Open AccessLethal Encephalopathy in an Infant with Hypophosphatasia despite Enzyme Replacement Therapy
Author(s) -
Adalbert Raimann,
Christine Haberler,
Janina Patsch,
Diana-Alexandra Ertl,
Kambis Sadeghi,
Michael Freilinger,
Susanna Lang,
Maria T. Schmook,
Barbara Plecko,
Gabriele Haeusler
Publication year - 2021
Publication title -
hormone research in paediatrics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.816
H-Index - 89
eISSN - 1663-2826
pISSN - 1663-2818
DOI - 10.1159/000520341
Subject(s) - hypophosphatasia , enzyme replacement therapy , encephalopathy , medicine , neonatal encephalopathy , alkaline phosphatase , pathology , pediatrics , endocrinology , disease , biology , enzyme , biochemistry
Hypophosphatasia (HPP) is an inborn error of metabolism caused by loss-of-function mutations in the biomineralization-associated alkaline phosphatase gene, encoding tissue-nonspecific alkaline phosphatase (TNSALP). Symptoms include skeletal hypomineralization and extra-skeletal manifestations such as pyridoxine (B6)-responsive seizures due to impaired cerebral B6 passage. Since the introduction of enzyme replacement therapy (ERT), skeletal manifestations and B6-responsive seizures were reported to improve significantly. Nevertheless, there is an increasing evidence of B6-independent neurological manifestation of HPP including HPP-associated encephalopathy. Here, we present for the first time the brain alterations of an infant with neonatal HPP who died of neurological complications at the age of 5 months despite early initiation of ERT. CSF analysis showed normal concentrations of biogenic amines reflecting sufficient intracellular B6 availability. Postmortem histopathology revealed severe, localized affection of the cerebral cortex including cortical lesions in layers 2 and 3 in direct proximity to TNSALP-expressing neurons and hippocampal sclerosis. Our findings confirm that TNSALP deficiency may lead to a severe encephalopathy. We hypothesize that HPP-associated encephalopathy resistant to currently available ERT may develop in addition and probably independently of typical B6-responsive seizures in some patients. Prospective, controlled studies with close neurological follow-up including brain imaging are needed to identify patients at risk for severe neurological symptoms despite ERT.