Inborn Errors of Metabolism

Online Mendelian Inheritance in Man (OMIM)

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
                     Contrasts of 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 sickling phenotype

                  A mutation of the primary beta-globin gene DNA sequence

Huntington Disease (formerly 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 [sic] protein
                    in homozygotes and heterozygotes, irrespective of standard protein
             Huntington Disease therefore shows dominant expression:
                  Alleles with poly-CAG tract dominate expression of 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 ©2024 by Steven M. Carr