Search

The histone demethylase family plays a key role in chromatin structure and gene regulation during development. Mutations in the genes encoding the lysine demethylase 5 (KDM5) were reported in individuals with many diseases, including neurodevelopmental disorders such as intellectual disability. Recently, KDM5B has been identified as a gene regulator causative of recessive neurodevelopmental disorders. Although numerous variants in this gene have been identified, genotype / phenotype correlation remains variable. We report a patient with two de novo mutations, a frameshift KDM5B variant and a 2q deletion of 8.2 Mb, associated with a phenotype including facial and finger dysmorphisms, severe intellectual and motor disorders, and a rare epileptic syndrome identified as epilepsy of infancy with migrating focal seizures. Comparison with previous reports suggests that the KDM5B variant could play a potential role on dysmorphic features; conversely, the epileptic disorder is mainly caused by the haploinsufficiency of the Nav1 mediated gabaergic inhibition.

Fragile X syndrome (FXS; MIM 300624) is an X-linked genetic disorder characterized by physical abnormalities associated with intellectual disability and a wide spectrum of neurological and psychiatric impairments. FXS occurs more frequently in males, 1 in 5000 males and 1 in 8000 females accounting for 1-2% of overall intellectual disability (ID). In more than 99% of patients, FXS results from expansions of a CGG triplet repeat (>200 in male) of the FMR1 gene. In the last years an increasing number, albeit still limited, of FXS subjects carrying FMR1 mutations including deletions, splicing errors, missense, and nonsense variants was reported. Nevertheless, the studies concerning the functional consequences of mutations in the FMR1 gene are rare so far and, therefore, we do not have sufficient knowledge regarding the genotype/phenotype correlation. We report a child carrying a hemizygous missense FMR1 (NM_002024.5:c.1325G > A p.Arg442Gln) variant, maternally inherited, associated with facial abnormalities, developmental delay, and social and communication deficits assessed with formal neuropsychological tests. The study contributes to highlighting the clinical differences between the CGG triplet repeat dependent phenotype and FMR1variant dependent phenotype and it also confirms the pathogenicity of the variant being reported for the second time in the literature.

Cachexia is a multifactorial and multi-organ syndrome that is a major cause of morbidity and mortality in late-stage chronic diseases. The main clinical features of cancer-related cachexia are chronic inflammation, wasting of skeletal muscle and adipose tissue, insulin resistance, anorexia, and impaired myogenesis. A multimodal treatment has been suggested to approach the multifactorial genesis of cachexia. In this context, physical exercise has been found to have a general effect on maintaining homeostasis in a healthy life, involving multiple organs and their metabolism. The purpose of this review is to present the evidence for the relationship between inflammatory cytokines, skeletal muscle, and fat metabolism and the potential role of exercise training in breaking the vicious circle of this impaired tissue cross-talk. Due to the wide-ranging effects of exercise training, from the body to the behavior and cognition of the individual, it seems to be able to improve the quality of life in this syndrome. Therefore, studying the molecular effects of physical exercise could provide important information about the interactions between organs and the systemic mediators involved in the overall homeostasis of the body.

Background Early starting of migraine seems predictive for less favorable outcome in later ages, however follow-up investigations are very few and all with short-term prospective period. We report here the longest follow-up study in a population of children presenting with migraine under the age of 6. Methods We followed-up 74 children under 6 years of age, referred for headache to our department between 1997 and 2003. The study was carried out between October 2016 and March 2018. Headache diagnoses were made according to the IHS criteria. Results 23/74 patients, 31% of the original cohort, were found at follow-up in a period ranging between 15 to 21 years after the first visit. Seven of them were headache free. The remaining 16 patients had migraine. In the migraine group, the localization of pain changed in 75% of the subjects, 11/16 (68.7%) had allodynia and 9/16 (56.25%) had cranial autonomic symptoms. Conclusions Our results suggest that the onset of migraine at very young age represents unfavorable prognostic factor for persistence of the disease at later ages. Some clinical features may change during clinical course, and the active persistence of the disorder may lead to an increase in allodynia.

Wiedemann-Steiner syndrome (WDSTS) is a rare genetic disorder including developmental delay/intellectual disability (DD/ID), hypertrichosis cubiti, short stature, and distinctive facial features, caused by mutation in KMT2A gene, which encodes a histone methyltransferase (H3K4) that regulates chromatin-mediated transcription. Different neurodevelopmental phenotypes have been described within the WDSTS spectrum, including a peculiar Autism Spectrum Disorder (ASDs) subtype in some affected individuals. Here, we report a 9-year-old Caucasian male found by next-generation panel sequencing to carry a novel heterozygous de novo KMT2A frameshift variant (NM_001197104.2:c.4433delG; p. Arg1478LeufsTer108). This boy presented a WDSTS phenotype associated with broad neurodevelopmental features, including an unusual speech difficulty (i.e., palilalia), and brain imaging studies revealed an array of cortical anomalies (e.g., frontal simplified gyration, focal frontal cortical dysplasia). These clinical and radiological observations expand the known WDSTS-related neurodevelopmental phenotypes and further strengthen the important role of KMT2A in brain function and cortical development.

KBG syndrome (OMIM #148050) is a rare autosomal dominant disorder, typically characterized by macrodontia of the upper central incisors, distinct craniofacial findings, short stature, and skeletal anomalies associated with neurological involvement including intellectual disability, behaviour difficulties, and epilepsy. KBG syndrome is associated with mutations in ANKRD11 gene that plays a chromatin regulator role of histone acetylation and gene expression during neurogenesis in the embryonic brain.

N-methyl-D-aspartate receptors (NMDAR) are di- or tri-heterotetrameric ligand-gated ion channels composed of two obligate glycine-binding GluN1 subunits and two glutamate-binding GluN2 or GluN3 subunits, encoded by GRIN1, GRIN2A–D, and GRIN3A–B receptor genes respectively. Each NMDA receptor subtype has different temporal and spatial expression patterns in the brain and varies in the cell types and subcellular localization resulting in different functions. They play a crucial role in mediating the excitatory neurotransmission, but are also involved in neuronal development and synaptic plasticity, essential for learning, memory, and high cognitive functions. Among genes coding NMDAR subunits, GRIN2B is predominantly associated with neurodevelopmental disorders such as intellectual disability, developmental delay, autism, attention-deficit/hyperactivity disorder and, further, schizophrenia, Alzheimer's disease. The GRIN2A seems to be predominantly associated with a more definite phenotype including an epileptic spectrum ranging from Landau–Kleffner syndrome to benign childhood epilepsy with centrotemporal spikes, speech or language impairment, intellectual disability/developmental delay often in comorbidity. On the contrary, the occurrence of autism spectrum disorders, unlike GRIN2B-associated disorders, is questionable. To contribute to elucidate the latter issue and to better define the genotype/phenotype correlation, we report the clinical and neuropsychological profile of two patients featuring autism disorder, intellectual disability, language impairment, and focal epilepsy, associated with previously unreported heterozygous de novo GRIN2A pathogenic variants. We hypothesize that the unusual phenotype may be the result of interactions of tri-heterotetrameric 2GluN1/GluN2A-D/GluN3A-B subunits with mutated GluN2A subunit and/or the dysfunction may be influenced by other unknown modifier genes and/or environmental factors.

The autosomal recessive form of primary microcephaly (MCPH) is a rare disorder characterized by head circumference of at least 3 standard deviation below the mean. The MCPH exhibits genetic heterogeneity with thirteen loci (MCPH1-MCPH13) identified, and associated with variable degree of intellectual disability. It has been reported that WDR62 is the second causative gene of autosomal recessive microcephaly (MCPH2) playing a significant role in spindle formation and the proliferation of neuronal progenitor cells. We report a clinical feature, electroclinical findings, and clinical course of a patient with a severe phenotype of MCPH2 including microcephaly, refractory infantile spasms and intellectual disability. Genetic analysis detected a new homozygous splicing variant c.3335+1G>C in the WD repeat domain 62 ( WDR62 ) gene, inherited from both heterozygous healthy parents, and an additional new heterozygous missense mutation c.1706T>A of G protein-coupled receptor 56 ( GPR56 ) gene inherited from his healthy father. The study seeks to broaden the knowledge of clinical and electroclinical findings of MCPH2 and to contribute to a better characterization of the genotype-phenotype correlation.

Benign familial infantile epilepsy (BFIE) is the most genetically heterogeneous phenotype among early-onset familial infantile epilepsies. It has an autosomal dominant inheritance pattern with incomplete penetrance. Although PRRT2 is the most mutated gene detected in families with BFIE, other mutations in KCNQ2, SCN2A, and GABRA6 genes have also been described. To date, KCNQ3 mutations have been detected in only four patients with BFIE. Here, we describe the clinical pattern and course of an additional individual with BFIE associated with a novel missense heterozygous KCNQ3 c.1850G>C variant inherited by his unaffected father. The incidence of KCNQ3 mutations among BFIE patients is reported to be low in the literature, however, whether this is underestimated is unclear as not all current epilepsy gene panels include KCNQ3.

BACKGROUND: Dentatorubral-pallidoluysian atrophy is a hereditary neurodegenerative disease prevalently reported in Japan but rare in Caucasians. The objective of this study was to reconstruct the pedigree of Italian dentatorubral-pallidoluysian atrophy familial cases describing their clinical features. METHODS: We investigated 6 apparently unrelated dentatorubral-pallidoluysian atrophy families comprising a total of 51 affected individuals: 13 patients were clinically examined, and for 38 patients clinical data were collected from clinical sources. The dentatorubral-pallidoluysian atrophy diagnosis was genetically confirmed in 18 patients. Genealogical data from historical archives were analyzed. RESULTS: All 6 families were unified in a large pedigree deriving from a founder couple originating from Monte San Giuliano (Italy) in the late 1500s, with 51 affected subjects over the last 4 generations. Wide phenotypical variability in age at onset and clinical features was confirmed. Epilepsy was more frequent in juvenile cases than in late adults, with cognitive/psychiatric and motor disorders observed regardless of age at onset. CONCLUSIONS: We have described the largest Caucasian dentatorubral-pallidoluysian atrophy pedigree from a single founder couple. The introduction of the dentatorubral-pallidoluysian atrophy gene in Italy could have arisen as a result of trade relationships between the Spanish or Portuguese and the Japanese in the 1500s. © 2019 International Parkinson and Movement Disorder Society.