PIGN encephalopathy: Characterizing the epileptology.

OBJECTIVE: Epilepsy is common in patients with PIGN diseases due to biallelic variants; however, limited epilepsy phenotyping data have been reported. We describe the epileptology of PIGN encephalopathy. METHODS: We recruited patients with epilepsy due to biallelic PIGN variants and obtained clinical data regarding age at seizure onset/offset and semiology, development, medical history, examination, electroencephalogram, neuroimaging, and treatment. Seizure and epilepsy types were classified. RESULTS: Twenty six patients (13 female) from 26 families were identified, with mean age 7 years (range = 1 month to 21 years; three deceased). Abnormal development at seizure onset was present in 25 of 26. Developmental outcome was most frequently profound (14/26) or severe (11/26). Patients presented with focal motor (12/26), unknown onset motor (5/26), focal impaired awareness (1/26), absence (2/26), myoclonic (2/26), myoclonic-atonic (1/26), and generalized tonic-clonic (2/26) seizures. Twenty of 26 were classified as developmental and epileptic encephalopathy (DEE): 55% (11/20) focal DEE, 30% (6/20) generalized DEE, and 15% (3/20) combined DEE. Six had intellectual disability and epilepsy (ID+E): two generalized and four focal epilepsy. Mean age at seizure onset was 13 months (birth to 10 years), with a lower mean onset in DEE (7 months) compared with ID+E (33 months). Patients with DEE had drug-resistant epilepsy, compared to 4/6 ID+E patients, who were seizure-free. Hyperkinetic movement disorder occurred in 13 of 26 patients. Twenty-seven of 34 variants were novel. Variants were truncating (n = 7), intronic and predicted to affect splicing (n = 7), and missense or inframe indels (n = 20, of which 11 were predicted to affect splicing). Seven variants were recurrent, including p.Leu311Trp in 10 unrelated patients, nine with generalized seizures, accounting for nine of the 11 patients in this cohort with generalized seizures. SIGNIFICANCE: PIGN encephalopathy is a complex autosomal recessive disorder associated with a wide spectrum of epilepsy phenotypes, typically with substantial profound to severe developmental impairment.

Locus heterogeneity in two siblings presenting with developmental delay, intellectual disability and autism spectrum disorder.

Correct diagnosis of children presenting with developmental delay and intellectual disability remains challenging due to the complex and heterogeneous etiology. High throughput sequencing technologies like exome sequencing have become more commonly available and are significantly improving genetic testing. We present two siblings - a 14-year old male and an 8-year old female patient - with a similar clinical phenotype that was characterized by combined developmental delay primarily affecting speech, mild to moderate intellectual disability, behavioral abnormalities, and autism spectrum disorder, but with no congenital anomalies. The sister showed additional muscular hypotonia and more pronounced dysmorphic features compared to her brother. Both parents had psychiatric disorders and mild to moderate intellectual disability. A common genetic etiology in the siblings was suspected. Metabolic, psychological and neuroradiological examinations were complemented by basic genetic testing including chromosome analysis and array comparative genomics hybridization analysis (CGH), followed by exome sequencing and combined data analysis of the family. Exome sequencing identified two different underlying genetic conditions: in the sister, a maternally inherited pathogenic variant c.1661C > T, p.Pro554Leu in SLC6A8 (NM_005629.4) was identified causing cerebral creatine deficiency syndrome 1 (MIM #300352) which was confirmed by MR spectroscopy and treated accordingly. In the brother, a paternally inherited 16p13.11 duplication was identified by exome sequencing and considered to be likely associated with his and possibly his father's phenotype. The 16p13.11 duplication had been previously identified in an array CGH but had not been prioritized due to the lack of segregation in the siblings. In conclusion, we report a case of intra-familial locus heterogeneity of developmental delay in two siblings. We advocate for the need of unbiased and comprehensive genetic testing to provide accurate diagnosis despite locus heterogeneity.