Classic "PCH" Genes are a Rare Cause of Radiologic Pontocerebellar Hypoplasia.

The term Pontocerebellar Hypoplasia (PCH) was initially used to designate a heterogeneous group of fetal-onset genetic neurodegenerative disorders. As a descriptive term, PCH refers to pons and cerebellum of reduced volume. In addition to the classic PCH types described in OMIM, many other disorders can result in a similar imaging appearance. This study aims to review imaging, clinical and genetic features and underlying etiologies of a cohort of children with PCH on imaging. We systematically reviewed brain images and clinical charts of 38 patients with radiologic evidence of PCH. Our cohort included 21 males and 17 females, with ages ranging between 8 days to 15 years. All individuals had pons and cerebellar vermis hypoplasia, and 63% had cerebellar hemisphere hypoplasia. Supratentorial anomalies were found in 71%. An underlying etiology was identified in 68% and included chromosomal (21%), monogenic (34%) and acquired (13%) causes. Only one patient had pathogenic variants in an OMIM listed PCH gene. Outcomes were poor regardless of etiology, though no one had regression. Approximately one third of patients deceased at a median age of 8 months. All individuals had global developmental delay, 50% were non-verbal, 64% were non-ambulatory and 45% required gastrostomy feeding. This cohort demonstrates that radiologic PCH has heterogenous etiologies and the "classic" OMIM-listed PCH genes underlie only a minority of cases. Broad genetic testing, including chromosomal microarray and exome or multigene panels, is recommended in individuals with PCH-like imaging appearance. Our results strongly suggest that the term PCH should be used to designate radiologic findings, and not to imply neurogenerative disorders.

Holoprosencephaly: Review of Embryology, Clinical Phenotypes, Etiology and Management.

Holoprosencephaly (HPE) is the most common malformation of the prosencephalon in humans. It is characterized by a continuum of structural brain anomalies resulting from the failure of midline cleavage of the prosencephalon. The three classic subtypes of HPE are alobar, semilobar and lobar, although a few additional categories have been added to this original classification. The severity of the clinical phenotype is broad and usually mirrors the radiologic and associated facial features. The etiology of HPE includes both environmental and genetic factors. Disruption of sonic hedgehog (SHH) signaling is the main pathophysiologic mechanism underlying HPE. Aneuploidies, chromosomal copy number variants and monogenic disorders are identified in a large proportion of HPE patients. Despite the high postnatal mortality and the invariable presence of developmental delay, recent advances in diagnostic methods and improvements in patient management over the years have helped to increase survival rates. In this review, we provide an overview of the current knowledge related to HPE, and discuss the classification, clinical features, genetic and environmental etiologies and management.

Evaluation of Individuals with Non-Syndromic Global Developmental Delay and Intellectual Disability.

Global Developmental Delay (GDD) and Intellectual Disability (ID) are two of the most common presentations encountered by physicians taking care of children. GDD/ID is classified into non-syndromic GDD/ID, where GDD/ID is the sole evident clinical feature, or syndromic GDD/ID, where there are additional clinical features or co-morbidities present. Careful evaluation of children with GDD and ID, starting with detailed history followed by a thorough examination, remain the cornerstone for etiologic diagnosis. However, when initial history and examination fail to identify a probable underlying etiology, further genetic testing is warranted. In recent years, genetic testing has been shown to be the single most important diagnostic modality for clinicians evaluating children with non-syndromic GDD/ID. In this review, we discuss different genetic testing currently available, review common underlying copy-number variants and molecular pathways, explore the recent evidence and recommendations for genetic evaluation and discuss an approach to the diagnosis and management of children with non-syndromic GDD and ID.

Genetic susceptibility in Juvenile Myoclonic Epilepsy: Systematic review of genetic association studies.

BACKGROUND: Several genetic association investigations have been performed over the last three decades to identify variants underlying Juvenile Myoclonic Epilepsy (JME). Here, we evaluate the accumulating findings and provide an updated perspective of these studies. METHODOLOGY: A systematic literature search was conducted using the PubMed, Embase, Scopus, Lilacs, epiGAD, Google Scholar and Sigle up to February 12, 2016. The quality of the included studies was assessed by a score and classified as low and high quality. Beyond outcome measures, information was extracted on the setting for each study, characteristics of population samples and polymorphisms. RESULTS: Fifty studies met eligibility criteria and were used for data extraction. With a single exception, all studies used a candidate gene approach, providing data on 229 polymorphisms in or near 55 different genes. Of variants investigating in independent data sets, only rs2029461 SNP in GRM4, rs3743123 in CX36 and rs3918149 in BRD2 showed a significant association with JME in at least two different background populations. The lack of consistent associations might be due to variations in experimental design and/or limitations of the approach. CONCLUSIONS: Thus, despite intense research evidence established, specific genetic variants in JME susceptibility remain inconclusive. We discussed several issues that may compromise the quality of the results, including methodological bias, endophenotype and potential involvement of epigenetic factors. PROSPERO REGISTRATION NUMBER: CRD42016036063.

PER2 rs2304672, CLOCK rs1801260, and PER3 rs57875989 polymorphisms are not associated with juvenile myoclonic epilepsy.

Sleep disturbance is common in several epilepsy types, such as juvenile myoclonic epilepsy (JME). Genetic background could increase susceptibility to seizure and sleep abnormalities. From this perspective, a susceptibility gene for sleep disturbance or chronotype could contribute to the genetic susceptibility threshold for epilepsy and vice versa. Accordingly, we investigated whether functional clock gene polymorphisms (PER2 111C>G, CLOCK 3111T>C, and PER3 VNTR) might influence the risk for JME. All these polymorphisms have recently been reported to be associated with sleep disturbance, diurnal variation, and neurological diseases. The polymorphisms were genotyped in 97 patients and 212 controls using polymerase chain reaction or restriction fragment length polymorphism methods. No significant differences were observed in the genotypic and allelic frequencies of these polymorphisms between cases and controls even when analyses were restricted to patients that presented a diurnal preferential seizure occurrence. We also tested for interactions between polymorphisms by multifactor dimensionality reduction analysis. None of the combined genotypes differed significantly between the groups. These results present no evidence for an association of these polymorphisms with JME. Further studies including other types of epilepsy and/or other functional polymorphisms are required to investigate the possible relationship between clock genes and the genetic susceptibility to chronic seizure.