Clinical utility gene card for: Hypophosphatasia – update 2013

Mornet, Étienne; Hofmann, Christine; Bloch‐Zupan, Agnès; Girschick, Hermann; Merrer, Martine Le

doi:10.1038/ejhg.2013.177

Cited by 59 publications

(62 citation statements)

References 39 publications

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“…Depending on the age when HPP is diagnosed and the severity of disease, five clinical subtypes have been distinguished: perinatal (divided in perinatal lethal and prenatal benign), infantile, childhood, adult and odonto-HPP. 1 Prognosis is very poor in severe forms of HPP with most patients dying from respiratory failure. 2 Recently enzyme replacement therapy (ERT) has been reported to be efficient and improve the outcome in lifethreatening forms of HPP.…”

Section: Introductionmentioning

confidence: 99%

Unexpected high intrafamilial phenotypic variability observed in hypophosphatasia

et al. 2014

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Hypophosphatasia (HPP) is a clinically heterogeneous rare, inherited disorder of bone and mineral metabolism with extensive allelic heterogeneity in the ALPL gene. In this report, we present a family with heterozygous parents (maternal p.(Glu191Lys), paternal p.(Gly334Asp) mutations in the ALPL gene) and four children (one genotypically normal, one heterozygous carrier and two compound heterozygous) showing an unexpected high phenotypic variability. One of the compound heterozygous showed clinical symptoms of the mild childhood form mainly affecting the teeth. The other one was more seriously affected with severe failure to thrive, delayed motor development, need for oxygen supply and profound mineralization deficit compatible with an infantile form of HPP. Functional in vitro studies identified p.(Glu191Lys) as mild (68%, no dominant-negative effect) and p.(Gly334Asp) as severely affected allele (1.2%, dominant-negative effect). In vitro simulation of the children's genetic status showed a residual AP activity of 29%, while the biochemical AP activity in the serum was comparably reduced in both children (22 and 36 U/l). This family report indicates that mapping ALPL mutations within the gene does not necessarily help to predict the clinical severity of the phenotype. Therefore, results of prenatal diagnostics have to be interpreted with caution and prenatal genetic diagnosis and counseling for HPP should be provided within an experienced multidisciplinary team. Research about other confounding factors is urgently needed.

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Section: Introductionmentioning

confidence: 99%

Unexpected high intrafamilial phenotypic variability observed in hypophosphatasia

et al. 2014

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“…El gen tiene una alta heterogeneidad alélica y se han descrito más de 250 mutaciones. La mayoría son mutaciones sin sentido 2,5 .…”

Section: Etiologíaunclassified

“…De forma prenatal se debe tener en cuenta la osteogéne-sis imperfecta tipo II, displasia campomélica y condrodisplasias con defecto de la mineralización ósea que al nacimiento exteriormente son difíciles de identificar pero con las radiografías se logra. En la infancia y la niñez tener en cuenta los errores innatos del metabolismo energético, la acidemia orgánica, el raquitismo, la negligencia y trauma no accidental 5 .…”

Section: Diagnósticounclassified

Hipofosfatasia

Aragón¹,

Vélez²,

Gallego³

2016

rcslibre

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r e v i s t a c o l o m b i a n a salud libre 98Revista Colombiana Salud Libre. 2016; 11 (supl) ResumenLa hipofosfatasia es una enfermedad congénita caracterizada por una deficiencia de fosfatasa alcalina no específica de tejido, que genera una mineralización anormal del tejido óseo y dental. Las manifestaciones clínicas son variables, desde formas neonatales con alta mortalidad, hasta formas más leves del adulto con fracturas por fragilidad y osteomalacia. El diagnóstico bioquímico se basa en la determinación de valores séricos bajos de fosfatasa alcalina e incremento sérico o urinario de fosfoetanolamina, piridoxal 5'-fosfato y pirofosfato inorgánico. El tratamiento ha tenido resultados limitados. Dentro de estos se ha estudiado la administración de hormona paratiroidea en la hipofosfatasia del adulto y el tratamiento de sustitución enzimática con una forma soluble de fosfatasa alcalina recombinante humana en las formas clínicas más graves.Palabras clave: Fosfatasa alcalina, Hipofostasia, Raquitismo. AbstractHypophosphatasia is a congenital disorder characterized by a deficiency of non-specific alkaline phosphatase tissue, which generates an abnormal mineralization of bone and tooth tissue. The clinical manifestations are variable, from neonatal forms with high mortality, to milder forms of adult fragility fractures and osteomalacia. The biochemical diagnosis is based on the determination of low serum alkaline phosphatase and serum or increased urinary phosphoethanolamine, pyridoxal 5'-phosphate and inorganic pyrophosphate. The treatment has had limited results. Within these has studied the administration of parathyroid hormone in adult hypophosphatasia and enzyme replacement therapy with a soluble form of recombinant human alkaline phosphatase in the most severe clinical forms.

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“…With development of prenatal diagnosis through the use of echography, computed tomography, and genetic diagnosis, perinatal HPP can be correctly diagnosed in the fetus before birth. 48,49 To develop a fetal treatment for perinatal HPP, we previously examined the effect of transuterine intraperitoneal injection of an AAV vector harboring the TNALP-D 10 construct into fetal Akp2 -/-mice on day 15 of gestation. 18 The fetal treatment provided preferential transduction of growth plate chondrocytes by AAV vector in the epiphysis of the treated Akp2 -/-mice.…”

Section: Akp2mentioning

confidence: 99%