A recessive PRDM13 mutation results in congenital hypogonadotropic hypogonadism and cerebellar hypoplasia.

The positive regulatory (PR) domain containing 13 (PRDM13) putative chromatin modifier and transcriptional regulator functions downstream of the transcription factor PTF1A, which controls GABAergic fate in the spinal cord and neurogenesis in the hypothalamus. Here, we report a recessive syndrome associated with PRDM13 mutation. Patients exhibited intellectual disability, ataxia with cerebellar hypoplasia, scoliosis, and delayed puberty with congenital hypogonadotropic hypogonadism (CHH). Expression studies revealed Prdm13/PRDM13 transcripts in the developing hypothalamus and cerebellum in mouse and human. An analysis of hypothalamus and cerebellum development in mice homozygous for a Prdm13 mutant allele revealed a significant reduction in the number of Kisspeptin (Kiss1) neurons in the hypothalamus and PAX2+ progenitors emerging from the cerebellar ventricular zone. The latter was accompanied by ectopic expression of the glutamatergic lineage marker TLX3. Prdm13-deficient mice displayed cerebellar hypoplasia and normal gonadal structure, but delayed pubertal onset. Together, these findings identify PRDM13 as a critical regulator of GABAergic cell fate in the cerebellum and of hypothalamic kisspeptin neuron development, providing a mechanistic explanation for the cooccurrence of CHH and cerebellar hypoplasia in this syndrome. To our knowledge, this is the first evidence linking disrupted PRDM13-mediated regulation of Kiss1 neurons to CHH in humans.

MRI and clinical characteristics of suspected cerebrovascular accident in nine cats.

Objectives Cerebrovascular accidents (CVAs) are infrequently reported in cats. To date, clinical characteristics, including lesion localisation and MRI findings, have only been reported in two cats. The aim of the current study is to document MRI findings in cats presenting with CVAs over an 11 year period. Cases were reviewed according to initial clinical presentation, subsequent physical and neurological findings, predisposing systemic disease and short- and long-term (when available) outcome with a view to identifying any typical pattern in disease occurrence. Methods Patient records of cats presenting to a single referral centre from January 2005 to September 2016 with acute onset, non-progressive (after 24 h) intracranial signs compatible with a CVA and where an MRI was performed within 72 h were retrospectively reviewed. Results Nine cats met the inclusion criteria. All cats had ischaemic CVAs (presumptively diagnosed in eight cats and confirmed in one cat following post-mortem examination). No cases of haemorrhagic CVAs were identified. Four cats presented with territorial infarcts that were confined to the territory of the rostral or caudal cerebellar arteries (n = 4). Lacunar infarcts were identified in five cats in the location of the cerebrum (n = 1), the thalamus/midbrain (n = 2) and the medulla oblongata (n = 2). Concurrent systemic disease was identified in most (n = 8/9). In the present study short-term prognosis was favourable and 8/9 cats survived to 48 h following admission. Conclusions and relevance CVAs in cats occur in the same vascular territories as in dogs and have similar MRI features. This study notes that the presenting cats had a high likelihood of concurrent disease (8/9 cases) but had a favourable short-term prognosis, if neither the clinical presentation nor concurrent disease were severe.

Distinct cerebellar foliation anomalies in a CHD7 haploinsufficient mouse model of CHARGE syndrome.

Mutations in the gene encoding the ATP dependent chromatin-remodeling factor, CHD7 are the major cause of CHARGE (Coloboma, Heart defects, Atresia of the choanae, Retarded growth and development, Genital-urinary anomalies, and Ear defects) syndrome. Neurodevelopmental defects and a range of neurological signs have been identified in individuals with CHARGE syndrome, including developmental delay, lack of coordination, intellectual disability, and autistic traits. We previously identified cerebellar vermis hypoplasia and abnormal cerebellar foliation in individuals with CHARGE syndrome. Here, we report mild cerebellar hypoplasia and distinct cerebellar foliation anomalies in a Chd7 haploinsufficient mouse model. We describe specific alterations in the precise spatio-temporal sequence of fissure formation during perinatal cerebellar development responsible for these foliation anomalies. The altered cerebellar foliation pattern in Chd7 haploinsufficient mice show some similarities to those reported in mice with altered Engrailed, Fgf8 or Zic1 gene expression and we propose that mutations or polymorphisms in these genes may modify the cerebellar phenotype in CHARGE syndrome. Our findings in a mouse model of CHARGE syndrome indicate that a careful analysis of cerebellar foliation may be warranted in patients with CHARGE syndrome, particularly in patients with cerebellar hypoplasia and developmental delay.

The chromatin remodeling factor CHD7 controls cerebellar development by regulating reelin expression.

The mechanisms underlying the neurodevelopmental deficits associated with CHARGE syndrome, which include cerebellar hypoplasia, developmental delay, coordination problems, and autistic features, have not been identified. CHARGE syndrome has been associated with mutations in the gene encoding the ATP-dependent chromatin remodeler CHD7. CHD7 is expressed in neural stem and progenitor cells, but its role in neurogenesis during brain development remains unknown. Here we have shown that deletion of Chd7 from cerebellar granule cell progenitors (GCps) results in reduced GCp proliferation, cerebellar hypoplasia, developmental delay, and motor deficits in mice. Genome-wide expression profiling revealed downregulated expression of the gene encoding the glycoprotein reelin (Reln) in Chd7-deficient GCps. Recessive RELN mutations have been associated with severe cerebellar hypoplasia in humans. We found molecular and genetic evidence that reductions in Reln expression contribute to GCp proliferative defects and cerebellar hypoplasia in GCp-specific Chd7 mouse mutants. Finally, we showed that CHD7 is necessary for maintaining an open, accessible chromatin state at the Reln locus. Taken together, this study shows that Reln gene expression is regulated by chromatin remodeling, identifies CHD7 as a previously unrecognized upstream regulator of Reln, and provides direct in vivo evidence that a mammalian CHD protein can control brain development by modulating chromatin accessibility in neuronal progenitors.

Evaluation of cerebrospinal fluid in Cavalier King Charles Spaniel dogs diagnosed with Chiari-like malformation with or without concurrent syringomyelia.

Syringomyelia is a common clinical problem in the Cavalier King Charles Spaniel dog population. The underlying pathophysiology of the development and progression of syringes is currently unknown. The primary aim of the current study was to determine whether development of syringomyelia is accompanied by alterations in cerebrospinal fluid composition. Patient records of Cavalier King Charles Spaniels with Chiari-like malformations, with or without concurrent syringomyelia, that had magnetic resonance imaging and cerebrospinal fluid analysis between December 2004 and December 2009, were retrospectively reviewed. Total nucleated cell count per microliter, with differential count, red blood cell count per microliter, and protein concentration (g/l), were reviewed. Data were analyzed with the Mann-Whitney U-test. Spearman rank test was used to test association between cerebrospinal fluid composition and syrinx size, and the Fisher exact test was used to compare the presence of macrophages, reactive lymphocytes, and myelin. A P value of ≤ 0.05 was considered significant for statistical tests. Dogs with syringomyelia had a higher total nucleated cell count (syringomyelia: 4/µl [range, 0-15/µl] vs. without syringomyelia: 2/µl [0-8/µl]; P  =  0.0047), higher protein concentration (syringomyelia: 0.26 g/l [0.07-0.42 g/l] vs. without syringomyelia: 0.2 g/l [0.12-0.39 g/l]; P  =  0.039), and an increased neutrophil percentage (syringomyelia: 0% [0-37%] vs. without syringomyelia: 0% [0-21%]; P  =  0.0203) than those with the Chiari-like malformation alone. There was a positive correlation between total nucleated cell count and syrinx size (r  =  0.51; P  =  0.0068). Development of syringomyelia is accompanied by alterations in cerebrospinal fluid composition. The pathogenesis of syringomyelia has not been fully elucidated; therefore, the exact origin of cerebrospinal fluid changes remains unclear.