucosidase
Pompe’s Disease
Lysosomal defect (also a lysosomal storage disease), results in cardiomegaly and early death; normal glycogen accumulates
Type III Defect in α-1,6-glucosidase
Cori’s Disease
Defect in debranching enzyme results in accumulation of glycogen with short outer chains; affects liver, heart, muscle predominately
Type IV Defect in amylo(1,4 à1,6) transglycosylase
Andersen’s Disease
Defect in branching enzyme results in accumulation of glycogen with long unbranched chains; affects liver mostly
Type V Defect in skeletal muscle glycogen phosphorylase
McArdle’s Disease
Results in inability to break down glycogen in muscle, causing cramps, myoglobinuria with exertion
Type VI Defect in liver glycogen phosphorylase
Her’s Disease
Results in accumulation in liver, leukocytes
Type VII Defect in muscle phosphofructokinase
Type VIII Defect in liver phosphorylase kinase
Type IX Defect in glycogen synthase
Results in deficient quality of glycogen
Robbins’ Subgroups
- Hepatic Forms e.g. von Gierke Disease (type I)
Hepatomegaly, renomegaly
Results in hypoglycemia, hyperlipidemias, platelet dysfunction
Can result in hepatic adenomas
- Myopathic Forms e.g. McArdle’s Syndrome (type V)
Results in painful cramps, myoglobinuria; adult onset; normal longevity
- Miscellaneous Forms e.g. Pompe Disease (type II)
Results in mild hepatomegaly, cardiomegaly, myomegaly
Cardiomegaly and respiratory failure within 2 yrs.
Lysosomal Storage Diseases
Sphingolipidoses defects cause accumulations in gangliosides; predominately neurological symptoms
- GM1 gangliosidosis defect in GM1 ganglioside β-galactosidase
includes Type I (infantile) and Type II (juvenile)
- GM2 gangliosidosis defect in hexosaminidase activity
- Tay-Sachs Disease defect in hexosaminidase-α subunit
Askenazic Jew carrier rate 1:30
GM2 ganglioside accumulates in heart, liver, spleen, CNS
Histo: ballooned neurons with vacuoles, positive for fat stains (old red O, Sudan black B)
Clinical sign: cherry red spot in macula
Results in motor, mental deterioration beginning at 6 months, death occurs ~ 2 yrs.
- Sandhoff Disease defect in hexosaminidase-β subunit
pathophysiology similar to Tay-Sachs
Sulfatidoses
- Fabry Disease defect in α-galactosidase A
X-linked recessive inheritance
Results in accumulation of ceramide trihexoside
Causes skin lesions (angiokeratomas) and results in renal failure; death in early adult
- Krabbe Disease defect in galactosylceramidase-β-galactosidase
results in the accumulation of galactocerebroside
aka Globoid Cell Leukodystrophy, since monocytes accumulate cerebroside in white matter
Causes progressive spasticity, dementia, seizures, optic atrophy; death in infancy
- Gaucher Disease defect in β-glucocerebrosidase
Most common lysosomal storage disorder
accumulation of glucocerebrosidase, predominantly in phagocytes
Histo: Gaucher cells, enlarged histiocytes with “wrinkled tissue paper” cytoplasm
Causes hepatosplenomegaly, femoral head erosion, mild anemia, pancytopenia
Type I: adult Gaucher, normal lifespan; accounts for 99%, does not involve CNS, found in Ashkenazic Jews
Type II: infantile Gaucher, severe CNS deficits; infant death
Type III: juvenile Gaucher, both viscera and CNS affected; onset in childhood
- Niemann-Pick Disease defect in sphingomyelinase
accumulation of sphingomyelin, predominantly in phagocytes
found in Askenazic Jews
Histo: “foamy histiocytes” with “zebra bodies” in liver, spleen, lymph nodes, skin
Type A: most common; includes neurological and visceral effects, may have cherry-red spot in macula; death by 3
Type B: only visceral effects: hepatosplenomegaly, anemia, fever
- Metachromatic Leukodystrophy defect in arylsulfatase A
accumulation in sulfatide
affects brain, kidney, liver, peripheral nn
leads to regression in milestones; dementia, optic atrophy; gradual decline over 5-10 yrs.
Mucopolysaccharidoses (MPS) deficiencies in degradation of MPS (aka glycosaminoglycans), which form the matrix of connective tissue
There are seven MPS variants
In general, are progressive disorders with multiple organ involvement, joint stiffness, and coarse facial features
Histo: balloon cells with zebra lines
- Hurler Syndrome (MPS I H) defect in α-L-iduronidase
accumulation of heparan sulfate, dermatan sulfate
very severe MPS; hepatomegaly develops around age 1, death by age 10
corneal clouding and mental retardation
other S/Sx: dwarfism, gargoyle facies
- Hunter Syndrome (MPS II) defect in L-iduronosulfate sulfatase
X-Linked
Similar to Hurler Syndrome, with milder course and no corneal clouding
Mucolipidoses (ML)
- I Cell Disease defect in formation of mannose-6-phosphate marker for lysosomal trafficking, resulting in the secretion of acid hydrolases
accumulation in mucopolysaccharide, glycolipids
principle enzyme defect is in N-acetyl-glucosaminyl tranferase, catabolic subunit
Histo: Inclusions in cells, filled with undegraded substances
Causes myopathy, cardiomegaly, hepatosplenomegaly, mental retardation; death by age 5
- Pseudo-Hurler polydystrophy less severe variant of I cell disease
some appropriate trafficking is maintained
3. Porphyrias: defects, clinical presentation, effect of barbiturates.
See Cecil’s 5th
edition, pg 536, figure 62-1
General Definition partial defect in one of eight enzymes involved in heme production
Symptoms Neurological and Skin Photosensitivity
Photosensitivity occurs in all porphyries except those with defects before porphyrin production
Barbiturate Effect Many drugs precipitate attacks, in those types that have neurological symptoms
Drug effect mediated by induction of cytochrome P450
Hepatic Porphyrias May cause both neurological and skin photosensitivity manifestations
- ALA dehydrogenase P. very rare; neurological effects only
- Acute Intermittent P. Autosomal Dominant defect in porphobilinogen (PBG) deaminase
Most patients do not develop symptoms
Results in accumulation of aminolevulinic acid (ALA) and PBG
Neurological symptoms predominate
Symptoms: abdominal pain, tachycardia, hypertension, neuropathy, affective disorders
Attacks precipitated by drugs, stresses, puberty onset
Rx: avoidance of precipitators, analgesia, hemin transfusions
-
Porphyria Cutanea Tarda Defect in uroporphyrinogen decarboxylase
Results in accumulation of uroporphyrin
Symptoms develop in adulthood with damage to light-exposed skin: vesicles, bullae, hyperpigmentation, etc.
Can be both familial and acquired
Acquired from alcoholism, OCP, chronic infections (HCV, HIV)
Rx: avoidance of precipitators
- Hereditary Coporphyria rare; both neuro and skin manifestations
- Variegate Porphyria not rare; both neuro and skin manifestations
Example of founder effect among Afrikaner population in South Africa
Bone Marrow Porphyrias Skin Photosensitivity only
- Congenital Erythropoietic P. rare; only skin manifestations
- Erythropoeitic Protoporphyria several hundred worldwide; only skin manifestations
Defect in ferrochelatase, the final step in heme synthesis
Results in accumulation of protophyrin
Symptoms develop in childhood: redness and edema following sun exposure
Rx: avoidance of precipitators, some photoprotection from B-carotene
4. Inherited defects in amino acid metabolism.
See Robbins 6th,
page 475-476 for PKU.
See Robbins 6th,
page 162 for alkaptonuria.
Phenylketonuria deficiency of phenylalanine hydroxylase (or deficiency of tetrahydrobiopterin cofactor)
Inability to convert phenylalanine to tyrosine; results in buildup of phenylalanine and phenylketones, causes tyrosine to be an essential amino acid
Causes mental retardation by age 1, fair skin (usually blond/blue eyed), musty body odor (from phenylacetate)
Treated by removing phenylalanine from diet and increasing tyrosine intake
Screened for in neonates
Alkaptonuria deficiency of homogentisic oxidase
Inability to completely metabolize phenylalanine and tyrosine; metabolism stops at homogentisic acid
Accumulation of homogentisic acid
Causes dark urine and ochronosis (dark soft tissue), arthritis
Albinism deficiency of tyrosinase
Inability to convert tyrosine to melanin
Includes two variants:
Ocular Albinism: X-linked disorder, limited to eyes
Oculocutaneous Albinism: usually autosomal recessive; occurs in eyes and skin; predisposes to skin cancers
Maple Sugar Urine Disease deficiency in α-ketoacid dehydrogenase
Impaired degradation of branched amino acids (Ile, Val, Leu)
Urine smells like maple syrup
Causes CNS defects, retardation, early death
Urea Cycle Disorders urea cycle in liver processes amino acid nitrogen into uric acid
Disorders result in accumulation in ammonia, causing neurotoxicity
Specific deficit is determined by urine electrophoresis of urea cycle intermediates