Neurological Symptoms of Hypophosphatasia

Abstract

Hypophosphatasia (HPP) is a bone metabolic disorder caused by mutations in the liver/bone/kidney alkaline phosphatase gene (ALPL), which encodes tissue-nonspecific alkaline phosphatase (TNAP). This disease is characterized by disrupted bone and tooth mineralization, and reduced serum AP activity. Along with bone and tooth symptoms, many neurological symptoms, seizure, encephalopathy, intracranial hypertension, mental retardation, deafness, and growth hormone deficiency (GHD), are frequently found in HPP patients. Seizure occurs in severe HPP types soon after birth, and responds to pyridoxine, but is an indicator of lethal prognosis. Encephalopathy rarely presents in severe HPP types, but has severe sequelae. Intracranial hypertension complicated in mild HPP types develops after the age of 1 year and sometimes need neurosurgical intervention. Mental retardation, deafness and GHD are more frequently found in Japanese HPP patients. Mental retardation occurs in all HPP types. Deafness in perinatal lethal type is both conductive and sensorineural. GHD develops in all but perinatal lethal type and the diagnosis tends to delay. The pathogenesis of these neural features of HPP might be due to impairment of both vitamin B6 metabolism and central nervous system development by ALPL mutations.

A homozygous missense variant in the alkaline phosphatase gene ALPL is associated with a severe form of canine hypophosphatasia

“…The earlier onset disease progressed to owner-elected euthanasia before 3 weeks of age due to seizures and failure to thrive (litters 2 and 3), whereas the other form became apparent after one month of age and developed into a generalized ossification defect (litter 1). In humans, seizures have been described in perinatal and infantile HPP and they serve as a strong indicator for a lethal outcome 58 . The underlying cause of the neonatal seizures is not well understood.…”

Identification of altered brain metabolites associated with TNAP activity in a mouse model of hypophosphatasia using untargeted NMR‐based metabolomics analysis

“…The severe forms of HPP often present with seizures, apnea, deafness, and encephalopathy (Hofmann et al . ; Taketani ). These disorders were initially considered to be consequences of deficient TNAP activity in other tissues, especially bone tissue in which TNAP plays an essential role in mineralization.…”

“…; Taillandier et al . ; Taketani ) and from mice in which TNAP gene function has been ablated (Waymire et al . ; Narisawa et al .…”

Neurological and Neurosurgical Aspects of Hypophosphatasia

“…1): поражаются многие системы и органы, в большинстве случаев преобладают нарушение минерализации костной ткани с развитием остеопении/ остеопороза со склонностью к переломам, деформации костей и поражение зубочелюстной системы с потерей зубов [1]. Педиатрам малоизвестно, что в клинической картине гипофосфатазии, особенно при перинатальной и инфантильной формах, ведущими могут стать неврологические нарушения, что затрудняет диагностику и своевременное начало лечения [2].…”

“…Развитие эпилептических приступов у пациентов с ГФФ прогностически является крайне неблагоприятным признаком: так, до появления специфической терапии все пациенты погибали в возрасте до 18 мес жизни [2].…”