Prenatal Ultrasound Diagnosis of Megalencephaly-Polymicrogyria-Polydactyly-Hydrocephalus Syndrome with Persistent Hyperplastic Primary Vitreous: A Case Report.

INTRODUCTION: Megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) syndrome is a rare autosomal dominant disorder characterized by megalencephaly (i.e., overgrowth of the brain), polymicrogyria, focal hypoplasia of the cerebral cortex, and polydactyly. Persistent hyperplastic primary vitreous (PHPV) involves a spectrum of congenital ocular abnormalities that are characterized by the presence of a vascular membrane behind the lens. CASE PRESENTATION: Here, we present a case of foetal MPPH with PHPV that was diagnosed using prenatal ultrasound. Ultrasound revealed the presence of megalencephaly, multiple cerebellar gyri, and hydrocephalus. Whole-exome sequencing confirmed the mutation of the AKT3 gene, which led to the consideration of MPPH syndrome. Moreover, an echogenic band with an irregular surface was observed between the lens and the posterior wall of the left eye; therefore, MPPH with PHPV was suspected. CONCLUSION: MPPH syndrome with PHPV can be diagnosed prenatally.

Unilateral perirolandic polymicrogyria with ipsilateral brainstem hypoplasia and compensatory contralateral hyperplasia.

Polymicrogyria (PMG) is a malformation of cortical development that occurs mostly in the perisylvian region bilaterally (60-70%), most often presenting with epilepsy. Unilateral cases are much rarer with hemiparesis being the predominant symptom. We report a case of a 71-year-old man with right perirolandic PMG with ipsilateral hypoplasia and contralateral hyperplasia of the brainstem, with only non-progressive left-sided mild spastic hemiparesis. This imaging pattern is thought to occur due to the normal process of withdrawal of the axons of the corticospinal tract (CST) connected to aberrant cortex, possibly with compensatory contralateral CST hyperplasia. However, the majority of cases is additionally present with epilepsy. We believe it is worthwhile to investigate imaging patterns of PMG with symptoms' correlation, particularly with the help of techniques such as advanced brain imaging to assist in the study of cortical development along with adaptive somatotopic organization of the cerebral cortex in MCD with possible clinical applications.

Defining the phenotypical spectrum associated with variants in TUBB2A.

BACKGROUND: Variants in genes belonging to the tubulin superfamily account for a heterogeneous spectrum of brain malformations referred to as tubulinopathies. Variants in TUBB2A have been reported in 10 patients with a broad spectrum of brain imaging features, ranging from a normal cortex to polymicrogyria, while one patient has been reported with progressive atrophy of the cerebellar vermis. METHODS: In order to further refine the phenotypical spectrum associated with TUBB2A, clinical and imaging features of 12 patients with pathogenic TUBB2A variants, recruited via the international network of the authors, were reviewed. RESULTS: We report 12 patients with eight novel and one recurrent variants spread throughout the TUBB2A gene but encoding for amino acids clustering at the protein surface. Eleven patients (91.7%) developed seizures in early life. All patients suffered from intellectual disability, and 11 patients had severe motor developmental delay, with 4 patients (36.4 %) being non-ambulatory. The cerebral cortex was normal in five individuals and showed dysgyria of variable severity in seven patients. Associated brain malformations were less frequent in TUBB2A patients compared with other tubulinopathies. None of the patients had progressive cerebellar atrophy. CONCLUSION: The imaging phenotype associated with pathogenic variants in TUBB2A is highly variable, ranging from a normal cortex to extensive dysgyria with associated brain malformations. For recurrent variants, no clear genotype-phenotype correlations could be established, suggesting the role of additional modifiers.

Polymicrogyria, aventriculy, polydactyly, encephalocele, callosal agenesis (PAPEC): a new syndrome?

INTRODUCTION: Aventriculy is a very rare observation and is generally associated with holoprosencephaly. We report here a case of polymalformation affecting the brain, hands, and feet observed in a highly consanguineous family in Niger. CASE REPORT: A boy was born from a highly consanguineous family presenting multiple malformations (aventriculy, extreme microcephaly, polydactyly, polymicrogyria, callosal agenesis, and parietal encephalocele). To the best of our knowledge, such association has never been reported so far. DISCUSSION: We propose to name this association PAPEC (for polymicrogyria, aventriculy, polydactyly, encephalocele, and callosal agenesis). The occurrence of this disease in a highly consanguineous family suggests a genetic origin. Furthermore, we propose hypotheses that could explain pathophysiology of this defect.

Hypothalamic hamartoma associated with polymicrogyria and periventricular nodular heterotopia in children: report of three cases and discussion of the origin of the seizures.

PURPOSE: Hypothalamic hamartomas (HH) are malformations responsible for drug-resistant epilepsy. HH are usually isolated or part of a genetic syndrome, such as Pallister-Hall. Exceptionally they can be associated with other brain malformations such as polymicrogyria (PMG) and periventricular nodular heterotopia (PNH). We discuss the origin of the seizures associated with this combination of malformations, through electrophysiological studies, and review the literature on this rarely reported syndrome. METHODS: We retrospectively reviewed the patients with HH who had surgery between 1998 and 2020 and selected those with associated focal PMG and PNH, detected on MRIs. All patients had comprehensive clinical evaluation and surface video-EEG and one underwent stereoelectroencephalography (SEEG). RESULTS: Three male patients out of 182 were identified with a mean age at surgery of 7.5 years. MRI showed unilateral focal PMG (fronto-insulo-parietal, fronto-insulo-parieto-opercular, and fronto-insular, respectively) and multiple PNH homolateral to the main HH implantation side. In two patients, there were strong clinical and scalp EEG arguments for seizure onset within the HH. In the third, due to abnormalities on scalp video-EEG in the same area as PMG and the lack of gelastic seizures, SEEG was indicated and demonstrated seizure onset within the hamartoma. With a mean follow-up of 6 years, two patients were seizure-free. CONCLUSION: Our results show that HH is the trigger of epilepsy, which confirms the high epileptogenic potential of this malformation. In patients such as ours, as in those with isolated HH, we recommend to begin by operating the HH independently of seizure semiology or electrophysiological abnormalities.

Diverse genetic causes of polymicrogyria with epilepsy.

OBJECTIVE: We sought to identify novel genes and to establish the contribution of known genes in a large cohort of patients with nonsyndromic sporadic polymicrogyria and epilepsy. METHODS: We enrolled participants with polymicrogyria and their parents through the Epilepsy Phenome/Genome Project. We performed phenotyping and whole exome sequencing (WES), trio analysis, and gene-level collapsing analysis to identify de novo or inherited variants, including germline or mosaic (postzygotic) single nucleotide variants, small insertion-deletion (indel) variants, and copy number variants present in leukocyte-derived DNA. RESULTS: Across the cohort of 86 individuals with polymicrogyria and epilepsy, we identified seven with pathogenic or likely pathogenic variants in PIK3R2, including four germline and three mosaic variants. PIK3R2 was the only gene harboring more than expected de novo variants across the entire cohort, and likewise the only gene that passed the genome-wide threshold of significance in the gene-level rare variant collapsing analysis. Consistent with previous reports, the PIK3R2 phenotype consisted of bilateral polymicrogyria concentrated in the perisylvian region with macrocephaly. Beyond PIK3R2, we also identified one case each with likely causal de novo variants in CCND2 and DYNC1H1 and biallelic variants in WDR62, all genes previously associated with polymicrogyria. Candidate genetic explanations in this cohort included single nucleotide de novo variants in other epilepsy-associated and neurodevelopmental disease-associated genes (SCN2A in two individuals, GRIA3, CACNA1C) and a 597-kb deletion at 15q25, a neurodevelopmental disease susceptibility locus. SIGNIFICANCE: This study confirms germline and postzygotically acquired de novo variants in PIK3R2 as an important cause of bilateral perisylvian polymicrogyria, notably with macrocephaly. In total, trio-based WES identified a genetic diagnosis in 12% and a candidate diagnosis in 6% of our polymicrogyria cohort. Our results suggest possible roles for SCN2A, GRIA3, CACNA1C, and 15q25 deletion in polymicrogyria, each already associated with epilepsy or other neurodevelopmental conditions without brain malformations. The role of these genes in polymicrogyria will be further understood as more patients with polymicrogyria undergo genetic evaluation.

MN1 C-terminal truncation syndrome is a novel neurodevelopmental and craniofacial disorder with partial rhombencephalosynapsis.

MN1 encodes a transcriptional co-regulator without homology to other proteins, previously implicated in acute myeloid leukaemia and development of the palate. Large deletions encompassing MN1 have been reported in individuals with variable neurodevelopmental anomalies and non-specific facial features. We identified a cluster of de novo truncating mutations in MN1 in a cohort of 23 individuals with strikingly similar dysmorphic facial features, especially midface hypoplasia, and intellectual disability with severe expressive language delay. Imaging revealed an atypical form of rhombencephalosynapsis, a distinctive brain malformation characterized by partial or complete loss of the cerebellar vermis with fusion of the cerebellar hemispheres, in 8/10 individuals. Rhombencephalosynapsis has no previously known definitive genetic or environmental causes. Other frequent features included perisylvian polymicrogyria, abnormal posterior clinoid processes and persistent trigeminal artery. MN1 is encoded by only two exons. All mutations, including the recurrent variant p.Arg1295* observed in 8/21 probands, fall in the terminal exon or the extreme 3' region of exon 1, and are therefore predicted to result in escape from nonsense-mediated mRNA decay. This was confirmed in fibroblasts from three individuals. We propose that the condition described here, MN1 C-terminal truncation (MCTT) syndrome, is not due to MN1 haploinsufficiency but rather is the result of dominantly acting C-terminally truncated MN1 protein. Our data show that MN1 plays a critical role in human craniofacial and brain development, and opens the door to understanding the biological mechanisms underlying rhombencephalosynapsis.

Bilateral polymicrogyria associated with dystonia: A new neurogenetic syndrome?

The clinical presentation of bilateral perisylvian polymicrogyria (PMG) is highly variable, including oromotor dysfunction, epilepsy, intellectual disability, and pyramidal signs. Extrapyramidal features are extremely rare. We present four apparently unrelated patients with a unique association of PMG with dystonia. The clinical, genetic, and radiologic features are described and possible mechanisms of dystonia are discussed. All patients were female and two were born to consanguineous families. All presented with early childhood onset dystonia. Other neurologic symptoms and signs classically seen in bilateral perisylvian PMG were observed, including oromotor dysfunction and speech abnormalities ranging from dysarthria to anarthria (4/4), pyramidal signs (3/4), hypotonia (3/4), postnatal microcephaly (1/4), and seizures (1/4). Neuroimaging showed a unique pattern of bilateral PMG with an infolded cortex originating primarily from the perisylvian region in three out of four patients. Whole exome sequencing was performed in two out of four patients and did not reveal pathogenic variants in known genes for cortical malformations or movement disorders. The dystonia seen in our patients is not described in bilateral PMG and suggests an underlying mechanism of impaired connectivity within the motor network or compromised cortical inhibition. The association of bilateral PMG with dystonia in our patients may represent a new neurogenetic disorder.

Tensor-valued diffusion MRI differentiates cortex and white matter in malformations of cortical development associated with epilepsy.

OBJECTIVE: Delineation of malformations of cortical development (MCD) is central in presurgical evaluation of drug-resistant epilepsy. Delineation using magnetic resonance imaging (MRI) can be ambiguous, however, because the conventional T1 - and T2 -weighted contrasts depend strongly on myelin for differentiation of cortical tissue and white matter. Variations in myelin content within both cortex and white matter may cause MCD findings on MRI to change size, become undetectable, or disagree with histopathology. The novel tensor-valued diffusion MRI (dMRI) technique maps microscopic diffusion anisotropy, which is sensitive to axons rather than myelin. This work investigated whether tensor-valued dMRI may improve differentiation of cortex and white matter in the delineation of MCD. METHODS: Tensor-valued dMRI was performed on a 7 T MRI scanner in 13 MCD patients (age = 32 ± 13 years) featuring periventricular heterotopia, subcortical heterotopia, focal cortical dysplasia, and polymicrogyria. Data analysis yielded maps of microscopic anisotropy that were compared with T1 -weighted and T2 -fluid-attenuated inversion recovery images and with the fractional anisotropy from diffusion tensor imaging. RESULTS: Maps of microscopic anisotropy revealed large white matter-like regions within MCD that were uniformly cortex-like in the conventional MRI contrasts. These regions were seen particularly in the deep white matter parts of subcortical heterotopias and near the gray-white boundaries of focal cortical dysplasias and polymicrogyrias. SIGNIFICANCE: By being sensitive to axons rather than myelin, mapping of microscopic anisotropy may yield a more robust differentiation of cortex and white matter and improve MCD delineation in presurgical evaluation of epilepsy.

Continuous epileptiform discharges during sleep as an evolutionary pattern in patients with congenital Zika virus syndrome.

Congenital Zika virus syndrome (CZVS) is associated with severe neurological deficits. Clinical characteristics of epilepsy and the electroencephalographic (EEG) pattern in CZVS were documented in infancy. In this study, we aimed to describe the EEG findings observed during the follow-up of children with CZVS. Seventy-six EEGs of 55 children (60% female; mean age = 50 months) with confirmed CZVS were analyzed, considering the background, interictal, and ictal epileptiform discharges. Continuous (or almost continuous) epileptiform discharges during non-rapid eye movement sleep were identified in 22 (40%) patients. In 20 (90.1%) patients, the pattern was symmetrical, with an anterior predominance of the epileptiform activity. All patients with this pattern had epilepsy, which was severe in 15 (68.2%) and demanded polytherapy in 19 (86.4%). Subcortical calcifications (77.3%) and multifocal EEGs (72.8%) in earlier ages occurred more often in patients with this pattern. Other unspecific interictal EEG patterns were focal epileptiform discharges in 23 (41.8%) and multifocal activity in six (10.9%). In CZVS, continuous (or almost continuous) epileptiform discharges during sleep emerge as a pattern after the second year of life. This was associated with severe and drug-resistant epilepsy, but not necessarily with an apparent regression. Subcortical calcifications and multifocal epileptiform discharges in infancy are associated with this pattern.

Maternal mosaicism underlies the inheritance of a rare germline AKT3 variant which is responsible for megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome in two Roma half-siblings.

Megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) syndrome is a developmental brain disorder characterized by an enlarged brain size with bilateral perisylvian polymicrogyria and a variable degree of ventriculomegaly. MPPH syndrome is associated with oromotor dysfunction, epilepsy, intellectual disability and postaxial hexadactyly. The molecular diagnosis of this disorder is established by the identification of a pathogenic variant in either AKT3, CCND2 or PIK3R2. Previously reported AKT3 variants are associated with various brain abnormalities and may lead to megalencephaly. MPPH syndrome is usually due to germline pathogenic AKT3 variants. Somatic mosaic pathogenic variants associated with hemimegalencephaly, which is similar to MPPH, have also been observed. A Hungarian Roma family with two half-siblings, which present with intellectual disability, dysmorphic features, epilepsy, brain malformations, and megalencephaly was studied. Whole exome sequencing (WES) analysis was performed. WES analysis revealed a heterozygous c.1393C > T p.(Arg465Trp) pathogenic missense AKT3 variant in both affected half-siblings. The variant was verified via Sanger sequencing and was not present in the DNA sample from the healthy mother, which was derived from peripheral blood, suggesting maternal germline mosaicism. In conclusion, this is the first report in which maternal germline mosaicism of a rare pathogenic AKT3 variant leads to autosomal dominantly inherited MPPH syndrome.

Megalencephaly-Capillary Malformation-Polymicrogyria with Cerebral Venous Thrombosis.

Megalencephaly-capillary malformation-polymicrogyria (MCAP) syndrome (OMIM #602501) is characterized by megalencephaly, midline capillary malformations, and cortical malformations. This genetic overgrowth syndrome is associated with mosaic gain-of-function pathogenic PIK3CA variants (OMIM #171834).

Agenesis of the septum pellucidum: Prenatal diagnosis and outcome.

OBJECTIVE: The purpose of this study is to describe the imaging findings in a group of fetuses with suspected agenesis of the septum pellucidum (ASP) and to evaluate their clinical outcome. METHODS: This is a retrospective multicenter study on a cohort of fetuses diagnosed with suspected ASP, between 2008 and 2017. The records of each patient, including ultrasound (US) and magnetic resonance studies, were reviewed and compared with the postnatal findings. RESULTS: Forty-seven patients were included in the study at a mean gestational age of 26.6 weeks. In 17 patients, the ASP was considered isolated. Fourteen patients delivered live-born, and all 14 are developing normally. Three were lost to follow-up. Twenty-four patients had associated malformations involving the central nervous system (CNS); 13 were delivered (normal development [5], abnormal [6] and no follow-up [2]). Nine patients opted for termination, and two pregnancies were lost to follow-up. Six patients had non-CNS associated findings, two were delivered with normal neurological development and four had a termination. CONCLUSIONS: Isolated ASP is usually associated with a favorable outcome; but in the presence of associated malformations, there is at least a 50% risk of abnormal development. Current imaging techniques can provide an accurate prognosis in cases when ASP appears isolated.

De novo mutations in GRIN1 cause extensive bilateral polymicrogyria.

Polymicrogyria is a malformation of cortical development. The aetiology of polymicrogyria remains poorly understood. Using whole-exome sequencing we found de novo heterozygous missense GRIN1 mutations in 2 of 57 parent-offspring trios with polymicrogyria. We found nine further de novo missense GRIN1 mutations in additional cortical malformation patients. Shared features in the patients were extensive bilateral polymicrogyria associated with severe developmental delay, postnatal microcephaly, cortical visual impairment and intractable epilepsy. GRIN1 encodes GluN1, the essential subunit of the N-methyl-d-aspartate receptor. The polymicrogyria-associated GRIN1 mutations tended to cluster in the S2 region (part of the ligand-binding domain of GluN1) or the adjacent M3 helix. These regions are rarely mutated in the normal population or in GRIN1 patients without polymicrogyria. Using two-electrode and whole-cell voltage-clamp analysis, we showed that the polymicrogyria-associated GRIN1 mutations significantly alter the in vitro activity of the receptor. Three of the mutations increased agonist potency while one reduced proton inhibition of the receptor. These results are striking because previous GRIN1 mutations have generally caused loss of function, and because N-methyl-d-aspartate receptor agonists have been used for many years to generate animal models of polymicrogyria. Overall, our results expand the phenotypic spectrum associated with GRIN1 mutations and highlight the important role of N-methyl-d-aspartate receptor signalling in the pathogenesis of polymicrogyria.

Relationships Between Morphologic and Functional Patterns in the Polymicrogyric Cortex.

Polymicrogyria is a malformation of cortical folding and layering underlying different cognitive and neurological manifestations. The polymicrogyric cortex has heterogeneous morphofunctional patterns, qualitatively described at magnetic resonance imaging (MRI) by variable severity gradients and functional activations. We investigated the link between abnormal cortical folding and cortical function in order to improve surgical planning for patients with polymicrogyria and intractable epilepsy. We performed structural and functional MRI on 14 patients with perisylvian polymicrogyria and adopted surface-based methods to detect alterations of cortical thickness (CT) and local gyrification index (LGI) compared with normal cortex (30 age-matched subjects). We quantitatively assessed the grade of anatomic disruption of the polymicrogyric cortex and defined its relationship with decreased cortical function. We observed a good matching between visual analysis and morphometric measurements. CT maps revealed sparse clusters of thickening, while LGI maps disclosed circumscribed regions of maximal alteration with a uniformly decreasing centrifugal gradient. In polymicrogyric areas in which gyral and sulcal patterns were preserved, functional activation maintained the expected location, but was reduced in extent. Morphofunctional correlations, evaluated along cortico-cortical paths between maximum morphologic alterations and significant activations, identified an interindividual threshold for LGI (z-value = -1.09) beyond which functional activations were no longer identifiable.

A novel mutation in LAMC3 associated with generalized polymicrogyria of the cortex and epilepsy.

Occipital cortical malformation is a rare neurodevelopmental disorder characterized by pachygyria and polymicrogyria of the occipital lobes as well as global developmental delays and seizures. This condition is due to biallelic, loss-of-function mutations in LAMC3 and has been reported in four unrelated families to date. We report an individual with global delays, seizures, and polymicrogyria that extends beyond the occipital lobes and includes the frontal, parietal, temporal, and occipital lobes. Next-generation sequencing identified a homozygous nonsense mutation in LAMC3: c.3190C>T (p.Gln1064*). This finding extends the cortical phenotype associated with LAMC3 mutations.

The role of surgery in refractory epilepsy secondary to polymicrogyria in the pediatric population.

OBJECTIVE: Polymicrogyria (PMG) is a common malformation of cortical development. Many patients with PMG will have medically refractory epilepsy but the role of epilepsy surgery is unclear. The objective of this study was to assess the efficacy of surgical resection/disconnection in achieving seizure control in pediatric patients with PMG. METHODS: A retrospective review of children undergoing epilepsy surgery for PMG between 2002 and 2017 at The Hospital for Sick Children in Toronto, Canada, was performed. RESULTS: A total of 12 children aged 6 months to 17.8 years (median 8.8 years) underwent resective surgery (7 children) or functional hemispherectomy (5 children). Gross total resection or complete disconnection of PMG was carried out in 7 of 12 children. Follow-up duration was between 1 and 9 years (median 2.1 years). Nine children remained seizure-free at last follow-up. Complete resection or disconnection of PMG led to seizure freedom in 6 of 7 patients (86%), whereas subtotal resection produced seizure freedom in 3 of 5 patients (60%). SIGNIFICANCE: We present one of the largest surgical series of pediatric PMG patients. Seizure outcomes were best with complete resection/disconnection of PMG. However, tailored resections based on electroclinical and neuroradiologic data can produce good outcomes and remain an appropriate strategy for patients with extensive PMG.

Band-like calcification with simplified gyration and polymicrogyria: report of 10 new families and identification of five novel OCLN mutations.

Band-like calcification with simplified gyration and polymicrogyria (BLC-PMG) is an extremely rare autosomal recessive disorder with distinctive clinical and neuroimaging findings. To date, only 17 patients from 9 unrelated families with BLC-PMG have been reported worldwide. Herein, we describe a series of 13 new patients derived from 10 unrelated Egyptian families. Patients presented at early life with the classic phenotype including severe microcephaly, failure to acquire developmental skills, growth failure and the distinguished calcification patterns involving the cortex, thalami, basal ganglia and pons. Additional features not reported before included calcification of the cerebellum (eight patients: 61.5%) and imperforate anus and undescended testis in a single patient. Molecular studies of the OCLN gene (NM_001205254) identified six distinct candidate mutations. Interestingly, the deletion mutation of the transmembrane domain in exons 3 and 4 (c.51-?_730-?del, p.Lys18_Glu243) was found in five unrelated families (50%), suggesting a founder mutation in our population. On the other hand, five novel truncating mutations (c.809delA (p.K270Rfs*62), c.858_861delTTAT (p.I286Mfs*45), c.1037+5G>C, c.1169C>G (p.S390*) and c.1180delG (p.E394Sfs*91)) were detected, each in one family. To our knowledge, this is the largest series of patients with BLC-PMG. Cerebellum calcification is an additional relevant finding in our series, thus expanding the neuroradiological phenotype of this syndrome.