Although ribosomes are ubiquitous and essential for life, recent data indicate that monogenic causes of ribosomal dysfunction can confer a remarkable degree of specificity in terms of human disease ...phenotype. Box C/D small nucleolar RNAs (snoRNAs) are evolutionarily conserved non-protein-coding RNAs involved in ribosome biogenesis. Here we show that biallelic mutations in the gene SNORD118, encoding the box C/D snoRNA U8, cause the cerebral microangiopathy leukoencephalopathy with calcifications and cysts (LCC), presenting at any age from early childhood to late adulthood. These mutations affect U8 expression, processing and protein binding and thus implicate U8 as essential in cerebral vascular homeostasis.
Aicardi-Goutières syndrome is a mendelian mimic of congenital infection and also shows overlap with systemic lupus erythematosus at both a clinical and biochemical level. The recent identification of ...mutations in TREX1 and genes encoding the RNASEH2 complex and studies of the function of TREX1 in DNA metabolism have defined a previously unknown mechanism for the initiation of autoimmunity by interferon-stimulatory nucleic acid. Here we describe mutations in SAMHD1 as the cause of AGS at the AGS5 locus and present data to show that SAMHD1 may act as a negative regulator of the cell-intrinsic antiviral response.
Abstract With an incidence of 1/2800 to 1/5000 live-births, perinatal arterial ischemic stroke is the most frequent form of cerebral infarction in children. About 40% of the children do not have ...specific symptoms in the neonatal period, and are only recognized later with the emergence of motor impairment, developmental delay, specific cognitive deficiency or seizures. In the remaining 60%, children present with early symptoms, mostly recurrent focal seizures in the first 3 days of life. The diagnosis is easily confirmed by cranial ultrasounds and MRI. Early MRI has both a key role in the diagnosis, dating the injury, but also an important prognostic value to predict the motor outcome of the child. Indeed, although the infarct does not recur, the majority of children show subsequent sequels: cerebral palsy, epilepsy, cognitive or behavioural problems. Finding predictors of outcome regarding these latter concerns (and the way to prevent or alleviate them) is of major interest. The main etiological hypothesis for perinatal AIS is a cerebral embolus, originating from the placenta through the foramen ovale. Most of the established risk factors are indeed either determinants or biomarkers of vasculo-placental pathology. Injury to the cervico-cerebral arteries, giving rise to thrombus/embolus during the birthing process is also suggested. Both placento-embolic and traumatic theories are supported by a few, but well-analysed pathological or arteriographic reports. Nevertheless, their relative frequency, the implication of other mechanisms, and their repercussions to evidence-based preventive strategies remain to be determined. Moreover, the mechanism of stroke in the different groups of newborns with stroke (term vs. preterm; symptomatic neonates vs. those with a delayed presentation) is likely to be different, and there is a need for future studies to assess all populations as different entities. Neonatal supportive care remains important for all infants while there is no evidence for preventive anticoagulant use at present. In an effort to reduce neurological dysfunction, and in adjunction with ongoing physical therapy and pharmacological treatment, new rehabilitative interventions, such as constraint-induced movement therapy and mirror therapy, are increasingly being used.
We aimed to correlate early imaging data with motor outcomes in a large, homogeneous, cohort of infants with neonatal (diagnosed before 29 days of life) arterial ischemic stroke (AIS).
From a ...prospective cohort of 100 children with neonatal AIS, we analyzed the MRI studies performed within the 28 first days of life for 80 infants evaluated at 2 years of age. The relationships between infarction location and corticospinal tract (CST) involvement and motor outcomes were studied
Seventy-three infarctions involved the middle cerebral artery (MCA) territory. Of those, 50 were superficial infarctions, 5 deep infarctions, and 18 mixed infarctions. The CST was involved in 24 cases. Nineteen patients with MCA infarctions (26% 95% confidence interval: 16%-34%) developed hemiplegia. Mixed infarctions (P<.0001) and CST involvement (P<.0001) were highly predictive of hemiplegia. In contrast, 88% of children with isolated superficial MCA infarctions did not exhibit impairment.
Accurate prediction of motor outcomes can be obtained from early MRI scans after neonatal AIS. The absence of involvement of the CST resulted in normal motor development in 94% of cases. CST involvement resulted in congenital hemiplegia in 66% of cases.
Late-onset central hypoventilation syndrome (LO-CHS) is a rare disorder that may manifest as early as infancy or as late as during adulthood. The potential overlap of LO-CHS with congenital CHS is ...under debate, even though both disorders can result from heterozygous PHOX2B gene mutations.
To characterize the PHOX2B status in a series of 25 patients with LO-CHS referred from 3 months of age to adulthood. Whenever a PHOX2B mutation was identified, we ascertained its germline or somatic origin in both patients with LO-CHS and in 15 parents of probands with congenital CHS found to harbor a PHOX2B mutation.
The PHOX2B gene was analyzed by direct DNA sequencing and origin of the mutation evaluated by fluorescent PCR.
We have identified a heterozygous PHOX2B gene mutation in 17 of 25 patients with LO-CHS. The far most frequent mutation results in a germline +5 alanine expansion in the series of 20 alanines (15 cases) that show incomplete penetrance and variable expressivity, possibly resulting from combined environmental and genetic factors. PHOX2B frameshift and missense mutations have also been identified in patients with LO-CHS. Importantly, one parent found to harbor a somatic mosaic for a +8 alanine expansion developed alveolar hypoventilation in his 40s.
These data indicate that PHOX2B gene mutations should be systematically examined in any adult with unexplained central hypoventilation and raise the question of follow-up for apparently healthy parents found to harbor a somatic mosaic for the PHOX2B mutation identified in their child.
Disorganization of the neurofilament network is a prominent feature of
several neurodegenerative disorders including amyotrophic lateral sclerosis
(ALS), infantile spinal muscular atrophy and axonal ...Charcot-Marie-Tooth disease. Giant axonal neuropathy (GAN, MIM 256850), a severe, autosomal
recessive sensorimotor neuropathy affecting both the peripheral nerves and
the central nervous system, is characterized by neurofilament accumulation,
leading to segmental distension of the axons. GAN corresponds
to a generalized disorganization of the cytoskeletal intermediate filaments
(IFs), to which neurofilaments belong, as abnormal aggregation of multiple
tissue-specific IFs has been reported: vimentin in endothelial cells, Schwann
cells and cultured skin fibroblasts, and glial fibrillary acidic protein (GFAP)
in astrocytes. Keratin IFs also seem to be alterated,
as most patients present characteristic curly or kinky hairs.
We report here identification of the gene GAN, which encodes a novel,
ubiquitously expressed protein we have named gigaxonin. We found one frameshift,
four nonsense and nine missense mutations in GAN of GAN patients. Gigaxonin
is composed of an amino-terminal BTB (for Broad-Complex, Tramtrack and Bric
a brac) domain followed by a six kelch repeats, which are predicted to adopt
a β-propeller shape. Distantly related proteins sharing
a similar domain organization have various functions associated with the cytoskeleton,
predicting that gigaxonin is a novel and distinct cytoskeletal protein that
may represent a general pathological target for other neurodegenerative disorders
with alterations in the neurofilament network.
Hereditary neuropathies (HN) are categorized according to clinical presentation, pathogenic mechanism based on electrophysiology, genetic transmission, age of occurrence, and, in selected cases, ...pathological findings. The combination of these parameters frequently orients towards specific genetic disorders.
Ruling out a neuropathy secondary to a generalized metabolic disorder remains the first pediatric concern.
Primary, motor-sensory are the most frequent HN and are dominated by demyelinating AD forms (CMT1). Others are demyelinating AR forms, axonal AD/AR forms, and forms with “intermediate” electrophysiological phenotype.
Pure motor HN represent<10% of HN but exhibit large clinical and genetic heterogeneity.
Sensory/dysautonomic HN cover five classical subtypes, each one related to specific genes. However, genetic heterogeneity is largly greater than initially suspected.
Syndromic HN distinguish: “purely neurological syndromes”, which are multisystemic, usually AD disorders, such as spinocerebellar atrophies +, spastic paraplegias +, etc. Peripheral Neuropathy may be the presenting feature, including in childhood. Clearly degenerative, AR forms prompt to investigate a large set of pleiotropic genes. Other syndromes, expressed in the perinatal period and comprising malformative features, are mainly developmental disorders, sometimes related to specific transcription factors.
Altogether, >40 genes with various biological functions have been found responsible for HN. Many are responsible for various phenotypes, including some without the polyneuropathic trait: for the pediatric neurologist, phenotype/genotype correlations constitute a permanent bidirectional exercise.
In childhood, widening of Virchow-Robin spaces is rarely secondary to specific progressive disorders, but more often appears in poorly characterized developmental conditions. From data collected in a ...neuropediatric department, we examined whether clinical data associated with “constitutional widening of Virchow-Robin spaces” allowed delineation of recognizable entities. Signs in 10 patients, mostly boys, suggested nonspecific cerebral dysfunctions, e.g., developmental delay, nonspecific epilepsy, headaches, or benign macrocephaly. Spaces were sometimes round, subsequently mimicking microcystic malacic lesions. In two patients, abnormal magnetic resonance imaging signals were evident in white matter contiguous to widened perivascular spaces, suggesting a broader disorder of fluid exchanges. Four cases occurred in two sibships. In two families, other patients exhibited early developmental difficulties. Long-term clinical and magnetic resonance imaging surveillance will clarify which cases of primary Virchow-Robin space dilatation imply a benign prognosis. Performance of magnetic resonance imaging on any relative exhibiting minor neuropsychologic handicaps would permit estimations of real genetic incidence.
Dissection of craniocervical arteries is the most common non-atherosclerotic cause of stroke in young adults. During childhood, it is described primarily as isolated reports.
Among 59 patients with ...arterial ischaemic stroke seen consecutively in the same institution, 12 had a dissection of a cervical or cerebral artery. The diagnosis was established through imaging features.
The dissection involved the cervical arteries in five patients and intracranial arteries in seven. A cervical or facial trauma preceded the onset of cerebral ischaemic symptoms in four patients with extracranial dissection by a few minutes to 10 days. For another six patients, the stroke occurred during physical exertion. The neurological deficit was preceded or associated with an intense headache or neck pain in nine patients. Initial treatment consisted of anticoagulation therapy in two patients with extracranial dissection, and aspirin in nine. There was only one recurrence of stroke after a mean follow-up of 3 years and 6 months. Four patients had persistent disabling neurological deficit.
Dissection of cervical or cerebral arteries appears to be a common cause of stroke in childhood.
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