Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mabry syndrome, hyperphosphatasia mental retardation syndrome (HPMRS), is an autosomal recessive disease characterized by increased serum levels of alkaline phosphatase (ALP), severe developmental delay, intellectual disability, and seizures. Recent studies have revealed mutations in PIGV, PIGW, PIGO, PGAP2, and PGAP3 (genes that encode molecules of the glycosylphosphatidylinositol (GPI)-anchor biosynthesis pathway) in patients with HPMRS. We performed whole-exome sequencing of a patient with severe intellectual disability, distinctive facial appearance, fragile nails, and persistent increased serum levels of ALP. The result revealed a compound heterozygote with a 13-bp deletion in exon 1 (c.36_48del) and a two-base deletion in exon 2 (c.254_255del) in phosphatidylinositol glycan anchor, class L (PIGL) that caused frameshifts resulting in premature terminations. The 13-bp deletion was inherited from the father, and the two-base deletion was inherited from the mother. Expressing c.36_48del or c.254_255del cDNA with an HA-tag at the C- or N-terminus in PIGL-deficient CHO cells only partially restored the surface expression of GPI-anchored proteins (GPI-APs). Nonsynonymous changes or frameshift mutations in PIGL have been identified in patients with CHIME syndrome, a rare autosomal recessive disorder characterized by colobomas, congenital heart defects, early onset migratory ichthyosiform dermatosis, intellectual disability, and ear abnormalities. Our patient did not have colobomas, congenital heart defects, or early onset migratory ichthyosiform dermatosis and hence was diagnosed with HPMRS, and not CHIME syndrome. These results suggest that frameshift mutations that result in premature termination in PIGL cause a phenotype that is consistent with HPMRS.
 ...
PMID:Mutations in PIGL in a patient with Mabry syndrome. 2570 56

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.
 ...
PMID:A novel PGAP3 mutation in a Croatian boy with brachytelephalangy and a thin corpus callosum. 2953 74

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.
 ...
PMID:Hyperphosphatasia with mental retardation syndrome type 4 In two siblings-expanding the phenotypic and mutational spectrum. 3021 54

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.
 ...
PMID:PGAP3 Associated with Hyperphosphatasia with Mental Retardation Plays a Novel Role in Brain Morphogenesis and Neuronal Wiring at Early Development. 3272 39

Hyperphosphatasia with mental retardation syndrome (HPMRS) is a rare autosomal recessive disorder caused by pathogenic variants in genes involved in glycosylphosphatidylinositol metabolism that result in a similar phenotype. We describe the first three patients with HPMRS from sub-Saharan Africa. Detection was assisted by Face2Gene phenotype matching and confirmed by the presence of elevated serum alkaline phosphatase. All three patients had severe intellectual disability, absent speech, hypotonia and palatal abnormality (cleft palate in two, very high-arched palate in one), no or minimal brachytelephalangy, and high serum alkaline phosphatase levels. Additional findings included seizures in two, and brain imaging abnormalities in two. In all three patients HPMRS was a top-20 gestalt match using Face2Gene. The overall phenotype is consistent with descriptions in the literature of HPMRS type 4, although not specific to it. Whole exome sequencing in the index patient and his mother detected a candidate variant in a homozygous state in the index patient (PGAP3:c.557G>C, p.Arg186Thr) and heterozygous in the mother. Further variant interpretation indicated pathogenicity. Sanger sequencing of another two patients identified the same homozygous, pathogenic variant, confirming a diagnosis of HPMRS type 4. The shared homozygous variant in apparently unrelated families, and in the absence of consanguinity, suggests the possibility of genetic drift due to a population bottleneck effect, and further research is recommended.
 ...
PMID:Hyperphosphatasia with mental retardation syndrome type 4 in three unrelated South African patients. 3284 56