CHD2-related neurodevelopmental disorders are characterized by early-onset epileptic encephalopathy (i.e., refractory seizures and cognitive slowing or regression associated with frequent ongoing epileptiform activity). Seizure onset is typically between ages six months and four years. Seizure types typically include drop attacks, myoclonus, and rapid onset of multiple seizure types associated with generalized spike-wave on EEG, atonic-myoclonic-absence seizures, and clinical photosensitivity. Intellectual disability and/or autism spectrum disorders are common.

Developmental and epileptic encephalopathy-41 (DEE41) is a neurologic disorder characterized by the onset of seizures in the first days or weeks of life. Affected infants show severely impaired psychomotor development with hypotonia, spasticity, lack of speech, poor visual fixation, feeding difficulties sometimes necessitating tube feeding, poor overall growth and microcephaly, and contractures. Brain imaging may show delayed myelination, thin corpus callosum, and cerebral atrophy (summary by the EPI4K Consortium, 2016). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.

HNRNPU-related neurodevelopmental disorder (HNRNPU-NDD) is characterized by developmental delay and intellectual disability – typically moderate to severe – with speech and language delay and/or absent speech. Affected individuals may also display autistic features. There may be feeding difficulties during the neonatal period as well as hypotonia, which often remains lifelong. Dysmorphic features have been described but they are nonspecific. Affected individuals are likely to experience seizures (most commonly tonic-clonic or absence) that may be refractory to treatment. Nonspecific brain MRI findings include ventriculomegaly and thinning of the corpus callosum. Less common findings include cardiac abnormalities, strabismus, undescended testes in males, renal anomalies, and skeletal features, including joint laxity, polydactyly, and scoliosis. Rarely, abnormal breathing patterns, including hyperventilation and apnea, may be present and can lead to sleep disturbance.

SCN1A seizure disorders encompass a spectrum that ranges from simple febrile seizures and generalized epilepsy with febrile seizures plus (GEFS+) at the mild end to Dravet syndrome and intractable childhood epilepsy with generalized tonic-clonic seizures (ICE-GTC) at the severe end. Phenotypes with intractable seizures including Dravet syndrome are often associated with cognitive decline. Less commonly observed phenotypes include myoclonic astatic epilepsy (MAE), Lennox-Gastaut syndrome, infantile spasms, epilepsy with focal seizures, and vaccine-related encephalopathy and seizures. The phenotype of SCN1A seizure disorders can vary even within the same family.

Neuronal ceroid lipofuscinosis-6B (CLN6B) is an autosomal recessive form of 'Kufs disease,' which refers in general to adult-onset neuronal ceroid lipofuscinosis without retinal involvement. CLN6B is a neurodegenerative disorder with a mean onset of symptoms at around age 28 years, although onset in the teens and later adulthood may also occur. Patients typically present with progressive myoclonus epilepsy, ataxia, loss of motor function, dysarthria, progressive dementia, and progressive cerebral and cerebellar atrophy on brain imaging. Ultrastructural examination typically shows fingerprint profiles and granular osmiophilic deposits in some tissues, including brain samples (summary by Arsov et al., 2011 and Berkovic et al., 2019). However, pathologic findings in peripheral tissues in adults is not as accurate for diagnosis as it is in children with the disease (Cherian et al., 2021). For a general phenotypic description and a discussion of genetic heterogeneity of CLN, see CLN1 (256730).