Many body proteins are in such abundant supply that if a person has only half as much of that protein (i.e., has one good gene where most people have two), there is no obvious problem. However, if a person has no good gene where most people have two, the person is sick. Therefore, the known autosomal recessive diseases are either:
(1) deficiencies or defects in highly specialized proteins (enzymes, transport proteins), or
(2) hemoglobinopathies requiring more than one dose of a gene
In contrast to autosomal dominant diseases, autosomal recessive diseases:
-- often result from consanguineous matings.
-- are often apparent at, or shortly after, birth;
-- have unknown mutation rates;
-- generally show complete penetrance (if there are several alleles, expressivity may vary; the most conspicuous exception is à1-protease inhibitor deficiency);
Heterozygote advantage accounts for the success of these diseases in Darwin's world in certain ethnic groups. Sickle cell and some of the other hemoglobinopathies protect heterozygotes from malaria. Hemochromatosis heterozygotes are protected from iron deficiency. Cystic fibrosis protects from cholera and other bacterial diarrheas. Tay-Sachs protects from TB.
The major autosomal recessive disorders which you'll meet:
Deficiencies or defects in highly specialized proteins
Known proteins
-- Cystic fibrosis ("mucoviscidosis")
-- Phenylketonuria
-- Galactosemia (two kinds)
-- Adenosine deaminase deficiency (immunodeficiency)
-- à1-protease inhibitor ("antitrypsin") deficiency
-- Common albinism
-- The lysosomal storage diseases (except Fabry's)
-- Most glycogen storage diseases
-- Alkaptonuria
-- Really bad von Willebrand's variants
-- Abetalipoproteinemia (missing apoprotein B; spiny red
cells, malabsorption):
-- The bad kind of epidermolysis bullosa (bad type VII
collagen, therefore bad anchoring fibers)
-- Chediak-Higashi
-- hereditary fructose intolerance (aldolase B)
-- homocystinuria (cystathione synthetase)
-- hereditary tyrosinemia (fumarylacetoacetate hydrolase)
-- Various inborn errors of hormone metabolism
-- metachromatic leukodystrophy (arylsulfatase A)
-- Krabbe's (galactosylceramidase)
Proteins awaiting discovery
-- Werdnig-Hoffman ("floppy baby") disease
-- Wilson's family of copper problems
-- Unusual albinism syndromes
-- Some Ehlers-Danlos variants
-- Around 16 different familial deafness syndromes
-- Hartnup (can't absorb tryptophan well from gut)
-- At least two malignant hyperthermia genes (neurochemists
and anesthesiologists take note)
Major hemoglobin problems
-- Sickle cell anemia
-- Hemoglobin C disease
-- á-thalassemia major
-- Three and four-dose à-thalassemia syndromes
-- Combinations of the above
Albinism: Can't make melanin. Twelve or so different loci. The best understood is tyrosinase deficiency.
Alkaptonuria ("ochronosis"): lack of homogentisic acid oxidase. Precocious osteoarthritis, black urine, black cartilage (check those ears).
Lysosomal storage diseases, of course, result from failure of catabolism of large molecules within lysosomes, which accumulate.
Tay-Sachs disease ("amaurotic, i.e., blind, familial idiocy"): lack of hexosaminidase A, causing accumulation of GM2-ganglioside. Mostly neurons. Born normal, become retarded, blind, floppy. Head becomes huge. Cherry spot on macula is normal red seen amidst cloudy neurons.
Niemann-Pick disease: lack of any one of several proteins required to break down sphingomyelin molecules. Many types. Lipid-laden, foamy- looking affected cells. Electron microscopy shows lamellar lipid masses ("zebra bodies", other forms).
Gaucher's disease: Lack of glucocerebrosidase. Several types. Type I is a semi-disease with a big spleen and liver; pancytopenia (hypersplenism) and bone fractures are a problem. Type II is the kiddie form; replacement enzyme is $400,000 per year for life. In either form, pathologists see "Gaucher cells", huge reticuloendothelial cells bloated with glucocerebroside.
The mucopolysaccharidoses: Problems degrading glycosaminoglycans ("mucopolysaccharides", such as heparan sulfate, dermatan sulfate, keratan sulfate, chondroitin sulfate, and/or others). These include the very severe Hurler's syndrome ("gargoyle" children with progressive mental retardation) to the variable Sanfilippo (severely mental deterioration, near normal-looking) and Morquio (dwarves with bad aortic valves and normal intelligence) syndromes. Hunter's (MPS-II) is sex-lined, but all the others are autosomal recessives. Expect mild to severe accumulation of mucopolysaccharides in the spleen, liver, etc. Pathologists see PAS-positive material in affected cells.
Metachromatic leukodystrophy: deficiency of arylsulfatase A; galactosyl sulfatide accumulates; brain deteriorates after infancy.
Krabbe's globoid cell leukodystrophy: deficiency of galactocerebroside B galactosidase; galactocerebroside accumulates; brain deteriorates in infancy.
Adrenoleukodystrophy ("Lorenzo's oil", etc.): a family of diseases, some X-linked, with problems breaking down long-chain fatty acids; both white matter and adrenal cortical problems. "Lorenzo's oil" was a heroic failure.
Glycogen storage diseases: The clinical application of a "Biochemistry" unit. Type I (Von Gierke's disease, glucose-6-phosphatase deficiency): Big livers, hypoglycemia. A mild disease. Type II (Pompe's disease, lysosomal glucosidase deficiency, "acid maltase" deficiency): All organs, and die young of heart disease. Type III (Cori's disease, limit dextrin disease, de-branching enzyme deficiency); Rare, patients have liver storage problems. Type IV (branching enzyme deficiency): accumulation of abnormal glycogen in all organs, including the brain; death in infancy. Type V (McArdle's disease, muscle glycogen phosphorylase deficiency): Patients are poor athletes, and get bad cramps and muscle damage when they try. Glycogen is deposited beneath the sarcolemma. Type VI (liver glycogen phosphorylase deficiency): Big liver, hypoglycemia, mild disease. There are others.
Note: Copyrights: "The Pathology Guy" - Ed Friedlander MD. Reproduced with permission.
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