The genotypic and phenotypic spectrum of PIGA deficiency

Abstract

BackgroundPhosphatidylinositol glycan biosynthesis class A protein (PIGA) is one of the enzymes involved in the biosynthesis of glycosylphosphatidylinositol (GPI) anchor proteins, which function as enzymes, adhesion molecules, complement regulators and co-receptors in signal transduction pathways. Until recently, only somatic PIGA mutations had been reported in patients with paroxysmal nocturnal hemoglobinuria (PNH), while germline mutations had not been observed, and were suspected to result in lethality. However, in just two years, whole exome sequencing (WES) analyses have identified germline PIGA mutations in male patients with XLIDD (X-linked intellectual developmental disorder) with a wide spectrum of clinical presentations.Methods and resultsHere, we report on a new missense PIGA germline mutation [g.15342986C>T (p.S330N)] identified via WES followed by Sanger sequencing, in a Chinese male infant presenting with developmental arrest, infantile spasms, a pattern of lesion distribution on brain MRI resembling that typical of maple syrup urine disease, contractures, dysmorphism, elevated alkaline phosphatase, mixed hearing loss (a combination of conductive and sensorineural), liver dysfunction, mitochondrial complex I and V deficiency, and therapy-responsive dyslipidemia with confirmed lipoprotein lipase deficiency. X-inactivation studies showed skewing in the clinically unaffected carrier mother, and CD109 surface expression in patient fibroblasts was 57% of that measured in controls; together these data support pathogenicity of this mutation. Furthermore, we review all reported germline PIGA mutations (1 nonsense, 1 frameshift, 1 in-frame deletion, five missense) in 8 unrelated families.ConclusionsOur case further delineates the heterogeneous phenotype of this condition for which we propose the term ‘PIGA deficiency’. While the phenotypic spectrum is wide, it could be classified into two types (severe and less severe) with shared hallmarks of infantile spasms with hypsarrhythmia on EEG and profound XLIDD. In severe PIGA deficiency, as described in our patient, patients also present with dysmorphic facial features, multiple CNS abnormalities, such as thin corpus callosum and delayed myelination, as well as hypotonia and elevated alkaline phosphatase along with liver, renal, and cardiac involvement; its course is often fatal. The less severe form of PIGA deficiency does not involve facial dysmorphism and multiple CNS abnormalities; instead, patients present with milder IDD, treatable seizures and generally a longer lifespan.

Clinical variability in inherited glycosylphosphatidylinositol deficiency disorders

“…Other phenotypes such as polyhydramnios, elevated alkaline phosphatase (ALP), cardiac anomalies, dental problems, visual impairment and deafness were also seen in these patients although less frequently, and some phenotypes were reported only once such as nephrocalcinosis, short fingers or hands, and skeletal anomalies. These widespread clinical features are consistent with the findings that the PIGA protein is expressed in a wide variety of tissues including brain, liver, heart and blood cells . In the 21 patients reported, about half of them died in which the cause of death was mainly due to liver failure and respiration pneumonia.…”

“…In the 21 patients reported, about half of them died in which the cause of death was mainly due to liver failure and respiration pneumonia. Some patients also have evidence of mitochondrial dysfunction, although the mechanism for this phenomenon is not known . Studies in induced pluripotent stem cells showed decreased proliferation, abnormal synapse formation, membrane depolarization and an increased susceptibility to complement‐mediated cytotoxicity …”

“…These widespread clinical features are consistent with the findings that the PIGA protein is expressed in a wide variety of tissues including brain, liver, heart and blood cells. 4 In the 21 patients reported, about half of them died in which the cause of death was mainly due to liver failure and respiration pneumonia. Some patients also have evidence of mitochondrial dysfunction, although the mechanism for this phenomenon is not known.…”

Thematic Review Series: Glycosylphosphatidylinositol (GPI) Anchors: Biochemistry and Cell Biology Biosynthesis of GPI-anchored proteins: special emphasis on GPI lipid remodeling

“…In cells defective in early steps in the GPI biosynthetic pathway, GPI transamidase action to preproproteins is less effi cient and preproproteins are degraded by ER-associated degradation. Indeed, hyperphosphatasia does not occur, or occurs only mildly, in PIGA -, PIGQ -, and PIGL -defi ciencies (119)(120)(121). Balance between degradation and secretion due to cleavage by GPI transamidase seems to be affected by other unknown factors, such as genetic backgrounds, because highly elevated hyperphosphatasia associated with PIGL -defi ciency was recently reported ( 122 ).…”

A Neonate with aPIGAc.1234C>T Mutation as a Novel Cause of Neonatal Early Infantile Epileptic Encephalopathy

“…The clinical characteristics of our case were very similar to those reported previously by Kato et al 11 The phenotype of our case could be classified into severe PIGA deficiency in cluding refractory epileptiform discharges with a burstsuppression pattern on EEG, dysmorphic features and anomalies of other organs. 12 Our case showed no anemia or paroxysmal nocturnal hemoglobinuria that is caused by somatic PIGA mutations. In contrast to other cases with mutations in PIGA, our case exhibited congenital malformation with omphalocele.…”