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Cureus Apr 2024Pontocerebellar hypoplasia type 9 (PCH9) is a rare, autosomal, recessive, neurodevelopmental disorder caused by a mutation in the AMPD2 gene. Despite its rarity, it...
Pontocerebellar hypoplasia type 9 (PCH9) is a rare, autosomal, recessive, neurodevelopmental disorder caused by a mutation in the AMPD2 gene. Despite its rarity, it presents distinctive clinical and neuroradiological features. Diagnosing it is challenging yet crucial for appropriate management. We describe a 21-month-old boy with clinical and neuroradiological manifestations of the diagnosis, including characteristic signs such as an eight-configured midbrain and hypoplasia of the brainstem and cerebellar structures. Genetic evaluation confirmed homozygous missense mutations in the AMPD2 gene. This case highlights the pathognomonic neuroradiological features of pontocerebellar hypoplasia type 9 that point toward diagnosis.
PubMed: 38957830
DOI: 10.7759/cureus.58522 -
Hormone Research in Paediatrics Jun 2024Introduction The clinical features of bi-allelic IGF1 defects are well established, i.e. severe growth failure and microcephaly, delayed psychomotor development, and...
Introduction The clinical features of bi-allelic IGF1 defects are well established, i.e. severe growth failure and microcephaly, delayed psychomotor development, and sensorineural deafness. However, information on clinical and endocrine consequences of heterozygous IGF1 variants and treatment options is scarce. We aimed at extending the knowledge base of the clinical presentation and growth response to recombinant human growth hormone (rhGH) of patients carrying such variants. Methods Retrospective case series of patients with pathogenic heterozygous IGF1 variants. Results Nine patients from six families were included, harbouring five whole or partial gene deletions and one frameshift variant resulting in a premature stop codon (three de novo, one unknown inheritance). In the other two families variants segregated with short stature. Mean (SD) birth length was -1.9 (1.3) SDS (n=7), height -3.8 (0.6) SDS, head circumference -2.5 (0.6) SDS, serum IGF-I -1.9 (0.7) SDS, serum IGFBP-3 1.1 (0.4) SDS (n=7) and GH peak range 5-31 μg/L (n=4). Five patients showed feeding problems in infancy. Average height increased after 1 and 2 years of rhGH treatment by 0.8 SDS (range 0.3-1.3 SDS) and 1.3 SDS (range 0.5-2.0 SDS), respectively. Adult height in two patients was -2.8 and -1.3 SDS, which was respectively 1.3 and 2.9 SDS taller than predicted before start of treatment. Conclusion Haploinsufficiency of IGF1 causes a variable phenotype of prenatal and postnatal growth failure, microcephaly, feeding difficulties, low/low-normal serum IGF-I values in contrast to serum IGFBP-3 in the upper-normal range. Treatment with rhGH increased growth in the first two years of treatment, and in two patients adult height after treatment was higher than predicted at treatment initiation.
PubMed: 38952118
DOI: 10.1159/000540053 -
Stem Cell Reviews and Reports Jun 2024Mutations in STAMBP have been well-established to cause congenital human microcephaly-capillary malformation (MIC-CAP) syndrome, a rare genetic disorder characterized by...
Mutations in STAMBP have been well-established to cause congenital human microcephaly-capillary malformation (MIC-CAP) syndrome, a rare genetic disorder characterized by global developmental delay, severe microcephaly, capillary malformations, etc. Previous biochemical investigations and loss-of-function studies in mice have provided insights into the mechanism of STAMBP, however, it remains controversial how STAMBP deficiency leads to malformation of those affected tissues in patients. In this study, we investigated the function and underlying mechanism of STAMBP during neural differentiation of human embryonic stem cells (hESCs). We found that STAMBP is dispensable for the pluripotency maintenance or neural differentiation of hESCs. However, neural progenitor cells (NPCs) derived from STAMBP-deficient hESCs fail to be long-term maintained/expanded in vitro. We identified the anti-apoptotic protein CFLAR is down-regulated in those affected NPCs and ectopic expression of CFLAR rescues NPC defects induced by STAMBP-deficiency. Our study not only provides novel insight into the mechanism of neural defects in STAMBP mutant patients, it also indicates that the death receptor mediated apoptosis is an obstacle for long-term maintenance/expansion of NPCs in vitro thus counteracting this cell death pathway could be beneficial to the generation of NPCs in vitro.
PubMed: 38951308
DOI: 10.1007/s12015-024-10751-1 -
Nucleic Acids Research Jul 2024In higher eukaryotes, tRNA methyltransferase 10A (TRMT10A) is responsible for N1-methylguanosine modification at position nine of various cytoplasmic tRNAs. Pathogenic...
In higher eukaryotes, tRNA methyltransferase 10A (TRMT10A) is responsible for N1-methylguanosine modification at position nine of various cytoplasmic tRNAs. Pathogenic mutations in TRMT10A cause intellectual disability, microcephaly, diabetes, and short stature in humans, and generate cytotoxic tRNA fragments in cultured cells; however, it is not clear how TRMT10A supports codon translation or brain functions. Here, we generated Trmt10a null mice and showed that tRNAGln(CUG) and initiator methionine tRNA levels were universally decreased in various tissues; the same was true in a human cell line lacking TRMT10A. Ribosome profiling of mouse brain revealed that dysfunction of TRMT10A causes ribosome slowdown at the Gln(CAG) codon and increases translation of Atf4 due to higher frequency of leaky scanning of its upstream open reading frames. Broadly speaking, translation of a subset of mRNAs, especially those for neuronal structures, is perturbed in the mutant brain. Despite not showing discernable defects in the pancreas, liver, or kidney, Trmt10a null mice showed lower body weight and smaller hippocampal postsynaptic densities, which is associated with defective synaptic plasticity and memory. Taken together, our study provides mechanistic insight into the roles of TRMT10A in the brain, and exemplifies the importance of universal tRNA modification during translation of specific codons.
PubMed: 38950903
DOI: 10.1093/nar/gkae520 -
Singapore Medical Journal Jun 2024
PubMed: 38949060
DOI: 10.4103/singaporemedj.SMJ-2023-134 -
Biochemistry Research International 2024Eg5 is a protein encoded by KIF11 gene and is primarily involved in correct mitotic cell division. It is also involved in nonmitotic processes such as polypeptide... (Review)
Review
Eg5 is a protein encoded by KIF11 gene and is primarily involved in correct mitotic cell division. It is also involved in nonmitotic processes such as polypeptide synthesis, protein transport, and angiogenesis. The scientific literature sheds light on the ubiquitous functions of KIF11 and its involvement in the onset and progression of different pathologies. This review focuses attention on two main points: (1) the correlation between Eg5 and cancer and (2) the involvement of Eg5 in noncancerous conditions. Regarding the first point, several tumors revealed an overexpression of this kinesin, thus pushing to look for new Eg5 inhibitors for clinical practice. In addition, the evaluation of Eg5 expression represents a crucial step, as its overexpression could predict a poor prognosis for cancer patients. Referring to the second point, in specific pathological conditions, the reduced activity of Eg5 can be one of the causes of pathological onset. This is the case of Alzheimer's disease (AD), in which A and Tau work as Eg5 inhibitors, or in acquired immune deficiency syndrome (AIDS), in which Tat-mediated Eg5 determines the loss of CD T-lymphocytes. Reduced Eg5 activity, due to mutations of KIF11 gene, is also responsible for pathological conditions such as microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability (MCLRI) and familial exudative vitreous retinopathy (FEVR). In conclusion, this review highlights the double impact that overexpression or loss of function of Eg5 could have in the onset and progression of different pathological situations. This emphasizes, on one hand, a possible role of Eg5 as a potential biomarker and new target in cancer and, on the other hand, the promotion of Eg5 expression/activity as a new therapeutic strategy in different noncancerous diseases.
PubMed: 38939361
DOI: 10.1155/2024/3649912 -
Biochemistry and Biophysics Reports Sep 2024Zika virus represents the primary cause of infection during pregnancy and can lead to various neurological disorders such as microcephaly and Guillain-Barré syndrome...
Zika virus represents the primary cause of infection during pregnancy and can lead to various neurological disorders such as microcephaly and Guillain-Barré syndrome affecting both children and adults. This infection is also associated with urological and nephrological problems. So far, evidence of mosquito-borne Zika virus infection has been reported in a total of 89 countries and territories. However, surveillance efforts primarily concentrate on outbreaks that this virus can cause, yet the measures implemented are typically limited. Currently, there are no specific treatments or vaccines designed for the prevention or treatment of Zika virus infection or its associated disease. The development of effective therapeutic agents presents an urgent need. Importantly, an alternative for advancing the discovery of new molecules could be dermaseptins, a family of antimicrobial peptides known for their potential antiviral properties. In this study, we carried out the synthesis of dermaseptins and their analogs and subsequently assessed the bioactivity tests against Zika virus (ZIKV PF13) of dermaseptins B2 and S4 and their derivatives. The cytotoxicity of these peptides was investigated on HMC3 cell line and HeLa cells by CellTiter-Glo® Luminescent Cell Viability Assay. Thereafter, we evaluated the antiviral activity caused by the action of our dermaseptins on the viral envelope using the Fluorescence Activated Cell Sorting (FACS). The cytotoxicity of our molecules was concentration-dependent at microgram concentrations Expect for dermaseptin B2 and its derivative which present no toxicity against HeLa and HMC3 cell lines. It was observed that all tested analogs from S4 family exhibited antiviral activity with low concentrations ranging from 3 to 12.5 μg/ml , unlike the native B2 and its derivative which increased the infectivity. Pre-incubating of dermaseptins with ZIKV PF13 before infection revealed that these derivatives inhibit the initial stages of virus infection. In summary, these results suggest that dermaseptins could serve as novel lead structures for the development of potent antiviral agents against Zika virus infections.
PubMed: 38939125
DOI: 10.1016/j.bbrep.2024.101747 -
Pediatric Neurology Jun 2024Neurodevelopmental disorder with dysmorphic facies and distal limb anomalies (NEDDFL) is associated to BPTF gene haploinsufficiency. Epilepsy was not included in the...
BACKGROUND
Neurodevelopmental disorder with dysmorphic facies and distal limb anomalies (NEDDFL) is associated to BPTF gene haploinsufficiency. Epilepsy was not included in the initial descriptions of NEDDFL, but emerging evidence indicates that epileptic seizures occur in some affected individuals. This study aims to investigate the electroclinical epilepsy features in individuals with NEDDFL.
METHODS
We enrolled individuals with BPTF-related seizures or interictal epileptiform discharges (IEDs) on electroencephalography (EEG). Demographic, clinical, genetic, raw EEG, and neuroimaging data as well as response to antiseizure medication were assessed.
RESULTS
We studied 11 individuals with a null variant in BPTF, including five previously unpublished ones. Median age at last observation was 9 years (range: 4 to 43 years). Eight individuals had epilepsy, one had a single unprovoked seizure, and two showed IEDs only. Key features included (1) early childhood epilepsy onset (median 4 years, range: 10 months to 7 years), (2) well-organized EEG background (all cases) and brief bursts of spikes and slow waves (50% of individuals), and (3) developmental delay preceding seizure onset. Spectrum of epilepsy severity varied from drug-resistant epilepsy (27%) to isolated IEDs without seizures (18%). Levetiracetam was widely used and reduced seizure frequency in 67% of the cases.
CONCLUSIONS
Our study provides the first characterization of BPTF-related epilepsy. Early-childhood-onset epilepsy occurs in 19% of subjects, all presenting with a well-organized EEG background associated with generalized interictal epileptiform abnormalities in half of these cases. Drug resistance is rare.
PubMed: 38936258
DOI: 10.1016/j.pediatrneurol.2024.06.001 -
Viruses May 2024Humans continue to be at risk from the Zika virus. Although there have been significant research advancements regarding Zika, the absence of a vaccine or approved...
Humans continue to be at risk from the Zika virus. Although there have been significant research advancements regarding Zika, the absence of a vaccine or approved treatment poses further challenges for healthcare providers. In this study, we developed a microparticulate Zika vaccine using an inactivated whole Zika virus as the antigen that can be administered pain-free via intranasal (IN) immunization. These microparticles (MP) were formulated using a double emulsion method developed by our lab. We explored a prime dose and two-booster-dose vaccination strategy using MPL-A and Alhydrogel as adjuvants to further stimulate the immune response. MPL-A induces a Th1-mediated immune response and Alhydrogel (alum) induces a Th2-mediated immune response. There was a high recovery yield of MPs, less than 5 µm in size, and particle charge of -19.42 ± 0.66 mV. IN immunization of Zika MP vaccine and the adjuvanted Zika MP vaccine showed a robust humoral response as indicated by several antibodies (IgA, IgM, and IgG) and several IgG subtypes (IgG1, IgG2a, and IgG3). Vaccine MP elicited a balance Th1- and Th2-mediated immune response. Immune organs, such as the spleen and lymph nodes, exhibited a significant increase in CD4 helper and CD8 cytotoxic T-cell cellular response in both vaccine groups. Zika MP vaccine and adjuvanted Zika MP vaccine displayed a robust memory response (CD27 and CD45R) in the spleen and lymph nodes. Adjuvanted vaccine-induced higher Zika-specific intracellular cytokines than the unadjuvanted vaccine. Our results suggest that more than one dose or multiple doses may be necessary to achieve necessary immunological responses. Compared to unvaccinated mice, the Zika vaccine MP and adjuvanted MP vaccine when administered via intranasal route demonstrated robust humoral, cellular, and memory responses. In this pre-clinical study, we established a pain-free microparticulate Zika vaccine that produced a significant immune response when administered intranasally.
Topics: Animals; Administration, Intranasal; Zika Virus Infection; Zika Virus; Mice; Antibodies, Viral; Viral Vaccines; Female; Immunization; Adjuvants, Immunologic; Disease Models, Animal; Adjuvants, Vaccine; Vaccination; Cytokines; Antibodies, Neutralizing
PubMed: 38932158
DOI: 10.3390/v16060865 -
Journal of Clinical Medicine Jun 2024Floating-Harbor syndrome (FHS) is an extremely rare genetic disorder connected with a distinctive facial appearance, various skeletal malformations, delayed bone age,...
Floating-Harbor syndrome (FHS) is an extremely rare genetic disorder connected with a distinctive facial appearance, various skeletal malformations, delayed bone age, and expressive language delays. It is caused by heterozygous mutations in the Snf2-related CREBBP activator protein (SRCAP) gene. The aim of this paper is to describe the case of a 14-year-old male with FHS, referring to a review of the literature, and to collect all reported symptoms. In addition, the orthodontic treatment of the patient is described. For this, the electronic databases PubMed and Scopus were searched using the keyword "Floating-Harbor syndrome". Similar to previous cases in the literature, the patient presented with short stature; a triangular face with a large bulbous nose; deep-set eyes and narrow eyelid gaps; a wide mouth with a thin vermilion border of the upper lip; and dorsally rotated, small ears. They also presented some less-described symptoms, such as macrodontia and micrognathia. Moreover, mild mental retardation, microcephaly, and delayed psychomotor development were found. On the basis of an extraoral, intraoral examination, X-rays, and CBCT, he was diagnosed with overbite, canine class I and angle class III, on both sides. To the best of our knowledge, orthodontic treatment of this disease has not been assessed in detail so far, so this is the first case.
PubMed: 38929963
DOI: 10.3390/jcm13123435