<i>PIGN</i>encephalopathy: Characterizing the epileptology

Bayat, Allan; Valles-Ibáñez, Guillem de; Pendziwiat, Manuela; Knaus, Alexej; Alt, Kerstin; Biamino, Elisa; Bley, Annette; Calvert, Sophie; Carney, Patrick; Caro-Llopis, Alfonso; Ceulemans, Berten; Cousin, Janice; Davis, Suzanne L.; Portes, Vincent Des; Edery, Patrick; England, Eleina; Ferreira, Carlos R.; Freeman, Jeremy L.; Gener, Blanca; Gorce, Magali; Héron, Delphine; Hildebrand, Michael S.; Jezela‐Stanek, Aleksandra; Jouk, Pierre-Simon; Keren, Boris; Kloth, Katja; Kluger, Gerhard; Kuhn, Marius; Lemke, Johannes R.; Li, Hong; Martı́nez, Francisco; Maxton, Caroline; Mefford, Heather C; Merla, Giuseppe; Mierzewska, Hanna; Muir, Alison M.; Monfort, Sandra; Nicolai, Joost; Norman, Jennifer; O’Grady, Gina L.; Oleksy, Barbara; Orellana, Carmen; Orec, Laura; Peinhardt, Charlotte; Pronicka, Ewa; Roselló, Mónica; Santos‐Simarro, Fernando; Schwaibold, Eva Maria Christina; Stegmann, Alexander P.A.; Stumpel, Constance T. R. M.; Szczepanik, Elżbieta; Terczyńska, Iwona; Thévenon, Julien; Tzschach, Andreas; Bogaert, Patrick Van; Vittorini, Roberta; Walsh, Sonja; Weckhuysen, Sarah; Weissman, Barbara; Wolfe, Lynne A.; Reymond, Alexandre; Nittis, Pasquelena De; Poduri, Annapurna; Olson, Heather E.; Striano, Pasquale; Lesca, Gaëtan; Scheffer, Ingrid E.; Møller, Rikke S.; Sadleir, Lynette G.

doi:10.1111/epi.17173

Cited by 5 publications

(4 citation statements)

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“… 69-71 Though PIGN -IGD is the only IGD with recently described—albeit heterogenous—epileptology, this is expanded to include focal emotional and sensory seizures in addition to generalized myoclonic-atonic seizures. 72 We also show the differential severity of variants in genes of the synthesis versus the transamidase and remodelling stage of the GPI-AP in time to seizure onset—providing original data to support the hypothesis of a recent review. 73 …”

Section: Discussionsupporting

confidence: 63%

The clinical and genetic spectrum of inherited glycosylphosphatidylinositol deficiency disorders

Sidpra,

Sudhakar,

Biswas

et al. 2024

Brain

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Inherited glycosylphosphatidylinositol deficiency disorders (IGDs) are a group of rare multisystem disorders arising from pathogenic variants in glycosylphosphatidylinositol anchor pathway (GPI-AP) genes. Despite associating 24 of at least 31 GPI-AP genes with human neurogenetic disease, prior reports are limited to single genes without consideration of the GPI-AP as a whole and with limited natural history data. In this multinational retrospective observational study, we systematically analyse the molecular spectrum, phenotypic characteristics, and natural history of 83 individuals from 75 unique families with IGDs, including 70 newly reported individuals: the largest single cohort to date. Core clinical features were developmental delay or intellectual disability (DD/ID, 90%), seizures (83%), hypotonia (72%), and motor symptoms (64%). Prognostic and biologically significant neuroimaging features included cerebral atrophy (75%), cerebellar atrophy (60%), callosal anomalies (57%), and symmetric restricted diffusion of the central tegmental tracts (60%). Sixty-one individuals had multisystem involvement including gastrointestinal (66%), cardiac (19%), and renal (14%) anomalies. Though dysmorphic features were appreciated in 82%, no single dysmorphic feature had a prevalence >30%, indicating substantial phenotypic heterogeneity. Follow-up data were available for all individuals, 15 of whom were deceased at the time of writing. Median age at seizure onset was 6 months. Individuals with variants in synthesis stage genes of the GPI-AP exhibited a significantly shorter time to seizure onset than individuals with variants in transamidase and remodelling stage genes of the GPI-AP (P=0.046). Forty individuals had intractable epilepsy. The majority of individuals experienced delayed or absent speech (95%); motor delay with non-ambulance (64%); and severe-to-profound DD/ID (59%). Individuals with a developmental epileptic encephalopathy (51%) were at greater risk of intractable epilepsy (P=0.003), non-ambulance (P=0.035), ongoing enteral feeds (P<0.001), and cortical visual impairment (P=0.007). Serial neuroimaging showed progressive cerebral volume loss in 87.5% and progressive cerebellar atrophy in 70.8%, indicating a neurodegenerative process. Genetic analyses identified 93 unique variants (106 total), including 22 novel variants. Exploratory analyses of genotype-phenotype correlations using unsupervised hierarchical clustering identified novel genotypic predictors of clinical phenotype and long-term outcome with meaningful implications for management. In summary, we expand both the mild and severe phenotypic extremities of the IGDs; provide insights into their neurological basis; and, vitally, enable meaningful genetic counselling for affected individuals and their families.

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Section: Discussionsupporting

confidence: 63%

The clinical and genetic spectrum of inherited glycosylphosphatidylinositol deficiency disorders

Sidpra,

Sudhakar,

Biswas

et al. 2024

Brain

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“…Pathogenic loss‐of‐function variants in 24 of these genes have been linked to human disease 2 . Less than 400 patients have been reported with GPI‐AD 2–6 . Inheritance is X‐linked recessive for phosphatidylinositol‐glycan‐anchor‐biosynthesis‐class‐A protein (PIGA) related GPI‐AD and autosomal recessive for all other known GPI‐ADs 2 .…”

Section: Introductionmentioning

confidence: 99%

“…2 Less than 400 patients have been reported with GPI-AD. [2][3][4][5][6] Inheritance is X-linked recessive for phosphatidylinositol-glycan-anchorbiosynthesis-class-A protein (PIGA) related GPI-AD and autosomal recessive for all other known GPI-ADs. 2 Common features include developmental and cognitive impairment, early-onset and often treatment-resistant seizures, movement disorders and dysmorphic features.…”

Section: Introductionmentioning

confidence: 99%

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GPI‐anchoring disorders and the heart: Is cardiomyopathy an overlooked feature?

Bayat,

Lindau,

Aledo‐Serrano

et al. 2023

Clinical Genetics

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Glycosylphosphatidylinositol anchoring disorders (GPI‐ADs) are a subgroup of congenital disorders of glycosylation. GPI biosynthesis requires proteins encoded by over 30 genes of which 24 genes are linked to neurodevelopmental disorders. Patients, especially those with PIGA‐encephalopathy, have a high risk of premature mortality which sometimes is attributed to cardiomyopathy. We aimed to explore the occurrence of cardiomyopathy among patients with GPI‐ADs and to raise awareness about this potentially lethal feature. Unpublished patients with genetically proven GPI‐ADs and cardiomyopathy were identified through an international collaboration and recruited through the respective clinicians. We also reviewed the literature for published patients with cardiomyopathy and GPI‐AD and contacted the corresponding authors for additional information. We identified four novel and unrelated patients with GPI‐AD and cardiomyopathy. Cardiomyopathy was diagnosed before adulthood and was the cause of early demise in two patients. Only one patients underwent cardiac workup after being diagnosed with a GPI‐AD. All were diagnosed with PIGA‐encephalopathy and three had a disease‐causing variant at the same residue. The literature reports five additional children with GPI‐AD related cardiomyopathy, three of which died before adulthood. We have shown that patients with GPI‐ADs are at risk of developing cardiomyopathy and that regular cardiac workup with echocardiography is necessary.

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