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Cerebral folate transporter deficiency syndrome, caused by FOLR-1 mutations is characterized by late infantile onset, severe developmental regression, epilepsy, and leukodystrophy. An extremely low concentration of 5-methyltetrahydrofolate in the cerebrospinal fluid provides a crucial clue to its diagnosis and is a treatment target. Oral or intravenous folinic acid (5-formyltetrahydrofolate) administration improves clinical symptoms and brain magnetic resonance imaging (MRI) findings. We describe three siblings carrying a novel homozygous FOLR1 nonsense mutation, that were referred due to intractable epilepsy and progressive neurological decline. Brain MRI showed hypomyelination and cerebellar atrophy. Folinic acid (oral and intravenous) supplementation, initiated after over 15 years illness, has failed to result in any sizeable clinical or neurophysiological improvement. Cerebral folate transport deficiency bears overlapping clinical features with many severe developmental encephalopathies. It is crucial to recognize FOLR1 signs and establish an early clinical and molecular diagnosis in order to provide timely folinic acid treatment and improve outcome.

AIM To monitor functional auditory and non-verbal cognitive skills in children with cochlear implants who had associated disabilities over a 24-month period and define how cochlear implantation may impact on non-verbal cognition by restoring functional auditory skills. METHOD Sixty-four children with cochlear implants (36 females, 28 males; mean age 4y 3mo, SD 3y 5mo, 9mo-14y 5mo) were recruited and divided into three groups: children with typical development group (TDG); children with associated disabilities not linked to non-verbal cognitive disorders group (ADG1); and children with associated disabilities linked to non-verbal cognitive disorders group (ADG2). Tests of functional auditory, communicative, and non-verbal cognitive skills were performed before cochlear implantation and at 12 and 24 months after cochlear implantation. RESULTS Functional auditory and communicative skills improved similarly in the three groups at 12 and 24 months after implantation. An increase in non-verbal cognitive scores was present in children in the ADG2 from baseline to 12 and 24 months (p

We report the case of two siblings presenting with failure to thrive in early years, progressive microcephaly, moderate intellectual disability, developmental delay, ataxic gait and seizures with an identical EEG pattern, and minimal cerebellar atrophy. We ruled out the syndromic and metabolic causes of microcephaly and subsequently conducted a panel of genetic diagnostic tests, including the clinical exome sequencing which revealed compound heterozygous mutations in MED 17 gene in both patients. p.Glu16fs was found to be inherited from the mother and p.Gly253Arg from the father. This case along with review of the literature suggests that mutations in MED17 may define a phenotype characterized by progressive microcephaly, intellectual disability, seizures, cerebellar atrophy of variable degree, and ataxia. More cases are needed to define the phenotype-genotype correlation in MED17 mutations. However, basing on our findings, we recommend testing MED17 mutations in any patient presenting with two or more of the aforementioned signs and symptoms.

To describe the clinical, neuropsychological, and psychopathologic features of a cohort of children with a new diagnosis of symptomatic or presumed symptomatic focal epilepsy at time of recruitment and through the first month. The selected population will be followed for 2-5 years after enrollment to investigate the epilepsy course and identify early predictors of drug resistance.In this observational, multicenter, nationwide study, children (age 1 month-12.9 years) with a new diagnosis of symptomatic or presumed symptomatic focal epilepsy were consecutively enrolled in 15 Italian tertiary childhood epilepsy centers. Inclusion criteria were as follows: (1) diagnosis of symptomatic focal epilepsy due to acquired and developmental etiologies, and presumed symptomatic focal epilepsy; (2) age at diagnosis older than 1 month and13 years; and (3) written informed consent. Children were subdivided into three groups: ≤3 years,3 to 6 years, and6 years. Clinical, electroencephalography (EEG), neuroimaging, and neuropsychological variables were identified for statistical analyses.Two hundred fifty-nine children were enrolled (116 female and 143 male). Median age: 4.4 years (range 1 month-12.9 years); 46.0% (n = 119) of children were younger than 3 years, 24% (61) from 3 to 6 years of age, and 30% (79) older than 6 years. Neurologic examination findings were normal in 71.8%. Brain magnetic resonance imaging (MRI) was abnormal in 59.9%. Children age ≤3 years experienced the highest seizure frequency in the first month after recruitment (p0.0001). Monotherapy in the first month was used in 67.2%. Cognitive tests at baseline revealed abnormal scores in 30%; behavioral problems were present in 21%. At multivariate analysis, higher chances to exhibit more than five seizures in the first month after epilepsy onset was confirmed for younger children and those with temporal lobe epilepsy.In this prospective cohort study, an extensive characterization of epilepsy onset in children with symptomatic or presumed symptomatic focal epilepsies is reported in relation to the age group and the localization of the epileptogenic zone.

SUMMARY Purpose: Duplications encompassing the MECP2 gene on the Xq28 region have been described in male patients with moderate to severe mental retardation, absent speech, neonatal hypotonia, progressive spasticity and/or ataxia, recurrent severe respiratory infections, gastrointestinal problems, mild facial dysmorphisms (midface hypoplasia, depressed nasal bridge, large ears) and epilepsy. Epilepsy can occur in >50% of cases, but the types of seizures and the electroclinical findings in affected male individuals have been poorly investigated up to the present. Herein we describe eight patients with MECP2 duplication syndrome and a specific clinical and electroencephalographic pattern. Methods: Array CGH of genomic DNA from the probands was performed, and an Xq28 duplication ranging from 209 kb to 6.36 Mb was found in each patient. Electroencephalography studies and clinical and seizure features of all the patients were analyzed. Key findings: We found that epilepsy tended to occur between late childhood and adolescence. Episodes of loss of tone of the head and/or the trunk were the most represented seizure types. Generalized tonic‐clonic seizures were rarely observed. The typical interictal EEG pattern showed abnormal background activity, with generalized slow spike and wave asynchronous discharge with frontotemporal predominance. Sleep electroencephalography studies also demonstrated abnormal background activity; spindles and K complex were often abnormal in morphology and amplitude. Response to therapy was generally poor and drug resistance was a significant feature. Significance: Although these cases and a review of the literature indicate that epilepsy associated with MECP2 duplication syndrome cannot be considered a useful marker for early diagnosis, epilepsy is present in >90% of adolescent patients and shows a peculiar electroclinical pattern. Consequently, it should be considered a significant sign of the syndrome, and an EEG follow-up of these patients should be encouraged from early childhood. Moreover, the definition of a more specific epileptic phenotype could be useful in order to suspect MECP2 duplication syndrome in older undiagnosed patients.

We report on a girl affected with tuberous sclerosis, carrying a germline de novo TSC2 mutation, c.4934-4935delTT, leading to a p.F1645CfsX7, who developed a unilateral Wilms tumor (WT). Molecular investigation of the tumor biopsy at diagnosis revealed the loss of the constitutional wild-type TSC2 allele, and loss of heterozygosity for the WT1 gene. Deletion of the WTX gene was also present, but it involved the functionally inactive X chromosome. No mutation affecting the remaining WT1 and WTX alleles, as well as the CTNNB1 gene was found. Pathological examination of the surgical specimen documented the presence of diffuse anaplasia and p53 immunoreactivity. To the best of our knowledge, this is the second report of a patient with tuberous sclerosis who developed a WT, and it represents the first case in which a detailed clinical and molecular description is provided.

The lines of Blaschko are a cutaneous pattern of mosaicism present in a variety of skin disorders. Developmental abnormalities affecting other tissues derived from the embryonic ectoderm and mesoderm are sometimes associated. Here, we describe a 5-year-old boy with basaloid follicular hamartoma affecting the left side of the body in linear multiple bands, following Blaschko lines. Lesions were predominantly hypopigmented macules and streaks, but among these, we could observe brownish atrophic patches and brown papules. Furthermore, ipsilateral hemimegaloencephaly and microphthalmia were present. These findings suggest a neurocutaneous condition recently described by Happle and Tinschert. Its nosologic classification will be discussed.

We recently reported mutations in the sodium channel gene SCN2A in two families with benign familial neonatal-infantile seizures (BFNISs). Here, we aimed to refine the molecular-clinical correlation of SCN2A mutations in early childhood epilepsies. SCN2A was analyzed in 2 families with probable BFNIS, 9 with possible BFNIS, 10 with benign familial infantile seizures, and in 93 additional families with various early childhood epilepsies. Mutations effecting changes in conserved amino acids were found in two of two probable BFNIS families, in four of nine possible BFNIS families, and in none of the others. Our eight families had six different SCN2A mutations; one mutation (R1319Q) occurred in three families. BFNIS is an autosomal dominant disorder presenting between day 2 and 7 months (mean, 11.2 +/- 9.2 weeks) with afebrile secondarily generalized partial seizures; neonatal seizures were not seen in all families. The frequency of seizures varied; some individuals had only a few attacks without treatment and others had clusters of many per day. Febrile seizures were rare. All cases remitted by 12 months. Ictal recordings in four subjects showed onset in the posterior quadrants. SCN2A mutations appear specific for BFNIS; the disorder can now be strongly suspected clinically and the families can be given an excellent prognosis.

This is a case study of a child who developed roseola infantum first, then varicella, and was later affected by acute cerebellar syndrome, severe truncal ataxia, and myoclonic dystonia. Human herpesvirus 6 (HHV-6) A and B were detected in the cerebrospinal fluid (CSF) and peripheral blood, respectively, upon ataxia onset. The intricacy of this case suggests multifaceted conclusions ranging from the need for a multidirectional approach to neurological diseases, to confirmation of a more pronounced neurotropism of HHV-6A and a possible role of viruses in myoclonic dystonia syndrome, although this last hypothesis should be confirmed by larger studies.

Crisponi syndrome was described in the original paper in 17 patients form 12 families [Crisponi, 1996: Am J Med Genet 62:365-371]. It is characterised by episodes of muscle contraction in response to external stimuli and intermittent hypethermia with neonatal onset. The disease is often lethal in the first infancy. We describe a patient with the same unusual phenotype.

The synthesis of some N,N-disubstituted 4-amino-5,6-dihydro-3-phenyl-2H-thieno[2,3-h]-1-benzopyran-2-ones (4a-f), by reaction of phenylchloroketene with a series of N,N-disubstituted (E)-5-aminomethylene-6,7-dihydrobenzo[b]thiophen-4(5)-ones, followed by dehydrochlorination in situ of the primary adducts with DBN, is described. A moderate local anaesthetic activity was observed in the title compounds, particularly in 4e.