Clinical Recommendation to the Diagnostics and Treatment of Hypophosphatasia in Children

Баранов, А. А.; Намазова-Баранова, Л. С.; Савостьянов, К. В.; Маргиева, Т. В.; Вишнёва, Е. А.; Яхяева, Г. Т.

doi:10.15690/pf.v13i6.1665

Cited by 5 publications

(5 citation statements)

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“…Сложности в диагностике гипофосфатазии В соответствии с международными и российскими клиническими рекомендациями по ведению пациентов с ГФФ, наличие клинических проявлений заболевания в сочетании со стойким снижением активности ЩФ является достаточным основанием для постановки диагноза [19,20].…”

Section: педиатрическая фармакология /2018/ том 15/ №unclassified

Neurological and Neurosurgical Aspects of Hypophosphatasia

Ivanov¹,

Satanin²,

Ким³

et al. 2018

Pediatr. farmakol.

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Hypophosphatasia is a rare hereditary progressive disease caused by a mutation in ALPL gene and characterized by low activity of alkaline phosphatase. Due to the disruption of the bone mineralization process, ricket-like deformations of the skeleton occur in the clinic picture more frequently but other systemic manifestations can be also observed as respiratory insufficiency, urinary tract damage, and neurological disorders. Seizures, delayed physical and psychomotor development, attention deficit disorder, muscle weakness, fatigue, intracranial hypertension associated with the development of craniosynostosis are revealed in these patients. The severity of the disease depends on age: the highest mortality is reported in younger patients, in perinatal and infantile forms of hypophosphatasia. Diagnosis is based on the identification of specific clinical manifestations: retardation of growth and development, skeletal deformities, pain in muscles and joints, premature tooth loss. In laboratory tests, a steady decrease in alkaline phosphatase level is detected taking into account age and sex specification. If possible, alkaline phosphatase substrates are measured: levels of pyridoxal-5-phosphate in the blood and phosphoethanolamine in urine are higher at low enzyme activity. Radiographs of long bones typically reveal characteristic ‘tongues’ of lucency projecting from growth plates into metaphyses, hypomineralization, osteopenia, various kinds of deformation. All patients with suspected hypophosphatasia should be consulted by a clinical geneticist and evaluated to identify possible mutation in the ALPL gene.

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Section: педиатрическая фармакология /2018/ том 15/ №unclassified

Neurological and Neurosurgical Aspects of Hypophosphatasia

Ivanov¹,

Satanin²,

Ким³

et al. 2018

Pediatr. farmakol.

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“…The most severe perinatal form of HPP manifests in utero or can be obviously diagnosed at birth based on profound skeletal hypomineralization, caput membraneceum, shorted and deformed limbs, and pyridoxine-dependent seizures. These patients have a very high risk of death in the first days of life due to the hypomineralization of the ribs, pulmonary hypoplasia, and asphyxia [ 11 ]. The infantile type is characterized by respiratory complications, total demineralization, skeletal deformities, and rickets, with symptoms present in the first six months of life [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

Clinical and Genetic Characteristics of Pediatric Patients with Hypophosphatasia in the Russian Population

Glotov

Savostyanov

Нагорнова

et al. 2022

IJMS

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(1) Hypophosphatasia (HPP) is a rare inherited disease caused by mutations (pathogenic variants) in the ALPL gene which encodes tissue-nonspecific alkaline phosphatase (TNSALP). HPP is characterized by impaired bone mineral metabolism due to the low enzymatic activity of TNSALP. Knowledge about the structure of the gene and the features and functions of various ALPL gene variants, taking into account population specificity, gives an understanding of the hereditary nature of the disease, and contributes to the diagnosis, prevention, and treatment of the disease. The purpose of the study was to describe the spectrum and analyze the functional features of the ALPL gene variants, considering various HPP subtypes and clinical symptoms in Russian children. (2) From 2014–2021, the study included the blood samples obtained from 1612 patients with reduced alkaline phosphatase activity. The patients underwent an examination with an assessment of their clinical symptoms and biochemical levels of TNSALP. DNA was isolated from dried blood spots (DBSs) or blood from the patients to search for mutations in the exons of the ALPL gene using Sanger sequencing. The PCR products were sequenced using a reagent BigDye Terminator 3.1 kit (Applied Biosystems). Statistical analysis was performed using the GraphPad Prism 8.01 software. (3) The most common clinical symptoms in Russian patients with HPP and two of its variants (n = 22) were bone disorders (75%), hypomyotonia (50%), and respiratory failure (50%). The heterozygous carriage of the causal variants of the ALPL gene was detected in 225 patients. A total of 2 variants were found in 27 patients. In this group (n = 27), we identified 28 unique variants of the ALPL gene, of which 75.0% were missense, 17.9% were frameshift, 3.6% were splicing variants, and 3.6% were duplications. A total of 39.3% (11/28) of the variants were pathogenic, with two variants being probably pathogenic, and 15 variants had unknown clinical significance (VUS). Among the VUS group, 28.6% of the variants (7/28) were discovered by us for the first time. The most common variants were c.571G > A (p.Glu191Lys) and c.1171del (Arg391Valfs*12), with frequencies of 48.2% (13/28) and 11% (3/28), respectively. It was found that the frequency of nonsense variants of the ALPL gene was higher (p < 0.0001) in patients with the perinatal form compared to the infantile and childhood forms of HPP. Additionally, the number of homozygotes in patients with the perinatal form exceeded (p < 0.01) the frequencies of these genotypes in children with infantile and childhood forms of HPP. On the contrary, the frequencies of the compound-heterozygous and heterozygous genotypes were higher (p < 0.01) in patients with infantile childhood HPP than in perinatal HPP. In the perinatal form, residual TNSALP activity was lower (p < 0.0005) in comparison to the infantile and childhood (p < 0.05) forms of HPP. At the same time, patients with the heterozygous and compound-heterozygous genotypes (mainly missense variants) of the ALPL gene had greater residual activity (of the TNSALP protein) regarding those homozygous patients who were carriers of the nonsense variants (deletions and duplications) of the ALPL gene. Residual TNSALP activity was lower (p < 0.0001) in patients with pathogenic variants encoding the amino acids from the active site and the calcium and crown domains in comparison with the nonspecific region of the protein.

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“…The prevalence of severe HPP forms is 1:300 000 in Europe and 1:100 000 in Canada . In Russia, the expected prevalence is 1:100 000 …”

Section: Introductionmentioning

confidence: 99%

Dental manifestations of hypophosphatasia in children and the effects of enzyme replacement therapy on dental status: A series of clinical cases

Kiselnikova

Vislobokova

Voinova

2020

Clinical Case Reports

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The most frequent dental signs of hypophosphatasia in children are premature loss of primary teeth, decrease in height of alveolar bone, and malocclusions. Enzyme replacement therapy with Asfotase alfa might be associated with stabilization of dental status. K E Y W O R D Sasfotase alfa, dental signs, enzyme replacement therapy, hypophosphatasia, premature loss of primary teeth 912 | KISELNIKOVA Et AL.

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Clinical Recommendation to the Diagnostics and Treatment of Hypophosphatasia in Children

Cited by 5 publications

References 1 publication

Neurological and Neurosurgical Aspects of Hypophosphatasia

Neurological and Neurosurgical Aspects of Hypophosphatasia

Clinical and Genetic Characteristics of Pediatric Patients with Hypophosphatasia in the Russian Population

Dental manifestations of hypophosphatasia in children and the effects of enzyme replacement therapy on dental status: A series of clinical cases

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