Delineating the epilepsy phenotype of NGLY1 deficiency

Abstract

We delineated the phenotypic spectrum of epilepsy in individuals with NGLY1 deficiency from an international cohort. We collected detailed clinical and electroencephalographic data from 29 individuals with bi‐allelic (likely) pathogenic variants in NGLY1 as part of an ongoing prospective natural history study. Participants were evaluated in‐person at a single center and/or remotely. Historical medical records were reviewed. Published cases were included for comprehensive phenotyping. Of 29 individuals (mean 11.4 years, range 3–27 years), 17 (58.6%) participants had a history of epilepsy. Seizure onset was in early childhood (mean 43 months, range 2 months to 19 years). The most common seizure types were myoclonic and atonic. Epilepsy course was variable, but 35.2% (6/17) of participants with epilepsy achieved seizure freedom. The most common medications included levetiracetam, valproate, lamotrigine, and clobazam. Electroencephalogram (EEGs) were abnormal in 80% (12/15) of participants with or without epilepsy, although encephalopathy was uncommon. There was a trend in neurodevelopmental outcomes that participants with epilepsy had more developmental delays. In summary, epilepsy is common in NGLY1 deficiency. Over half of the participants had a history of epilepsy and nearly all had EEG abnormalities indicating an increased risk of epilepsy. This work expands the electroclinical phenotype of NGLY1 deficiency and supports a high clinical suspicion for seizures. Some of the more common seizure types (epileptic spasms, myoclonic, and atonic seizures) can be subtle and require counseling to ensure early recognition and treatment to ensure the best possible outcomes. Despite transient liver enzyme abnormalities in this disorder, hepatically metabolized medications were well tolerated.

NGLY1 Deficiency, a Congenital Disorder of Deglycosylation: From Disease Gene Function to Pathophysiology

“…Since then, more than 100 patients with this disorder have been identified [ 17 ], thanks in no small part to the efforts of the first two families in raising awareness about this disease, as well as advances in and the growing accessibility of next-generation sequencing technologies around the world. More than 60 of these patients have already been formally reported in one or more publications [ 13 ]. Figure 2 shows the types of variants reported in patients with NGLY1 deficiency and the location of those that affect the protein sequence on a schematic of the NGLY1 proteins.…”

“…Recessive mutations in human NGLY1 lead to a disorder called NGLY1 deficiency (OMIM# 615273), which presents with multiple phenotypes, including but not limited to global developmental delay, movement disorder, seizures, microcephaly, liver disorders, and chronic constipation [ 11 , 12 , 13 , 14 ]. It is categorized as the first known congenital disorder of deglycosylation (CDDG) [ 15 ].…”

NGLY1 deficiency: estimated incidence, clinical features, and genotypic spectrum from the NGLY1 Registry

“…Additional signs and symptoms of the disease may include epilepsy, feeding difficulties, failure to thrive, hypotonia, central and/or obstructive sleep apnea, microcephaly, non-specific findings on brain MRI (delayed myelination; small corpus callosum, anterior commissure, and/or cerebellar atrophy; prominent cisterna magna and/or enlarged ventricles) [ 3 ], and orthopedic complications such as progressive scoliosis and joint contractures [ 4 ]. Caregivers commonly report regression of motor and/or cognitive function [ 2 ]. As NGLY1 Deficiency presents with a complex neurologic phenotype, the differential diagnosis is broad and may include congenital disorders of glycosylation (CDG), mitochondrial disorders, MECP2-related disorders, and neurotransmitter disorders.…”

“…Patients may be given a non-specific diagnosis of cerebral palsy. The constellation of symptoms and the range of severity varies between patients, making diagnosis and prognosis challenging [ 2 , 3 ].…”

“…NGLY1 is located on chromosome 3p24.2. To date, 46 pathogenic variants in NGLY1 have been described in the literature [ 2 ]. Pathogenic variants include missense variants, truncations, small deletions, and splice-site variants.…”