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![Facial photos of our 10 patients. Note the closed distinct facial dysmorphism including wide palpebral fissures, arched eye brows, hypertelorism, broad nasal bridge, short prominent nose and tented upper lip. [Color figure can be viewed at wileyonlinelibrary.com]](profile/Mahmoud-Issa/publication/315833040/figure/fig2/AS:613200642985986@1523209834761/Facial-photos-of-our-10-patients-Note-the-closed-distinct-facial-dysmorphism-including.png)
Facial photos of our 10 patients. Note the closed distinct facial dysmorphism including wide palpebral fissures, arched eye brows, hypertelorism, broad nasal bridge, short prominent nose and tented upper lip. [Color figure can be viewed at wileyonlinelibrary.com]
Source publication
Background:
Hyperphosphatasia with mental retardation syndrome (HPMRS) is caused by recessive mutations in genes involved in the glycosylphosphatidylinsitol pathway, including PGAP3.
Materials and methods:
We describe 10 patients from 8 Egyptian families presenting with developmental delay, severe intellectual disability, distinct facial dysmorp...
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IntroductionSpinocerebellar ataxia type-3 (SCA3) is an adult-onset autosomal dominant neurodegenerative disease. It is caused by expanding of CAG repeat in ATXN3 gene that later on would affect brain structures. This brain changes could be evaluated using brain MRI volumetric. However, findings across published brain volumetric studies have been in...
Citations
... Hyperphoshphatasia with mental disorder (HPMRS) is referred to as Mabry syndrome, a rare autosomal recessive disease with a wide spectrum of phenotypic features including mental disability, seizures, increased alkaline phosphatase levels, brachytelephalangy, and coarse facial characteristics (wide nasal bridge, hypertelorism, tented narrow upper lip, and prolonged palpebral fssure) [4,5]. Tere are six diferent subclasses of HPMRS, and mutation in these genes afects the remodeling (PGAP2 and PGAP3) or synthesis (PIGO, PIGW, PIGY, and PIGV) of anchor proteins [6]. A mutation in post-GPI attachment to protein 3 (PGAP3) gene is linked with HPMRS type-4 that encodes a glycosylphosphatidylinositol (GPI)-specifc phospholipase, which is responsible for the synthesis of GPIanchored proteins (GPI-APs). ...
... A mutation in post-GPI attachment to protein 3 (PGAP3) gene is linked with HPMRS type-4 that encodes a glycosylphosphatidylinositol (GPI)-specifc phospholipase, which is responsible for the synthesis of GPIanchored proteins (GPI-APs). Several lines of evidence have reported the association between compound heterozygous or homozygous mutation with HPRMS type-4 [6][7][8][9]. ...
... MRI brain showed a thin corpus callosum with dilated lateral ventricles (Figure 1). A previous study by Abdel-Hamid et al. [6] reported abnormalities in the brain on an MRI scan for PGAP3 mutation. ...
Hyperphosphatasia with mental disorder (HPMRS) is a rare autosomal recessive disease caused by gene mutations in enzymes involved in the synthesis and remodeling of lipids. Seven-month-old boy diagnosed with bilateral glaucoma had a cleft palate, facial dysmorphism, hypertelorism, a broad nasal bridge, and large fleshy earlobes. A brain MRI scan also revealed brain abnormalities. The observed phenotype in a seven-month-old boy is in agreement with the phenotypic features of HPRMS type-4. Whole exome sequencing revealed a possible pathogenic variant of PGAP3 in a homozygous state (c.320C > T, p.Ser107Leu) which supported the diagnosis of HPRMS type-4. We report an unusual presentation for HPMRS and suggest adding this syndrome to the list of differential diagnoses of syndromic congenital glaucoma.
... Type of mutation Ethnicity Reference The most commonly reported clinical features of HPMRS are hypertelorism, upslanted palpebral fissures, broad nasal bridge, short nose, seizure disorder, long philtrum, and cleft-palate [3][4][5][6][7][8][9][10][11][15][16]. There are certain uncommon features that were reported in HPMRS4 such as gum hypertrophy, ear pits, and large anterior fontanelle [9]. ...
Hyperphosphatasia with mental retardation syndrome 4 (HPMRS4) is a rare autosomal recessive disorder caused by glycosylphosphatidylinositol (GPI) deficiency. GPI deficiency results from a mutation in one of six known genes. Mutation in post-GPI attachment to protein phospholipase 3 gene (PGAP3) is linked to HPMRS4. Patients usually present with dysmorphic features, developmental delay, central hypotonia, and seizure. However, in our case, we report a novel homozygous missense mutation of PGAP3 gene in a female child who presented with megalocornea, which is an unusual clinical presentation for HPMRS4. Megalocornea, in her first days of life, led to a misdiagnosis of primary congenital glaucoma. Later, other common clinical features of HPMRS4 became apparent.
... Focal seizures were always myoclonic, whereas generalized onset seizures were in 67% tonic-clonic, in 22% myoclonic, and 3 of the patients presented 3 unknown onset epilepsy (one tonic-clonic). The summary of symptoms is given below in Table 4 (28)(29)(30)(31)(32)(33)(34). ...
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.
... У пациентов с СМ описаны макроцефалия и микроцефалия, атрофия лобной доли головного мозга, гипотрофия мозолистого тела, мальформация Денди-Уокера [2,6,21,23,[27][28][29]. ...
The article presents a literature review of a rare congenital disease, hyperphosphatasia syndrome with mental retardation (Mabry's syndrome) in children. This syndrome is characterized by a triad of symptoms: hyperphosphatasia, epilepsy and mental retardation, often associated developmental defects. To date, 114 patients have been described. The review presents the available literary sources with clinical observations of patients since 1970, when the syndrome was first described by the pediatrician Ch. Mabry. The data on genetic defects leading to the disease are presented. The scheme of development of pyridoxine-sensitive epilepsy, the most severe manifestation of the syndrome, is described. The first clinical case of the patient with Mabry's syndrome in combination with Hirschsprung's disease in Russia is described.
... It has been found that RNASE1 has myocardial protective effect [43,44], however, the role of RNASE1 in tumors has not been paid much attention. Previous studies have demonstrated that mutation in PGAP3 is closely related to the occurrence of HPMRS (hyperphosphatasia with mental retardation syndrome) [45][46][47]. TACR2, also known as NK2R, is a G proteincoupled neurokinin receptor [48]. Tachykinin belongs to the neuropeptide family and is an effective regulator of smooth muscle function. ...
Background
Increasing studies have shown the important clinical role of immune and stromal cells in gastric cancer microenvironment. Based on information of immune and stromal cells in The Cancer Genome Atlas, this study aimed to construct a prognostic risk assessment model for gastric cancer.
Material/Methods
Based on the immune/structural scores, differentially expressed genes (DEGs) were filtered and analyzed. Afterwards, DEGs associated with prognosis were screened and the risk assessment model was constructed in the training set. Moreover, the validity of the model was verified both in the testing set and the overall sample.
Results
In this study, patients were divided into high-score and low-score groups based on immune/stromal score, and 919 DEGs were identified. By applying least absolute shrinkage and selection operator (LASSO) and Cox analysis, 10 mRNAs were selected to form a prognostic risk assessment model, risk score=(0.294*SLC17A9) + (−0.477*FERMT3) + (0.866*NRP1) + (0.350*MMRN1) + (0.381*RNASE1) + (0.189*TRIB3) + (0.230*PGAP3) + (0.087*MAGEA3) + (0.182*TACR2) + (0.368*CYP51A1). In the training set, the low-risk group divided by the model was found to have better overall survival, and the prediction efficiency of the model was demonstrated to be good. Multivariate Cox analysis indicated that the model could work as a prognostic factor independently. Similar results were shown in the testing group and overall patients cohort group. Finally, the risk assessment model and other clinical variables were integrated to construct a nomogram.
Conclusions
In general, this study constructs a prognostic risk assessment model for gastric cancer, which could improve the prognosis stratification of patients combined with other clinical indicators.
... Mutations in PGAP3 result in hyperphosphatasia with the mental retardation-4 disorder (HPMRS4, OMIM # 615716), a rare autosomal recessive neurologic disorder characterized by structural brain anomalies, severely delayed psychomotor development, mental retardation, hypotonia, seizures, lack of speech acquisition, and dysmorphic facial features. To date, less than 50 patients have been reported worldwide [2][3][4], typically presenting with brain anomalies, including a thin corpus callosum, abnormalities in the periventricular zones, ventriculomegaly, cerebellar hypoplasia, and white matter loss [2,5,6]. One of the hallmarks of HPMRS4 is agenesis or hypoplasia of the corpus callosum affecting the connection between the right and left cerebral hemispheres of the brain [3,7]. ...
... Thus far, all reported HPMRS4 patients presented with hypotonia, developmental delay, and intellectual disability, while >50% of these patients have seizures and brain malformations. These reported brain anomalies include thin corpus callosum, dilated ventricles [1], cerebellar vermis hypoplasia, cortical dysplasia, and Dandy-Walker malformation [42], cerebellar vermis hypoplasia, and a mild ventriculomegaly [5], brain atrophy of the temporal lobes, mega cisterna magna, and small capsula interna [43]. More anomalies were as well reported by Pagnementa et al. [44] in a family with PGAP3 mutations-MRI detected a mild variant of Dandy-Walker malformation. ...
Recessive mutations in Post-GPI attachment to proteins 3 (PGAP3) cause the rare neurological disorder hyperphosphatasia with mental retardation syndrome 4 type (HPMRS4). Here, we report a novel homozygous nonsense mutation in PGAP3 (c.265C>T-p.Gln89*), in a 3-year-old boy with unique novel clinical features. These include decreased intrauterine fetal movements, dysgenesis of the corpus callosum, olfactory bulb agenesis, dysmorphic features, cleft palate, left ear constriction, global developmental delay, and hypotonia. The zebrafish functional modeling of PGAP3 loss resulted in HPMRS4-like features, including structural brain abnormalities, dysmorphic cranial and facial features, hypotonia, and seizure-like behavior. Remarkably, morphants displayed defective neural tube formation during the early stages of nervous system development, affecting brain morphogenesis. The significant aberrant midbrain and hindbrain formation demonstrated by separation of the left and right tectal ventricles, defects in the cerebellar corpus, and caudal hindbrain formation disrupted oligodendrocytes expression leading to shorter motor neurons axons. Assessment of zebrafish neuromuscular responses revealed epileptic-like movements at early development, followed by seizure-like behavior, loss of touch response, and hypotonia, mimicking the clinical phenotype human patients. Altogether, we report a novel pathogenic PGAP3 variant associated with unique phenotypic hallmarks, which may be related to the gene’s novel role in brain morphogenesis and neuronal wiring.
... Hyperphosphatasia with mental retardation syndrome (HPMRS) (OMIM # 239300) was first described in 1970, and was later designated as Mabry Syndrome [4,17]. Typical facial dysmorphic signs such as cleft palate, intellectual disability, cardiac abnormalities, and brachytelephalangy are frequently described in affected individuals [1,11,15]. Elevated serum levels of alkaline phosphatase (ALP) have been recorded in several patients [1,8]. ...
... Typical facial dysmorphic signs such as cleft palate, intellectual disability, cardiac abnormalities, and brachytelephalangy are frequently described in affected individuals [1,11,15]. Elevated serum levels of alkaline phosphatase (ALP) have been recorded in several patients [1,8]. ...
... To date, only 16 pathogenic PGAP3 mutations have been identified in patients with HPMRS [1,2,12,14,20,21,24,26]. Ten out of the 16 mutations are in exon 3 and exon 7 which are considered hotspots for mutations. ...
Background:
Hyperphosphatasia with mental retardation syndrome (HPMRS) is a recessive disorder characterized by high blood levels of alkaline phosphatase together with typical dysmorphic signs such as cleft palate, intellectual disability, cardiac abnormalities, and developmental delay. Genes involved in the glycosylphosphatidylinositol pathway and known to be mutated in HPMRS have never been characterized in the Lebanese population.
Case presentation:
Herein, we describe a pair of monozygotic twins presenting with severe intellectual disability, distinct facial dysmorphism, developmental delay, and increased alkaline phosphatase level. Two individuals underwent whole exome sequencing followed by Sanger sequencing to confirm the co-segregation of the mutation in the consanguineous family. A biallelic loss of function mutation in PGAP3 was detected. Both patients were homozygous for the c.203delC (p.C68LfsX88) mutation and the parents were carriers confirming the founder effect of the mutation. High ALP serum levels confirmed the molecular diagnosis.
Conclusion:
Our findings have illustrated the genomic profile of PGAP3-related HPMRS which is essential for targeted molecular and genetic testing. Moreover, we found previously unreported clinical findings such as hypodontia and skin hyperpigmentation. These features, together with the novel mutation expand the phenotypic and genotypic spectrum of this rare recessive disorder.
... To date, 15 mutations in PGAP3 have been reported in 30 patients with HPMRS 4 (Figure 1b). 7,8,[11][12][13][14][15] More than half of the mutations (9/15; 60%) are in exon 3 and exon 7, and these regions are considered hotspots for mutations. 13,14 The mutation identified in our proband is also located within this hotspot in exon 3. ...
... 7,8,[11][12][13][14][15] More than half of the mutations (9/15; 60%) are in exon 3 and exon 7, and these regions are considered hotspots for mutations. 13,14 The mutation identified in our proband is also located within this hotspot in exon 3. ...
... However, while brachytelephalangy has never been reported in HPMRS4 caused by the PGAP3 mutation, broad fingers and toenails have been reported in some patients with the PGAP3 mutation. 7,8,[11][12][13][14][15] This finding indicates that the PGAP3 mutation can cause brachytelephalangy, as the other types of HPMRS. ...
Biallelic mutations in the post-GPI attachment to proteins 3 (PGAP3) gene cause hyperphosphatasia with mental retardation syndrome 4 (HPMRS4), which is characterized by elevated serum alkaline phosphatase, severe psychomotor developmental delay, seizures, and facial dysmorphism. To date, 15 PGAP3 mutations have been reported in humans. Here we report a novel homozygous PGAP3 mutation (c.314C>A, p.Pro105Gln) in a Croatian patient and fully describe the clinical features.
... Psychomotor delay, ID, and variable AP elevation are the only consistent features of all individuals with pathogenic mutations in PIGV [9,[28][29][30][31][32][33][34], PIGO [7,16,17,31,[35][36][37], PGAP2 [4,8,18,38], PGAP3 [5,19,[39][40][41], and PIGY [6]. Speech development, especially expressive language, is more severely affected than motor skills in the majority of the affected individuals (Table 1). ...
... Cleft palate is the malformation with the highest frequency in the group of affected individuals with PGAP3 mutations with a prevalence of almost 60%, whereas other malformations are rarely observed. Exceptional is a group of ten Egyptian individuals with the same founder mutation and a high incidence of structural brain anomalies (thin corpus callosum (8/10), vermis hypoplasia (4/10), ventriculomegaly (3/10), and Dandy-Walker malformation (1/10)) [39]. To date these are the few individuals with a presumably complete loss of function for this gene (NM_033419.3:c.402dupC, ...
... We therefore evaluated the area under the receiver operating characteristics curve (AUC) and found the correct gene prediction more often than randomly expected, including PIGV versus PGAP3 (Additional file 1: Figure S3). The differences in pair-wise comparison between PIGV and PGAP3 could be confounded by the large number of Egyptian cases in the PGAP3 cohort [39], the effect of which we could not further analyze due to the limited set of patient photos. ...
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.
Crohn’s disease (CD) is regarded as a lifelong progressive disease affecting all segments of the intestinal tract and multiple organs. Based on genome-wide association studies (GWAS) and gene expression data, transcriptome-wide association studies (TWAS) can help identify susceptibility genes associated with pathogenesis and disease behavior. In this review, we overview seven reported TWASs of CD, summarize their study designs, and discuss the key methods and steps used in TWAS, which affect the prioritization of susceptibility genes. This article summarized the screening of tissue-specific susceptibility genes for CD, and discussed the reported potential pathological mechanisms of overlapping susceptibility genes related to CD in a certain tissue type. We observed that ileal lipid-related metabolism and colonic extracellular vesicles may be involved in the pathogenesis of CD by performing GO pathway enrichment analysis for susceptibility genes. We further pointed the low reproducibility of TWAS associated with CD and discussed the reasons for these issues, strategies for solving them. In the future, more TWAS are needed to be designed into large-scale, unified cohorts, unified analysis pipelines, and fully classified databases of expression trait loci.
