Malformations of cerebral cortical development include a wide range of developmental disorders that are common causes of neurodevelopmental delay and epilepsy. In addition, study of these disorders contributes greatly to the understanding of normal brain development and its perturbations. The rapid recent evolution of molecular biology, genetics and imaging has resulted in an explosive increase in our knowledge of cerebral cortex development and in the number and types of malformations of cortical development that have been reported. These advances continue to modify our perception of these malformations. This review addresses recent changes in our perception of these disorders and proposes a modified classification based upon updates in our knowledge of cerebral cortical development.

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A Developmental and Genetic Classification for Malformations of Cortical Development: Update 2012.

Malformations of cortical development are common causes of developmental delay and epilepsy. Some patients have early, severe neurological impairment, but others have epilepsy or unexpected deficits that are detectable only by screening. The rapid evolution of molecular biology, genetics, and imaging has resulted in a substantial increase in knowledge about the development of the cerebral cortex and the number and types of malformations reported. Genetic studies have identified several genes that might disrupt each of the main stages of cell proliferation and specification, neuronal migration, and late cortical organisation. Many of these malformations are caused by de-novo dominant or X-linked mutations occurring in sporadic cases. Genetic testing needs accurate assessment of imaging features, and familial distribution, if any, and can be straightforward in some disorders but requires a complex diagnostic algorithm in others. Because of substantial genotypic and phenotypic heterogeneity for most of these genes, a comprehensive analysis of clinical, imaging, and genetic data is needed to properly define these disorders. Exome sequencing and high-field MRI are rapidly modifying the classification of these disorders.

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Malformations of cortical development: clinical features and genetic causes

SUMMARY Purpose: Epilepsies have a highly heterogeneous background with a strong genetic contribution. The variety of unspecific and overlapping syndromic and nonsyndromic phenotypes often hampers a clear clinical diagnosis and prevents straightforward genetic testing. Knowing the genetic basis of a patient’s epilepsy can be valuable not only for diagnosis but also for guiding treatment and estimating recurrence risks. Methods: To overcome these diagnostic restrictions, we composed a panel of genes for Next Generation Sequencing containing the most relevant epilepsy genes and covering the most relevant epilepsy phenotypes known so far. With this method, 265 genes were analyzed per patient in a single step. We evaluated this panel on a pilot cohort of 33 index patients with concise epilepsy phenotypes or with a severe but unspecific seizure disorder covering

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1528-1167.2012.03516.x

Targeted next generation sequencing as a diagnostic tool in epileptic disorders

Summary Genetic factors are now recognised to have an even more important role in epilepsies than previously appreciated. Rare mendelian forms of epilepsy are now well recognised, and there is evidence of complex inheritance due to multiple susceptibility genes in most idiopathic epilepsies. The complexities of epilepsy classification and the variety of clinical genetic methodologies (family aggregation, twin, and multiplex family studies) have led to an apparently confusing picture. Molecular approaches have revealed genes for many mendelian epilepsies. Most encode ion-channel subunits, but major challenges remain in understanding phenotype–genotype relationships. These challenges are even greater in complex epilepsies in which gene discovery is still in its infancy. In this Review, we synthesise clinical genetic data, discuss the strengths and weaknesses of different approaches, and integrate molecular findings about the epilepsies. This knowledge not only informs clinicians about the biology of the epilepsies but also has important consequences for clinical practice and genetic counselling.

https://www.thelancet.com/pdfs/journals/laneur/PIIS1474-4422(08)70039-5.pdf

Navigating the channels and beyond: unravelling the genetics of the epilepsies.

In this review, we detail the history, molecular diagnosis, epidemiology, and clinical features of the MECP2 duplication syndrome, including considerations for the care of patients with this X-linked neurodevelopmental disorder. MECP2 duplication syndrome is 100% penetrant in affected males and is associated with infantile hypotonia, severe to profound mental retardation, autism or autistic features, poor speech development, recurrent infections, epilepsy, progressive spasticity, and, in some cases, developmental regression. Most of the reported cases are inherited, however, de novo cases have been documented. While carrier females have been reported to be unaffected, more recent research demonstrates that despite normal intelligence, female carriers display a range of neuropsychiatric phenotypes that pre-date the birth of an affected son. Given what we know of the syndrome to date, we propose that genetic testing is warranted in cases of males with infantile hypotonia and in cases of boys with mental retardation and autistic features with or without recurrent infections, progressive spasticity, epilepsy, or developmental regression. We discuss recommendations for clinical management and surveillance as well as the need for further clinical, genotype-phenotype, and molecular studies to assist the patients and their families who are affected by this syndrome.

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The MECP2 Duplication Syndrome

Periventricular heterotopia (PH) occurs when collections of neurons lay along the lateral ventricles or just beneath. Human Filamin A gene (FLNA) mutations are associated with classical X-linked bilateral periventricular nodular heterotopia (PNH), featuring contiguous heterotopic nodules, mega cisterna magna, cardiovascular malformations and epilepsy. FLNA encodes an F-actin-binding cytoplasmic phosphoprotein and is involved in early brain neurogenesis and neuronal migration. A rare, recessive form of bilateral PNH with microcephaly and severe delay is associated with mutations of the ADP-ribosylation factor guanine nucleotide-exchange factor-2 (ARFGEF2) gene, required for vesicle and membrane trafficking from the trans-Golgi. However, PH is a heterogeneous disorder. We studied clinical and brain MRI of 182 patients with PH and, based on its anatomic distribution and associated birth defects, identified 15 subtypes. Classical bilateral PNH represented the largest group (98 patients: 54%). The 14 additional phenotypes (84 patients: 46%) included PNH with Ehlers-Danlos syndrome (EDS), temporo-occipital PNH with hippocampal malformation and cerebellar hypoplasia, PNH with fronto-perisylvian or temporo-occipital polymicrogyria, posterior PNH with hydrocephalus, PNH with microcephaly, PNH with frontonasal dysplasia, PNH with limb abnormalities, PNH with fragile-X syndrome, PNH with ambiguous genitalia, micronodular PH, unilateral PNH, laminar ribbon-like and linear PH. We performed mutation analysis of FLNA in 120 patients, of whom 72 (60%) had classical bilateral PNH and 48 (40%) other PH phenotypes, and identified 25 mutations in 40 individuals. Sixteen mutations had not been reported previously. Mutations were found in 35 patients with classical bilateral PNH, in three with PNH with EDS and in two with unilateral PNH. Twenty one mutations were nonsense and frame-shift and four missense. The high prevalence of mutations causing protein truncations confirms that loss of function is the major cause of the disorder. FLNA mutations were found in 100% of familial cases with X-linked PNH (10 families: 8 with classical bilateral PNH, 1 with EDS and 1 with unilateral PH) and in 26% of sporadic patients with classical bilateral PNH. Overall, mutations occurred in 49% of individuals with classical bilateral PNH irrespective of their being familial or sporadic. However, the chances of finding a mutation were exceedingly gender biased with 93% of mutations occurring in females and 7% in males. The probability of finding FLNA mutations in other phenotypes was 4% but was limited to the minor variants of PNH with EDS and unilateral PNH. Statistical analysis considering all 42 mutations described so far identifies a hotspot region for PNH in the actin-binding domain (P < 0.05).

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S. Palmeri

Papers

Periventricular heterotopia: phenotypic heterogeneity and correlation with Filamin A mutations