Bone Abstracts (2013) 2 P8 | DOI: 10.1530/boneabs.2.P8

Compound heterozygosity of two functional null mutations in the ALPL gene associated with deleterious neurological outcome in an infant with hypophosphatasia

Christine Hofmann1, Johannes Liese1, Hermann Girschick2, Franz Jakob3 & Birgit Mentrup3


1Children’s Hospital, University of Würzburg, Würzburg, Germany; 2Children’s Hospital, Vivantes Hospital im Friedrichshain, Berlin, Germany; 3Orthopedic Department, Orthopedic Center for Musculoskeletal Research, University of Würzburg, Würzburg, Germany.


Background: Hypophosphatasia (HPP) is a heterogeneous rare, inherited disorder of bone and mineral metabolism caused by different mutations in the ALPL gene encoding the isoenzyme, tissue-nonspecific alkaline phosphatase (TNAP). Prognosis is very poor in severe perinatal forms with most patients dying from pulmonary complications of their skeletal disease. TNAP, a ubiquitous enzyme, is mostly known for its role in bone mineralization. TNAP deficiency, however, may also result in neurological symptoms such as neonatal seizures. The exact biological role of TNAP in the human brain is still not known and the pathophysiology of neurological symptoms due to TNAP deficiency in HPP are not understood in detail.

Presenting problem and clinical management: In this report, we describe the clinical features and functional studies of a patient with severe perinatal HPP which presented with rapidly progressive encephalopathy caused by new compound heterozygous mutations in the ALPL gene which result in a functional ALPL ‘knock out’, demonstrated in vitro. In contrast, an in vitro simulation of the genetic status of his currently asymptomatic parents who are both heterozygous for one mutation, showed a residual in vitro AP activity of above 50%. Interestingly, in our patient, the fatal outcome was due to progressive encephalopathy which was refractory to antiepileptic therapy including pyridoxine, rather than hypomineralization and respiratory insufficiency often seen in HPP patients. The patient`s cranial MRI showed progressive cystic degradation of the white matter and nearly complete destruction of the cerebrum. To our knowledge, this is the first MRI-based report of a deleterious neurological clinical outcome due to a progressive encephalopathy in an infant harboring a functional human ALPL ‘knock out’.

Conclusion: This clinical course of disease suggests that TNAP is involved in development and may be responsible for multiple functions of the human brain. According to our data, a certain amount of residual TNAP activity might be mandatory for normal CNS function in newborns and early childhood.

Funding: CH received a scholarship from the Interdisciplinary Centre for Clinical Research IZKF Wuerzburg, Germany, B Mentrup is supported by Bundesministerium für Bildung und Forschung BMBF, Berlin, Germany. J Liese and C Hofmann received a study grant for a phase two study on Asfotase alpha treatment for severe forms of HPP.

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