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Journal of Neuromuscular Diseases 2023LAMA2-related muscular dystrophy is a disorder that causes muscle weakness and varies in severity, from a severe, congenital type to a milder, late-onset form. However,... (Observational Study)
Observational Study
BACKGROUND
LAMA2-related muscular dystrophy is a disorder that causes muscle weakness and varies in severity, from a severe, congenital type to a milder, late-onset form. However, the disease does not only affect the muscles, but has systemic involvement and can lead to alterations such as brain malformation, epilepsy and intellectual disability.
OBJECTIVE
Describe the frequency of cortical malformations, epilepsy and intellectual disability in LAMA2-RD in a Brazilian cohort and correlate the neurological findings to genetic and motor function.
METHODS
This is an observational study of 52 LAMA2-RD patients, who were divided into motor function subgroups and compared based on brain MRI findings, epilepsy, intellectual disability, and type of variants and variant domains.
RESULTS
44 patients (84.6%) were only able to sit, and 8 patients (15.4%) were able to walk. 10 patients (19.2%) presented with cortical malformations (polymicrogyria, lissencephaly-pachygyria, and cobblestone),10 patients (19.2%) presented with epilepsy, and 8 (15.4%) had intellectual disability. CNS manifestations correlated with a more severe motor phenotype and none of the patients able to walk presented with cortical malformation or epilepsy. There was a relation between gene variants affecting the laminin-α2 LG-domain and the presence of brain malformation (P = 0.016). There was also a relation between the presence of null variants and central nervous system involvement. A new brazilian possible founder variant was found in 11 patients (21,15%) (c.1255del; p. Ile419Leufs*4).
CONCLUSION
Cortical malformations, epilepsy and intellectual disability are more frequent among LAMA2-RD patients than previously reported and correlate with motor function severity and the presence of variants affecting the laminin-α2 LG domain. This brings more insight fore phenotype-genotype correlations, shows the importance of reviewing the brain MRI of patients with LAMA2-RD and allows greater attention to the risk of brain malformation, epilepsy, and intellectual disability in those patients with variants that affect the LG domain.
Topics: Humans; Brain; Epilepsy; Genotype; Intellectual Disability; Laminin; Magnetic Resonance Imaging; Phenotype
PubMed: 37182895
DOI: 10.3233/JND-221638 -
Journal of Neurosciences in Rural... 2023Atretic cephaloceles (ACs) are congenital skull defects with herniation of rudimentary intracranial structures through the defect and associated with persistent falcine...
Atretic cephaloceles (ACs) are congenital skull defects with herniation of rudimentary intracranial structures through the defect and associated with persistent falcine sinus or embryonic positioning of straight sinus. We describe five cases of ACs, out of which only one had embryonic straight sinus. Three cases had other intracranial malformations such as hypoplasia of corpus callosum, dysplastic tectum in one child and parieto-occipital polymicrogyria with falcotentorial dehiscence in the other, and frontal horn deformity and cortical dysplasia in the third. The prognosis of AC depends on the coexistent intracranial abnormalities and this highlights the role of magnetic resonance imaging in diagnosing the other associated anomalies for prediction of prognosis and planning of necessary surgical management.
PubMed: 37181183
DOI: 10.25259/JNRP_46_2022 -
The Journal of Gene Medicine Oct 2023Population diversity is important and rare disease isolates can frequently reveal novel homozygous or biallelic mutations that lead to expanded clinical heterogeneity,...
BACKGROUND
Population diversity is important and rare disease isolates can frequently reveal novel homozygous or biallelic mutations that lead to expanded clinical heterogeneity, with diverse clinical presentations.
METHODS
The present study describes two consanguineous families with a total of seven affected individuals suffering from a clinically similar severe syndromic neurological disorder, with abnormal development and central nervous system (CNS) and peripheral nervous system (PNS) abnormalities. Whole exome sequencing (WES) and Sanger sequencing followed by 3D protein modeling was performed to identify the disease-causing gene. RNA was extracted from the fresh blood of both families affected and healthy individuals.
RESULTS
The families were clinically assessed in the field in different regions of Khyber Pakhtunkhwa. Magnetic resonance imagining was obtained in the probands and blood was collected for DNA extraction and WES was performed. Sanger sequencing confirmed a homozygous, likely pathogenic mutation (GRCh38: chr17:42684199G>C; (NM_003632.3): c.333G>C);(NP_003623.1): p.(Trp111Cys) in the CNTNAP1 gene in family A, previously associated with Congenital Hypo myelinating Neuropathy 3 (CHN3; OMIM # 618186) and a novel nonsense variant in family B, (GRCh38: chr16: 57654086C>T; NC_000016.10 (NM_001370440.1): c.721C>T); (NP_001357369.1): p.(Gln241Ter) in the ADGRG1 gene previously associated with bilateral frontoparietal polymicrogyria (OMIM # 606854); both families have extended CNS and PNS clinical manifestations. In addition, 3D protein modeling was performed for the missense variant, p.(Trp111Cys), identified in the CNTNAP1, suggesting extensive secondary structure changes that might lead to improper function or downstream signaling. No RNA expression was observed in both families affected and healthy individuals hence showing that these genes are not expressed in blood.
CONCLUSIONS
In the present study, two novel biallelic variants in the CNTNAP1 and ADGRG1 genes in two different consanguineous families with a clinical overlap in the phenotype were identified. Thus, the clinical and mutation spectrum is expanded to provide further evidence that CNTNAP1 and ADGRG1 are very important for widespread neurological development.
Topics: Humans; Consanguinity; Mutation; Mutation, Missense; Genes, Recessive; Phenotype; Cell Adhesion Molecules, Neuronal
PubMed: 37178061
DOI: 10.1002/jgm.3513 -
The American Journal of Case Reports May 2023BACKGROUND The Col4a1 gene encodes a portion of type IV collagen, a major component of the tissue basement membrane. Col4a1 mutations are rare, most frequently affect...
BACKGROUND The Col4a1 gene encodes a portion of type IV collagen, a major component of the tissue basement membrane. Col4a1 mutations are rare, most frequently affect neonates, and occur at a de novo mutation rate between 27% and 40%. Mutations are commonly missense and pleiotropic, presenting with cerebrovascular, renal, ophthalmological, and muscular abnormalities, collectively known as Gould Syndrome. Cerebral small vessel disease is commonly associated with Gould Syndrome and Col4a1 mutations. Children can present with infantile hemiplegia/quadriplegia, stroke, epilepsy, motor dysfunction, or white matter changes of the eye. CASE REPORT A male infant at 38-week, 4-day gestation presented with microcephaly, scattered multifocal hemorrhagic/ischemic infarcts, ex-vacuo dilatation, polymicrogyria, ventricular septal defect, and narrowed aortic arch, seen on prenatal ultrasound and confirmed by fetal echocardiogram and fetal brain magnetic resonance imaging (MRI). Electroencephalogram showed frequent subclinical seizures that were difficult to control, requiring multiple agents. Ophthalmology evaluation demonstrated small, hypoplastic optic nerves of both eyes, concerning for septo-optic dysplasia. Postnatal brain MRI confirmed fetal findings. Postnatal genetic testing showed a de novo heterozygous variant of Col4a1 and 1 nonspecific contiguous region of copy neutral absence of heterozygosity on chromosome 11. CONCLUSIONS This neonate was prenatally diagnosed with central nervous system (CNS) abnormalities and postnatally found to have a de novo heterozygous Col4a1 variant. CNS, cardiac, renal, and hematological findings were likely associated with the Col4a1 mutation and, possibly, a recessive genetic disorder of chromosome 11. Col4a1 mutations are rare and have no definitive treatments. Subspecialist follow-up and supportive care are essential to reduce long-term complications.
Topics: Child; Infant; Infant, Newborn; Pregnancy; Female; Humans; Male; Central Nervous System; Collagen Type IV; Stroke; Magnetic Resonance Imaging; Mutation
PubMed: 37157232
DOI: 10.12659/AJCR.938651 -
Prenatal Diagnosis Jul 2023To develop novel fetal reference ranges for the characterization of the normal appearance of the Sylvian fissures (SF) along gestation and to apply them to fetuses with...
OBJECTIVE
To develop novel fetal reference ranges for the characterization of the normal appearance of the Sylvian fissures (SF) along gestation and to apply them to fetuses with cortical abnormalities affecting the SF.
METHODS
In this cross-sectional study, we used three-dimensional sonographic multiplanar reformatting (3D-MPR) to examine the fetal SF. Normal development was assessed in the second and third trimesters. SF parameters were evaluated in predefined axial and coronal planes: insular height and length, SF depth, and the extent of the coverage of the insula by the frontal and temporal lobes. Intra-observer variability and inter-rater reliability for the studied parameters were evaluated. The new reference charts were applied to 19 fetuses with cortical abnormalities involving the SF who had appropriate sonographic volumes for 3D-MPR analysis. Their diagnoses were confirmed by autopsy, fetal or postnatal MRI, genetic findings related to cortical malformations, or an abnormal cortical imaging pattern with similar MRI findings in an affected sibling. We applied the two previously published references for the evaluation of fetal SF development to these cases and compared the ability of the references to correctly detect SF abnormalities.
RESULTS
The study included 189 fetuses of low-risk singleton pregnancies between 24 and 34 gestational weeks. The insular length or height increased with gestational age in the axial and coronal planes with adjusted R = 0.621, p < 0.0001 and R = 0.384, p < 0.0001, respectively. The SF depth also increased with gestational age in the axial and coronal planes with adjusted R = 0.695, p < 0.0001 and R = 0.219, p = 0.008, respectively. The extent of the coverage of the insula by the frontal and temporal lobes in the coronal plane increased with gestational age (adjusted R = 0.627, p < 0.0001 and R = 0.589, p < 0.0001, respectively). The interclass correlation coefficients of the intra- and inter-rater reliability of the studied parameters ranged between 0.71 and 0.97. The cortical anomalies in the 19 fetuses were polymicrogyria (7), simplified gyral pattern (3), dysgyria (3), lissencephaly (2), cortical malformation related to tubulinopathy (1), brain atrophy (1), cortical dysplasia (1), and cobblestone malformation (1). Three of the fetuses had multiple cortical anomalies. In 17 of 19 (89%) cases, at least one of our 6 SF parameters was found to be out of the normal range. In the coronal plane, SF height and depth were measured below 2SD in 9 (47%) and 4 (21%) cases, respectively. In the axial plane, SF length and depth were out of the normal ranges in six (31.5%) and four (21%), correspondingly. In the coronal plane, the opercular coverage by the frontal and temporal lobes was below 2 SD in 10 (52%) and 11 (57%), respectively. The scoring of the SF operculization by Quarello et al. was abnormal in 8 cases (42%). The measurement of the SF angle according to Poon et al. was abnormal in 14 cases (74%).
CONCLUSIONS
The fetal SF is a complex developing structure that can be reliably characterized by sonographic parameters. One abnormal parameter is sufficient to raise the suspicion of SF malformation. Our new SF parameters might facilitate the detection of prenatal cortical abnormalities affecting the SF.
Topics: Pregnancy; Female; Humans; Cross-Sectional Studies; Reproducibility of Results; Ultrasonography, Prenatal; Fetus; Gestational Age; Malformations of Cortical Development; Biometry; Reference Values
PubMed: 37115172
DOI: 10.1002/pd.6359 -
Radiology Case Reports Jun 2023Congenital bilateral perisylvian syndrome, also known as bilateral periopercular syndrome or perisylvian polymicrogyria, is an exceptionally rare neurological...
Congenital bilateral perisylvian syndrome, also known as bilateral periopercular syndrome or perisylvian polymicrogyria, is an exceptionally rare neurological disorder characterized by homogeneous clinicoradiological symptoms. There are consequently wide spectrums of clinical manifestations. In perisylvian syndrome. MRI is the preferred imaging technique. We describe the case of a female 8-year-old child who has a history of generalized tonic-clonic seizures. and was identified to have bilateral perisylvian syndrome based on MR imaging findings.
PubMed: 37064080
DOI: 10.1016/j.radcr.2023.03.013 -
Stereotactic and Functional Neurosurgery 2023In carefully selected patients with medically refractory epilepsy, disconnective hemispherotomy can result in significant seizure freedom; however, incomplete...
INTRODUCTION
In carefully selected patients with medically refractory epilepsy, disconnective hemispherotomy can result in significant seizure freedom; however, incomplete disconnection can result in ongoing seizures and poses a significant challenge. Completion hemispherotomy provides an opportunity to finish the disconnection. We describe the use of magnetic resonance-guided laser interstitial thermal ablation (MRgLITT) for completion hemispherotomy.
METHODS
Patients treated with completion hemispherotomy using MRgLITT at our institution were identified. Procedural and seizure outcomes were evaluated retrospectively.
RESULTS
Five patients (3 males) underwent six MRgLITT procedures (one child treated twice) for completion hemispherotomy at a median age of 6 years (range 1.8-12.9). Two children had hemimegalencephaly, two had Rasmussen encephalitis, and one had polymicrogyria. All five children had persistent seizures likely secondary to incomplete disconnection after their functional hemispherotomy. The mean time from open hemispherotomy to MRgLITT was 569.5 ± 272.4 days (median 424, range 342-1,095). One patient underwent stereoelectroencephalography before MRgLITT. The mean number of ablation targets was 2.3 ± 0.47 (median 2, range 2-3). The mean length of the procedure was 373 min ± 68.9 (median 374, range 246-475). Four of the five patients were afforded improvement in their neurocognitive functioning and speech performance after ablation, with mean daily seizure frequency at 1 year of 1.03 ± 1.98 (median 0, range 0-5). Two patients achieved Engel Class I outcomes at 1 year after ablation, one was Engel Class III, and two were Engel Class IV. The mean follow-up time was 646.8 ± 179.5 days (median 634, range 384-918). No MRgLITT-related complications occurred. Delayed retreatment (>1 year) occurred in three patients: one child underwent redo ablation and two underwent anatomic hemispherectomy.
CONCLUSION
We have demonstrated the feasibility of a minimally invasive approach for completion hemispherotomy using MRgLITT. Delayed retreatment was needed in three patients; thus, further study of this technique with comparison to other surgical techniques is warranted.
Topics: Child; Male; Humans; Infant; Child, Preschool; Retrospective Studies; Treatment Outcome; Magnetic Resonance Imaging; Drug Resistant Epilepsy; Seizures; Laser Therapy; Hemispherectomy; Magnetic Resonance Spectroscopy
PubMed: 37062282
DOI: 10.1159/000528452 -
Acta Obstetricia Et Gynecologica... Jun 2023The objective of this study was to describe a cohort of fetuses with an ultrasound prenatal diagnosis of obliterated cavum septi pellucidi (oCSP) with the aim to explore...
INTRODUCTION
The objective of this study was to describe a cohort of fetuses with an ultrasound prenatal diagnosis of obliterated cavum septi pellucidi (oCSP) with the aim to explore the rate of associated malformations, the progression during pregnancy and the role of fetal magnetic resonance imaging (MRI).
MATERIAL AND METHODS
This was a retrospective multicenter international study of fetuses diagnosed with oCSP in the second trimester with available fetal MRI and subsequent ultrasound and/or fetal MRI follow-up in the third trimester. Where available, postnatal data were collected to obtain information on neurodevelopment.
RESULTS
We identified 45 fetuses with oCSP at 20.5 weeks (interquartile range 20.1-21.1). oCSP was apparently isolated at ultrasound in 89% (40/45) and fetal MRI found additional findings in 5% (2/40) of cases, including polymicrogyria and microencephaly. In the remaining 38 fetuses, fetal MRI found a variable amount of fluid in CSP in 74% (28/38) and no fluid in 26% (10/38). Ultrasound follow-up at or after 30 weeks confirmed the diagnosis of oCSP in 32% (12/38) while fluid was visible in 68% (26/38). At follow-up MRI, performed in eight pregnancies, there were periventricular cysts and delayed sulcation with persistent oCSP in one case. Among the remaining cases with normal follow-up ultrasound and fetal MRI findings, the postnatal outcome was normal in 89% of cases (33/37) and abnormal in 11% (4/37): two with isolated speech delay, and two with neurodevelopmental delay secondary to postnatal diagnosis of Noonan syndrome at 5 years in one case and microcephaly with delayed cortical maturation at 5 months in the other.
CONCLUSIONS
Apparently isolated oCSP at mid-pregnancy is a transient finding with the visualization of the fluid later in pregnancy in up to 70% of cases. At referral, associated defects can be found in around 11% of cases at ultrasound and 8% at fetal MRI indicating the need for a detailed evaluation by expert physicians when oCSP is suspected.
Topics: Female; Pregnancy; Humans; Clinical Relevance; Ultrasonography, Prenatal; Magnetic Resonance Imaging; Fetus; Retrospective Studies; Microcephaly; Magnetic Resonance Spectroscopy
PubMed: 37059118
DOI: 10.1111/aogs.14575 -
Genetics in Medicine : Official Journal... Jul 2023Mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) regulates cell growth in response to nutritional status. Central to the mTORC1 function is the Rag-GTPase...
PURPOSE
Mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) regulates cell growth in response to nutritional status. Central to the mTORC1 function is the Rag-GTPase heterodimer. One component of the Rag heterodimer is RagC (Ras-related GTP-binding protein C), which is encoded by the RRAGC gene.
METHODS
Genetic testing via trio exome sequencing was applied to identify the underlying disease cause in 3 infants with dilated cardiomyopathy, hepatopathy, and brain abnormalities, including pachygyria, polymicrogyria, and septo-optic dysplasia. Studies in patient-derived skin fibroblasts and in a HEK293 cell model were performed to investigate the cellular consequences.
RESULTS
We identified 3 de novo missense variants in RRAGC (NM_022157.4: c.269C>A, p.(Thr90Asn), c.353C>T, p.(Pro118Leu), and c.343T>C, p.(Trp115Arg)), which were previously reported as occurring somatically in follicular lymphoma. Studies of patient-derived fibroblasts carrying the p.(Thr90Asn) variant revealed increased cell size, as well as dysregulation of mTOR-related p70S6K (ribosomal protein S6 kinase 1) and transcription factor EB signaling. Moreover, subcellular localization of mTOR was decoupled from metabolic state. We confirmed the key findings for all RRAGC variants described in this study in a HEK293 cell model.
CONCLUSION
The above results are in line with a constitutive overactivation of the mTORC1 pathway. Our study establishes de novo missense variants in RRAGC as cause of an early-onset mTORopathy with unfavorable prognosis.
Topics: Humans; Infant; Fibroblasts; Genetic Diseases, Inborn; HEK293 Cells; Mechanistic Target of Rapamycin Complex 1; Monomeric GTP-Binding Proteins; Multiprotein Complexes; Mutation, Missense; TOR Serine-Threonine Kinases
PubMed: 37057673
DOI: 10.1016/j.gim.2023.100838 -
Basic & Clinical Pharmacology &... Oct 2023GPR56/ADGRG1 is an adhesion G protein-coupled receptor (GPCR) and mutations on this receptor cause cortical malformation due to the over-migration of neural progenitor...
GPR56/ADGRG1 is an adhesion G protein-coupled receptor (GPCR) and mutations on this receptor cause cortical malformation due to the over-migration of neural progenitor cells on brain surface. At pial surface, GPR56 interacts with collagen III, induces Rho-dependent activation through Gα and inhibits the neuronal migration. In human glioma cells, GPR56 inhibits cell migration through Gα -dependent Rho pathway. GPR56-tetraspanin complex is known to couple Gα . GPR56 is an aGPCR that couples with various G proteins and signals through different downstream pathways. In this study, bilateral frontoparietal polymicrogyria (BFPP) mutants disrupting GPR56 function but remaining to be expressed on plasma membrane were used to study receptor signalling through Gα , Gα and Gα with BRET biosensors. GPR56 showed coupling with all three G proteins and activated heterotrimeric G protein signalling upon stimulation with Stachel peptide. However, BFPP mutants showed different signalling defects for each G protein indicative of distinct activation and signalling properties of GPR56 for Gα , Gα or Gα . β-arrestin recruitment was also investigated following the activation of GPR56 with Stachel peptide using BRET biosensors. N-terminally truncated GPR56 showed enhanced β-arrestin recruitment; however, neither wild-type receptor nor BFPP mutants gave any measurable recruitment upon Stachel stimulation, pointing different activation mechanisms for β-arrestin involvement.
Topics: Humans; Receptors, G-Protein-Coupled; Mutation; GTP-Binding Proteins; Peptides; beta-Arrestins
PubMed: 37056198
DOI: 10.1111/bcpt.13873