Atypical presentation of pediatric BRAF RASopathy with acute encephalopathy.

We report a 9-year-old girl with hypotonia, severe motor delay, absent speech, and facial dysmorphism who developed acute encephalopathy with severe neurological outcome. Trio-based whole exome sequencing (WES) analysis detected a de novo heterozygous mutation in the BRAF gene leading to the diagnosis of an atypical presentation of cardiofaciocutaneous (CFC) syndrome. This is the second case of CFC syndrome complicated with acute encephalopathy reported in the literature and supports the hypothesis that acute encephalopathy might be one of the complications of the syndrome due to an intrinsic susceptibility to this acute event. The report furthermore highlights the role of WES in providing a fast diagnosis in patients in critical conditions with atypical presentation of rare genetic syndromes.

Defining the electroclinical phenotype and outcome of PCDH19-related epilepsy: A multicenter study.

OBJECTIVE: PCDH19-related epilepsy is an epileptic syndrome with infantile onset, characterized by clustered and fever-induced seizures, often associated with intellectual disability (ID) and autistic features. The aim of this study was to analyze a large cohort of patients with PCDH19-related epilepsy and better define the epileptic phenotype, genotype-phenotype correlations, and related outcome-predicting factors. METHODS: We retrospectively collected genetic, clinical, and electroencephalogram (EEG) data of 61 patients with PCDH19-related epilepsy followed at 15 epilepsy centers. All consecutively performed EEGs were analyzed, totaling 551. We considered as outcome measures the development of ID, autistic spectrum disorder (ASD), and seizure persistence. The analyzed variables were the following: gender, age at onset, age at study, genetic variant, fever sensitivity, seizure type, cluster occurrence, status epilepticus, EEG abnormalities, and cognitive and behavioral disorders. Receiver operating characteristic curve analysis was performed to evaluate the age at which seizures might decrease in frequency. RESULTS: At last follow-up (median = 12 years, range = 1.9-42.1 years), 48 patients (78.7%) had annual seizures/clusters, 13 patients (21.3%) had monthly to weekly seizures, and 12 patients (19.7%) were seizure-free for ≥2 years. Receiver operating characteristic analysis showed a significant decrease of seizure frequency after the age of 10.5 years (sensitivity = 81.0%, specificity = 70.0%). Thirty-six patients (59.0%) had ID and behavioral disturbances. ASD was present in 31 patients. An earlier age at epilepsy onset emerged as the only predictive factor for ID (P = 0.047) and ASD (P = 0.014). Conversely, age at onset was not a predictive factor for seizure outcome (P = 0.124). SIGNIFICANCE: We found that earlier age at epilepsy onset is related to a significant risk for ID and ASD. Furthermore, long-term follow-up showed that after the age of 10 years, seizures decrease in frequency and cognitive and behavioral disturbances remain the primary clinical problems.

A novel mutation in COL4A1 gene: a possible cause of early postnatal cerebrovascular events.

COL4A1 is located in humans on chromosome13q34 and it encodes the alpha 1 chain of type IV collagen, a component of basal membrane. It is expressed mainly in the brain, muscles, kidneys and eyes. Different COL4A1 mutations have been reported in many patients who present a very wide spectrum of clinical symptoms. They typically show a multisystemic phenotype. Here we report on the case of a patient carrying a novel de novo splicing mutation of COL4A1 associated with a distinctive clinical picture characterized by onset in infancy and an unusual evolution of the neuroradiological features. At three months of age, the child was diagnosed with a congenital cataract, while his brain MRI was normal. Over the following years, the patient developed focal epilepsy, mild diplegia, asymptomatic microhematuria, raised creatine kinase levels, MRI white matter abnormalities and brain calcification on CT. During the neuroradiological follow-up the extension and intensity of the brain lesions progressively decreased. The significance of a second variant in COL4A1 carried by the child and inherited from his father remains to be clarified. In conclusion, our patient shows new aspects of this collagenopathy and possibly a COL4A1 compound heterozygosity.

Novel PTRF mutation in a child with mild myopathy and very mild congenital lipodystrophy.

BACKGROUND: Mutations in the PTRF gene, coding for cavin-1, cause congenital generalized lipodystrophy type 4 (CGL4) associated with myopathy. In CGL4, symptoms are variable comprising, in addition to myopathy, smooth and skeletal muscle hypertrophy, cardiac arrhythmias, and skeletal abnormalities. Secondary features are atlantoaxial instability, acanthosis nigricans, hepatomegaly, umbilical prominence and metabolic abnormalities related to insulin resistance, such as diabetes mellitus, hyperlipidemia and hepatic steatosis. CASE PRESENTATION: We describe a 3 year-old child of Moroccan origin with mild muscle phenotype, mainly characterized by mounding, muscle pain, hyperCKemia and mild caveolin 3 reduction on muscle biopsy. No CAV3 gene mutation was detected; instead we found a novel mutation, a homozygous single base pair deletion, in the PTRF gene. Only after detection of this mutation a mild generalized loss of subcutaneous fat, at first underestimated, was noticed and the diagnosis of lipodystrophy inferred. CONCLUSIONS: The PTRF gene should be investigated in patients with hyperCKemia, mild myopathy associated with spontaneous or percussion-induced muscle contractions like rippling or mounding, and no CAV3 mutation. The analysis should be performed even if cardiac or metabolic alterations are absent, particularly in young patients in whom lipodystrophy may be difficult to ascertain.

Genetic testing in benign familial epilepsies of the first year of life: clinical and diagnostic significance.

PURPOSE: To dissect the genetics of benign familial epilepsies of the first year of life and to assess the extent of the genetic overlap between benign familial neonatal seizures (BFNS), benign familial neonatal-infantile seizures (BFNIS), and benign familial infantile seizures (BFIS). METHODS: Families with at least two first-degree relatives affected by focal seizures starting within the first year of life and normal development before seizure onset were included. Families were classified as BFNS when all family members experienced neonatal seizures, BFNIS when the onset of seizures in family members was between 1 and 4 months of age or showed both neonatal and infantile seizures, and BFIS when the onset of seizures was after 4 months of age in all family members. SCN2A, KCNQ2, KCNQ3, PPRT2 point mutations were analyzed by direct sequencing of amplified genomic DNA. Genomic deletions involving KCNQ2 and KCNQ3 were analyzed by multiple-dependent probe amplification method. KEY FINDINGS: A total of 46 families including 165 affected members were collected. Eight families were classified as BFNS, 9 as BFNIS, and 29 as BFIS. Genetic analysis led to the identification of 41 mutations, 14 affecting KCNQ2, 1 affecting KCNQ3, 5 affecting SCN2A, and 21 affecting PRRT2. The detection rate of mutations in the entire cohort was 89%. In BFNS, mutations specifically involve KCNQ2. In BFNIS two genes are involved (KCNQ2, six families; SCN2A, two families). BFIS families are the most genetically heterogeneous, with all four genes involved, although about 70% of them carry a PRRT2 mutation. SIGNIFICANCE: Our data highlight the important role of KCNQ2 in the entire spectrum of disorders, although progressively decreasing as the age of onset advances. The occurrence of afebrile seizures during follow-up is associated with KCNQ2 mutations and may represent a predictive factor. In addition, we showed that KCNQ3 mutations might be also involved in families with infantile seizures. Taken together our data indicate an important role of K-channel genes beyond the typical neonatal epilepsies. The identification of a novel SCN2A mutation in a family with infantile seizures with onset between 6 and 8 months provides further confirmation that this gene is not specifically associated with BFNIS and is also involved in families with a delayed age of onset. Our data indicate that PRRT2 mutations are clustered in families with BFIS. Paroxysmal kinesigenic dyskinesia emerges as a distinctive feature of PRRT2 families, although uncommon in our series. We showed that the age of onset of seizures is significantly correlated with underlying genetics, as about 90% of the typical BFNS families are linked to KCNQ2 compared to only 3% of the BFIS families, for which PRRT2 represents the major gene.

Focal seizures with affective symptoms are a major feature of PCDH19 gene-related epilepsy.

PURPOSE: Mutations of the protocadherin19 gene (PCDH19) cause a female-related epilepsy of variable severity, with or without mental retardation and autistic features. Despite the increasing number of patients and mutations reported, the epilepsy phenotype associated with PCDH19 mutations is still unclear. We analyzed seizure semiology through ictal video-electroencephalography (EEG) recordings in a large series of patients. METHODS: We studied 35 patients with PCDH19 gene-related epilepsy and analyzed clinical history and ictal video-EEG recordings obtained in 34 of them. KEY FINDINGS: Clusters of focal febrile and afebrile seizures had occurred in 34 patients, at a mean age of 10 months. The predominant and more consistent ictal sign was fearful screaming, occurring in 24 patients (70.5%); it was present since epilepsy onset in 12 and appeared later on, during the course in the remaining 12 patients. In infancy, fearful screaming mainly appeared within the context of seizures with prominent hypomotor semiology, whereas during follow-up it was associated with prominent early motor manifestations. In 16 patients, seizures were video-EEG recorded both at onset and during follow-up: in five patients (31%) seizure semiology remained identical, in 7 (44%) semiology varied and in four patients it was unclear whether ictal semiology changed with age. Three patients (9%) had both focal and generalized seizures, the latter consisting of absences and myoclonus. Ictal EEG during focal seizures showed a prominent involvement of the frontotemporal regions (22 patients). About 45% of patients had an alternating EEG pattern, with the ictal discharge migrating from one hemisphere to the contralateral during the same ictal event. Status epilepticus occurred in 30% of patients. Cognitive impairment occurred in 70%, ranging from mild (42%) to moderate (54%) and severe (4%); autistic features occurred in 28.5%. Direct sequencing detected 33 different heterozygous candidate mutations, 8 of which were novel. Mutations were missense substitutions (48.5%), premature termination (10 frameshift, 4 nonsense, and 2 splice-site mutations; 48.5%), and one in-frame deletion. Thirty candidate mutations (91%) were de novo. No specific genotype-phenotype correlation could be established, as missense and truncating mutations were associated with phenotypes of comparable severity. SIGNIFICANCE: Most patients with PCDH19 mutations exhibit a distinctive electroclinical pattern of focal seizures with affective symptoms, suggesting an epileptogenic dysfunction involving the frontotemporal limbic system. Awareness of this distinctive phenotype will likely enhance recognition of this disorder.

Clinical spectrum and genotype-phenotype correlations in PRRT2 Italian patients.

Prrt2 is a neuron-specific protein expressed at axonal and pre-synaptic domains, involved in synaptic neurotransmitter release and modulation of intrinsic excitability. Mutations in PRRT2 cause a spectrum of autosomal dominant paroxysmal neurological disorders including epilepsy, movement disorders, and hemiplegic migraine and show incomplete penetrance and variable expressivity. We assessed the diagnostic rate of PRRT2 in a cohort of Italian patients with epilepsy and/or paroxysmal kinesigenic dyskinesia (PKD) and evaluated genotype-phenotype correlations. Clinical data were collected using a structured questionnaire. Twenty-seven out of 55 (49.1%) probands carried PRRT2 heterozygous pathogenic variants, including six previously known genotypes and one novel missense mutation. A family history of epilepsy starting in the first year of life and/or PKD was strongly suggestive of a PRRT2 pathogenic variant. Epilepsy patients harbouring PRRT2 pathogenic variants showed earlier seizure onset and more frequent clusters compared with PRRT2-negative individuals with epilepsy. Moreover, we did also identify individuals with PRRT2 pathogenic variants with atypical age at onset, i.e. childhood-onset epilepsy and infantile-onset PKD. However, the lack of a clear correlation between specific PRRT2 genotypes and clinical manifestations and the high incidence of asymptomatic carriers suggest the involvement of additional factors in modulating expressivity of PRRT2-related disorders. Finally, our study supports the pleiotropic and multifaceted physiological role of PRRT2 gene which is emerging from experimental neuroscience.

A questionnaire on sleep behaviour in the first years of life: preliminary results from a normative sample.

The authors developed a questionnaire in Italian for investigating sleep problems in infants and toddlers. Applying the questionnaire, they conducted an exploratory investigation into the sleep behaviour of a sample of normal children during their first three years of life in order to gather preliminary data regarding the ease of use of the instrument. The questionnaire and the results of its first application (in an Italian sample of 50 healthy children aged 10-39 months) are presented. The results provide interesting information on the sleep behaviour of the young children in our sample and prompt reflections in relation to the instrument employed. The sleep behaviour questionnaire emerged, above all, as easy to use and readily comprehensible to those participating in this research study. Furthermore, it provided parents with an opportunity to reflect upon their child and his/her rhythms (in particular sleep-wake rhythms) and upon their own ability to manage these rhythms. This instrument seems, on the basis of these preliminary data, to allow the tracing of a well-defined and complete picture of the sleep behaviour of the healthy child in the first years of life.