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Epilepsy is rarely associated with Joubert's syndrome and related disorders (JSRD), being reported only in 3% of cases. Few patients have been described, moreover, with poor evidences of specific seizures' semiology or standard of practice for pharmacological treatment. Epilepsy is likely to be related to brain malformations in ciliopathies. Beyond the typical hindbrain malformation, the molar tooth sign, other cerebral anomalies variably reported in JSRD, such as generalized polymicrogyria, hamartomas, periventricular nodular heterotopia, and hippocampal defects, have been described. Herein, we aimed to revise the main clinical and etiopathogenetic characteristics of epilepsy associated with JSRD.

Alström syndrome (ALMS) is a rare ciliopathy with pleiotropic and wide spectrum of clinical features. It is autosomal recessively inherited and associated with mutations in ALMS1, a gene involved in cilia functioning. High clinical heterogeneity is the main feature of ALMS. Cone-rod dystrophy with blindness, hearing loss, obesity, insulin resistance and hyperinsulinemia, type 2 diabetes mellitus, hypertriglyceridemia, endocrine abnormalities, cardiomyopathy, and renal, hepatic, and pulmonary anomalies are the most common signs and symptoms.

Bardet–Biedl syndrome is a genetically pleiotropic disorder characterized by high clinical heterogeneity with severe multiorgan impairment. Clinically, it encompasses primary and secondary manifestations, mainly including retinal dystrophy, mental retardation, obesity, polydactyly, hypogonadism in male, and renal abnormalities. At least 21 different genes have been identified, all involved into primary cilium structure or function. To date, genotype–phenotype correlation is still poor.

The SLC25A22 (Solute Carrier Family 25, Member 22) gene encodes for a mitochondrial glutamate/H+ symporter and is involved in the mitochondrial transport of metabolites across the mitochondrial membrane. We hereby report a 12-year-old girl presenting with early-onset epileptic encephalopathy, hypotonia, and global developmental delay. Whole exome sequencing identified a novel homozygous missense mutation in SLC25A22 gene (c.97A>G; p.Lys33Glu), as the likely cause of the disease. The phenotype of our patient and EEG recordings do not completely overlap with the phenotypes previously described, leading to a new and more complex form of disease associated with SLC25A22 variants, characterized by dyskinetic movements and oculogyric crisis.

Purpose: The mediator (MED) multisubunit-complex modulates the activity of the transcriptional machinery, and genetic defects in different MED subunits (17, 20, 27) have been implicated in neurologic diseases. In this study, we identified a recurrent homozygous variant in MED11 (c.325C>T; p.Arg109Ter) in 7 affected individuals from 5 unrelated families. Methods: To investigate the genetic cause of the disease, exome or genome sequencing were performed in 5 unrelated families identified via different research networks and Matchmaker Exchange. Deep clinical and brain imaging evaluations were performed by clinical pediatric neurologists and neuroradiologists. The functional effect of the candidate variant on both MED11 RNA and protein was assessed using reverse transcriptase polymerase chain reaction and western blotting using fibroblast cell lines derived from 1 affected individual and controls and through computational approaches. Knockouts in zebrafish were generated using clustered regularly interspaced short palindromic repeats/Cas9. Results: The disease was characterized by microcephaly, profound neurodevelopmental impairment, exaggerated startle response, myoclonic seizures, progressive widespread neurodegeneration, and premature death. Functional studies on patient-derived fibroblasts did not show a loss of protein function but rather disruption of the C-terminal of MED11, likely impairing binding to other MED subunits. A zebrafish knockout model recapitulates key clinical phenotypes. Conclusion: Loss of the C-terminal ofMED subunit 11 may affect its binding efficiency to otherMED subunits, thus implicating the MED-complex stability in brain development and neurodegeneration.

Joubert syndrome (JS) is a rare inherited disorder of central nervous system with neonatal/infantile onset, mainly affecting cerebellum and brainstem, and clinically characterized by agenesis or dysgenesis of the cerebellar vermis with accompanying brainstem malformations. More than 20 disease-causing genes have been associated with JS but a clear genotype–phenotype correlation has not been assessed yet. Diagnosis is usually confirmed by detection of the JS neuroradiological hallmark, the molar tooth sign. Patients with JS typically present with neurological manifestations, moreover, a heterogeneous spectrum of multisystemic anomalies may be observed. Signs and symptoms onset varies according to the age range and clinical diagnosis might become complicated. Moreover, specific neurodevelopmental disorders can be associated with JS such as autism spectrum disorders, attention deficit with hyperactivity, and a wide range of behavioral disturbances. Here, we examined the main neurological and neurodevelopmental features of JS according to an age-dependent mode of presentation. Furthermore, differential diagnosis with other neurological syndromes was closely reviewed.

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Mutations in genes involved in chromatin remodelling have been implicated in broad phenotypes of congenital abnormalities and neurodevelopment. However, limited genotype–phenotype correlations are available for some of the rarest genetic disorders that affect chromatin regulation. We hereby describe a 12-year-old girl presented at birth with severe hypotonia, developmental delay, a mid-line capillary malformation and distinctive craniofacial features. During the natural history of her disease, the girl developed severe spasticity and drug-resistant seizures, leading to a diagnosis of Bohring–Opitz syndrome (BOS). We performed whole-exome sequencing (WES) and identified a de novo mutation in ASXL1 (c.2033dupG) which results in the introduction of a premature stop codon (p.R678fs*6). ASXL1 encodes a polycomb repressive complex protein implicated in chromatin regulation and de novo mutations are a known cause of BOS. Phenotypes with segmental craniofacial overgrowth associated to midline capillary malformations enlarge the clinical spectrum of BOS at onset and further expand the differential diagnosis in ASXL1 mutation carriers.

Microduplication of chromosome 8q22.1 is mainly associated to Leri’s pleonosteosis syndrome phenotype, an extremely rare autosomal dominant disease encompassing the GDF6 and SDC2 genes. To date, most of the authors focus their attention only on skeletal symptoms of the disease, and they do not systematically research or describe the co-occurrence of psychiatric illnesses or mental disorders with these muscular-skeletal diseases. In this report, we provide a description of an 8-year-old girl, with a positive family history for both skeletal malformations and bipolar disorders (BD). We suggest a possible association between Leri’s pleonosteosis features and psychiatric symptoms. Furthermore, our report could be added to the large amount of reports that describe the correlation between genetic regions and disease risk for both psychiatric and rheumatological disorders.

Biallelic mutations in the SLC1A4 gene have been identified as a very rare cause of neurodevelopmental disorders. l-serine transport deficiency has been regarded as the causal molecular mechanism underlying the neurological phenotype of SLC1A4 mutation patients. To date this genetic condition has been reported almost exclusively in a limited number of Ashkenazi-Jewish individuals and as a result the SLC1A4 gene is not routinely included in the majority of the genetic diagnostic panels for neurological diseases. We hereby report a 7-year-old boy from a Southern Italian family, presenting with epileptic encephalopathy, congenital microcephaly, global developmental delay, severe hypotonia, spasticity predominant at the lower limbs, and thin corpus callosum. Whole exome sequencing identified a novel segregating SLC1A4 gene homozygous mutation (c.1141G > A: p.Gly381Arg) as the likely cause of the disease in our family. In order to deeply characterize the electro-clinical and neurological phenotype in our index patient, long-term systematic video-electroencephalograms (EEG) as well as repeated brain imaging studies (which included tractographic reconstructions) were performed on a regular basis during a 7 years follow-up time. In conclusion, we suggest to carefully considering SLC1A4 biallelic mutations in individuals presenting an early onset severe neurodevelopmental disorder with variable spasticity and seizures, regardless the patients' ethnic background.

Mutations in genes involved in chromatin remodelling have been implicated in broad phenotypes of congenital abnormalities and neurodevelopment. However, limited genotype-phenotype correlations are available for some of the rarest genetic disorders that affect chromatin regulation. We hereby describe a 12-year-old girl presented at birth with severe hypotonia, developmental delay, a mid-line capillary malformation and distinctive craniofacial features. During the natural history of her disease, the girl developed severe spasticity and drug-resistant seizures, leading to a diagnosis of Bohring-Opitz syndrome (BOS). We performed whole-exome sequencing (WES) and identified a de novo mutation in ASXL1 (c.2033dupG) which results in the introduction of a premature stop codon (p.R678fs*6). ASXL1 encodes a polycomb repressive complex protein implicated in chromatin regulation and de novo mutations are a known cause of BOS. Phenotypes with segmental craniofacial overgrowth associated to midline capillary malformations enlarge the clinical spectrum of BOS at onset and further expand the differential diagnosis in ASXL1 mutation carriers.

De novo mutations in the GRIN1 gene have been recently reported as the molecular cause of a broad-spectrum early-onset neurological phenotype. Here, we describe a five-year-old girl with an early-onset epileptic encephalopathy associated with an infantile hyperkinetic movement disorder and oculomotor abnormalities. Whole-exome sequencing identified a novel p.Met641Leu de novo variant in the GRIN1 gene as the cause of the phenotype. In silico analysis suggested that the p.Met641Leu variant would alter the gating property of the ion channel, with the involved methionine residue facing towards the ion pore. Long-term systematic video-EEG allowed us to report on the electroclinical history and, specifically, on the semiology of the hyperkinetic movement disorder and oculomotor abnormalities resembling oculogyric crises in our patient. Our findings and a review of the recent literature reinforce the notion of GRIN1-encephalopathy as a recognizable neurological phenotype that should be suspected in early-onset epilepsy associated with hyperkinetic movement disorders. [Published with video sequence on www.epilepticdisorders.com].

In the last years second-generation antipsychotics are increasingly prescribed in the pediatric population for the treatment of several psychiatric disorders. Among the long term adverse effects, extrapyramidal symptoms (EPS) are less reported compared to first-generation antipsychotics. Tardive dyskinesia (TD) is a iatrogenic rare syndrome characterized by persistent slow writhing and sudden involuntary movements mainly involving the oral-buccal-lingual area with masticatory movements. We report a young girl with mood disorders accompanied by mild intellectual disability and behavioral problems who had TD after treatment with Aripiprazole, which responded to Biperiden therapy.

Purpose The present study aimed to assess the impact of the ketogenic diet on arterial morphology and endothelial function of the big vessels of the neck and on cardiac diastolic function, in a cohort of epileptic children and young adults treated with the ketogenic diet. Methods Patients were recruited based on the following inclusion criteria: (1) patients who were or had been on the ketogenic diet for a time period of at least six months. Each patient underwent measurement of carotid intima media thickness, carotid artery stiffness, echocardiography, and diastolic function assessment. Patients with drug resistant epilepsy, matched for number, age and sex and never treated with ketogenic diet, were recruited as controls. Results The population study was composed by 43 epilepsy patients (23 males), aged between 19 months and 31 years (mean 11 years). Twenty-three patients were or had been treated with ketogenic diet, and 20 had never been on it (control group). Subjects treated with the ketogenic diet had higher arterial stiffness parameters, including AIx and β-index and higher serum levels of cholesterol or triglycerides compared to those who had never been on the diet (control group) ( p Conclusions Arterial stiffness is increased in children and young adults treated with the ketogenic diet, before the increase of the intima media thickness. This supports that arterial stiffness is an early marker of vascular damage.

Sequencing of the KCNT1, PLCB1, SCN1A and TBC1D24 loci was performed in six children with typical features of malignant migrating partial seizures of infancy (MMPSI), to verify the presence of potential disease-causing mutations, including those already reported to be associated with the disease. Sanger sequencing failed to identify in these genes the previously reported pathogenic mutations in these patients, while a comprehensive mutational scanning analysis of these four loci by targeted re-sequencing led to detection of both intronic and exonic new variants. Based on the current knowledge, the sequence variants identified here do not allow to predict functional phenotypes that might explain, at least in part, MMPSI symptoms.

We report the case of a 11-year-old girl who developed an isolated hand-writing disorder with dysgraphia at the beginning of the school year in the sixth grade. A brain magnetic resonance angiography showed a round arteriovenous malformation sited in the left side of the midbrain extending to the ipsilateral medio-basal thalamus. Child neurologists should never neglect a thorough neurological evaluation in case of isolated worsening of handwriting, to rule out possible underlying organic causes.