-
Molecular Biology Reports Jun 2024Autosomal recessive primary microcephaly (MCPH) is a rare neurodevelopmental and genetically heterogeneous disorder, characterized by small cranium size (> - 3 SD...
Molecular genetics, neuroimaging outcomes, and structural analyses of novel and recurrent variants of WDR62 gene in two consanguineous Pakistani families with autosomal recessive primary microcephaly.
BACKGROUND
Autosomal recessive primary microcephaly (MCPH) is a rare neurodevelopmental and genetically heterogeneous disorder, characterized by small cranium size (> - 3 SD below mean) and often results in varying degree of intellectual disability. Thirty genes have been identified for the etiology of this disorder due to its clinical and genetic heterogeneity.
METHODS AND RESULTS
Here, we report two consanguineous Pakistani families affected with MCPH exhibiting mutation in WDR62 gene. The investigation approach involved Next Generation Sequencing (NGS) gene panel sequencing coupled with linkage analysis followed by validation of identified variants through automated Sanger sequencing and Barcode-Tagged (BT) sequencing. The molecular genetic analysis revealed one novel splice site variant (NM_001083961.2(WDR62):c.1372-1del) in Family A and one known exonic variant NM_001083961.2(WDR62):c.3936dup (p.Val1313Argfs*18) in Family B. Magnetic Resonance Imaging (MRI) scans were also employed to gain insights into the structural architecture of affected individuals. Neurological assessments showed the reduced gyral and sulcal patterns along with normal corpus callosum in affected individuals harboring novel variant. In silico assessments of the identified variants were conducted using different tools to confirm the pathogenicity of these variants. Through In silico analyses, both variants were identified as disease causing and protein modeling of exonic variant indicates subtle conformational alterations in prophesied protein structure.
CONCLUSION
This study identifies a novel variant (c.1372-1del) and a recurrent pathogenic variant c.3936dup (p.Val1313Argfs*18) in the WDR62 gene among the Pakistani population, expanding the mutation spectrum for MCPH. These findings emphasize the importance of genetic counseling and awareness to reduce consanguinity and address the burden of this disorder.
Topics: Humans; Microcephaly; Female; Male; Pedigree; Pakistan; Consanguinity; Mutation; Nerve Tissue Proteins; Neuroimaging; Child; Magnetic Resonance Imaging; High-Throughput Nucleotide Sequencing; Child, Preschool; Adolescent; Cell Cycle Proteins
PubMed: 38926176
DOI: 10.1007/s11033-024-09728-7 -
Pediatric Neurology Jun 2024Pontocerebellar hypoplasia type 10 (PCH10) due to CLP1 gene mutations is characterized by structural brain anomalies, progressive microcephaly, severe intellectual and...
BACKGROUND
Pontocerebellar hypoplasia type 10 (PCH10) due to CLP1 gene mutations is characterized by structural brain anomalies, progressive microcephaly, severe intellectual and physical disabilities, and spasticity. In this follow-up study, evolution of phenotypic and neurological characteristics of patients with PCH10 is discussed.
METHODS
Phenotype, growth parameters, motor functions, developmental tests, spasticity assessments, functional independence assessments, electroencephalography (EEG), and brain magnetic resonance imaging (MRI) of 10 patients with PCH10 were monitored on separate examinations. Alterations were recorded.
RESULTS
Patients were followed-up for an average of 2.83 years. The tone of the upper extremities was significantly higher than that of the lower extremities, according to Modified Ashworth Scale (MAS) values. Sixty percent of patients could sit unsupported; 20% achieved supported sitting initially but lost the ability during follow-up. Absence of grabbing or sitting was observed in 20% of patients. During follow-up, one person achieved supported sitting and one person achieved head holding. Only one patient was able to speak a few words. Cerebellar atrophy (two of 10), pons hypoplasia (four of 10), cortical atrophy (seven of 10), enlarged ventricles (10 of 10), thinning of the corpus callosum (10 of 10), hypomyelination (six of 10), and increased white matter signal intensity (six of 10) were the observed MRI findings.
CONCLUSIONS
Progressive cerebral and cerebellar atrophy was demonstrated radiologically for the first time in a PCH10 cohort. It is of crucial importance to identify these patients promptly with the help of dysmorphic findings and spasticity being pronounced in the upper extremities. Furthermore, we note that phenotypic and neurological examination findings tend to change slightly over time.
PubMed: 38925092
DOI: 10.1016/j.pediatrneurol.2024.05.017 -
Cureus May 2024TUBG1, a tubulin gene, plays an important role in neurodevelopment. Here we describe a case of a novel TUGB1 mutation (NM_001070.4:c.821C>T) (p.Thr274Ile). This patient...
TUBG1, a tubulin gene, plays an important role in neurodevelopment. Here we describe a case of a novel TUGB1 mutation (NM_001070.4:c.821C>T) (p.Thr274Ile). This patient presented similarly to previous cases with features including microcephaly, epilepsy, and speech and motor delay. Unique characteristics were also present such as trigonocephaly, tethered frenulum, scoliosis, nystagmus, and a concurrent FBXW7 mutation. This case expands our breadth of knowledge on TUBG1 genotypic and phenotypic variation. However, further work is needed to fully understand this rare mutation and the associations between TUBG1 and FBXW7 mutations.
PubMed: 38919239
DOI: 10.7759/cureus.61132 -
Journal of Community Genetics Jun 2024Congenital anomalies (CAs) are an important cause of infant mortality and efficient surveillance is necessary for their prevention. Therefore, the objective of this...
Congenital anomalies (CAs) are an important cause of infant mortality and efficient surveillance is necessary for their prevention. Therefore, the objective of this study is to establish baselines of prevalence at birth of priority CAs for surveillance in the state of Santa Catarina, using data from the Live Birth Information System considering the period 2011-2019 (baseline) and 2020 (pandemic year). The analyses were carried out based on the mother's residence health macroregion. The CAs were selected following the ICD-10 coding for chapter XVII. Birth prevalence was calculated per 10,000 live births and the confidence interval was established at 95%. 2011-2019 recorded 88.8/10,000 births with CAs (total). For 2011-2019, limb defects (without polydactyly) were the most prevalent (14.1/10,000), followed by congenital heart defects (8.9), oral clefts (8.2), polydactyly (7.9), Down syndrome (5.6), hypospadias (5.4), neural tube defects (4.7), gastroschisis (3.3), undefined sex (1.2), microcephaly (0.8) and omphalocele (0.3). There were no significant differences in temporal and spatial distribution. However, unusual fluctuations were observed in 2020, which may reflect the pandemic in CAs notifications. In the base period, Santa Catarina recorded CAs below the expected level of being identified at birth. With this, we conclude that the training and awareness of teams are essential for the surveillance of CAs in Santa Catarina.
PubMed: 38918275
DOI: 10.1007/s12687-024-00716-9 -
Cureus May 2024Macrothrompocytopenia (MTP) is a rare group of hereditary disorders that lead to impaired hemostasis. Macrothrompocytopenia mostly results from genetic mutations in...
Macrothrompocytopenia (MTP) is a rare group of hereditary disorders that lead to impaired hemostasis. Macrothrompocytopenia mostly results from genetic mutations in genes implicated in megakaryocyte differentiation and function. Diaphanous-related formin 1 (DIAPH1) is a protein-coding gene. Dominant gain-of-function DIAPH1 variants cause macrothrombocytopenia and sensorineural deafness (autosomal dominant non-syndromic hearing loss 1 (DFNA1)), while homozygous loss of DIAPH1 results in seizures, cortical blindness, and microcephaly syndrome (SCBMS). This rare genetic disease is characterized by progressive and severe hearing loss with onset in the first decade of life, is associated with mild thrombocytopenia, and has no significant bleeding tendency. This case report presents the clinical findings of a 14-year-old Saudi pediatric girl. We investigated the potential association of DIAPH1 as a novel candidate gene linked to dominant MTP and autosomal dominant non-syndromic hearing loss (ADNSHL), which was evaluated through audiometry. Notably, a novel variant, c.3633_3636del, was identified in the DIAPH1 gene. To date, only a small number of mutations in this gene have been reported as the cause of MTP and ADNSHL.
PubMed: 38915998
DOI: 10.7759/cureus.61044 -
Cureus May 2024Congenital toxoplasmosis is caused by transplacental infection of during pregnancy. We present a case of a congenital toxoplasma with intracranial calcifications,...
Congenital toxoplasmosis is caused by transplacental infection of during pregnancy. We present a case of a congenital toxoplasma with intracranial calcifications, microcephaly, growth restriction, a unilateral cataract that developed in the third trimester, and a coincidental post-axial-polydactyly. Antenatal imaging findings are important to guide further testing and confirmation of diagnosis, it is important to know all possible associations and prognoses for timely counseling, testing, and intervention. To our knowledge, no case has been published with findings of unilateral cataract in congenital toxoplasmosis and associated coincidental polydactyly. Therefore, we wish to add this case to the current scientific literature.
PubMed: 38915958
DOI: 10.7759/cureus.61058 -
Cureus Jun 2024Malformations of cortical development (MCD) are a group of disorders affecting the normal development of the human cortex and are significant causes of delay in...
Malformations of cortical development (MCD) are a group of disorders affecting the normal development of the human cortex and are significant causes of delay in psychomotor development and epilepsy in children. Lissencephaly (smooth brain) forms a major group of brain malformations. Microtubules help in the migration of neuronal cells. Defect in tubulin gene alpha-tubulin (TUBA), beta-tubulin (TUBB), and gamma-tubulin (TUBG) leads to defective neuronal migration. This group of disorders is termed as "tubulinopathies." The important genes implicated in causing lissencephaly are LIS1, XLIS, and TUBA1A gene. Recently, a mutation in the TUBG1 gene is associated with it. Here, we report a one-and-a-half-year-old girl with global developmental delay, microcephaly, infantile-onset epilepsy, epileptic spasms, dysmorphism, and motor signs. There was no significant birth history. Neuroimaging (MRI) showed a broad thick gyri and a decreased number of sulci suggestive of lissencephaly/pachygyria spectrum. There was dilatation of the ventricles, and no grey matter heterotopia was noted. Sleep EEG showed multifocal epileptiform discharges. The child was treated with multiple anti-seizure medicines (ASMs). A genetic test, whole exome sequencing, was done to determine the etiology of MCD. A heterozygous missense variation in exon 6 of the TUBG1 gene was identified and reported as a "variant of unknown significance." Still, because the genotype matched with the clinical phenotype of the patient, it was considered clinically significant. Therefore, a complete diagnosis of TUBG1 mutation-associated cortical malformation (lissencephaly/pachygyria) with microcephaly and early-onset epilepsy was established. TUBG1 mutation is de novo in most cases, but parental testing is recommended. The parents of such patients need to be counseled about the need for prenatal testing and the risk of the disease to siblings. The overall prognosis in such cases is poor because of refractory seizures, physical limitations, and intellectual disability.
PubMed: 38912084
DOI: 10.7759/cureus.62749 -
BioRxiv : the Preprint Server For... Mar 2024The transitioning of neural stem cells (NSCs) between quiescent and proliferative states is fundamental for brain development and homeostasis. Defects in NSC...
The transitioning of neural stem cells (NSCs) between quiescent and proliferative states is fundamental for brain development and homeostasis. Defects in NSC reactivation are associated with neurodevelopmental disorders. quiescent NSCs extend an actin-rich primary protrusion toward the neuropil. However, the function of the actin cytoskeleton during NSC reactivation is unknown. Here, we reveal the fine F-actin structures in the protrusions of quiescent NSCs by expansion and super-resolution microscopy. We show that F-actin polymerization promotes the nuclear translocation of Mrtf, a microcephaly-associated transcription factor, for NSC reactivation and brain development. F-actin polymerization is regulated by a signaling cascade composed of G-protein-coupled receptor (GPCR) Smog, G-protein αq subunit, Rho1 GTPase, and Diaphanous (Dia)/Formin during NSC reactivation. Further, astrocytes secrete a Smog ligand Fog to regulate Gαq-Rho1-Dia-mediated NSC reactivation. Together, we establish that the Smog-Gαq-Rho1 signaling axis derived from astrocytes, a NSC niche, regulates Dia-mediated F-actin dynamics in NSC reactivation.
PubMed: 38903085
DOI: 10.1101/2024.03.11.584337 -
Nature Communications Jun 2024Zika virus (ZikV) infection during pregnancy can cause congenital Zika syndrome (CZS) and neurodevelopmental delay in infants, of which the pathogenesis remains poorly...
Zika virus (ZikV) infection during pregnancy can cause congenital Zika syndrome (CZS) and neurodevelopmental delay in infants, of which the pathogenesis remains poorly understood. We utilize an established female pigtail macaque maternal-to-fetal ZikV infection/exposure model to study fetal brain pathophysiology of CZS manifesting from ZikV exposure in utero. We find prenatal ZikV exposure leads to profound disruption of fetal myelin, with extensive downregulation in gene expression for key components of oligodendrocyte maturation and myelin production. Immunohistochemical analyses reveal marked decreases in myelin basic protein intensity and myelinated fiber density in ZikV-exposed animals. At the ultrastructural level, the myelin sheath in ZikV-exposed animals shows multi-focal decompaction, occurring concomitant with dysregulation of oligodendrocyte gene expression and maturation. These findings define fetal neuropathological profiles of ZikV-linked brain injury underlying CZS resulting from ZikV exposure in utero. Because myelin is critical for cortical development, ZikV-related perturbations in oligodendrocyte function may have long-term consequences on childhood neurodevelopment, even in the absence of overt microcephaly.
Topics: Animals; Zika Virus Infection; Oligodendroglia; Female; Myelin Sheath; Pregnancy; Zika Virus; Disease Models, Animal; Pregnancy Complications, Infectious; Macaca nemestrina; Brain; Humans; Myelin Basic Protein
PubMed: 38890352
DOI: 10.1038/s41467-024-49524-2 -
Behavioural Brain Research Jun 2024Zika virus (ZIKV) is a neurotropic Orthoflavivirus that causes a myriad of neurological manifestations in newborns exposed in uterus. Despite the devastating...
Zika virus (ZIKV) is a neurotropic Orthoflavivirus that causes a myriad of neurological manifestations in newborns exposed in uterus. Despite the devastating consequences of ZIKV on the developing brain, strategies to prevent or treat the consequences of viral infection are not yet available. We previously showed that short-term treatment with the TNF-α neutralizing monoclonal antibody. Infliximab could prevent seizures at acute and chronic stages of ZIKV infection, but had no impact on long-term cognitive and motor dysfunction. Due to the central role of inflammation in ZIKV-neuropathology, we hypothesized that prolonged treatment with the anti-TNF-α monoclonal antibody Infliximab could provide complete rescue of long-term behavioral deficits associated with neonatal ZIKV infection in mice. Here, neonatal (post-natal day 3) Swiss mice were submitted to subcutaneous (s.c.) injection of 10 PFU of ZIKV or mock medium and were then treated with Infliximab (20 μg/day) or sterile saline intraperitoneally (i.p.), for 40 days starting on the day of infection, and behavioral assessment started at 60 days post-infection (dpi). Infliximab prevented ZIKV-induced cognitive and motor impairments in mice. In addition, microgliosis and cell death found in mice following ZIKV infection were partially reversed by TNF-α blockage. Altogether, these results suggest that TNF-α-mediated inflammation is central for late ZIKV-induced behavioral deficits and cell death and strategies targeting this cytokine may be promising approaches to treat subjects exposed to the virus during development.
PubMed: 38878972
DOI: 10.1016/j.bbr.2024.115114