Park S. Gerald

Tyrosinemia with plantar and palmar keratosis and keratitis

An 111/2-year-old boy, born of a consanguineous marriage, had mental retardation, painful plantar and palmar keratosis, and dendritic keratitis associated with tyrosinemia, p-hydroxyphenylpyruvicaciduria, p-hydroxylaceticaciduria, and p-hydroxyphenylaceticaciduria. Liver and renal functions were within normal ranges, and vitamin C loading did not correct the metabolic abnormalities. Maintenance on a low-tyrosine, low-phenylalanine diet was associated with resolution of the epithelial lesions and a decrease in the metabolic abnormalities. Four other patients with similar metabolic abnormalitiers may have had this clinical syndrome.

Chapter 18 Induction of Mammalian Somatic Cell Hybridization by Polyethylene Glycol1

Publisher Summary This chapter discusses the induction of mammalian somatic cell hybridization by polyethylene glycol (PEG). The hybridization of somatic cells is a technique for the study of the organization and regulation of the mammalian genome. PEG induces mammalian cell hybridization and procedures have been developed for treating cells with PEG that are simple, rapid, and effective. The chapter outlines experiments to optimize the conditions of PEG-induced hybridization of cells attached in monolayers. Among the parameters considered were: (1) PEG molecular weight, (2) PEG concentration, (3) cell density, (4) pH, (5) length of exposure to PEG, (6) temperature, (7) volume of residual medium at the time of PEG addition, and (8) the method of removing the PEG. The experience with PEG-induced hybridization of cells in suspension is less extensive than with cells in monolayer; however a simple procedure giving consistent success with certain cell combinations has been developed. Although only a few variables have been examined for hybridization in suspension, it seems apparent that the principles established with monolayer fusions cannot be extrapolated to suspension fusions without some modification.

Infantile autism associated with the Fragile-X syndrome

A 6-year-old mentally retarded child presented with a clinical picture consistent with the diagnosis of childhood autism. Chromosomal studies revealed a male karyotype with approximately 11% of the cells counted containing a fragile site on the X chromosome. The possibility of a syndrome of autism occurring in children with the Fragile-X syndrome is discussed.

DNA polymorphism of the C4 genes. A new marker for analysis of the major histocompatibility complex

Polymorphisms of the proteins encoded by genes that lie within the major histocompatibility complex (MHC) have served as useful markers for organ transplantation and in genetic analysis of a large number of MHC-linked diseases. To extend the range of MHC polymorphic markers, we used a complementary-DNA probe specific for the fourth component of human complement (C4) to identify a new variant within the MHC. Polymorphic variants at the DNA level were detected among subjects with identical phenotypes of the corresponding protein. C4 genomic polymorphisms are inherited with the segment of the short arm of chromosome 6 that carries the HLA-DR and complement loci. The autosomal codominant mode of inheritance of this genetic marker and its utility for evaluation of 21-hydroxylase-deficiency congenital adrenal hyperplasia, one of the many MHC-linked diseases, were established.

Clinical and chromosomal studies of the 18q- syndrome.

Six patients with partial deletion of the long arm of chromosome No. 18 are described. The characteristic features of this syndrome include typical facies with reduced prominence of the midface region, prominent antihelix, “carp-shaped” mouth, nystagmus, funduscopic abnormalities, generalized hypotonia, congenital vertical tali, increased number of whorls on the fingertips, atretic or stenotic auditory canals, hearing loss, and mental retardation. In one family, a pericentric inversion of chromosome No. 18 was present in the father and several siblings of the propositus and was believed to be the cause of the deletion in the propositus. Two of the 5 patients examined for immune globulins had abnormally low levels of IgA.

EXTENDED MHC HAPLOTYPES IN 21-HYDROXYLASE-DEFICIENCY CONGENITAL ADRENAL HYPERPLASIA: SHARED GENOTYPES IN UNRELATED PATIENTS

HLA, complement, and glyoxalase I alleles were studied in 29 families in which at least one member has classical 21-hydroxylase-deficiency congenital adrenal hyperplasia. A rare complement allele, C4B*31, was found in over 20% of the haplotypes defined in these families and was always part of the complement haplotype BF*F, C2*C, C4A*Q0, C4B*31 (abbreviated FCO,31). The haplotype containing this rare set of complement alleles always carried the rare HLA allele, HLA-Bw47, usually carried HLA-A3, and almost always had the alleles HLA-Cw6, HLA-DR7, and the glyoxalase I (GLO) allele GLO1. Thus over 20% of the haplotypes in the population studied contained all or almost all of the rare extended haplotype HLA-(A3), Bw47, Cw6,DR7, FCO,31, GLO 1. 3 other haplotypes were each found twice in unrelated patients concordant for their disease phenotype and ethnic background. Extended MHC haplotypes may be markers for different genetic mutations causing 21-hydroxylase deficiency.

Identification of the abnormal polypeptide chain of haemoglobin GIb

The analyses of known haemoglobin mixtures in starch gel have been compared using borate, phosphate, and the discontinuous tris citrate-borate buffers. Hybrid haemoglobins formed during the neutralization of acid dissociated mixtures of appropriate haemoglobins may be detected using either alkaline phosphate or the discontinuous systems. The dissociation and recombination of Hb-G Ib with Hb-S produces Hb-A and a doubly abnormal haemoglobin migrating near the position of Hb-C. Hb-J Tr gives no new haemoglobin species when hybridized with Hb-S which has abnormal β -chains, but in contrast an additional haemoglobin zone appears in the position of Hb-A when Hb-J Tr is hybridized with Hb-G Ib . These experiments suggest that Hb-G Ib has abnormal α-chains and that in the hybridization with Hb-J Tr both Hb-A and another doubly abnormal haemoglobin whose net charge is similar to that of Hb-A are formed. Hb-G Ib , is therefore different from Hb-G Sa which has abnormal β -chains. It is postulated that Hb-G 2 is the naturally occurring hybrid of HbG Ib and Hb-A 2 .

Heterogeneity of ciliary morphology in the immotile-cilia syndrome in man.

Detailed ultrastructural analysis of the respiratory cilia of three male patients with the immotile-cilia syndrome is presented. They all had similar clinical manifestations, namely, situs inversus totalis, repeated respiratory infections, and sinusitis. The respiratory cilia, however, of these patients showed a variety of structural abnormalities some of which are described for the first time. In the cilia of the first patient both the dynein arms were lacking, and, almost 40% of the cilia had one to nine supernumerary microtubules peripheral to the nine outer doublets. The cilia of the second patient showed an absence of inner dynein arms, unusually prominent outer dynein arms, a spoke defect in 46% of cilia examined, and no morphologically detectable nexin links. The cilia of the last patient lacked both dynein arms but, in contrast to the first two patients, showed virtually no microtubular abnormalities. These patients demonstrate that a variety of structural abnormalities in respiratory cilia can result in virtually identical clinical manifestations.

Methylmalonyl Coenzyme A Racemase Defect: Another Cause of Methylmalonic Aciduria

Extract: Metabolism of 14C-propionate and methylmalonate was severely curtailed in fibro-blasts cultured from an infant with massive transient hyperammonemia (1370

Inherited Electrophoretic Hemoglobin Patterns among 20 Inbred Strains of Mice

mUg/100 ml), severe metabolic acidosis, and excretion of large amounts of methylmalonic acid (580 mg at 24°). Metabolism of succinate was normal.Metabolism of methylmalonate was not enhanced by the addition of excessive amounts of the cofactor, 5′-deoxyadenosylcobalamin (DBCC). The DBCG content of the liver was within normal limits.Homogenates of liver and fibroblasts metabolized methylmalonate approximately one-half as well as control samples when tritiated racemic methylmalonyl coenzyme A (CoA) was added. Inasmuch as L-methylmalonyl-CoA and not D-methylmalonyl-CoA is the substrate for the enzyme, methylmalonyl-CoA mutase, which converts L-methylmalonyl-CoA to succinyl-CoA, this indicates that the mutase was intact.Mitochondrial homogenate from liver, in contrast to normal samples, did not incorporate tritium during the metabolism of synthetic methylmalonyl-CoA, which indicates that activity of racemase was deficient.Activities of the urea cycle enzymes were low but not rate limiting.Speculation: A diet low in isoleucine, threonine, methionine, and valine may offer a rational therapeutic approach to other affected patients. The hyperammonemia observed resembles that reported in propionyl-CoA carboxylase deficiency and Reyes syndrome, which raises the possibility of a common denominator in these several disorders.