Mild forms of hypophosphatasia mostly result from dominant negative effect of severe alleles or from compound heterozygosity for severe and moderate alleles

Fauvert, Delphine; Brun-Heath, Isabelle; Lia-Baldini, Anne-Sophie; Bellazi, Linda; Taillandier, A.; Serre, Jean‐Louis; Mazancourt, Philippe de; Mornet, Étienne

doi:10.1186/1471-2350-10-51

Cited by 127 publications

(138 citation statements)

References 28 publications

Supporting

Mentioning

117

Contrasting

Unclassified

Order By: Relevance

“…7 It occurs with a high frequency (up to 55%) in HPP patients with European ancestry. 7,8 In our in vitro testing, this moderate mutation resulted in 68% WT AP enzyme activity and it has no dominant-negative effect. The paternal mutation p.(Gly334Asp) has been found previously in homozygous Mennonite patients with the perinatal lethal form.…”

Section: Enzymatic Activity Of Ap Mutantsmentioning

confidence: 79%

“…It can also be noticed that the penetrance of dominant HPP is incomplete and very variable so that recessive genotypes including a dominant mutation may also undergo variable expressivity. 8 Nevertheless, carriers especially of a dominant-negative mutation may develop relevant clinical problems in later life and therefore should be followed by an experienced multidisciplinary team.…”

Section: Enzymatic Activity Of Ap Mutantsmentioning

confidence: 99%

See 1 more Smart Citation

Unexpected high intrafamilial phenotypic variability observed in hypophosphatasia

et al. 2014

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Enzymatic Activity Of Ap Mutantsmentioning

confidence: 79%

Section: Enzymatic Activity Of Ap Mutantsmentioning

confidence: 99%

Unexpected high intrafamilial phenotypic variability observed in hypophosphatasia

et al. 2014

Self Cite

View full text Add to dashboard Cite

show abstract

“…26,33,34 In trials not placebo-controlled, an anti-inflammatory treatment using NSAIDs resulted in a significant improvement of physical activity, a reduction in pain-related complaints and normalisation of prostaglandin (PG) levels. 26 After drug withdrawal, the positive effect persisted for another [3][4][5][6] weeks. NSAID treatment was safe and should be considered in patients with significant complaints about pain.…”

Section: Prognosis (Please Describe)mentioning

confidence: 99%

Clinical utility gene card for: Hypophosphatasia – update 2013

et al. 2013

Self Cite

View full text Add to dashboard Cite

“…Наиболее тяжелые формы наследуются аутосомно-рецессивным пу-тем, при более легких формах может иметь место и доминантный тип наследования [6,7,11]. У транс-генных мышей с гомозиготной мутацией гена ALPL активность ЩФ практически полностью отсутство-вала (менее 1%), а у гетерозигот снижена на 50% [12].…”

Section: Discussionunclassified

Hypophosphatasia: the clinical description of 3 cases of the disease with the molecular-genetic verification of the diagnosis

Kulikova¹,

Kalinchenko

Калинченко³

et al. 2015

Probl Endokrinol (Mosk)

View full text Add to dashboard Cite

Гипофосфатазия -редкое наследственное рахитоподобное заболевание, обусловленное снижением активности тка-ненеспецифической щелочной фосфатазы, кодируемой геном ALPL. Различают несколько форм данного заболевания в зависимости от тяжести течения и возраста манифестации. Основными клиническими признаками гипофосфатазии являются рахитические деформации костей скелета, мышечная гипотония и дыхательная недостаточность в раннем дет-ском возрасте, задержка физического и моторного развития, раннее выпадение зубов. В зрелом возрасте наблюдаются стресс-переломы, мышечные боли, кальцификация связок и суставов. Биохимическими маркерами патологии служат сниженный уровень щелочной фосфатазы, повышенное содержание фосфоэтаноламина в моче; при тяжелых формах заболевания -гиперкальциемия, гиперфосфатемия, снижения уровня паратгормона. Приведено клиническое описание пациентов с гипофосфатазией различной тяжести, у которых впервые в России проведена молекулярно-генетическая верификация диагноза.

show abstract

Mild forms of hypophosphatasia mostly result from dominant negative effect of severe alleles or from compound heterozygosity for severe and moderate alleles

Cited by 127 publications

References 28 publications

Unexpected high intrafamilial phenotypic variability observed in hypophosphatasia

Unexpected high intrafamilial phenotypic variability observed in hypophosphatasia

Clinical utility gene card for: Hypophosphatasia – update 2013

Hypophosphatasia: the clinical description of 3 cases of the disease with the molecular-genetic verification of the diagnosis

Contact Info

Product

Resources

About