Aminoacyl-tRNA synthetases (ARSs) aminoacylate tRNA molecules with their cognate amino acid, enabling information transmission and providing substrates for protein biosynthesis. They also take part ...in nontranslational functions, mediated by the presence of other proteins domains. Mutations in ARS genes have been described as responsive to numerous factors, including neurological, autoimmune, and oncological. Variants of the ARS genes, both in heterozygosity and homozygosity, have been reported to be responsible for different pathological pictures in humankind. We present the case of a patient referred in infancy for failure to thrive and acquired microcephaly (head circumference: -5 SD). During follow-up we highlighted: dysphagia (which became increasingly severe until it became incompatible with oral feeding, with gastrostomy implantation, resulting in resolution of feeding difficulties), strabismus, hypotonia. NCV (Nerve Conduction Velocity) showed four limbs neuropathy, neurophysiological examination performed at 2 years of age mainly sensory and demyelinating. Exome sequencing (ES) was performed, detecting two novel compound heterozygous variants in the NARS1 gene (OMIM *108410): NM_004539:c.662 A > G; 1155dup, p.(Asn221Ser); (Arg386Thrfs*19), inherited from mother and father respectively. In this article, we would like to focus on the presence of progressive dysphagia and severe neurodevelopmental disorder, associated with two novel variants in the NARS1 gene.
Basel-Vanagaite-Smirin-Yosef syndrome (BVSYS) is an extremely rare autosomal recessive genetic disorder caused by variants in the
MED25
gene. It is characterized by severe developmental delay and ...variable craniofacial, neurological, ocular, and cardiac anomalies. Since 2015, through whole exome sequencing, 20 patients have been described with common clinical features and biallelic variants in
MED25
, leading to a better definition of the phenotype associated with BVSYS. We report two young sisters, born to consanguineous parents, presenting with intellectual disability, neurological findings, and dysmorphic features typical of BVSYS, and also with bilateral perisylvian polymicrogyria. The younger sister died at the age of 1 year without autoptic examination. Whole exome sequencing detected a homozygous frameshift variant in the
MED25
gene: NM_030973.3:c.1778_1779delAG, p.(Gln593Argfs). This report further delineates the most common clinical features of BVSYS and points to polymicrogyria as a distinctive neuroradiological feature of this syndrome.
One of the recently described syndromes emerging from the massive study of cohorts of undiagnosed patients with autism spectrum disorders (ASD) and syndromic intellectual disability (ID) is ...White-Sutton syndrome (WHSUS) (MIM #616364), caused by variants in the
gene (MIM *614787), located on the long arm of chromosome 1 (1q21.3). So far, more than 50 individuals have been reported worldwide, although phenotypic features and natural history have not been exhaustively characterized yet. The phenotypic spectrum of the WHSUS is broad and includes moderate to severe ID, microcephaly, variable cerebral malformations, short stature, brachydactyly, visual abnormalities, sensorineural hearing loss, hypotonia, sleep difficulties, autistic features, self-injurious behaviour, feeding difficulties, gastroesophageal reflux, and other less frequent features. Here, we report the case of a girl with microcephaly, brain malformations, developmental delay (DD), peripheral polyneuropathy, and adducted thumb-a remarkable clinical feature in the first years of life-and heterozygous for a previously unreported, de novo splicing variant in
. This report contributes to strengthen and expand the knowledge of the clinical spectrum of WHSUS, pointing out the importance of less frequent clinical signs as diagnostic handles in suspecting this condition.
The ability of pathogens to sequester iron from their host cells and proteins affects their virulence. Moreover, iron is required for various innate host defense mechanisms as well as for acquired ...immune responses. Therefore, intracellular iron concentration may influence the interplay between pathogens and immune system. Here, we investigated whether changes in iron concentrations and intracellular ferritin heavy chain (FTH) abundance may modulate the expression of Major Histocompatibility Complex molecules (MHC), and susceptibility to Natural Killer (NK) cell cytotoxicity. FTH downregulation, either by shRNA transfection or iron chelation, led to MHC surface reduction in primary cancer cells and macrophages. On the contrary, mouse embryonic fibroblasts (MEFs) from NCOA4 null mice accumulated FTH for ferritinophagy impairment and displayed MHC class I cell surface overexpression. Low iron concentration, but not FTH, interfered with IFN-γ receptor signaling, preventing the increase of MHC-class I molecules on the membrane by obstructing STAT1 phosphorylation and nuclear translocation. Finally, iron depletion and FTH downregulation increased the target susceptibility of both primary cancer cells and macrophages to NK cell recognition. In conclusion, the reduction of iron and FTH may influence the expression of MHC class I molecules leading to NK cells activation.
Lissencephaly describes a group of conditions characterized by the absence of normal cerebral convolutions and abnormalities of cortical development. To date, at least 20 genes have been identified ...as involved in the pathogenesis of this condition. Variants in
, encoding a protein involved in the regulation of neuronal migration, have been recently described as causative of lissencephaly with a posterior-prevalent involvement of the cerebral cortex and an autosomal dominant pattern of inheritance. Here, we describe a 3-year-old boy with slightly delayed psychomotor development and mild dysmorphic features, including bitemporal narrowing, protruding ears with up-lifted lobes and posterior plagiocephaly. Brain MRI at birth identified type 1 lissencephaly, prevalently in the temporo-occipito-parietal regions of both hemispheres with "double-cortex" (Dobyns' 1-2 degree) periventricular band alterations. Whole-exome sequencing revealed a previously unreported de novo pathogenic variant in the
gene (NM_001042475.3:c.232+1del). Only 20 patients have been reported as carriers of pathogenic
variants to date. They show lissencephaly with prevalent posterior involvement, variable cognitive deficits and epilepsy. The present case report indicates the clinical variability associated with
variants that are not invariantly associated with severe phenotypes and poor outcome, and underscores the importance of including this gene in diagnostic panels for lissencephaly.
Pseudoxanthoma elasticum is an autosomal recessive heritable disorder caused by mutations in
. We describe two siblings showing typical skin lesions and a clinical diagnosis of pseudoxanthoma ...elasticum. Genetic analysis of
revealed a novel homozygous c.4041G > A variant located in the last position of exon 28 that compromises the splicing donor site, resulting in a shorter messenger RNA. The deletion impairs the nucleotide-binding fold region, which is crucial for
function.
KBG syndrome is caused by haploinsufficiency of
and is characterised by macrodontia of upper central incisors, distinctive facial features, short stature, skeletal anomalies, developmental delay, ...brain malformations and seizures. The central nervous system (CNS) and skeletal features remain poorly defined.
CNS and/or skeletal imaging were collected from molecularly confirmed individuals with KBG syndrome through an international network. We evaluated the original imaging and compared our results with data in the literature.
We identified 53 individuals, 44 with CNS and 40 with skeletal imaging. Common CNS findings included incomplete hippocampal inversion and posterior fossa malformations; these were significantly more common than previously reported (63.4% and 65.9% vs 1.1% and 24.7%, respectively). Additional features included patulous internal auditory canal, never described before in KBG syndrome, and the recurrence of ventriculomegaly, encephalic cysts, empty sella and low-lying conus medullaris. We found no correlation between these structural anomalies and epilepsy or intellectual disability. Prevalent skeletal findings comprised abnormalities of the spine including scoliosis, coccygeal anomalies and cervical ribs. Hand X-rays revealed frequent abnormalities of carpal bone morphology and maturation, including a greater delay in ossification compared with metacarpal/phalanx bones.
This cohort enabled us to describe the prevalence of very heterogeneous neuroradiological and skeletal anomalies in KBG syndrome. Knowledge of the spectrum of such anomalies will aid diagnostic accuracy, improve patient care and provide a reference for future research on the effects of
variants in skeletal and brain development.
The blood-brain barrier (BBB) is an essential gatekeeper for the central nervous system and incidence of neurodevelopmental disorders (NDDs) is higher in infants with a history of intracerebral ...hemorrhage (ICH). We discovered a rare disease trait in thirteen individuals, including four fetuses, from eight unrelated families associated with homozygous loss-of-function variant alleles of ESAM which encodes an endothelial cell adhesion molecule. The c.115del (p.Arg39Glyfs∗33) variant, identified in six individuals from four independent families of Southeastern Anatolia, severely impaired the in vitro tubulogenic process of endothelial colony-forming cells, recapitulating previous evidence in null mice, and caused lack of ESAM expression in the capillary endothelial cells of damaged brain. Affected individuals with bi-allelic ESAM variants showed profound global developmental delay/unspecified intellectual disability, epilepsy, absent or severely delayed speech, varying degrees of spasticity, ventriculomegaly, and ICH/cerebral calcifications, the latter being also observed in the fetuses. Phenotypic traits observed in individuals with bi-allelic ESAM variants overlap very closely with other known conditions characterized by endothelial dysfunction due to mutation of genes encoding tight junction molecules. Our findings emphasize the role of brain endothelial dysfunction in NDDs and contribute to the expansion of an emerging group of diseases that we propose to rename as “tightjunctionopathies.”
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We identified homozygous loss-of-function variants in ESAM, encoding an endothelial cell adhesion molecule, in thirteen individuals (including four fetuses) showing intracerebral hemorrhage in prenatal age and neurodevelopmental disorders. Our findings contribute to expand an emerging group of diseases caused by alterations of tight-junction genes (e.g., JAM2, JAM3, OCLN).
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