Hyperphosphatasia With Mental Retardation Syndrome Research Articles

Two South African patients with PGAP3-related Mabry syndrome with unusually low alkaline phosphatase levels


 
 
 
 Hyperphosphatasia with mental retardation syndrome (HPMRS), also known as Mabry syndrome, is an autosomal recessive disease that is associated with inherited glycosylphosphatidylinositol (GPI) deficiencies. This genetically heterogeneous disorder can be caused by variants in seven genes that encode molecules of the glycosylphosphatidylinositol (GPI)-anchor biosynthesis pathway, namely PIGL, PIGO, PIGV, PIGW, PIGY, PGAP2 and PGAP3. Recently, a pathogenic variant in PGAP3 was identified in 3 unrelated South African patients with HMPRS. Here, two further patients with the exact variant in PGAP3 are described. Classically, HMPRS is associated with elevated alkaline phosphatase (ALP) levels. Interestingly, these two patients had unusually low ALP levels at initial presentation. This is an important observation, as the ALP level is often used as a screening test to decide whether to proceed to confirmatory genetic testing. These patients illustrate that in PGAP3-related Mabry syndrome, ALP levels can be low, albeit a rare finding. Hence, a high suspicion for the disorder should be maintained in patients with typical facial dysmorphic features and severe neurodevelopmental delay, even in the absence of elevated ALP.
 
 
 

50 Years Ago in TheJournal ofPediatrics: Familial Hyperphosphatasia with Mental Retardation, Seizures, and Neurologic Deficits

Mabry C, Bautista A, Kirk RFH, Dublilier LD, Braunstein H, Koepke JA. J Pediatr 1970;77:74-85. Mabry et al reported the first 4 patients with hyperphosphatasia with mental retardation syndrome (HPMRS) to present with generalized seizures and facial dysmorphism. The syndrome can be distinguished from other developmental disabilities by the stable elevation of alkaline phosphatase without bone disease.1Thompson M.D. Nezarati M.M. Gillessen-Kaesbach G. Meinecke P. Mendoza-Londono R. Mornet E. et al.Hyperphosphatasia with seizures, neurologic deficit, and characteristic facial features: five new patients with Mabry syndrome.Am J Med Genet A. 2010; 152A: 1661-1669Crossref PubMed Scopus (36) Google Scholar Few published reports of the syndrome appeared before we identified a patient whose seizures responded to pyridoxine.2Cole D.E. Thompson M.D. Neurogenic aspects of Mabry syndrome.Subcell Biochem. 2015; 76: 343-361Crossref PubMed Scopus (12) Google Scholar Improved syndromology1Thompson M.D. Nezarati M.M. Gillessen-Kaesbach G. Meinecke P. Mendoza-Londono R. Mornet E. et al.Hyperphosphatasia with seizures, neurologic deficit, and characteristic facial features: five new patients with Mabry syndrome.Am J Med Genet A. 2010; 152A: 1661-1669Crossref PubMed Scopus (36) Google Scholar made it possible to use next-generation sequencing to identify the recessive mutations that cause what became known as Mabry syndrome (OMIM 239300).2Cole D.E. Thompson M.D. Neurogenic aspects of Mabry syndrome.Subcell Biochem. 2015; 76: 343-361Crossref PubMed Scopus (12) Google Scholar There are at least 6 phenotypes. HPMRS 1, 2, 5, and 6 result from disruption of 4 genes encoding phosphatidylinositol glycan (PIG) anchor biosynthesis enzymes that act in the endoplasmic reticulum: type V (PIGV) type O (PIGO), type W (PIGW), and type Y (PIGY). HPMRS 4 and 3 result from disruption of 2 genes encoding postattachment to proteins (PGAP) enzymes that stabilize glycosylphosphatidylinositol attachment to proteins in the golgi: PGAP3 and PGAP2.3Carmody L. Blau H. Danis D. Gourdine J.-P. Vasilevsky N. Krawitz P. et al.Significantly different clinical phenotypes associated with mutations in synthesis and transamidase+remodeling glycosylphosphatidylinositol (GPI)-anchor biosynthesis genes.Orphanet J Rare Dis. 2020; 15: 40Crossref PubMed Scopus (13) Google Scholar The report by Mabry et al describes the first of at least 21 inherited glycosylphosphatidylinositol biosynthesis defects (GPIBDs) that together compose approximately 0.15% of all developmental disabilities.4Pagnamenta A.T. Murakami Y. Taylor J.M. Anzilotti C. Howard M.F. Miller V. et al.Analysis of exome data for 4293 trios suggests GPI-anchor biogenesis defects are a rare cause of developmental disorders.Eur J Hum Genet. 2017; 25: 669-679Crossref PubMed Scopus (48) Google Scholar The HPMRS3 (GPIBD8 [MIM: 614207]) phenotype presented by Mabry et al, resulting from biallelic inheritance of PGAP2 mutations, is the prototypical HPMRS phenotype among GPIBDs.5Thompson M.D. Knaus A.A. Barshop B.A. Caliebe A. Muhle H. Nguyen T.T.M. et al.A post glycosylphosphatidylinositol (GPI) attachment to proteins, type 2 (PGAP2) variant identified in Mabry syndrome index cases: Molecular genetics of the prototypical inherited GPI disorder.Eur J Med Genet. 2019; (https://www.ncbi.nlm.nih.gov/pubmed/31805394. Accessed May 15, 2020)PubMed Google Scholar This work demonstrates the value of case studies to basic science, clinical innovation, and patient follow-up.

Hyperphosphatasia with mental retardation syndrome type 4 In two siblings-expanding the phenotypic and mutational spectrum

Hyperphosphatasia with mental retardation syndrome (HPMRS) (OMIM # 239300), is an autosomal recessive disease with phenotypic variability, ranging from mild nonsyndromic intellectual disability to syndromic form with severe intellectual disability, seizures, elevated alkaline phosphatase, brachytelephalangy and facial dysmorphism, Six subgroups of HPMRS were defined in which pathogenic mutations affect genes involved in either synthesis or remodeling of the anchor proteins. Among these, PGAP3 mutations are associated with HPMRS type 4. We report two siblings with a novel homozygous variant in PGAP3 expanding both the phenotypic findings and the mutational spectrum of HPMRS type 4. Developmental delay, hypotonia, facial dysmorphism were the consistent findings with HPMRS in our patients. Large anterior fontanel size, gum hypertrophy, pes equinovarus, concentric ventricle hypertrophy, frontoparietal atrophy and dysphagia were the findings of our patients that have been reported for the first time in this syndrome. Although there is an extensive list of differential diagnoses in patients with developmental delay and hypotonia, the recognizable pattern of facial features, parental consanguinity and mild to moderate serum ALP elevation should be sufficiently suggestive of HPMRS type 4.

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

BackgroundGlycosylphosphatidylinositol 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.MethodsWe 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.ResultsWe 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.ConclusionsDue 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.

PGAP3-related hyperphosphatasia with mental retardation syndrome: Report of 10 new patients and a homozygous founder mutation.

Hyperphosphatasia with mental retardation syndrome (HPMRS) is caused by recessive mutations in genes involved in the glycosylphosphatidylinsitol pathway, including PGAP3. We describe 10 patients from 8 Egyptian families presenting with developmental delay, severe intellectual disability, distinct facial dysmorphism and increased alkaline phosphatase. Sanger sequencing of PGAP3 was performed. Eight patients had cleft palate, 4 had postnatal microcephaly and 5 had seizures. Neuro-imaging findings showed thin corpus callosum in 9 patients, mild ventriculomegaly in 3 patients and variable degrees of cerebellar vermis hypoplasia in 4 patients, a finding not previously reported in patients with HPMRS. Additional manifestations included double row teeth, hypogenitalism and congenital heart disease. Biallelic loss of function mutations in the PGAP3 gene were detected in all patients. Nine patients were homozygous for the c.402dupC (p.M135Hfs*28) mutation strongly suggesting a founder effect. On the other hand, 1 patient had a novel mutation, c.817_820delGACT (p.D273Sfs*37). This is the largest series of patients with HPMRS from same ethnic group. Our results reinforce the distinct clinical and facial features of PGAP3-related HPMRS which are the clue for targeted genetic testing. Moreover, we present additional unreported clinical and neuro-imaging findings and a novel mutation thus expanding the phenotypic and mutational spectrum of this rare disorder.

PIGO mutations in intractable epilepsy and severe developmental delay with mild elevation of alkaline phosphatase levels

Aberrations in the glycosylphosphatidylinositol (GPI)-anchor biosynthesis pathway constitute a subclass of congenital disorders of glycosylation, and mutations in seven genes involved in this pathway have been identified. Among them, mutations in PIGV and PIGO, which are involved in the late stages of GPI-anchor synthesis, and PGAP2, which is involved in fatty-acid GPI-anchor remodeling, are all causative for hyperphosphatasia with mental retardation syndrome (HPMRS). Using whole exome sequencing, we identified novel compound heterozygous PIGO mutations (c.389C>A [p.Thr130Asn] and c.1288C>T [p.Gln430*]) in two siblings, one of them having epileptic encephalopathy. GPI-anchored proteins (CD16 and CD24) on blood granulocytes were slightly decreased compared with a control and his mother. Our patients lacked the characteristic features of HPMRS, such as facial dysmorphology (showing only a tented mouth) and hypoplasia of distal phalanges, and had only a mild elevation of serum alkaline phosphatase (ALP). Our findings therefore expand the clinical spectrum of GPI-anchor deficiencies involving PIGO mutations to include epileptic encephalopathy with mild elevation of ALP.

PGAP2 Mutations, Affecting the GPI-Anchor-Synthesis Pathway, Cause Hyperphosphatasia with Mental Retardation Syndrome

Recently, mutations in genes involved in the biosynthesis of the glycosylphosphatidylinositol (GPI) anchor have been identified in a new subclass of congenital disorders of glycosylation (CDGs) with a distinct spectrum of clinical features. To date, mutations have been identified in six genes (PIGA, PIGL, PIGM, PIGN, PIGO, and PIGV) encoding proteins in the GPI-anchor-synthesis pathway in individuals with severe neurological features, including seizures, muscular hypotonia, and intellectual disability. We developed a diagnostic gene panel for targeting all known genes encoding proteins in the GPI-anchor-synthesis pathway to screen individuals matching these features, and we detected three missense mutations in PGAP2, c.46C>T, c.380T>C, and c.479C>T, in two unrelated individuals with hyperphosphatasia with mental retardation syndrome (HPMRS). The mutations cosegregated in the investigated families. PGAP2 is involved in fatty-acid GPI-anchor remodeling, which occurs in the Golgi apparatus and is required for stable association between GPI-anchored proteins and the cell-surface membrane rafts. Transfection of the altered protein constructs, p.Arg16Trp (NP_001243169.1), p.Leu127Ser, and p.Thr160Ile, into PGAP2-null cells showed only partial restoration of GPI-anchored marker proteins, CD55 and CD59, on the cell surface. In this work, we show that an impairment of GPI-anchor remodeling also causes HPMRS and conclude that targeted sequencing of the genes encoding proteins in the GPI-anchor-synthesis pathway is an effective diagnostic approach for this subclass of CDGs.

Mutations in PIGO, a Member of the GPI-Anchor-Synthesis Pathway, Cause Hyperphosphatasia with Mental Retardation

Hyperphosphatasia with mental retardation syndrome (HPMRS), an autosomal-recessive form of intellectual disability characterized by facial dysmorphism, seizures, brachytelephalangy, and persistent elevated serum alkaline phosphatase (hyperphosphatasia), was recently shown to be caused by mutations in PIGV, a member of the glycosylphosphatidylinositol (GPI)-anchor-synthesis pathway. However, not all individuals with HPMRS harbor mutations in this gene. By exome sequencing, we detected compound-heterozygous mutations in PIGO, a gene coding for a membrane protein of the same molecular pathway, in two siblings with HPMRS, and we then found by Sanger sequencing further mutations in another affected individual; these mutations cosegregated in the investigated families. The mutant transcripts are aberrantly spliced, decrease the membrane stability of the protein, or impair enzyme function such that GPI-anchor synthesis is affected and the level of GPI-anchored substrates localized at the cell surface is reduced. Our data identify PIGO as the second gene associated with HPMRS and suggest that a deficiency in GPI-anchor synthesis is the underlying molecular pathomechanism of HPMRS.