Biallelic variants in the
NARS2
gene are the cause of a continuous spectrum of neurodegenerative disorders presenting with various severity-from spastic paraplegia, progressive neurodegeneration to ...Leigh and Alpers syndrome. Common clinical signs result from a mitochondrial dysfunction based on OXPHOS deficiency. Here, we present a patient with infantile-onset severe epilepsy leading to fatal refractory status epilepticus. Whole exome sequencing with Exomiser analysis based on HPO terms detected two novel
NARS2
variants in a compound heterozygous state. To date, 18 different
NARS2
disease-causing mutations have been described. Our study adds to the understanding of this mitochondrial disorder.
Kabuki syndrome (KS) is a dominantly inherited disorder mainly due to de novo pathogenic variation in KMT2D or KDM6A genes. Initially, a representative cohort of 14 Czech cases with clinical features ...suggestive of KS was analyzed by experienced clinical geneticists in collaboration with other specialties, and observed disease features were evaluated according to the ‘MLL2‐Kabuki score’ defined by Makrythanasis et al. Subsequently, the aforementioned genes were Sanger sequenced and copy number variation analysis was performed by MLPA, followed by genome‐wide array CGH testing. Pathogenic variants in KMT2D resulting in protein truncation in 43% (6/14; of which 3 are novel) of all cases were detected, while analysis of KDM6A was negative. MLPA analysis was negative in all instances. One female patient bears a 6.6 Mb duplication of the Xp21.2–Xp21.3 region that is probably disease causing. Subjective KS phenotyping identified predictive clinical features associated with the presence of a pathogenic variant in KMT2D. We provide additional evidence that this scoring approach fosters prioritization of patients prior to KMT2D sequencing. We conclude that KMT2D sequencing followed by array CGH is a diagnostic strategy with the highest diagnostic yield.
Both gain- and loss-of-function mutations have recently implicated HCFC1 in neurodevelopmental disorders. Here, we extend our previous HCFC1 over-expression studies by employing short hairpin RNA to ...reduce the expression of Hcfc1 in embryonic neural cells. We show that in contrast to over-expression, loss of Hcfc1 favoured proliferation of neural progenitor cells at the expense of differentiation and promoted axonal growth of post-mitotic neurons. To further support the involvement of HCFC1 in neurological disorders, we report two novel HCFC1 missense variants found in individuals with intellectual disability (ID). One of these variants, together with three previously reported HCFC1 missense variants of unknown pathogenicity, were functionally assessed using multiple cell-based assays. We show that three out of the four variants tested result in a partial loss of HCFC1 function. While over-expression of the wild-type HCFC1 caused reduction in HEK293T cell proliferation and axonal growth of neurons, these effects were alleviated upon over-expression of three of the four HCFC1 variants tested. One of these partial loss-of-function variants disrupted a nuclear localization sequence and the resulting protein displayed reduced ability to localize to the cell nucleus. The other two variants displayed negative effects on the expression of the HCFC1 target gene MMACHC, which is responsible for the metabolism of cobalamin, suggesting that these individuals may also be susceptible to cobalamin deficiency. Together, our work identifies plausible cellular consequences of missense HCFC1 variants and identifies likely and relevant disease mechanisms that converge on embryonic stages of brain development.
Electrophoretic and photometric experiments strongly indicate that monovalent anions, which arise by deprotonation of the nitrogen atom in zwitterionic Good’s buffers ...3-(cyclohexylamino)-2-hydroxy-1-propanesulfonic acid (CAPSO) and 3-morpholinopropanesulfonic acid (MOPS), spontaneously aggregate. Cationic migration of sanguinarine (SA) and chelerythrine (CHE) in highly alkaline 1,3-bistris(hydroxymethyl)methylaminopropane (Bis–Tris–propane), in which the concentration of cations of both alkaloids is negligible, may be explained by the existence of an aggregate, which contains uncharged sanguinarine or chelerythrine and one monovalent cation of Bis–Tris–propane at least. Tendency of tris(hydroxymethyl)aminomethane (Tris), bis (2-hydroxyethyl)iminotris(hydroxymethyl)methane (Bis–Tris) and Bis–Tris–propane cations to ion pairing with synthetic cluster borane anions and with fused silica markedly rises up with the size and charge of these cations. The drop in mobility of cluster borane compounds sometimes exceeds 50% of their mobility found at identical pH and ionic strength in buffers with sodium cation. The electroosmosis drop approached 70% if background electrolyte contained Bis–Tris–propane cations instead of sodium cations. Nitrate, taken as a model inorganic ion, and four randomly chosen organic anions interacted markedly less with Tris, Bis–Tris and Bis–Tris–propane cations than cluster borane anions. 2-(
N-morpholino)ethanesulfonic (MES) acid anions present in background electrolyte affect the ion pairing of Tris, Bis–Tris and Bis–Tris–propane cations with anionic analytes and, in this way influence also mobilites of these anionic analytes. Limited hydrophilicity at least one of interacting species appears to be the most probable cause of observed intermolecular interactions of biological buffers.
Summary
Keratoacanthoma centrifugum marginatum (KCM) is an extremely rare variant of keratoacanthoma (KA), with about 30 cases reported since it was first described in 1962. Clinically, KA is an ...exoendophytic lesion of 10–25 mm with a horn‐filled crater that resolves spontaneously within 6 months. In contrast, KCM is characterized by a larger diameter continuous centrifugal spread, concurrent central atrophy and lack of spontaneous remission. Histologically, KCM is similar to KA, with a central keratin‐filled crater, overhanging lips of epithelium, a sharp outline between the tumour nests and stroma, and lack of anaplasia and stroma desmoplasia. We describe a 63‐year‐old agricultural worker with a 9‐month history of a multinodular tumour, 70–75 mm in size, on his right hand. The clinical diagnosis of KCM was confirmed by histological examination. Local radiotherapy proved effective, with no recurrence during a 4‐year follow‐up.
Proximal 6q deletions have a milder phenotype than middle and distal 6q deletions. We describe 2 patients with non-overlapping deletions of about 15 and 19 Mb, respectively, which subdivide the ...proximal 6q region into 2 parts. The aberrations were identified using karyotyping and analysed using mBAND and array CGH. The unaffected mother of the first patient carried a mosaic karyotype with the deletion in all metaphases analysed and a small supernumerary marker formed by the deleted material in about 77% of cells. Her chromosome 6 centromeric signal was split between the deleted chromosome and the marker, suggesting that this deletion arose through the centromere fission mechanism. In this family the location of the proximal breakpoint in the centromere prevented cloning of the deletion junction, but the junction of the more distal deletion in the second patient was cloned and sequenced. This analysis showed that the latter aberration was most likely caused by non-homologous end joining. The second patient also had a remarkably more severe phenotype which could indicate a partial overlap of his deletion with the middle 6q interval. The phenotypes of both patients could be partly correlated with the gene content of their deletions and with phenotypes of other published patients.
ABSTRACT
Pustulosis palmoplantaris (PPP; synonyms: pustulosis palmaris et plantaris, palmoplantar amicrobic pustulosis) is a common chronic, relapsing, pustular eruption affecting the palms and ...soles. The authors report the successful treatment of six therapy‐experienced patients with histologically confirmed PPP with oral itraconazole (100 mg/day for 1 month, followed by a month of 100 mg/day every other day). Three of six patients showed complete clearance of pustules, significant reduction of erythema, and unnoticeable desquamation, whereas the other three patients had no new pustules appearing and had modest reduction of erythema and desquamation. All patients experienced relapses within a month of therapy cessation. Two of the three complete responders reinitiated itraconazole therapy at 100 mg/day for another 2 weeks, followed by a maintenance dose of 50 mg/day until achieving remission. As complete responses are not commonly observed in placebo treatments in placebo‐controlled trials for PPP, the authors believe that the present study shows that itraconazole is an effective treatment for treatment‐resistant PPP.
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