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Title: Identification of adult hypophosphatasia
Author: Nicklin, Philip
ISNI:       0000 0004 8506 5224
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2020
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Serum PLP, the circulatory form of vitamin B6 is a substrate of the enzyme alkaline phosphatase (ALP). In adult hypophosphatasia (HPP), mutation of the ALPL gene leads to deficient ALP activity and accumulation of PLP.Four tested factors (inflammation, reduced kidney function, low ALP, and vitamin B6 supplementation) are associated with significant differences in PLP. PLP is lower in cases of inflammation and reduced kidney function, and higher in cases of low ALP and vitamin B6 supplementation. In a representative U.S. population sample, PLP levels are significantly different based on age and gender, and race. Reference intervals have been reported that are stratified to reflect these differences, following the exclusion of factors known to confound PLP.In a U.K. population PLP levels are gender dependent and different in lean compared to obese individuals. 95% reference intervals are reported for PLP, BAP and a novel formation marker ratio (BAP:PINP).Biochemical indicators of HPP including low BAP, elevated PLP, and low BAP:PINP ratio were present in 23 of 679 subjects from a metabolic bone clinic cohort. These subjects were younger than subjects with biochemical indicators within the normal range. Mutations associated with HPP were observed in 7 of these subjects (1% of the study population), including 3 novel mutations. Subjects with a mutation display a wide range of clinical symptoms including: foot fractures, femoral fractures, vertebral fractures, stress fractures, chronic pain, and dental abnormalities. There is no observed genotype-phenotype correlation in adult HPP; clinical symptoms of adult HPP are more severe in women. The symptomatic variability of HPP is high. 100% displayed musculoskeletal pain or weakness, 50% had dental problems and 50% had mental health problems. The fracture prevalence (71.4%) was higher than the general population. 86% of patients had a gene mutation and the average time to diagnosis was 13.4 years.
Supervisor: Eastell, Richard Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available