Pontocerebellar hypoplasias (PCH) comprise a group of genetically heterogeneous disorders characterised by concurrent hypoplasia of the pons and the cerebellum and variable clinical and imaging ...features. The current classification includes 13 subtypes, with ~20 known causative genes. Attempts have been made to delineate the phenotypic spectrum associated to specific PCH genes, yet clinical and neuroradiological features are not consistent across studies, making it difficult to define gene-specific outcomes.
We performed deep clinical and imaging phenotyping in 56 probands with a neuroradiological diagnosis of PCH, who underwent NGS-based panel sequencing of PCH genes and MLPA for
rearrangements. Next, we conducted a phenotype-based unsupervised hierarchical cluster analysis to investigate associations between genes and specific phenotypic clusters.
A genetic diagnosis was obtained in 43 probands (77%). The most common causative gene was
, which accounted for nearly half cases (45%) and was mutated in females and occasionally in males. The European founder mutation p.Ala307Ser in
and pathogenic variants in
accounted for 18% and 9% of cases, respectively.
,
and
were mutated in single patients. We were able to confirm only few previously reported associations, including jitteriness and clonus with
and lower motor neuron signs with
. When considering multiple features simultaneously, a clear association with a phenotypic cluster only emerged for
.
represents the major PCH causative gene in Italy. Phenotypic variability associated with the most common genetic causes of PCH is wider than previously thought, with marked overlap between
and
-associated disorders.
The definition of ischaemic stroke has been recently updated as an acute episode of neurological dysfunction caused by focal brain, spinal cord, or retinal ischaemia in the presence of a cerebral ...infarction. This "tissular" definition has highlighted the importance of pathophysiological processes underlying cerebral damage. In particular, post- ischaemic inflammation in the brain and in the blood stream could influence crucial steps of the tissue injury/repair cascade. CC and CXC chemokines orchestrate the inflammatory response in atherosclerotic plaque vulnerability and cerebral infarction. These molecules exert their activities through the binding to selective transmembrane receptors. CC and CXC chemokines modulate crucial processes (such as inflammatory cell recruitment and activation, neuronal survival, neoangiogenesis). On the other hand, CXC chemokines could also modulate stem cell homing, thus favouring tissue repair. Given this evidence, both CC and CXC chemokines could represent promising therapeutic targets in primary and secondary prevention of ischaemic stroke. Only preliminary studies have been performed investigating treatments with selective chemokine agonists/antagonists. In this review, we will update evidence on the role and the potential therapeutic strategies targeting CC and CXC chemokines in the pathophysiology of ischaemic stroke.
Defective primary ciliogenesis or cilium stability forms the basis of human ciliopathies, including Joubert syndrome (JS), with defective cerebellar vermis development. We performed a high-content ...genome-wide small interfering RNA (siRNA) screen to identify genes regulating ciliogenesis as candidates for JS. We analyzed results with a supervised-learning approach, using SYSCILIA gold standard, Cildb3.0, a centriole siRNA screen and the GTex project, identifying 591 likely candidates. Intersection of this data with whole exome results from 145 individuals with unexplained JS identified six families with predominantly compound heterozygous mutations in KIAA0586. A c.428del base deletion in 0.1% of the general population was found in trans with a second mutation in an additional set of 9 of 163 unexplained JS patients. KIAA0586 is an orthologue of chick Talpid3, required for ciliogenesis and Sonic hedgehog signaling. Our results uncover a relatively high frequency cause for JS and contribute a list of candidates for future gene discoveries in ciliopathies.
Deletions and duplications of the PAFAH1B1 and YWHAE genes in 17p13.3 are associated with different clinical phenotypes. In particular, deletion of PAFAH1B1 causes isolated lissencephaly while ...deletions involving both PAFAH1B1 and YWHAE cause Miller-Dieker syndrome. Isolated duplications of PAFAH1B1 have been associated with mild developmental delay and hypotonia, while isolated duplications of YWHAE have been associated with autism. In particular, different dysmorphic features associated with PAFAH1B1 or YWHAE duplication have suggested the need to classify the patient clinical features in two groups according to which gene is involved in the chromosomal duplication.
We analyze the proband and his family by classical cytogenetic and array-CGH analyses. The putative rearrangement was confirmed by fluorescence in situ hybridization.
We have identified a family segregating a 17p13.3 duplication extending 329.5 kilobases by FISH and array-CGH involving the YWHAE gene, but not PAFAH1B1, affected by a mild dysmorphic phenotype with associated autism and mental retardation. We propose that BHLHA9, YWHAE, and CRK genes contribute to the phenotype of our patient. The small chromosomal duplication was inherited from his mother who was affected by a bipolar and borderline disorder and was alcohol addicted.
We report an additional familial case of small 17p13.3 chromosomal duplication including only BHLHA9, YWHAE, and CRK genes. Our observation and further cases with similar microduplications are expected to be diagnosed, and will help better characterise the clinical spectrum of phenotypes associated with 17p13.3 microduplications.
Anti- N -methyl-D-aspartate-receptor encephalitis is a recently identified autoimmune disorder. We report on a 4-year-old girl presenting with seizures after nonspecific viral-like symptoms, ...progressing to severe aphasia, upper limb dyskinesias, fluctuation in consciousness, and inability to walk. Anti- N -methyl-D-aspartate-receptor encephalitis should be included in the differential diagnosis of acute/subacute encephalitis in children.
Eur J Clin Invest 2012; 42 (7): 784–794
Ischaemic stroke is one of the major causes of death and lifelong disability also in the paediatric population. Strong scientific effort has been put to ...clarify the pathophysiology of this disease in adults. However, only few studies have been performed in children. Preliminary results indicate that pathophysiological processes might differently affect the poststroke neuronal injury in neonates as compared to children. During the neural development, selective molecular mechanisms might be differently triggered by an ischaemic insult, thus potentially resulting in defined postischaemic clinical outcomes. Basic research studies in neonatal animal models of cerebral ischaemia have recently shown a potential role of soluble inflammatory molecules (such as cytokines, chemokines and oxidants) as pivotal players of neuronal injury in both perinatal and childhood ischaemic stroke. Although larger clinical trials are still needed to confirm these preliminary results, the potential benefits of selective treatments targeting inflammation in perinatal asphyxia encephalopathy might represent a promising investigation field in the near future. In this review, we will update evidence on the pathophysiological role of soluble inflammatory mediators in neonatal and childhood ischaemic stroke. Recent evidence on potential anti‐inflammatory treatments to improve paediatric stroke prognosis will be discussed.
Pontocerebellar hypoplasia (PCH) type 1 is characterized by the co-occurrence of spinal anterior horn involvement and hypoplasia of the cerebellum and pons.
EXOSC3
has been recently defined as a ...major cause of PCH type 1. Three different phenotypes showing variable severity have been reported. We identified a homozygous mutation c.395A > C/p.D132A in
EXOSC3
in four patients with muscle hypotonia, developmental delay, spinal anterior horn involvement, and prolonged survival, consistent with the “mild PCH1 phenotype”. Interestingly, isolated cerebellar hypoplasia limited to the hemispheres or involving both hemispheres and vermis was the main neuroradiologic finding, whereas the pontine volume was in the normal range for age. These findings strongly suggest that analysis of the
EXOSC3
gene should be recommended also in patients with spinal anterior horn involvement and isolated cerebellar hypoplasia.
3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (also known as statins) are drugs active in the blockade of cholesterol synthesis and thus lowering cholesterol serum levels. ...Since their discovery, experimental evidence showed that statins strongly reduced atherogenesis and the risk of acute ischemic complications, such as acute myocardial infarction and stroke. More recently, direct anti-atherosclerotic effects of statins (independently of lipid profile improvement) have been also shown, suggesting new potential applications for these drugs in both primary and secondary prevention of acute cardiovascular events. Despite some controversies exist, the use of statins has been shown to improve both incidence and survival in acute ischemic stroke. The molecular mechanisms underlying statin-mediated clinical benefits were recently identified in the reduction of carotid plaque vulnerability and the increase of neuroprotection. In the present review, we will update evidence on the promising results with statins to improve ischemic stroke outcomes.
Since the introduction of the array-CGH technique in the diagnostic workup of mental retardation, new recurrent copy number variations and novel microdeletion/microduplication syndromes were ...identified. These findings suggest that some genomic disorders have high penetrance but a wide range of phenotypic severity.
We present the clinical and molecular description of four unrelated patients affected by neurodevelopmental disorders and overlapping 7q31.1 microdeletion/microduplication, identified by array-CGH and involving only part of the IMMP2L gene.
IMMP2L encodes an inner mitochondrial membrane protease-like protein, which is required for processing of cytochromes inside mitochondria. Numerous studies reported that this gene is implicated in behavioural disorders such as autistic spectrum disorders, attention-deficit hyperactivity disorders, and Gilles de la Tourette syndrome. We discuss the functions of the gene suggesting that IMMP2L may act as risk factor for neurological disease.
Mucolipidosis type IV (MLIV) is a very rare disorder of late endosome/lysosome transport, characterized by neurodevelopmental abnormalities and progressive visual impairment owing to corneal clouding ...and retinal dystrophy. Greater than 70 % of MLIV patients are of Ashkenazi Jewish ancestry. Here we report a novel
MCOLN1
double mutant allele c.395_397delCTG;c.468_474dupTTGGACC which introduces a premature stop codon p.Ala132del; p.Asn159LeufsX27 leading to almost complete abrogation of the region coding mucolipin-1, a member of the transient receptor potential (TRP) cation channel family. The genomic lesion was identified in homozygous state, in a non-Jewish Italian MLIV patient, who also presented abnormal serum gastrin levels. Conventional and advanced MRI sequences, including diffusion tensor imaging and tractography, were used for the assessment of white matter involvement in the patient.
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