P.F. Benson

REVERSAL OF CLINICAL FEATURES OF HURLER'S DISEASE AND BIOCHEMICAL IMPROVEMENT AFTER TREATMENT BY BONE-MARROW TRANSPLANTATION

Abstract A one-year-old boy with type I H mucopoly saccharidosis (Hurlers disease) was given a bone-marrow transplant (BMT) from his mother in an attempt to replace the deficient enzyme, alpha-L-iduronidase (iduronidase). There is definite evidence of engraftment, the enzyme activity of the recipients leucocytes reaching heterozygote levels within 37 days of the BMT. Graft-versus-host disease (GVHD) developed but was partially controlled by steroids. From 3-4 months after graft until the present (13 months after the graft) iduronidase activity has been present in the serum and the urine and there has been evidence of considerable degradation of glycosaminoglycans excreted in the urine. The hepatosplenomegaly has disappeared, corneal clouding has cleared, and deterioration in the childs development seems to have been arrested.

Enzyme replacement therapy by fibroblast transplantation in a case of Hunter syndrome

SUPPLEMENTATION of deficient enzymes essential for complete catabolism of glycosaminoglycans (GAG) has been used with limited success in several types of mucopolysaccharidosis1–4. The beneficial effects and concomitant changes in urinary GAG after this form of treatment, however, have been only transient, presumably because of the short life in vivo of the enzymes involved5–7. Because of this limitation, we recently tried, by means of skin transplantation, to provide a more permanent source of corrective enzymes in a patient with Hunter syndrome8. Although two HLA antigens from each donor were incompatible with those of the patient and both grafts had been visibly rejected within 3 months, there was a marked increase in breakdown and excretion of GAG subsequent to treatment, which lasted for more than 9 months. In addition, the activity of Hunter corrective enzyme isolated from the patients urine, was also significantly increased. We attributed the effectiveness of the skin transplant to the release of Hunter corrective factor by donor cells and its uptake by host cells, in a manner analogous to that described for fibroblasts in vitro9–11. We have now attempted to increase further both the effectiveness and longevity of replacement therapy, using fully histocompatible skin fibroblasts injected sub-cutaneously as a source of corrective enzyme. An advantage of this procedure is that surgery is not required and it would in principle be applicable to other genetic deficiency diseases of lysosomal enzymes.

Fibroblast phosphodiesterase deficiency in Niemann-Pick disease.

Abstract Cultured skin fibroblasts from patients with Niemann-Pick disease types A and B were found to have diminished activity towards the synthetic substrates bis(4-methylumbelliferyl) pyrophosphate diester and bis(4-methylumbelliferyl) phosphate. Fibroblasts from a patient with Niemann-Pick disease type C exhibited less diminished activity. No reduction in activity was found towards bis(p-nitrophenyl) phosphate in types A, B or C fibroblasts. Maximum deficiency in types A and B fibroblasts was towards bis(4-methylumbelliferyl) pyrophosphate diester at pH 5.0, no deficiency being found at pH 7.2, either in the presence or absence of Mg++ and cysteine.

A rapid method for assay of branched-chain keto acid decarboxylation in cultured cells and its application to prenatal diagnosis of maple syrup urine disease.

A sensitive assay for measurement of branched-chain keto acid decarboxylation in small numbers of fibroblasts or amniotic cells grown in the wells of a microtitre plate using [1-14C]leucine as substrate is described. The method was applied to the amniotic cells from a pregnancy at risk for maple syrup urine disease and a heterozygous fetus predicted.

Lumbar kyphosis in Hunter's disease (MPS II)

Although radiological involvement of the lower dorsal and upper lumbar vertebrae is common in the severe form of Hunters disease (MPS II), there are reports in the literature that clinical kyphosis does not occur. We report a boy with marked clinical kyphosis in whom the diagnosis of MPS II was proved by demonstrating a severe deficiency of serum and leucocyte iduronate‐sulphate sulphatase and an accelerated incorporation of radiosulphate into his cultured fibroblast glycosaminoglycans, which could not be corrected by the product of other typed reference MPS II cells. The existence of several other genetic diseases, sometimes complicated by kyphosis, was excluded by assay of fibroblast lysosomal enzymes.

Letter to the Editor: Effectiveness of HLA-Compatible Fibroblasts for Enzyme Replacement Therapy in the Mucopolysaccharidoses

Letter to the Editor: Effectiveness of HLA-Compatible Fibroblasts for Enzyme Replacement Therapy in the Mucopolysaccharidoses

POLIOMYELITIS ANTIBODY TITRES IN CHILDREN AND EFFECT OF LIVE AND INACTIVATED POLIOVACCINE

Abstract A survey of 228 children aged between three and six years revealed that there was no demonstrable antibody to poliovirus type I in 14%, to type II in 2%, and to type III in 7%. In a second investigation to compare the serological response evoked by a dose of inactivated or live poliomyelitis vaccine at this age, both vaccines stimulated antibody production in children who did not already possess antibody. In those children with pre-existing circulating antibody, inactivated vaccine produced a response in almost every child, but many of the children did not respond to live vaccine. The reason for this failure requires further examination.

Prenatal diagnosis of galactosaemia in six pregnancies -- possible complications with rare alleles of the galactose 1-phosphate uridyl transferase locus.

We describe our experience in prenatal diagnosis of six foetuses at risk for galactosaemia. In one family the parents were both shown to be double heterozygotes at the galactose 1‐phosphate uridyl transferase (Gal‐PUT) locus, the mother having a Duarte Suppl.Los Angeles and the father a Duarte Suppl.galactosaemia genotype. The foetus (and an older brother previously thought to have classical galactosaemia) was also a Duarte/galactosaemia double heterozygote. In the other five families, the parents and three foetuses were heterozygous carriers of the galactosaemia gene, one of the foetuses had galactosaemia, and one was homozygous for the normal gene. It is concluded that by a combination of family studies and assay of cultured amniotic cell Gal‐PUT, accurate prediction of the foetal Gal‐PUT genotype is now possible.

GESTATIONAL AGE AT TERMINATION OF PREGNANCY ON MEDICAL INDICATIONS

our experience as a regional genetics center could be of interest to those concerned with the gestational age at the termination of pregnancies for medical reasons. Here there are 4 sets of indications for termination--neural tube defects, unbalanced chromosome disorders, serious and untreatable X-linked disorders, and grave and incurable inborn errors of metabolism. Most determinations for neural tube defects are performed earlier than those for chromosome abnormalities because the alpha fetoproteins assay is done directly on the fluid, while tissue culture and cytology are lengthy procedures. Specific biochemical errors can be quickly identified in those cases where tests can be done directly on the fluid or be based on modest numbers of amniotic cells, but when the specific tests require a large number of cultured cells, a long time lag may be involved. The figures show not what happens under theoretically ideal circumstances, but the real life pattern which emerges in the face of such variables as womans booking habits, amniocentesis failure, culture failure, and the need for repeat amniocentesis.