Inspired by the Movement Disorders Special Interest group session at the 2018 Child Neurology Society meeting.
Nguyen TTM, Murakami Y, Wigby KM, Baratang NV, Rousseau J, St-Denis A, Rosenfeld JA, Laniewski SC, Jones J, Iglesias AD, Jones MC, Masser-Frye D, Scheuerle AE, Perry DL, Taft RJ, Le Deist F, Thompson M, Kinoshita T, Campeau PM. Mutations in PIGS, Encoding a GPI Transamidase, Cause a Neurological Syndrome Ranging from Fetal Akinesia to Epileptic Encephalopathy. Am J Hum Genet. 2018 Oct 4;103(4):602-611.
Inherited GPI deficiencies (IGDs) are a subset of congenital disorders of glycosylation that are increasingly recognized as a result of advances in whole-exome sequencing (WES) and whole-genome sequencing (WGS). IGDs cause a series of overlapping phenotypes consisting of seizures, dysmorphic features, multiple congenital malformations, and severe intellectual disability. We present a study of six individuals from three unrelated families in which WES or WGS identified bi-allelic phosphatidylinositol glycan class S (PIGS) biosynthesis mutations. Phenotypes included severe global developmental delay, seizures (partly responding to pyridoxine), hypotonia, weakness, ataxia, and dysmorphic facial features. Two of them had compound-heterozygous variants c.108G>A (p.Trp36∗) and c.101T>C (p.Leu34Pro), and two siblings of another family were homozygous for a deletion and insertion leading to p.Thr439_Lys451delinsArgLeuLeu. The third family had two fetuses with multiple joint contractures consistent with fetal akinesia. They were compound heterozygous for c.923A>G (p.Glu308Gly) and c.468+1G>C, a splicing mutation. Flow-cytometry analyses demonstrated that the individuals with PIGS mutations show a GPI-AP deficiency profile. Expression of the p.Trp36∗ variant in PIGS-deficient HEK293 cells revealed only partial restoration of cell-surface GPI-APs. In terms of both biochemistry and phenotype, loss of function of PIGS shares features with PIGT deficiency and other IGDs. This study contributes to the understanding of the GPI-AP biosynthesis pathway by describing the consequences of PIGS disruption in humans and extending the family of IGDs.
Xu YF, Li N, Li GQ, Wang XM, Zhou YF, Yin L, Wang J. [Multiple congenital anomalies-hypotonia-seizures syndrome 1: case report and review of literature]. Zhonghua Er Ke Za Zhi. 2017 Mar 2;55(3):215-219. doi:10.3760/cma.j.issn.0578-1310.2017.03.010. Review. Chinese.
Objective: To analyze and summarize the clinical and molecular characteristics of the patients with multiple congenital anomalies- hypotonia-seizures syndrome 1 (MCAHS 1). Method: Clinical data and test results were collected from a patient who was diagnosed with confirmed genetic basis of MCAHS 1 in Shanghai Children's Medical Center since December 2015. The patient and his parents were examined by the next generation sequencing (NGS) technology using peripheral blood genomic DNA, and the relevant mutations identified by NGS were verified with Sanger sequencing. Related literature was searched from PubMed and Embase databases (from their establishment to January 2017) by using "PIGN gene" as a keyword, the retrieved articles were further reviewed for the clinical manifestations, results and prognosis of PIGN related variants. Result: A nearly 4-month-old Chinese boy was presented with epilepsy, hypotonia, developmental delay, accompanied by nearly normal laboratory test results.
The NGS analysis revealed a compound heterozygous variations in the PIGN gene, included a known splice site mutation (c.963G>A) which was inherited from his father, and a novel nonsense mutation (c.2773A>T, p.Lys925*) which was inherited from his mother. Nine associated articles were retrieved. Including our patient, a total of 22 cases were identified as the PIGN variants. The most common clinical manifestations were developmental delay, hypotonia, and epilepsy. Missense varients were most frequently found. Prognosis was poor. Eight cases died, while survived cased suffered from refractory epilepsy, profound mental retardation, muscle weakness, etc. Conclusion: MCAHS1 is characterized by epilepsy, severe developmental delay, hypotonia, and may be accompanied by multiple malformations of other systems. Homozygous or compound heterozygous variants in PIGN gene are the cause of the disease.
Khayat M, Tilghman JM, Chervinsky I, Zalman L, Chakravarti A, Shalev SA. A PIGN mutation responsible for multiple congenital anomalies-hypotonia-seizures syndrome 1 (MCAHS1) in an Israeli-Arab family. Am J Med Genet A. 2016 Jan;170A(1):176-82.
Mutations in the PIGN gene involved in the glycosylphoshatidylinositol (GPI) anchor biosynthesis pathway cause Multiple Congenital Anomalies-Hypotonia-Seizures syndrome 1 (MCAHS1). The syndrome manifests developmental delay, hypotonia, and epilepsy, combined with multiple congenital anomalies. We report on the identification of a homozygous novel c.755A>T (p.D252V) deleterious mutation in a patient with Israeli-Arab origin with MCAHS1. The mutated PIGN caused a significant decrease of the overall GPI-anchored proteins and CD24 expression. Our results, strongly support previously published data, that partial depletion of GPI-anchored proteins is sufficient to cause severe phenotypic expression.
Fleming L, Lemmon M, Beck N, Johnson M, Mu W, Murdock D, Bodurtha J, Hoover-Fong J, Cohn R, Bosemani T, Barañano K, Hamosh A. Genotype-phenotype correlation of congenital anomalies in multiple congenital anomalies hypotonia seizures syndrome (MCAHS1)/PIGN-related epilepsy. Am J Med Genet A. 2016 Jan;170A(1):77-86.
Mutations in PIGN, resulting in multiple congenital anomalies-hypotonia-seizures syndrome, a glycosylphosphatidylinositol anchor deficiency, have been published in four families to date. We report four patients from three unrelated families with epilepsy and hypotonia in whom whole exome sequencing yielded compound heterozygous variants in PIGN. As with previous reports Patients 1 and 2 (full siblings) have severe global developmental delay, gastroesophageal reflux disease, and minor dysmorphic features, including high palate, bitemporal narrowing, depressed nasal bridge, and micrognathia; Patient 3 had early global developmental delay with later progressive spastic quadriparesis, intellectual disability, and intractable generalized epilepsy; Patient 4 had bilateral narrowing as well but differed by the presence of hypertelorism, markedly narrow palpebral fissures, and long philtrum, had small distal phalanges of fingers 2, 3, and 4, absent distal phalanx of finger 5 and similar toe anomalies, underdeveloped nails, unusual brain anomalies, and a more severe early clinical course. These patients expand the known clinical spectrum of the disease. The severity of the presentations in conjunction with the patients' mutations suggest a genotype-phenotype correlation in which congenital anomalies are only seen in patients with biallelic loss-of-function. In addition, PIGN mutations appear to be panethnic and may be an underappreciated cause of epilepsy.