TY - JOUR

T1 - Deciphering the premature mortality in PIGA-CDG – An untold story

AU - Bayat, Allan

AU - Kløvgaard, Marius

AU - Johannesen, Katrine M.

AU - Stefan Barakat, Tahsin

AU - Kievit, Anneke

AU - Montomoli, Martino

AU - Parrini, Elena

AU - Pietrafusa, Nicola

AU - Schelhaas, Jurgen

AU - van Slegtenhorst, Marjon

AU - Miya, Kazushi

AU - Guerrini, Renzo

AU - Tranebjærg, Lisbeth

AU - Tümer, Zeynep

AU - Rubboli, Guido

AU - Møller, Rikke S.

PY - 2021

Y1 - 2021

N2 - Objective: Congenital disorder of glycosylation (CDG) due to a defective phosphatidylinositol glycan anchor biosynthesis class A protein (PIGA) is a severe X-linked developmental and epileptic encephalopathy. Seizures are often treatment refractory, and patients have intellectual disability and global developmental delay. Previous reports have suggested that patients with PIGA-CDG have a high risk of premature mortality. This study aimed to evaluate the observed high mortality and the causes of death in PIGA-CDG patients. Methods: We reviewed the literature and collected additional unpublished patients through an international network. Results: In total, we reviewed the data of 88 patients of whom 30 patients born alive were deceased, and the overall mortality before the age of 20 years was 30 % (26/88). Age at death ranged from 15 days to 48 years of life. The median age at death was two years and more than half of the patients deceased in early childhood. The PIGA-specific mortality rate/1000 person-years was 44.9/1000 person-years (95 %, CI 31.4–64.3). There were no cases of definite or probable sudden unexpected death in epilepsy (SUDEP) and half of the patients died due to respiratory failure (15/30, 50 %) or possible SUDEP (3/30, 10 %). Three patients (10 %) died from severe cardiomyopathy, liver failure and gastrointestinal bleeding, respectively. The cause of death was unclassified in nine patients (30 %). Autopsies were rarely performed and the true cause of death remains unknown for the majority of patients. Significance: Our data indicate an increased risk of premature death in patients with PIGA-CDG when compared to most monogenic developmental and epileptic encephalopathies.

AB - Objective: Congenital disorder of glycosylation (CDG) due to a defective phosphatidylinositol glycan anchor biosynthesis class A protein (PIGA) is a severe X-linked developmental and epileptic encephalopathy. Seizures are often treatment refractory, and patients have intellectual disability and global developmental delay. Previous reports have suggested that patients with PIGA-CDG have a high risk of premature mortality. This study aimed to evaluate the observed high mortality and the causes of death in PIGA-CDG patients. Methods: We reviewed the literature and collected additional unpublished patients through an international network. Results: In total, we reviewed the data of 88 patients of whom 30 patients born alive were deceased, and the overall mortality before the age of 20 years was 30 % (26/88). Age at death ranged from 15 days to 48 years of life. The median age at death was two years and more than half of the patients deceased in early childhood. The PIGA-specific mortality rate/1000 person-years was 44.9/1000 person-years (95 %, CI 31.4–64.3). There were no cases of definite or probable sudden unexpected death in epilepsy (SUDEP) and half of the patients died due to respiratory failure (15/30, 50 %) or possible SUDEP (3/30, 10 %). Three patients (10 %) died from severe cardiomyopathy, liver failure and gastrointestinal bleeding, respectively. The cause of death was unclassified in nine patients (30 %). Autopsies were rarely performed and the true cause of death remains unknown for the majority of patients. Significance: Our data indicate an increased risk of premature death in patients with PIGA-CDG when compared to most monogenic developmental and epileptic encephalopathies.

KW - Cardiomyopathy

KW - Early cardiopulmonary death

KW - Early infantile epileptic encephalopathy

KW - Glycosylphosphatidylinositol biosynthesis defects

KW - Mortality

KW - PIGA

KW - SUDEP

U2 - 10.1016/j.eplepsyres.2020.106530

DO - 10.1016/j.eplepsyres.2020.106530

M3 - Journal article

C2 - 33508693

AN - SCOPUS:85099969537

VL - 170

JO - Journal of Epilepsy

JF - Journal of Epilepsy

SN - 0920-1211

M1 - 106530

ER -