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Studies of a human low activity galactose-1-phosphate uridyl transferase variant
ABSTRACTS OF ANNUAL MEETING
1979 139
PRENATAL DIAGNOSIS OF LYSOSOMAL STORAGE DISEASES: A REVIEW OF 23 CASES
W. F. CAREY,P. V. NELSON & A. C. POLLARDDepartment of Chemical Pathology, The Adelaide Children’s Hospital During the pre3ous 2 yr, 23 pregnancies were monitored for the presence of 9 different lysosomal storage diseases. There were 3 possible cases of G M l gangliosidosis, 4 of GM2 gangliosidosis Type I and one of Type 11, 4 of glucosylceramidosis, 3 of sulphatide lipidosis, one of galactosylceramidosis, 2 of glycogen storage disease Type I I , 2 of mucolipidosis Type I1 and 3 of nephropathic cystinosis. Twelve foetuses were predicted to be homozygous affected and these pregnancies were terminated. Analysis of tissues (cultured fibroblasts, brain, liver, spleen) from 11 of these foetuses confirmed the prenatal diagnosis: one foetus was lost to biochemical follow-up. Of the remaining 11 pregnancies, one terminated spontaneously (4 wk after amniocentesis). Five children have been born and considered to be unaffected by the disease for which they were at risk both by clinical and biochemical evaluation: 5 further children have not yet been tested. In 22 cases cultured amniotic cells were used for the diagnosis and sufficient cells were grown to perform the analysis before the 20th wk of gestation. In one case of mucolipidosis Type 11, cells failed to proliferate in culture and cell free amniotic fluid was used for assay. It is concluded that the techniques currently employed for the above tests are diagnostic. Even so, a multidirectional approach to each diagnosis, bringing to bear all available technology in our laboratory, is still used to ensure that diagnostic errors are not made. STUDIES OF A HUMAN LOW ACTIVITY GALACTOSE-1-PHOSPHATE URIDYL TRANSFERASE VARIANT
I. c.T. LYON*,C. M. YOUNG*, B. TABAREKT & W.G. NGt
*Human Genetics Division, Department
of Community Health, School of Medicine, Auckland. New Zealand; tDivision of Medical Genetics, Children’s Hospital of Los Angeles, California, United States of America
A low activity galactose-1-phosphate uridyl transferase (GALT) variant in siblings has been demonstrated by biochemical studies on erythrocytes and cultured skin fibroblasts. The index case was identified during routine Beutler screening in the newborn period but was not clinically studied until y mth, when the child presented as normal in all respects. However, early biochemical studies showed a marked reduction in GALT, increased plasma and urinary galactose and substantial amounts of RBC galactose-1-phosphate. Extended studies of this child and a younger affected sibling have shown: (1) The RBC‘s contain ‘real’ but reduced GALT; (2) The cultured fibroblasts contain ‘real’ but reduced GALT; (3) On gel electrophoresis, the RBC GALT has similar mobility to the normal enzyme; (4) The RBC galactose-1-phosphate response to an oral galactose tolerance test is similar to that for a patient heterozygous for both Duarte and classical galactosaemia (DG); ( 5 ) During dietary restriction of galactose intake the RBC galactose-I-phosphate and the urinary excretion of galactitol is significantly lower than found in those homozygous for ‘classicalgalactosaemia’ (GG) under treatment; ( 6 ) The GALT in haemolysate appears to be more heat labile. Our present conclusion is that these children are heterozygotes for the classical galactosaemia gene and a ‘new variant’ (GG*). A NEW CLASSIFICATION OF OSTEOGENESIS IMPERFECTA
DAVICSILLENCE*, DAVIDRIMON*& DAVIDM. DANKST *Harbor-UCLA Medical Center, Torrance, California; ?Department of Paediatrics and Genetics Research Unit, Royal Children’s Hospital, Melbourne Osteogenesis Imperfecta is a group of genetic conditions leading to osteoporosis with varying degrees of liability to fractures. Some patients die at birth with severe deformity and numerous fractures while others have few or no fractures and survive a natural life span. Associated features in some but not all patients i.nclude blueness of the sclerae, presenile hearing loss, dentinogenesis irnperfecta, hyper-extensibility of the ligaments, and cardiovascular complications. Clinical, radiological and genetic studies have permitted the separation of at least 4 distinct syndromes. 0.1.type I is a dominantly inherited syndrome of liability to fractures with distinctly blue sclerae (which remain so throughout life) associated withpresenile hearing loss or a family history of otosclerotic hearing loss. 0.1. type I1 is an autosomal recessive syndrome of lethal perinatal 0.1.characterized by extreme hypoplasia of the skeleton with radiographic evidence at birth of crumpled long bones and continuously beaded ribs due to multiple fractures. 0.1. type 111 is an autosomal recessive syndrome, often with multiple fractures at birth, severe progressive type IV is a dominantly deformity of the skeleton and sclerae which are progressively less blue with age. 0.1.
1979 139
PRENATAL DIAGNOSIS OF LYSOSOMAL STORAGE DISEASES: A REVIEW OF 23 CASES
W. F. CAREY,P. V. NELSON & A. C. POLLARDDepartment of Chemical Pathology, The Adelaide Children’s Hospital During the pre3ous 2 yr, 23 pregnancies were monitored for the presence of 9 different lysosomal storage diseases. There were 3 possible cases of G M l gangliosidosis, 4 of GM2 gangliosidosis Type I and one of Type 11, 4 of glucosylceramidosis, 3 of sulphatide lipidosis, one of galactosylceramidosis, 2 of glycogen storage disease Type I I , 2 of mucolipidosis Type I1 and 3 of nephropathic cystinosis. Twelve foetuses were predicted to be homozygous affected and these pregnancies were terminated. Analysis of tissues (cultured fibroblasts, brain, liver, spleen) from 11 of these foetuses confirmed the prenatal diagnosis: one foetus was lost to biochemical follow-up. Of the remaining 11 pregnancies, one terminated spontaneously (4 wk after amniocentesis). Five children have been born and considered to be unaffected by the disease for which they were at risk both by clinical and biochemical evaluation: 5 further children have not yet been tested. In 22 cases cultured amniotic cells were used for the diagnosis and sufficient cells were grown to perform the analysis before the 20th wk of gestation. In one case of mucolipidosis Type 11, cells failed to proliferate in culture and cell free amniotic fluid was used for assay. It is concluded that the techniques currently employed for the above tests are diagnostic. Even so, a multidirectional approach to each diagnosis, bringing to bear all available technology in our laboratory, is still used to ensure that diagnostic errors are not made. STUDIES OF A HUMAN LOW ACTIVITY GALACTOSE-1-PHOSPHATE URIDYL TRANSFERASE VARIANT
I. c.T. LYON*,C. M. YOUNG*, B. TABAREKT & W.G. NGt
*Human Genetics Division, Department
of Community Health, School of Medicine, Auckland. New Zealand; tDivision of Medical Genetics, Children’s Hospital of Los Angeles, California, United States of America
A low activity galactose-1-phosphate uridyl transferase (GALT) variant in siblings has been demonstrated by biochemical studies on erythrocytes and cultured skin fibroblasts. The index case was identified during routine Beutler screening in the newborn period but was not clinically studied until y mth, when the child presented as normal in all respects. However, early biochemical studies showed a marked reduction in GALT, increased plasma and urinary galactose and substantial amounts of RBC galactose-1-phosphate. Extended studies of this child and a younger affected sibling have shown: (1) The RBC‘s contain ‘real’ but reduced GALT; (2) The cultured fibroblasts contain ‘real’ but reduced GALT; (3) On gel electrophoresis, the RBC GALT has similar mobility to the normal enzyme; (4) The RBC galactose-1-phosphate response to an oral galactose tolerance test is similar to that for a patient heterozygous for both Duarte and classical galactosaemia (DG); ( 5 ) During dietary restriction of galactose intake the RBC galactose-I-phosphate and the urinary excretion of galactitol is significantly lower than found in those homozygous for ‘classicalgalactosaemia’ (GG) under treatment; ( 6 ) The GALT in haemolysate appears to be more heat labile. Our present conclusion is that these children are heterozygotes for the classical galactosaemia gene and a ‘new variant’ (GG*). A NEW CLASSIFICATION OF OSTEOGENESIS IMPERFECTA
DAVICSILLENCE*, DAVIDRIMON*& DAVIDM. DANKST *Harbor-UCLA Medical Center, Torrance, California; ?Department of Paediatrics and Genetics Research Unit, Royal Children’s Hospital, Melbourne Osteogenesis Imperfecta is a group of genetic conditions leading to osteoporosis with varying degrees of liability to fractures. Some patients die at birth with severe deformity and numerous fractures while others have few or no fractures and survive a natural life span. Associated features in some but not all patients i.nclude blueness of the sclerae, presenile hearing loss, dentinogenesis irnperfecta, hyper-extensibility of the ligaments, and cardiovascular complications. Clinical, radiological and genetic studies have permitted the separation of at least 4 distinct syndromes. 0.1.type I is a dominantly inherited syndrome of liability to fractures with distinctly blue sclerae (which remain so throughout life) associated withpresenile hearing loss or a family history of otosclerotic hearing loss. 0.1. type I1 is an autosomal recessive syndrome of lethal perinatal 0.1.characterized by extreme hypoplasia of the skeleton with radiographic evidence at birth of crumpled long bones and continuously beaded ribs due to multiple fractures. 0.1. type 111 is an autosomal recessive syndrome, often with multiple fractures at birth, severe progressive type IV is a dominantly deformity of the skeleton and sclerae which are progressively less blue with age. 0.1.