Hypophosphatasia is a rare disease characterized by low serum levels of tissue non-specific alkaline phosphatase (TNSALP) and a spectrum of skeletal disease varying from the severest form with death in utero to mild with no clinical abnormality in adults. Currently, the diagnosis of hypophosphatasia is made on the basis of clinical findings, radiography, low serum alkaline phosphatase levels and raised abnormal phosphorylated metabolites; there are elevations in serum pyridoxal 5′-phosphate, urinary phosphoethanolamine and inorganic pyrophosphate. In borderline cases the biochemical diagnosis remains uncertain. Prenatally, diagnosis is made using radiography and ultrasonography together with chorionic villus tissue biopsy, in which TNSALP levels are measured using an antibody-based assay. Since hypophosphatasia results from mutations in the TNSALP gene we have, for the first time in two U.K. families, undertaken restriction fragment length polymorphism (RFLP) analysis using three intragenic RFLPs for BclI and MspI at the ALPL locus. One family was informative, and a mutant-allele-specific haplotype with respect to three RFLPs was defined. In the other family the disease was shown to segregate with one allele of the BclI RFLP, but the MspI RFLPs were not informative. The disease segregated in the two families with different alleles of the BclI RFLP, suggesting that the mutations are likely to be different. We confirm that DNA analysis is likely to be the way ahead for diagnosing hypophosphatasia, and that standardized screening methods need to be developed for detecting mutations in these and other families.
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June 01 1999
Hypophosphatasia: diagnostic application of linked DNA markers in the dominantly inherited adult form
S. J. IQBAL;
*Department of Chemical Pathology, Leicester Royal Infirmary, Leicester LE1 5WW, U.K.
Correspondence: Dr S. J. Iqbal.
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D. S. PLAHA;
D. S. PLAHA
†Leicestershire Genetics Centre, Leicester Royal Infirmary, Leicester LE1 5WW, U.K.
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G. H. LINFORTH;
G. H. LINFORTH
‡Department of Genetics, University of Leicester, LeicesterLE1 7RH, U.K.
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R. DALGLEISH
R. DALGLEISH
‡Department of Genetics, University of Leicester, LeicesterLE1 7RH, U.K.
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Publisher: Portland Press Ltd
Received:
October 05 1998
Revision Received:
March 10 1999
Accepted:
April 01 1999
Online ISSN: 1470-8736
Print ISSN: 0143-5221
The Biochemical Society and the Medical Research Society © 1999
1999
Clin Sci (Lond) (1999) 97 (1): 73–78.
Article history
Received:
October 05 1998
Revision Received:
March 10 1999
Accepted:
April 01 1999
Citation
S. J. IQBAL, D. S. PLAHA, G. H. LINFORTH, R. DALGLEISH; Hypophosphatasia: diagnostic application of linked DNA markers in the dominantly inherited adult form. Clin Sci (Lond) 1 July 1999; 97 (1): 73–78. doi: https://doi.org/10.1042/cs0970073
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