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Transformative therapy in hypophosphatasia
  1. Nick Bishop1,
  2. Craig F Munns2,3,
  3. Keiichi Ozono4
  1. 1Department of Human Metabolism, University of Sheffield, Sheffield, UK
  2. 2Department of Endocrinology, The Children's Hospital at Westmead, Westmead, New South Wales, Australia
  3. 3Department of Paediatrics and Child Health, University of Sydney, Sydney, New South Wales, Australia
  4. 4Department of Pediatrics, Osaka University, Graduate School of Medicine, Suita, Osaka, Japan
  1. Correspondence to Dr Nick Bishop, Department of Human Metabolism, University of Sheffield, Sheffield S10 2TH, UK; n.j.bishop{at}

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Hypophosphatasia (HPP) is a rare, potentially life-threatening disease characterised by hypomineralisation of bones and teeth.1 The fundamental defect is reduced functional activity of the enzyme tissue-nonspecific alkaline phosphatase (usually just termed alkaline phosphatase [ALP] in clinical practice). Homozygous or compound heterozygous mutations in the ALPL gene result in the most severe phenotypes of HPP. However, dominant negative effects can also be observed when a single heterozygous mutation affects the binding site(s) of the ALP homodimer. ALP catabolises inorganic pyrophosphate (PPi), an inhibitor of bone mineralisation, and pyridoxal 5′-phosphate (PLP; major form of vitamin B6), allowing pyridoxal to cross the blood–brain barrier and enter pathways leading to neurotransmitter synthesis.

There are six clinical forms of HPP, four of which have clear relevance in paediatric practice—perinatal, benign prenatal, infantile and juvenile HPP. In some instances the adult form has unrecognised paediatric onset, while odonto-HPP simply affects the teeth.1 Bone-targeted enzyme-replacement therapy (ERT) with asfotase alfa (administered subcutaneously 3–6 times per week) is now available, having recently been approved in several regions. For those presenting early in life, such treatment has been shown to reduce mortality during the first year of life from ∼97% in perinatally presenting cases and close to 60% in cases presenting later in infancy to ∼10% overall.

In contrast to many other disorders treated with ERT, there is no accumulation of toxic metabolites. Thus, with ERT, many of the …

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