OBJECTIVE: To explore the genetic basis for a child with pachygyria.
METHODS: A proband who had visited Qinzhou Maternal and Child Health Care Hospital for pachygyria and mental retardation in June 2020 was selected as the study subject. Clinical data was collected. The child was subjected to whole exome sequencing (WES), and candidate variant was verified by Sanger sequencing.
RESULTS: The proband, a 4-year-and-6-month-old female, was clinically diagnosed with megagyrus deformity. WES revealed that she has harbored compound heterozygous variants of the ADGRG1 gene, namely c.781G>T (p.E261*) in exon 6 and c.1369A>C (p.S457R) in exon 11, which were verified by Sanger sequencing to be derived from her mother and father, respectively. Her younger sister was also heterozygous for the c.1369A>C (p.S457R) variant. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), both variants were rated as likely pathogenic (PVS1+PM2_ Supporting; PM1+PM2_Supporting+PM3+PP3).
CONCLUSIONS: The c.781G>T (p.E261*) and c.1369A>C (p.S457R) compound heterozygous variants of the ADGRG1 gene probably underlay the pachygyria malformation in this child.

Tubulinopathies are associated with malformations of cortical development but not Walker-Warburg Syndrome. Intensive monitoring of a Croatian infant presenting as Walker-Warburg Syndrome in utero began at 21 weeks due to increased growth of cerebral ventricles and foetal biparietal diameter. Monitoring continued until Caesarean delivery at 34 weeks where the infant was eutrophic. Clinical assessment of a progressive neurological disorder of unknown aetiology found a macrocephalic head and markedly hypoplastic genitalia with a micropenis. Neurological examination showed generalized hypotonia with very rare spontaneous movements, hypotonia-induced respiratory insufficiency and ventilator dependence, and generalized myoclonus intensifying during manipulation. With clinical features of hypotonia, lissencephaly, and brain malformations, Walker-Warburg Syndrome was suspected; however, eye anomalies were absent. Genetic trio analysis via whole-exome sequencing only identified a novel de novo mutation in the TUBA1A gene (NM_006009.4:c.848A>G; NP_006000.2:p.His283Arg) in the infant, who died at 2 months of age, as the likely cause. We report a previously unpublished, very rare heterozygous TUBA1A mutation with clinical features of macrocephaly and hypoplastic genitalia which have not previously been associated with the gene. The absence of eye phenotypes or mutations in Walker-Warburg-associated genes confirm this as not a new presentation of Walker-Warburg Syndrome but a novel TUBA1A tubulinopathy for neonatologists to be aware of.

The aim of this systematic review is to report the normal cortical development of different fetal cerebral fissures on ultrasound, describe associated anomalies in fetuses with cortical malformations, and evaluate the quality of published charts of cortical fissures. The inclusion criteria were studies reporting development, anomalies, and reference charts of fetal cortical structures on ultrasound. The outcomes observed were the timing of the appearance of different cortical fissures according to different gestational age windows, associated central nervous system (CNS) and extra-CNS anomalies detected at ultrasound in fetuses with cortical malformation, and rate of fetuses with isolated anomaly. Furthermore, we performed a critical evaluation of the published reference charts for cortical development on ultrasound. Random-effect meta-analyses of proportions were used to combine the data. Twenty-seven studies (6875 fetuses) were included. Sylvian fissure was visualized on ultrasound in 97.69% (95% CI 92.0-100) of cases at 18-19, 98.17% (95% CI 94.8-99.8) at 20-21, 98.94% (95% CI 97.0-99.9) at 22-23, and in all cases from 24 weeks of gestation. Parieto-occipital fissure was visualized in 81.56% (95% CI 48.4-99.3) of cases at 18-19, 96.59% (95% CI 83.2-99.8) at 20-21, 96.85% (95% CI 88.8-100) at 22-23, and in all cases from 24 weeks of gestation, while the corresponding figures for calcarine fissure were 37.27% (95% CI 0.5-89.6), 80.42% (95% CI 50.2-98.2), 89.18% (95% CI 74.0-98.2), and 96.02% (95% CI 96.9-100). Malformations of cortical development were diagnosed as an isolated finding at ultrasound in 6.21% (95% CI 2.9-10.9) of cases, while they were associated with additional CNS anomalies in 93.79% (95% CI 89.1-97.2) of cases. These findings highlight the need for large studies specifically looking at the timing of the appearance of the different brain sulci. Standardized algorithms for prenatal assessment of fetuses at high risk of malformations of cortical development are also warranted.

Type 1 lissencephaly is a genetic disorder of chromosomal abnormality. This case report glimpses at the physiotherapy rehabilitation for a two-year-old male brought by his parents with complaints of being unable to move his upper and lower limbs, delayed milestones as compared to his peer group, and difficulty in swallowing. Physiotherapy rehabilitation included Rood\'s approach to neurodevelopmental techniques, hippotherapy, vestibular ball rehabilitation exercises, oral sensorimotor stimulation, and tactile stimulation. The protocol lasted for 12 weeks. At the end of the rehabilitation, there was a significant improvement in the tone of the muscles and delayed developmental milestones. Through this case report, we conclude about the importance of genetic counseling to the parents of genetic disorders babies. We ought to improve awareness about the pivotal role of physiotherapy in managing such disorders. We conclude that physiotherapy significantly improved the symptoms and improved the quality of life of patients with type 1 lissencephaly.

Lissencephaly is a rare brain malformation for which our understanding remains limited due to the absence of suitable animal models that accurately represent human phenotypes. Here, we establish doublecortin (DCX) knockout ferrets as a model that faithfully replicates key features of the disorder. We reveal the critical roles of DCX in neural progenitor cell proliferation and radial glial fiber extension, processes essential for normal cortical development. Utilizing single-nucleus RNA sequencing (snRNA-seq) and spatial transcriptomics, we provide a detailed atlas of the lissencephalic cortex, illustrating disrupted neuronal lamination and the specific interactions between inhibitory and excitatory neurons. These findings enhance our understanding of the cellular and molecular mechanisms underlying lissencephaly and highlight the potential of DCX knockout ferrets as a valuable tool for neurodevelopmental research, offering insights into both the pathology of lissencephaly and the general principles of brain development.

Reelin (RELN) is a secreted glycoprotein essential for cerebral cortex development. In humans, recessive RELN variants cause cortical and cerebellar malformations, while heterozygous variants were associated with epilepsy, autism, and mild cortical abnormalities. However, the functional effects of RELN variants remain unknown. We identified inherited and de novo RELN missense variants in heterozygous patients with neuronal migration disorders (NMDs) as diverse as pachygyria and polymicrogyria. We investigated in culture and in the developing mouse cerebral cortex how different variants impacted RELN function. Polymicrogyria-associated variants behaved as gain-of-function, showing an enhanced ability to induce neuronal aggregation, while those linked to pachygyria behaved as loss-of-function, leading to defective neuronal aggregation/migration. The pachygyria-associated de novo heterozygous RELN variants acted as dominant-negative by preventing WT RELN secretion in culture, animal models, and patients, thereby causing dominant NMDs. We demonstrated how mutant RELN proteins in vitro and in vivo predict cortical malformation phenotypes, providing valuable insights into the pathogenesis of such disorders.

Proper topographically organized neural connections between the thalamus and the cerebral cortex are mandatory for thalamus function. Thalamocortical (TC) fiber growth begins during the embryonic period and completes by the third trimester of gestation, so that human neonates at birth have a thalamus with a near-facsimile of adult functional parcellation. Whether congenital neocortical anomaly (e.g., lissencephaly) affects TC connection in humans is unknown. Here, via diffusion MRI fiber-tractography analysis of long-term formalin-fixed postmortem fetal brain diagnosed as lissencephaly in comparison with an age-matched normal one, we found similar topological patterns of thalamic subregions and of internal capsule parcellated by TC fibers. However, lissencephaly fetal brain showed white matter structural changes, including fewer/less organized TC fibers and optic radiations, and much less cortical plate invasion by TC fibers - particularly around the shallow central sulcus. Diffusion MRI fiber tractography of normal fetal brains at 15, 23, and 26 gestational weeks (GW) revealed dynamic volumetric change of each parcellated thalamic subregion, suggesting coupled developmental progress of the thalamus with the corresponding cortex. Moreover, from GW23 and GW26 normal fetal brains, TC endings in the cortical plate could be delineated to reflect cumulative progressive TC invasion of cortical plate. By contrast, lissencephaly brain showed a dramatic decrease in TC invasion of the cortical plate. Our study thus shows the feasibility of diffusion MRI fiber tractography in postmortem long-term formalin-fixed fetal brains to disclose the developmental progress of TC tracts coordinating with thalamic and neocortical growth both in normal and lissencephaly fetal brains at mid-gestational stage.

Tubulin plays an essential role in cortical development, and TUBA1A encodes a major neuronal α-tubulin. Neonatal mutations in TUBA1A are associated with severe brain malformations, and approximately 70% of patients with reported cases of TUBA1A mutations exhibit lissencephaly. We report the case of a 1-year-old boy with the TUBA1A nascent mutation c.1204C >T, p.Arg402Cys, resulting in lissencephaly, developmental delay, and seizures, with a brain MRI showing normal cortical formation in the bilateral frontal lobes, smooth temporo-parieto-occipital gyri and shallow sulcus. This case has not been described in any previous report; thus, the present case provides new insights into the broad disease phenotype and diagnosis associated with TUBA1A mutations. In addition, we have summarized the gene mutation sites, neuroradiological findings, and clinical details of cases previously described in the literature and discussed the differences that exist between individual cases of TUBA1A mutations through a longitudinal comparative analysis of similar cases. The complexity of the disease is revealed, and the importance of confirming the genetic diagnosis from the beginning of the disease is emphasized, which can effectively shorten the diagnostic delay and help clinicians provide genetic and therapeutic counseling.

Miller-Dieker syndrome (MDS) is characterized by facial abnormalities and lissencephaly and is caused by a microdeletion in the region containing the LIS1 gene at chromosome 17p13.3. We report a case in which postnatal neuroimaging revealed severe lissencephaly. A 9-month-old boy presented with infantile spasms syndrome. Because of the refractory course of seizures and continued poor vitality, total corpus callosotomy was performed at 28 months of age. Intraoperative electroencephalogram (EEG) showed that the bilateral synchronous epileptiform discharges disappeared immediately after the disconnection. Postoperatively, the epileptic spasms (ES) in clusters disappeared, and single ES followed by focal seizures became the main symptom. The patient smiled more and became more responsive to stimuli. Postoperative scalp interictal EEG showed desynchronized multifocal spike and wave discharges with a marked decrease in the bilateral synchronous spike and wave discharges. Our findings suggest that the corpus callosum is involved in the mechanism ES in clusters in MDS-associated lissencephaly, and total callosotomy could be a therapeutic option.

Lissencephaly is a very rare clinical condition that affects the formation of the brain and causes severe psychomotor retardation, convulsions and muscular spasticity or hypotonia, often also associated with respiratory problems, facial dysmorphisms, abnormalities of the fingers and toes and difficulty swallowing resulting in reduced life expectancy. The clinical case described in the following article demonstrates the diagnostic process and rehabilitation treatment of a patient through a narrative review of the scientific literature and the presentation of this condition in order to provide indications to guide rehabilitation treatment in childhood.