The Natural History of Polyhydramnios, Megalencephaly, and Symptomatic Epilepsy Syndrome (PMSE) in the Old Order Mennonite Population of North America
Abstract number :
2.098
Submission category :
4. Clinical Epilepsy / 4A. Classification and Syndromes
Year :
2022
Submission ID :
2205044
Source :
www.aesnet.org
Presentation date :
12/4/2022 12:00:00 PM
Published date :
Nov 22, 2022, 05:27 AM
Authors :
Jordan Ibarra, MD – UPMC Children's Hospital of Pittsburgh; Emilienne Bolettieri, BA – Clinic for Special Children; Millie Young, RN – Clinic for Special Children; Karlla Brigatti, MS, CGC – Clinic for Special Children; Vincent Carson, MD – Clinic for Special Children
Rationale: Patients with polyhydramnios, megalencephaly, and symptomatic epilepsy syndrome (PMSE) develop intractable epilepsy and severe cognitive disability (Parker WE, et al. Rapamycin prevents seizures after depletion of STRADA in a rare neurodevelopmental disorder. Sci Transl Med. 2013;5(182):182ra53). PMSE patients are homozygous for a loss-of-function mutation in the LYK5/STRADA gene, and an estimated 4% of the Old Order Mennonite population in Ohio, Pennsylvania, and New York are hemizygous for this deletion (Parker, WE et al.; Puffenberger EG, et al. Polyhydramnios, megalencephaly and symptomatic epilepsy caused by a homozygous 7-kilobase deletion in LYK5. Brain. 2007;130(Pt 7):1929-1941). The LYK5/STRADA gene encodes the STRADA protein, an upstream inhibitor of mTORC1 (Zeqiraj E, et al. Structure of the LKB1-STRAD-MO25 complex reveals an allosteric mechanism of kinase activation. Science. 2009;326(5960):1707-1711). Therefore, therapies that inhibit mTORC1 such as rapamycin (sirolimus) could benefit patients with PMSE. A better understanding of the natural history of this disorder is necessary to provide control data to prospectively evaluate the efficacy of these therapies.
Methods: We used medical records and structured interviews to collect retrospective data on 45 patients with PMSE from the Mennonite community identified at the Clinic for Special Children between 2020 and 2022.
Results: Thirty-nine (87%) subjects with PMSE had seizures, with a median age of onset of 4 months, ranging from 1 hour to 18 months. Of the 6 subjects who were never diagnosed with seizures, 3 were stillborn and 3 died before 2 weeks of life from complications of prematurity. Infantile spasms occurred in 11 (28%) subjects diagnosed with seizures. Status epilepticus occurred in 58% of subjects, and 71% of subjects required hospitalization for seizures. All subjects with seizures were treated with medication, and 10% of subjects were treated with other therapies including ventriculoperitoneal shunt placement, vagal nerve stimulation, and ketogenic diet. 26% of subjects with seizures were treated with rapamycin. Regarding neurodevelopment, 64% of subjects achieved the ability to sit unsupported, 4% were able to walk independently, and 22% of subjects achieved the ability to say any words. Of these subjects, the median age at which unsupported sitting was achieved was 20 months, the median age for independent walking was 57 months, and the median age for talking was 24 months. Thirty-one percent of subjects who achieved any of these milestones experienced developmental regression. Forty-nine percent of subjects were deceased at the time of data collection with a median age at death of 3.5 years and a range from 1 day to 20 years. The most common causes of death were status epilepticus and respiratory failure.
Conclusions: Therapies directed toward mTORC1 inhibition could benefit patients with PMSE in reducing seizure severity and improving neurodevelopmental outcomes. An understanding of the natural history of PMSE will provide control data for future disease-modifying therapy trials.
Funding: Not applicable
Clinical Epilepsy