Inborn Errors of Metabolism

Alkaptonuria (Garrod 1902) (OMIM citation 203500)
        Homogentisic Acid (formerly alkapton) accumulates in urine  black diapers
             dark (ochronic) pigment deposited in cartilage of nose & ears

        Alkaptonuria is a defect of homogentisic acid oxidase
            homogentisic acid accumulates in urine, blood, & cartilage
               phenotype results from build-up of substrates: not life-threatening
                 [Alkaptonuria provides an excellent example of Ascertainment Bias in human genetics]

              Garrod (1902) analyzed 'unit factors' & 'ferments' (cf. genes & enzymes) 
                     First analysis of a genetic trait in humans
                     (MGA2-Foundations of Genetics 8-1)  contrasts classical vs "reverse" genetics


Albinism (OMIM citation 203100)  AKA Oculocutaneous Albinism (OCA1)         
            Defect of tyrosine / DOPA metabolism

                melanin pigments not produced  unpigmented hair, skin, & iris

            Defective of tyrosinase in melanocytes
                tyrosinase in other organs unaffected (separate locus)
 

Sickle Cell Anemia (Neel & Beet 1949) (OMIM citation 603903)
             Defect of beta-globin subunit of hemoglobin tetramer
                 recall: two alpha + two beta chains
             One beta-chain allele inherited from each parent
                 protein tetramers occur in ratio 1 MM : 2 FM : 1 FF      [M = Mother, F = Father]
                 Both alleles are expressed in molecular phenotype:
                      call this "co-dominant" expression

            Standard hemoglobin has standard allele (A) for beta chain
                 Alternative allele (S) when homozygous (SS) produces sickle-cell anemia
                     crystallization of hemoglobin molecule as parallel fibers & consequent
                        "sickling" of red blood cells at low [O2]
                               causes an infarctive crisis
                     pleiotropic  effects include anemia & skeletal anomalies
                 Heterozygotes (AS) show "sickle-cell trait": mild anemia
                         25% of hemoglobins are SS:   AA & AS tetramers don't crystallize readily
                         Both alleles are expressed in disease phenotype

             [A mutation of the primary beta-globin gene DNA sequence]

Huntington Disease (AKA Huntington's Chorea) (OMIM citation 143100)
     Progressive, degenerative neural disorder; uncontrolled ("choreic") movements
     Late onset: first symptoms may not appear until after child-bearing years
         Biochemical indications ambiguous in early stages
         A genetic counseling ethical dilemma:
              Tiresias' Dilemma: 'It is but sorrow to be wise when wisdom profits not.'

    Very common in some pedigrees
        huntingtin protein [sic] has extra Gln residues at N-terminus
                                              due to poly-CAG at  5' end of gene
         poly-glutamine tract forms plaques on Central Nervous System
             Phenotypic effect is a consequence of the presence of huntingtin protein
                    in homozygotes and heterozygotes, irrespective of standard protein
             Huntington Disease therefore shows dominant expression:
                  Alleles with poly-CAG tract dominate non-poly-CAG alleles

    (Woody Guthrie had it: some of his tunes; Last thoughts on Woody Guthrie by Bob Dylan)

        [Poly-CAG a consequence of a slipped-mismatch mutation: see next section]
 

All text material 2013 by Steven M. Carr