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Congenital muscular dystrophies (CMDs) are a group of rare muscle disorders characterized by early onset hypotonia and motor developmental delay associated with brain malformations with or without eye anomalies in the most severe cases. In this study, we aimed to uncover the genetic basis of severe CMD in Egypt and to determine the efficacy of whole exome sequencing (WES)-based genetic diagnosis in this population. We recruited twelve individuals from eleven families with a clinical diagnosis of CMD with brain malformations that fell into two groups: seven patients with suspected dystroglycanopathy and five patients with suspected merosin-deficient CMD. WES was analyzed by variant filtering using multiple approaches including splicing and copy number variant (CNV) analysis. We identified likely pathogenic variants in FKRP in two cases and variants in POMT1, POMK, and B3GALNT2 in three individuals. All individuals with merosin-deficient CMD had truncating variants in LAMA2. Further analysis in one of the two unsolved cases showed a homozygous protein-truncating variant in Feline Leukemia Virus subgroup C Receptor 1 (FLVCR1). FLVCR1 loss of function has never been previously reported. Yet, loss of function of its paralog, FLVCR2, causes lethal hydranencephaly-hydrocephaly syndrome (Fowler Syndrome) which should be considered in the differential diagnosis for dystroglycanopathy. Overall, we reached a diagnostic rate of 86% (6/7) for dystroglycanopathies and 100% (5/5) for merosinopathy. In conclusion, our results provide further evidence that WES is an important diagnostic method in CMD in developing countries to improve the diagnostic rate, management plan, and genetic counseling for these disorders., (© 2024. The Author(s).)

Symptoms of obsessive-compulsive disorder (OCD) may rarely occur in the context of genetic syndromes. So far, an association between obsessive-compulsive symptoms (OCS) and ACTG1-associated Baraitser-Winter cerebrofrontofacial syndrome has not been described as yet. A thoroughly phenotyped patient with OCS and ACTG1-associated Baraitser-Winter cerebrofrontofacial syndrome is presented. The 25-year-old male patient was admitted to in-patient psychiatric care due to OCD. A whole-exome sequencing analysis was initiated as the patient also showed an autistic personality structure, below average intelligence measures, craniofacial dysmorphia signs, sensorineural hearing loss, and sinus cavernoma as well as subtle cardiac and ophthalmological alterations. The diagnosis of Baraitser-Winter cerebrofrontofacial syndrome type 2 was confirmed by the detection of a heterozygous likely pathogenic variant in the ACTG1 gene [c.1003C > T; p.(Arg335Cys), ACMG class 4]. The automated analysis of magnetic resonance imaging (MRI) revealed changes in the orbitofrontal, parietal, and occipital cortex of both sides and in the right mesiotemporal cortex. Electroencephalography (EEG) revealed intermittent rhythmic delta activity in the occipital and right temporal areas. Right mesiotemporal MRI and EEG alterations could be caused by a small brain parenchymal defect with hemosiderin deposits after a cavernomectomy. This paradigmatic case provides evidence of syndromic OCS in ACTG1-associated Baraitser-Winter cerebrofrontofacial syndrome. The MRI findings are compatible with a dysfunction of the cortico-striato-thalamo-cortical loops involved in OCD. If a common pathophysiology is confirmed in future studies, corresponding patients with Baraitser-Winter cerebrofrontofacial syndrome type 2 should be screened for OCS. The association may also contribute to a better understanding of OCD pathophysiology., (© 2022. The Author(s).)

Dysfunction of the LIS1 gene causes lissencephaly, a drastic neurological disorder characterized by a deep disruption of the cortical structure. We aim to uncover alterations of the cortical neuronal networks related with the propagation of epileptiform activity in the Lis1/sLis1 mouse, a model lacking the LisH domain in heterozygosis. We did extracellular field-potential and intracellular recordings in brain slices of the anterior cingulate cortex (ACC) or the retrosplenial cortex (RSC) to study epileptiform activity evoked in the presence of bicuculline (10 µM), a blocker of GABA A receptors. The sensitivity to bicuculline of the generation of epileptiform discharges was similar in wild type (WT) and Lis1/sLis1 cortex (EC 50 1.99 and 2.24 µM, respectively). In the Lis1/sLis1 cortex, we observed a decreased frequency of the oscillatory post-discharges of the epileptiform events; also, the propagation of epileptiform events along layer 2/3 was slower in the Lis1/sLis1 cortex (WT 47.69 ± 2.16 mm/s, n = 25; Lis1/sLis1 37.34 ± 2.43 mm/s, n = 15; p = 0.004). The intrinsic electrophysiological properties of layer 2/3 pyramidal neurons were similar in WT and Lis1/sLis1 cortex, but the frequency of the spontaneous EPSCs was lower and their peak amplitude higher in Lis1/sLis1 pyramidal neurons. Finally, the propagation of epileptiform activity was differently affected by AMPA receptor blockers: CNQX had a larger effect in both ACC and RSC while GYKI53655 had a larger effect only in the ACC in the WT and Lis1/sLis1 cortex. All these changes indicate that the dysfunction of the LIS1 gene causes abnormalities in the properties of epileptiform discharges and in their propagation along the layer 2/3 in the anterior cingulate cortex and in the restrosplenial cortex., (© 2022. The Author(s).)

Purpose: To clarify brain abnormalities on magnetic resonance imaging (MRI) and its clinical implications in lissencephaly/subcortical band heterotopia (LIS/SBH) spectrum patients., Methods: The clinical severity and classification according to Di Donato were retrospectively reviewed in 23 LIS/SBH spectrum patients. The morphological and signal abnormalities of the brainstem, corpus callosum, and basal ganglia were also assessed. The brainstem distribution pattern of the corticospinal tract (CST) was analyzed by diffusion tensor imaging (DTI) and categorized into two types: normal pattern, in which the CST and medial lemniscus (ML) are separated by the dorsal portion of the transverse pontine fiber, and the abnormal pattern, in which the CST and ML are juxtaposed on the dorsal portion of a single transverse pontine fiber. Correlations between MR grading score and potential additional malformative findings of the brain and clinical symptoms were investigated., Results: All patients with grade 3 (n = 5) showed brainstem deformities, signal abnormalities of pontine surface and had a tendency of basal ganglia deformity and callosal hypoplasia whereas those abnormalities were rarely seen in patients with grade 1 and 2 (n = 18). For DTI analysis, the patients with grade 3 LIS/SBH had typically abnormal CST, whereas the patients with grade 1 and 2 LIS/SBH had normal CST. The classification was well correlated with CST and brainstem abnormalities and clinical severity., Conclusion: MR assessment including DTI analysis may be useful in assessing the clinical severity in LIS/BH spectrum and may provide insight into its developmental pathology., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Genetic mutations associated with brain malformations can lead to a spectrum of severity and it is often difficult to determine whether there are additional pathogenic variants contributing to the phenotype. Here, we present a family affected by a severe brain malformation including bilateral polymicrogyria, hydrocephalus, patchy white matter signal changes, and cerebellar and pontine hypoplasia with elongated cerebellar peduncles leading to the molar tooth sign. While the malformation is reminiscent of bilateral frontoparietal polymicrogyria (BFPP), the phenotype is more severe than previously reported and also includes features of Joubert syndrome (JBTS). Via exome sequencing, we identified homozygous truncating mutations in both ADGRG1/GPR56 and KIAA0556, which are known to cause BFPP and mild brain-specific JBTS, respectively. This study shows how two independent mutations can interact leading to complex brain malformations.

Kinesins play a critical role in the organization and dynamics of the microtubule cytoskeleton, making them central players in neuronal proliferation, neuronal migration, and postmigrational development. Recently, KIF2A mutations were identified in cortical malformation syndromes associated with microcephaly. Here, we detected two de novo p.Ser317Asn and p.His321Pro mutations in KIF2A in two patients with lissencephaly and microcephaly. In parallel, we re-evaluated the two previously reported cases showing de novo mutations of the same residues. The identification of mutations only in the residues Ser317 and His321 suggests these are hotspots for de novo mutations. Both mutations lead to a classic form of lissencephaly, with a posterior to anterior gradient, almost indistinguishable from LIS1-related lissencephaly. However, three fourths of patients also showed variable congenital and postnatal microcephaly, up to -5 SD. Located in the motor domain of the KIF2A protein, the Ser317 and His321 alterations are expected to disrupt binding or hydrolysis of ATP and consequently the MT depolymerizing activity. This report also establishes that KIF2A mutations represent significant causes of classic lissencephaly with microcephaly.