Charcot- Marie- Tooth (CMT) disease includes a group of clinically and genetically heterogeneous neuropathic disorders with an estimated frequency of 1 on 2.500 individuals. CMTs are differently classified according to the age of onset, type of inheritance, and type of inheritance plus clinical features. For these disorders, more than 100 genes have been implicated as causal factors, with mutations in the PMP22 being one of the most common. The demyelinating type (CMT1) affects more than 30% of the CMTs patients and manifests with motor and sensory dysfunctions of the peripheral nervous system mainly starting with slow progressive weakness of the lower extremities. We report here a 12 year- old boy presenting with typical features of CMT1 type, hearing impairment, and inguinal hernia who at the next-generation sequence analysis displayed a concomitant presence of two variants: the c.233 C>T p.Ser 78Leu of the MPZ gene (NM_000530.6) characterized as pathogenetic and the c.1403 G>A p.Arg 468His of the MFN2 gene (NM_014874.3) characterized as VUS. Concomitant variant mutations in CMTs have been uncommonly reported. The role of these gene mutations on the clinical expression and a literature review on this topic is discussed.

The Aristaless-related homeobox (ARX) transcription factor is involved in the development of GABAergic and cholinergic neurons in the forebrain. ARX mutations have been associated with a wide spectrum of neurodevelopmental disorders in humans and are responsible for both malformation (in particular lissencephaly) and nonmalformation complex phenotypes. The epilepsy phenotypes related to ARX mutations are West syndrome and X-linked infantile spasms, X-linked myoclonic epilepsy with spasticity and intellectual development and Ohtahara and early infantile epileptic encephalopathy syndrome, which are related in most of the cases to intellectual disability and are often drug resistant. In this article, we shortly reviewed current knowledge of the function of ARX with a particular attention on its consequences in the development of epilepsy during early childhood.

CDKL5 is a gene located in the X-chromosome (Xp22) encoding a serine/threonine kinase involved in various signaling pathways, implicated in cell proliferation, axon development, dendrite growth, synapse formation, and maintenance. Mutations occurring in this gene have been associated with drug-resistant early-onset epilepsy, with multiple seizures type, and deep cognitive and motor development delay with poor or absent speech, ataxic gait or inability to walk, hand stereotypies and in a few cases decrement of head growth. Many aspects remain unclear about the CDKL5 deficiency disorders, research will be fundamental to better understand the pathogenesis of neurological damage and consequently developed more targeted and profitable therapies, as there is not, at the present, a gene-based treatment and the seizures are in most of the cases drug resistant. In this article, we summarize the actual knowledge about CDKL5 gene function and mostly the consequence given by its dysfunction, also examining the possible therapeutic approaches.

KCNT1 gene encodes the sodium-dependent potassium channel reported as a causal factor for several different epileptic disorders. The gene has been also linked with cardiac disorders and in a family to sudden unexpected death in epilepsy. KCNT1 mutations, in most cases, result in a gain of function causing a neuronal hyperpolarization with loss of inhibition. Many early-onset epileptic encephalopathies related to gain of function of KCNT1 gene have been described, most often associated with two phenotypes: malignant migrating focal seizures of infancy and familial autosomal-dominant nocturnal frontal lobe epilepsy; however, there is no clear phenotype–genotype correlation, in fact same mutations have been represented in patients with West syndrome, Ohtahara syndrome, and early myoclonic encephalopathy. Additional neurologic features include intellectual disability, psychiatric disorders, hypotonia, microcephaly, strabismus, and movement disorders. Conventional anticonvulsant, vagal stimulation, and ketogenic diet have been used in the absence of clinical benefit in individuals with KCNT1-related epilepsy; in some patients, quinidine therapy off-label has been practiced successfully. This review aims to describe the characteristics of the gene, the phenotypes related to genetic mutations with the possible genotype–phenotype correlations and the treatments proposed to date, discussing the comorbidities reported in the literature.