Clinical characteristics KCNQ2-related disorders represent a continuum of overlapping neonatal epileptic phenotypes caused by a heterozygous pathogenic variant in KCNQ2. The clinical features of KCNQ2-related disorders range from KCNQ2-related benign familial neonatal epilepsy (KCNQ2-BFNE) at the mild end to KCNQ2-related neonatal epileptic encephalopathy (KCNQ2-NEE) at the severe end. KCNQ2-BFNE is characterized by a wide spectrum of seizure types (tonic or apneic episodes, focal clonic activity, or autonomic changes) that start in otherwise healthy infants between the second and eighth day of life and spontaneously disappear between the first and the sixth to 12th month of life. Motor activity may be confined to one body part, migrate to other body regions, or generalize. Seizures are generally brief, lasting one to two minutes. Rarely, KCNQ2-BFNE may evolve into status epilepticus. About 10%-15% of individuals with BFNE develop epileptic seizures later in life. KCNQ2-NEE is characterized by multiple daily seizures beginning in the first week of life that are mostly tonic, with associated focal motor and autonomic features. Seizures generally cease between ages nine months and four years. At onset, EEG shows a burst-suppression pattern or multifocal epileptiform activity; early brain MRI can show basal ganglia and thalamic hyperintensities that later resolve. Moderate to severe developmental impairment is present. Diagnosis/testing The diagnosis relies on the presence of characteristic clinical findings and heterozygous pathogenic variants in KCNQ2 (also known as Kv7.2), which codes for voltage-gated potassium channel subunits. Management Treatment of manifestations: KCNQ2-BFNE. The majority of children can be kept seizure-free by using phenobarbital (20 mg/kg as loading dose and 5 mg/kg/day as maintenance dose). In some affected individuals, seizures require other antiepileptic drugs (AEDs). KCNQ2-NEE. Children have multiple daily seizures resistant at onset to phenobarbital and other common old- and new-generation AEDs, alone or in combination. Sodium channel blockers like phenytoin (PHT) or carbamazepine (CBZ) were shown to control seizures in several patients and should be considered first-line treatment. Surveillance: KCNQ2-BFNE. EEG at age three, 12, and 24 months is appropriate. At 24 months EEG should be normal. KCNQ2-NEE. EEG monitoring is highly recommended, although specific guidelines are not available. Genetic counseling KCNQ2-related disorders are inherited in an autosomal dominant manner. Most individuals diagnosed with KCNQ2-BFNE have an affected parent; however, a proband may have KCNQ2-BFNE as the result of a de novo pathogenic variant. Almost all individuals with KCNQ2-NEE have a de novo pathogenic variant. Each child of an individual with a KCNQ2-related disorder has a 50% chance of inheriting the pathogenic variant. Prenatal diagnosis for pregnancies at increased risk is possible if the pathogenic variant in the family is known.

KCNQ2-Related Disorders

https://air.unimi.it/bitstream/2434/223548/2/Daber-R.D._Ring-chromosome-20_2012.pdf

Ring chromosome 20.

Ring chromosomes arise following breakage and rejoining in both chromosome arms. They are heterogeneous with variable size and genetic content and can originate from any chromosome. Phenotypes associated with ring chromosomes are highly variable as apart from any deletion caused by ring formation, imbalances from ring instability can also occur. Of interest is ring chromosome 20 which has a significant association with epilepsy with seizure onset in early childhood. Severe growth deficiency without major malformations is a common finding in the ring chromosome carrier. This phenotype associated with ring behaviour and mitotic instability and independent of the chromosome involved has been termed the “ring syndrome”. Precise genotype-phenotype correlations for ring chromosomes may not be possible as influencing factors vary depending on the extent of deletion in ring formation, ring instability and the level of mosaicism. Although ring chromosomes usually arise as de novo events, familial transmission of rings from carrier to offspring has been described and prenatal diagnosis for any pregnancies should always be considered.

Autosomal ring chromosomes in human genetic disorders

Ring chromosomes (RCs) are circular DNA molecules, which occur rarely in eukaryotic nuclear genomes. Lilian Vaughan Morgan first described them in the fruit fly. Human embryos very seldom have RCs, about 1:50,000. Carriers of RCs may have varying degrees of symptoms, from healthy phenotype to serious pathologies in physical and intellectual development. Many authors describe common symptoms of RC presence: short stature and some developmental delay that could be described as a “ring chromosome syndrome.” As a rule, RCs arise de novo through the end-joining of two DNA double-strand breaks, telomere-subtelomere junction, or inv dup del rearrangement in both meiosis and mitosis. There are family cases of RC inheritance. The presence of RCs causes numerous secondary chromosome rearrangements in vivo and in vitro. RCs can change their size, become lost, or increase their copy number and cause additional deletions, duplication, and translocations, affecting both RCs and other chromosomes. In this review, we examine RC inheritance, instability, mechanisms of formation, and potential clinical applications of artificially created RCs for large-scale chromosome rearrangement treatment.

Ring chromosomes: from formation to clinical potential.

16.01.14 – 15.01.2016 Ricercatrice Postdoc Studio dei meccanismi patogenetici e sviluppo di nuove terapie in modelli animali di epilessia associata a malformazione dello sviluppo corticale Tutor: Dr. Giorgio Battaglia Fondazione I.R.C.C.S. Istituto Neurologico “C. Besta”, Sede Bicocca, Via Temolo, 4 20126 Milano Tel: +39 02 23942605/606, Fax: +39 02 23942619; email: giorgio.battaglia@istituto-besta.it

Curriculum Vitae Europass Informazioni personali

Background
Mosaic Chromosome 20 ring [r(20)] is a chromosomal disorder associated with a rare syndrome characterized by a typical seizure phenotype, a particular electroclinical pattern, cognitive impairment, behavioural problems and absence of a consistent pattern of dysmorphology. The pathogenic mechanism underlying seizures disorders in r(20) syndrome is still unknown. We performed a detailed clinical and genetic study on 8 patients with r(20) chromosome, aimed at detecting the genetic mechanism underlying r(20) syndrome.

/pdf/genetic-investigations-on-8-patients-affected-by-ring-20-2r853bprdy.pdf

Genetic investigations on 8 patients affected by ring 20 chromosome syndrome

Rett syndrome caused by MECP2 variants is characterized by a heterogenous clinical spectrum accounted for in 60% of cases by hot-spot variants. Focusing on the most frequent variants, we generated in vitro iPSC-neurons from the blood of RTT girls with p.Arg133Cys and p.Arg255*, associated to mild and severe phenotype, respectively, and of an RTT male harboring the close to p.Arg255*, p.Gly252Argfs*7 variant. Truncated MeCP2 proteins were revealed by Western blot and immunofluorescence analysis. We compared the mutant versus control neurons at 42 days for morphological parameters and at 120 days for electrophysiology recordings, including girls’ isogenic clones. A precocious reduced morphological complexity was evident in neurons with truncating variants, while in p.Arg133Cys neurons any significant differences were observed in comparison with the isogenic wild-type clones. Reduced nuclear size and branch number show up as the most robust biomarkers. Patch clamp recordings on mature neurons allowed the assessment of cell biophysical properties, V-gated currents, and spiking pattern in the mutant and control cells. Immature spiking, altered cell capacitance, and membrane resistance of RTT neurons, were particularly pronounced in the Arg255* and Gly252Argfs*7 mutants. The overall results indicate that the specific markers of in vitro cellular phenotype mirror the clinical severity and may be amenable to drug testing for translational purposes.

/pdf/modeling-rtt-syndrome-by-ipsc-derived-neurons-from-male-and-iu3n2gsz.pdf

Nicole Camporeale

Papers

Genetic investigations on 8 patients affected by ring 20 chromosome syndrome

Modeling RTT Syndrome by iPSC-Derived Neurons from Male and Female Patients with Heterogeneously Severe Hot-Spot MECP2 Variants