Short CommunicationInfantile hypophosphatasia without bone deformities presenting with severe pyridoxine-resistant seizures
Introduction
Hypophosphatasia (HPP) is a recessively inherited disease caused by a generalized deficiency of the “tissue-nonspecific” alkaline phosphatase (TNSALP), due to inactivating mutations in ALPL [1]. The biochemical hallmark is reduced activity of serum alkaline phosphatase (ALP), resulting in accumulation of phosphoethanolamine and pyridoxal 5′-phosphate (PLP) [1], [2]. In the normal situation plasma TNSALP converts PLP to pyridoxal that crosses the blood–brain barrier. Brain cells convert pyridoxal back to PLP, an essential cofactor for multiple enzyme reactions [3].
Six clinical phenotypes of HPP have been defined: perinatal, prenatal benign, infantile, childhood, adult onset, and odontohypophosphatasia [4]. In the first 6 months of life infantile HPP patients may develop respiratory insufficiency, seizures, widespread bone demineralization, premature craniosynostosis and rickets in the physis. Approximately 50% of the patients die within one year from respiratory failure caused by undermineralization of the ribs [5], [6].
We report an infant with an exceptional neurological presentation of the infantile form consisting of severe therapy-resistant seizures without bone deformities.
Section snippets
Patient
The boy, first child of healthy non-consanguineous Caucasian parents, was born at 38 weeks (2705 g, 5th percentile), with APGAR scores 6/9/9 at 1, 5, and 10 min respectively.
At day 3 he presented with generalized seizures, poorly responding to phenobarbital and midazolam. All routine laboratory parameters were normal with exception of an extremely low serum alkaline phosphatase (< 5 IU/l, controls: 50–400 IU/l). Elevated plasma and urine phosphoethanolamine confirmed hypophosphatasia. Mutation
Discussion
The absence of bone deformities combined with the prominent neurological presentation are a highly unusual presentation of HPP. The origin of neonatal seizures in HPP is still unclear. Baumgartner-Sigl et al. have speculated on the role of pyridoxine in the development of seizures [7]. Peripheral TNSALP hydrolyses PLP, and forms PL that crosses the blood–brain barrier to be re-phosphorylated to PLP at the cell membrane of the brain cells. The seizures are usually treated with pyridoxine, but as
Acknowledgment
The mutation analysis was performed by Etienne Mornet PhD., Unite de Genetique Constitutionnelle, Centre Hospitalier de Versailles, Laboratoire SESEP. France.
References (13)
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Cited by (24)
A step closer in defining glycosylphosphatidylinositol anchored proteins role in health and glycosylation disorders
2018, Molecular Genetics and Metabolism ReportsCitation Excerpt :Patients with hypophosphatasia, caused by mutations in TNAP gene, present high PLP in plasma across childhood [24]. Infantile presentation is clinically associated with PLP dependent-seizures and biochemically with high plasma and cerebrospinal fluid PLP levels [25, 26]. This abnormal distribution could be explained by a normal maternal-dependent trans-placental B6 transport but deficient cellular uptake.
Hypophosphatasia
2018, Metabolism: Clinical and ExperimentalCitation Excerpt :Radiographs show widespread demineralization and rachitic changes in the metaphyses. Hypercalcemia is also present, explaining a history of irritability, poor feeding, anorexia, vomiting, polydypsia, polyuria, dehydration, constipation, hypotonia and, more rarely, vitamin B6-dependent seizures that may occur even before skeletal signs [6,7] and are linked to a poor prognosis. Increased excretion of calcium may lead to renal damage.
Infantile hypophosphatasia combined with vitamin B6-responsive seizures and reticular formation lesions on magnetic resonance imaging: A case report
2018, Brain and DevelopmentCitation Excerpt :de Roo et al. reported the head MRI findings of infants with HPP-related seizures. They detected changes in the dorsolateral medulla oblongata and lemniscus medias [12]. The reticular formation changes seen in our case might have been caused by encephalopathy due to seizures or a lack of vitamin B6 in the central nervous system, and could also help to explain why infantile HPP patients tend to develop severe respiratory failure.
Systemic Manifestations in Pyridox(am)ine 5′-Phosphate Oxidase Deficiency
2017, Pediatric NeurologyCitation Excerpt :To cross the blood-brain barrier, circulating P5P must first be dephosphorylated to pyridoxine by alkaline phosphatase. The effects of a failure of this process are exemplified by the autosomal recessive disorder hypophosphatasia, in which there is a deficiency in the production or function of alkaline phosphatase resulting in CSF pyridoxine deficiency.17-19 For this reason, hypophosphatasia has been associated with pyridoxine-dependent seizures.20,21
Neuromuscular features of hypophosphatasia
2017, Archives de PediatrieCitation Excerpt :ALPL is strongly expressed in the developing nervous system in mice and primates [10]. Moreover, brain imaging of children with HPP has evidenced various abnormalities such as cerebral atrophy, ventricular dilatation, low density of the white matter, polycystic encephalopathy and cortical laminar necrosis [11,12]. In mice in which the murine gene for ALPL (Akp2-KO) has been knocked out, thinner spinal nerves, hypomyelinization, axons of smaller caliber and delayed cerebral cortex synapse maturation have been evidenced [13,14].
Pyridoxine-Dependent Epilepsy: An Expanding Clinical Spectrum
2016, Pediatric NeurologyCitation Excerpt :The missense mutation, p.E399Q in exon 14, occurs in various populations and accounts for about 30% of published alleles.11,23,60 If biochemical/molecular analyses are negative, then other genetic causes of pyridoxine-responsive seizures should be considered, including (but not limited to) pyridoxamine 5-′-phosphate oxidase deficiency (MIM# 610090)61 and hypophosphatasia due to alkaline phosphatase deficiency (MIM #241500).62 The wide range of clinical presentations of pyridoxine-dependent epilepsy that hamper diagnostic recognition of this treatable neurometabolic disorder supports further development of a reliable and affordable method of newborn screening (e.g., via determination of α-AASA/P6C in blood spots63), followed by a pilot study to enable timely identification and immediate initiation of treatment to optimize patient outcomes.