Sibling absence

Fatal infantile cytochrome c oxidase (CCO) deficiency is characterized by total absence of catalytic activity in skeletal muscle. This often occurs within the context of the Fanconi syndrome, or less commonly in association with a cardiomyopathy. Although the deficiency is global in skeletal muscle, with all fibers affected, only isolated scattered fibers show abnormal aggregations of mitochondria (ragged-red fibers). Multiple affected siblings within one family are frequently encountered and suggest autosomal recessive inheritance. The condition normally proves fatal before the age of six months and is characterized by worsening intractable lactic acidemia. 

A 20-year-old man has had no retinoblastomas but has produced two ofifepring with multiple retinoblastomas. In addition, his father had two retinoblastomas as a young child, and one of his siblings has had three retinoblastomas. What is the most likely explanation for the absence of retinoblastomas in this individual ... 

An absence of R-type binding protein has been reported in two adult siblings by Carmel and Herbert (C20). R-Type protein was virtually absent from their leukocytes and saliva, and as was expected they had very low levels of serum vitamin B12. The absence of the protein did not appear to have any adverse effects. Other members of this family have also been found to have an absence of, or very low levels of, R-protein (H26). There was no general deficiency of plasma glycoproteins in these patients and the amounts of thyroid binding globulin, thyroxine, ceruloplasmin, and transferrin were all normal. 

The discussed chemical transfomiations can be visualized in the coordi nates of current chemical potential values (see Figure 2.4a), where chemi cal potentials of components R, Pj, and P2 are the external parameters. While this is the case of the absence of common intermediates, an indirect influence of the second reaction on the first reaction is possible only when chemical potential iTp2 of compound P2 (its thermodynamic rush P2) is higher than the chemical potential of compound R (its thermodynamic rush R). When so, the consecutive reaction P2 — R Pi becomes pos sible, and this compound P2 can be involved as an additional substrate into the main reaction R — Pi. In the considered example, the phenomenon of conjugation of chemical processes is not observed. The conjuga tion takes place only in the presence of common intermediates for both channels of the transformations. 

The accumulation in blood and the excessive urinary excretion of orotic acid are postulated to result from the absence of either decarboxylase or the pyrophos-phorylase. These enzyme activities could not be directly assayed in the patient s tissues, but assays in the parents and two of the siblings indicated that the activities of both decarboxylase and phosphorylase were defective. In the patients described, the orotic aciduria and the megaloblastic anemia that it causes could be relieved by injecting nucleotides (cytidylic and uridylic acid). And in addition to its therapeutic significance, this observation also provides some invaluable information on the functioning of the pyrimidine metabolic pathway in vivo. 

Increased urinary formiminoglutamic acid in the absence of folic acid deficiency or cobalamine C disease is indicative of formiminotransferase deficiency. Accumulation of imidazolonepropionic acid is not observed, but there is an abnormal excretion of its oxidation product, hydantoin-5-pro-pionic acid. Loading tests with histidine will enhance the excretion. Confirmation of the defect is made by enzyme analysis probably the liver is the only suitable tissue. Affected patients were mentally retarded and/or had convulsions however, a number of healthy siblings with the biochemical abnormality have been described. 

The disease has been named after the isle of Tangier off the coast of Virginia where the first cases have been observed. It is characterized by the almost complete absence of high-density lipoproteins and storage of cholesterol and its esters in various tissues. The first observation concerned a five year old boy and his six year old sister. They had no further siblings. Further inquiries revealed that the parents were distantly related. Meanwhile two more affected families have been found in Missouri and Kentucky. The affected families are unrelated (Fredrickson et al. 1962, 1964). 

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