Case ReportFindings of amplitude-integrated electroencephalogram recordings and serum vitamin B6 metabolites in perinatal lethal hypophosphatasia during enzyme replacement therapy
Introduction
Hypophosphatasia (HPP) is an inborn error of metabolism marked by low serum tissue non-specific alkaline phosphatase (TNSALP) activity due to hypomorphic mutations in the ALPL gene [1]. TNSALP is necessary for bone mineralization and vitamin B6 metabolism [1]. Therefore, TNSALP hypoactivity results in skeletal hypoplasia and bone fracture due to hypo-mineralization of the bone and teeth. Moreover, TNSALP converts pyridoxal 5′ phosphate (PLP) into pyridoxal (PL), which can cross the brood-brain barrier, and regulates inhibitory neurotransmitter gamma-aminobutyric acid (GABA) [2]. Since pyridoxal phosphate acts as a coenzyme for the synthesis of GABA in the brain, the ALP hypoactivity results in a decrease of GABA secretion and of seizure threshold. Hence, functional disorder of TNSALP results in pyridoxine-responsive seizures.
Depending on the age of onset and clinical symptoms, HPP is classified into several subtypes. Perinatal lethal type, the severest form, presents severe respiratory and circulatory failure due to pulmonary hypoplasia and is frequently accompanied by pyridoxine-responsive seizures [3]. Therefore, a suitable method to manage the symptoms is brain monitoring with amplitude-integrated electroencephalogram (aEEG). Recently, enzyme replacement therapy has shown good results in HPP patients [4], [5]. In Japan, in August 2015, the therapeutic agent asfotase alfa was approved. There are few reports that describe the vitamin B6 metabolite status and seizure status of the patient before and after asfotase alfa administration. This information is needed to decide when to start and discontinue pyridoxine administration safely.
We report a case of perinatal lethal HPP treated with asfotase alfa and vitamin B6 for pyridoxine-responsive seizures, focusing on the findings of aEEG and the serial measurements of serum vitamin B6 metabolites.
Section snippets
Case report
The female patient was born at a gestational age of 37 weeks 2 days to a 32-year-old G3P3 mother. The birth weight was 2614 g. Both the parents were Japanese. There was no family history of consanguineous marriage. The patient’s father had a history of bone fracture of the upper arm, clavicle, and pelvis due to traffic accidents. The mother got natural pregnancy and underwent regular prenatal checkup. At the 30th week of pregnancy, the fetal echogram showed shortening of the femurs (−7.0 SD),
Genetic testing
The genetic testing for diagnosis of HPP was approved by the Institutional Review Board of Osaka Women’s and Children’s Hospital. The parents provided informed consent. By sequencing the ALPL gene in this patient, p.H341Q missense mutation of exon 10 was detected in one allele, which is same mutation with her father. This novel mutation is assumed to decrease ALP activity by evolutionary molecular analysis [7]. In the other allele, a frame shift mutation c.1559delT in exon 12 with complete loss
Discussion
Whyte et al. reported that 13 of 37 HPP patients who received asfotase alfa developed pyridoxine responsive seizures [4]. If subclinical seizures are included, there may be more patients who suffered seizures. In our case, aEEG monitoring revealed that electrical seizures can develop within 24 h after birth. The presentation of the seizure was subclinical, but it may be masked by sedative drugs and muscle relaxant. Therefore, it was difficult to recognize without aEEG monitoring. The aEEG
Conclusion
This case showed that aEEG monitoring was useful for early treatment intervention and safe pyridoxine withdrawal. Moreover, it also showed that perinatal HPP patients can present pyridoxine-responsive seizure even 24 h after birth. Enzyme replacement therapy changed the vitamin B6 metabolism and made it possible to discontinue pyridoxine in one month.
Acknowledgements
T. Michigami received honoraria for lecture fees from Alexion Pharma.
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2021, Brain and DevelopmentCitation Excerpt :Among pyridoxine-responsive epilepsies, hypophosphatasia appears to share similar seizure pathophysiology with IGDs since it involves a lack of PLP de-phosphorylation on the neuronal surface. However, previous studies have reported that patients with hypophosphatasia show a similar pyridoxine response to that of typical pyridoxine responsive epilepsy [23–25]. The mechanism underlying the slow response of IGDs to pyridoxine remains unclear.
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