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Characterization of glycosylphosphatidylinositol biosynthesis defects by clinical features, flow cytometry, and automated image analysis.

ABSTRACT: BACKGROUND:Glycosylphosphatidylinositol biosynthesis defects (GPIBDs) cause a group of phenotypically overlapping recessive syndromes with intellectual disability, for which pathogenic mutations have been described in 16 genes of the corresponding molecular pathway. An elevated serum activity of alkaline phosphatase (AP), a GPI-linked enzyme, has been used to assign GPIBDs to the phenotypic series of hyperphosphatasia with mental retardation syndrome (HPMRS) and to distinguish them from another subset of GPIBDs, termed multiple congenital anomalies hypotonia seizures syndrome (MCAHS). However, the increasing number of individuals with a GPIBD shows that hyperphosphatasia is a variable feature that is not ideal for a clinical classification. METHODS:We studied the discriminatory power of multiple GPI-linked substrates that were assessed by flow cytometry in blood cells and fibroblasts of 39 and 14 individuals with a GPIBD, respectively. On the phenotypic level, we evaluated the frequency of occurrence of clinical symptoms and analyzed the performance of computer-assisted image analysis of the facial gestalt in 91 individuals. RESULTS:We found that certain malformations such as Morbus Hirschsprung and diaphragmatic defects are more likely to be associated with particular gene defects (PIGV, PGAP3, PIGN). However, especially at the severe end of the clinical spectrum of HPMRS, there is a high phenotypic overlap with MCAHS. Elevation of AP has also been documented in some of the individuals with MCAHS, namely those with PIGA mutations. Although the impairment of GPI-linked substrates is supposed to play the key role in the pathophysiology of GPIBDs, we could not observe gene-specific profiles for flow cytometric markers or a correlation between their cell surface levels and the severity of the phenotype. In contrast, it was facial recognition software that achieved the highest accuracy in predicting the disease-causing gene in a GPIBD. CONCLUSIONS:Due to the overlapping clinical spectrum of both HPMRS and MCAHS in the majority of affected individuals, the elevation of AP and the reduced surface levels of GPI-linked markers in both groups, a common classification as GPIBDs is recommended. The effectiveness of computer-assisted gestalt analysis for the correct gene inference in a GPIBD and probably beyond is remarkable and illustrates how the information contained in human faces is pivotal in the delineation of genetic entities.

SUBMITTER: Knaus A

PROVIDER: S-EPMC5759841 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Characterization of glycosylphosphatidylinositol biosynthesis defects by clinical features, flow cytometry, and automated image analysis.

Knaus Alexej A Pantel Jean Tori JT Pendziwiat Manuela M Hajjir Nurulhuda N Zhao Max M Hsieh Tzung-Chien TC Schubach Max M Gurovich Yaron Y Fleischer Nicole N Jäger Marten M Köhler Sebastian S Muhle Hiltrud H Korff Christian C Møller Rikke S RS Bayat Allan A Calvas Patrick P Chassaing Nicolas N Warren Hannah H Skinner Steven S Louie Raymond R Evers Christina C Bohn Marc M Christen Hans-Jürgen HJ van den Born Myrthe M Obersztyn Ewa E Charzewska Agnieszka A Endziniene Milda M Kortüm Fanny F Brown Natasha N Robinson Peter N PN Schelhaas Helenius J HJ Weber Yvonne Y Helbig Ingo I Mundlos Stefan S Horn Denise D Krawitz Peter M PM

Genome medicine 20180109 1

<h4>Background</h4>Glycosylphosphatidylinositol biosynthesis defects (GPIBDs) cause a group of phenotypically overlapping recessive syndromes with intellectual disability, for which pathogenic mutations have been described in 16 genes of the corresponding molecular pathway. An elevated serum activity of alkaline phosphatase (AP), a GPI-linked enzyme, has been used to assign GPIBDs to the phenotypic series of hyperphosphatasia with mental retardation syndrome (HPMRS) and to distinguish them from ...[more]

PMID: 29310717

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Project description:Background: Mutations of genes involved in the synthesis of glycosylphosphatidylinositol and glycosylphosphatidylinositol-anchored proteins lead to rare syndromes called glycosylphosphatidylinositol-anchored proteins biosynthesis defects. Alterations of their structure and function in these disorders impair often fundamental processes in cells, resulting in severe clinical image. This study aimed to provide a systematic review of GPIBD cases reports published in English-language literature. Methods: The browsing of open-access databases (PubMed, PubMed Central. and Medline) was conducted, followed by statistical analysis of gathered information concerning neurological symptomatology. The inclusion criteria were: studies on humans, age at onset (<18 y.o.), and report of GPIBD cases with adequate data on the genetic background and symptomatology. Exclusion criteria were: publication type (manuscripts, personal communication, review articles); reports of cases of GPI biosynthesis genes mutations in terms of other disorders; reports of GPIBD cases concentrating on non-neurological symptoms; or articles concentrating solely on the genetic issues of GPI biosynthesis. Risk of bias was assessed using Joanna Brigs Institute Critical Appraisal Checklists. Data synthesis was conducted using STATISTICA 13.3.721.1 (StatSoft Polska Sp. z.o.o.). Used tests were chi-square, Fisher's exact test (for differences in phenotype), and Mann-Whitney U test (for differences in onset of developmental delay). Results: Browsing returned a total of 973 articles which, after ruling out the repetitions and assessing the inclusion and exclusion criteria, led to final inclusion of 77 articles (337 GPIBD cases) in the analysis. The main outcomes were prevalence of neurological symptoms, onset and semiology of seizures and their response to treatment, and onset of developmental delay. Based on this data a synthesis of phenotypical differences between the groups of GPIBD cases and the general GPIBD cases population was made. Discussion: A synthetical analysis of neurological components in clinical image of GPIBD patients was presented. It highlights the main features of these disorders, which might be useful in clinical practice for consideration in differential diagnosis with children presenting with early-onset seizures and developmental delay. The limitation of this review is the scarcity of the specific data in some reports, concerning the semiology and onset of two main features of GPIBD.

Dataset Information

Characterization of glycosylphosphatidylinositol biosynthesis defects by clinical features, flow cytometry, and automated image analysis.

Publications

Characterization of glycosylphosphatidylinositol biosynthesis defects by clinical features, flow cytometry, and automated image analysis.

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