Clinical Consequences of Adults Presenting With hyPophOsphatasia With Special Focus on Gait, Bone micRosTRucture And cognITion: The PORTRAIT Study

Hypophosphatasia (HPP) is caused by mutations in the tissue non-specific alkaline phosphatase (TNSALP) gene with deficiency in TNSALP activity. This leads to accumulation of inorganic pyrophosphate, a potent inhibitor of bone mineralization, which causes rickets and osteomalacia, and of pyridoxal 5-phosphate (PLP) which causes seizures in neonates but no harm in adults. HPP is also associated with muscle weakness (which is very severe in perinatal and infantile forms) and early tooth loss. The most severe forms of HPP present in infancy, and were fatal until the recent development of TNSALP enzyme replacement therapy, Asfotase Alpha. Adult-onset HPP is less severe. It often presents with fractures of the femur or metatarsals, and so is likely to be misdiagnosed as osteoporosis. Correct diagnosis of HPP is important as the usual osteoporosis treatments, for example bisphosphonates, may be harmful and increase the risk of fracture.

High resolution peripheral quantitative computed tomography (HR-pQCT) is an imaging technique that allows the detailed assessment of BMD, microstructure and strength. HR-pQCT could reveal important information about the effects of HPP on bone microstructural properties.

HPP can also have a significant effect on physical functioning. In infantile HPP, motor function delay is usual but in adult-onset HPP effects on physical functioning are less apparent. These effects can be explored through the use of physical function testing and clinical gait analysis. Cognitive function may be affected by low levels of or inactivity of ALP in the neural tissue (TNALP). Patients with HPP have reported forgetfulness and 'fogginess'.

The aims of the study are to examine the effects of HPP on (i) bone structure and strength, (ii) physical functioning, (iii) cognition and (iv) quality of life (QoL). Researchers will study adults with HPP and healthy individuals. The results will help to determine if there should be a trial of a new drug treatment for adults with HPP. This study forms part of our wider programme of research into HPP.

Researchers will recruit 7 patients with childhood- or adult-presenting HPP (cases), who are known to the Metabolic Bone Clinic at the Metabolic Bone Centre (MBC), Northern General Hospital (NGH), Sheffield. Researchers will also recruit 7 healthy controls matched to the cases by gender and age. Researchers will approach first degree relatives (with their permission) of patients with HPP to offer them genetic testing for HPP. If HPP is confirmed, approach these first degree relatives to invite them to participate in the study, Fasting blood samples will be obtained for measurement of serum or plasma bone alkaline phosphatase (bone ALP), PLP, procollagen type I N-propeptide (PINP), C-terminal telopeptide (CTX) and genetic testing (if not already performed).