To estimate diagnostic yield and genotype-phenotype correlations in a cohort of 811 patients with lissencephaly or subcortical band heterotopia.
We collected DNA from 756 children with lissencephaly ...over 30 years. Many were tested for deletion 17p13.3 and mutations of LIS1, DCX, and ARX, but few other genes. Among those tested, 216 remained unsolved and were tested by a targeted panel of 17 genes (ACTB, ACTG1, ARX, CRADD, DCX, LIS1, TUBA1A, TUBA8, TUBB2B, TUBB, TUBB3, TUBG1, KIF2A, KIF5C, DYNC1H1, RELN, and VLDLR) or by whole-exome sequencing. Fifty-five patients studied at another institution were added as a validation cohort.
The overall mutation frequency in the entire cohort was 81%. LIS1 accounted for 40% of patients, followed by DCX (23%), TUBA1A (5%), and DYNC1H1 (3%). Other genes accounted for 1% or less of patients. Nineteen percent remained unsolved, which suggests that several additional genes remain to be discovered. The majority of unsolved patients had posterior pachygyria, subcortical band heterotopia, or mild frontal pachygyria.
The brain-imaging pattern correlates with mutations in single lissencephaly-associated genes, as well as in biological pathways. We propose the first LIS classification system based on the underlying molecular mechanisms.
Grey matter heterotopia (GMH) can cause of seizures and are associated with a wide range of neurodevelopmental disorders and syndromes. They are caused by a failure of neuronal migration during fetal ...development, leading to clusters of neurons that have not reached their final destination in the cerebral cortex.
We have performed an extensive literature search in Pubmed, OMIM, and Google scholar and provide an overview of known genetic associations with periventricular nodular heterotopia (PNVH), subcortical band heterotopia (SBH) and other subcortical heterotopia (SUBH). We classified the heterotopias as PVNH, SBH, SUBH or other and collected the genetic information, frequency, imaging features and salient features in tables for every subtype of heterotopia. This resulted in 105 PVNH, 16 SBH and 25 SUBH gene/locus associations, making a total of 146 genes and chromosomal loci.
Our study emphasizes the extreme genetic heterogeneity underlying GMH. It will aid the clinician in establishing an differential diagnosis and eventually a molecular diagnosis in GMH patients. A diagnosis enables proper counseling of prognosis and recurrence risks, and enables individualized patient management.
Lissencephaly (“smooth brain,” LIS) is a malformation of cortical development associated with deficient neuronal migration and abnormal formation of cerebral convolutions or gyri. The LIS spectrum ...includes agyria, pachygyria, and subcortical band heterotopia. Our first classification of LIS and subcortical band heterotopia (SBH) was developed to distinguish between the first two genetic causes of LIS—LIS1 (PAFAH1B1) and DCX. However, progress in molecular genetics has led to identification of 19 LIS‐associated genes, leaving the existing classification system insufficient to distinguish the increasingly diverse patterns of LIS. To address this challenge, we reviewed clinical, imaging and molecular data on 188 patients with LIS‐SBH ascertained during the last 5 years, and reviewed selected archival data on another ∼1,400 patients. Using these data plus published reports, we constructed a new imaging based classification system with 21 recognizable patterns that reliably predict the most likely causative genes. These patterns do not correlate consistently with the clinical outcome, leading us to also develop a new scale useful for predicting clinical severity and outcome. Taken together, our work provides new tools that should prove useful for clinical management and genetic counselling of patients with LIS‐SBH (imaging and severity based classifications), and guidance for prioritizing and interpreting genetic testing results (imaging based‐ classification).
Background
Periventricular nodular heterotopia (PVNH) is a congenital brain malformation often associated with seizures. We aimed to clarify the spectrum of epilepsy phenotypes in PVNH and the ...significance of specific brain malformation patterns.
Methods
In this retrospective cohort study, we recruited people with PVNH and a history of seizures, and collected data via medical record review and a standardized questionnaire.
Results
One hundred individuals were included, aged 1 month to 61 years. Mean seizure onset age was 7.9 years. Ten patients had a self-limited epilepsy course and 35 more were pharmacoresponsive. Fifty-five had ongoing seizures, of whom 23 met criteria for drug resistance. Patients were subdivided as follows: isolated PVNH (“PVNH-Only”) single nodule (18) or multiple nodules (21) and PVNH with additional brain malformations (“PVNH-Plus”) single nodule (8) or multiple nodules (53). Of PVNH-Only single nodule, none had drug-resistant seizures. Amongst PVNH-Plus, 55% with multiple unilateral nodules were pharmacoresponsive, compared to only 21% with bilateral nodules. PVNH-Plus with bilateral nodules demonstrated the highest proportion of drug resistance (39%). A review of genetic testing results revealed eight patients with pathogenic or likely pathogenic single-gene variants, two of which were
FLNA
. Five had copy number variants, two of which were pathogenic.
Conclusions
The spectrum of epilepsy phenotypes in PVNH is broad, and seizure patterns are variable; however, epilepsy course may be predicted to an extent by the pattern of malformation. Overall, drug-resistant epilepsy occurs in approximately one quarter of affected individuals. When identified, genetic etiologies are very heterogeneous.
Objective
To investigate the clinical and imaging features of gray matter heterotopia (GMH) and improve the clinicians’ understanding of the disease.
Methods
A retrospective study was performed on 15 ...patients with GMH diagnosed at The Affiliated Hospital of Xuzhou Medical University from November 2014 to November 2016. Their clinical and imaging features are also summarized.
Results
The proportion of male and female patients was 2:1. The age of onset was 2~45 years and the average age was 19.1 years. There were 13 patients with epilepsy who also had cognitive decline (5 cases) and neurological deficit (3 cases). There were 2 patients with headache or dizziness. The imaging findings of GMH are unilateral or multiple spots in the periventricular or subependymal, subcortical, and centrum semiovale and are often accompanied by other cerebral malformations. We found that 10 patients had the subcortical type of GMH and 5 patients had the subependymal type or periventricular nodular heterotopia type. There were 8 cases of ventricular compression, 5 cases of ventriculomegaly, 5 cases of cerebral fissure malformation, 3 cases of pachygyria, 1 case of callosal agenesis, and 1 case of undeveloped septum pellucidum. All the patients were given symptomatic and supportive therapies and 3 patients were treated with antiepileptic drugs. Seizures were, however, poorly controlled.
Conclusion
GMH should also be suspected in patients with juvenile onset of seizures, cognitive decline, and neurological deficits. Magnetic resonance scans may show lesions in the white matter of the brain with signals similar to the normal gray matter.
Summary
Objective
Periventricular nodular heterotopias (PNHs) are malformations of cortical development related to neuronal migration disorders, frequently associated with drug‐resistant epilepsy ...(DRE). Stereo‐electroencephalography (SEEG) is considered a very effective step of the presurgical evaluation, providing the recognition of the epileptogenic zone (EZ). At the same time, via the intracerebral electrodes it is possible to perform radiofrequency thermocoagulation (SEEG‐guided RF‐TC) with the aim of ablating and/or disrupting the EZ. The purpose of this study was to evaluate both the relationships between PNH and the EZ, and the efficacy of SEEG‐guided RF‐TC.
Methods
Twenty patients with DRE related to PNHs were studied. Inclusion criteria were the following: (1) patients with epilepsy and PNHs (unilateral or bilateral, single or multiple nodules) diagnosed on brain magnetic resonance imaging (MRI); (2) SEEG recordings available as part of the presurgical investigations, with at least one intracerebral electrode inside the heterotopia; (3) complete surgical workup with SEEG‐guided RF‐TC and/or with traditional neurosurgery, with a follow‐up of at least 12 months.
Results
Complex and heterogenic epileptic networks were found in these patients. SEEG‐guided RF‐TC both into the nodules and/or the cortex was efficacious in the 76% of patients. Single or multiple, unilateral or bilateral PNHs are the most suitable for this procedure, whereas patients with PNHs associated with complex cortical malformations obtained excellent outcome only with traditional resective surgery.
Significance
Each patient had a specific epileptogenic network, independent from the number, size, or location of nodules and from the cortical malformation associated with. SEEG‐guided RF‐TC appears as a new and very effective diagnostic and therapeutic approach for DRE related to PNHs.
Somatic mutations can cause brain malformations but may escape detection if their prevalence in blood is low. The authors of this study used deep-coverage targeting sequencing to gauge the extent to ...which somatic mutations cause relatively common forms of brain malformation.
Somatic mutation, a postzygotic event, leads to two or more populations of cells with distinct genotypes in an organism, despite development from a single fertilized egg.
1
,
2
Although the role of somatic mutation in cancer cells is well established,
3
an analogous role for somatic mutations that occur randomly during the normal mitotic cell divisions of embryonic development — and that are therefore present in clones of cells in one or more tissues of the body — has been recognized only recently. Somatic mutations have been described in several noncancerous disorders, including the McCune–Albright syndrome,
4
the Sturge–Weber syndrome,
5
the Proteus syndrome, . . .
Lissencephaly (LIS), denoting a “smooth brain,” is characterized by the absence of normal cerebral convolutions with abnormalities of cortical thickness. Pathogenic variants in over 20 genes are ...associated with LIS. The majority of posterior predominant LIS is caused by pathogenic variants in LIS1 (also known as PAFAH1B1), although a significant fraction remains without a known genetic etiology. We now implicate CEP85L as an important cause of posterior predominant LIS, identifying 13 individuals with rare, heterozygous CEP85L variants, including 2 families with autosomal dominant inheritance. We show that CEP85L is a centrosome protein localizing to the pericentriolar material, and knockdown of Cep85l causes a neuronal migration defect in mice. LIS1 also localizes to the centrosome, suggesting that this organelle is key to the mechanism of posterior predominant LIS.
•Autosomal dominant variants in CEP85L cause posterior predominant lissencephaly•Intellect ranges from normal to severely affected in CEP85L-associated lissencephaly•CEP85L is a centrosome protein localizing to the pericentriolar material•Knockdown of Cep85l in mouse causes a neuronal migration defect
Tsai et al. implicate CEP85L as an important cause of posterior predominant lissencephaly, identifying 13 individuals with rare, heterozygous CEP85L variants, including 2 families with autosomal dominant inheritance.
•Stereotactic RFTC is an effective option for treating NH-related epilepsy.•SEEG recording provides robust electro-clinical support to the RFTC strategy.•The same electrodes implanted for SEEG ...recording are employed to place RFTC.•Coagulation of the NH alone may be effective, but several cases require also extralesional RFTC.
Drug-resistant focal epilepsy is a common occurrence in patients with gray matter nodular heterotopia (NH), and surgical treatment is often considered in these cases. NH-related epileptogenicity is sustained by complex networks, which may involve the nodules and extralesional cortex in various combinations. Therefore, invasive EEG is usually required to identify the structures involved in seizure generation. It has been reported that surgery may be effective in cases with unilateral lesions, whereas bilateral cases are not optimal candidates for surgical success. Furthermore, violation of cortical and subcortical structures for approaching deep-seated nodules may result in neurological deficits. For these reasons, selective stereotactic ablation with radiofrequency thermocoagulation (RFTC) has been proposed as an alternative option in these patients. In particular, RFTC may be performed by using the same recording intracerebral electrodes implanted for stereo-electro-encephalo-graphy (SEEG) monitoring, with the advantage of a reliable electro-clinical guide. Excellent results on seizures have been initially reported following coagulation of single, unilateral NH. Subsequent experience has indicated that, basing on the evidence of SEEG recording, promising results may be obtained also in more extended unilateral and bilateral cases. In more complex cases, coagulation of both the nodules and of the involved extralesional cortical structures is often required. In a recently reported series, 67% of patients experienced sustained seizure freedom after the procedure. However, post RFTC seizure outcome in complex cases (NH plus other malformations of cortical development) is not as good as in other patterns of NH.
RFTC, especially if guided by SEEG evaluation, should be considered as a first-line treatment option in NH-related epilepsy. Satisfactory results may be obtained also in cases not amenable to traditional surgery. The procedure is safe and does not prevent eventual resective surgery in case of failure in seizure control. For these reasons, in patients undergoing SEEG evaluation, electrode arrangement should be planned with the aim to cover as extensively as possible the heterotopic and extralesional areas, which will presumably be the targets of RFTC.
Maintenance of endoplasmic reticulum (ER) proteostasis is controlled by a signalling network known as the unfolded protein response (UPR). Here, we identified filamin A as a major binding partner of ...the ER stress transducer IRE1α. Filamin A is an actin crosslinking factor involved in cytoskeleton remodelling. We show that IRE1α controls actin cytoskeleton dynamics and affects cell migration upstream of filamin A. The regulation of cytoskeleton dynamics by IRE1α is independent of its canonical role as a UPR mediator, serving instead as a scaffold that recruits and regulates filamin A. Targeting IRE1α expression in mice affected normal brain development, generating a phenotype resembling periventricular heterotopia, a disease linked to the loss of function of filamin A. IRE1α also modulated cell movement and cytoskeleton dynamics in fly and zebrafish models. This study unveils an unanticipated biological function of IRE1α in cell migration, whereby filamin A operates as an interphase between the UPR and the actin cytoskeleton.
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