Periventricular heterotopia, mental retardation, and epilepsy associated with 5q14.3-q15 deletion

Pediatric Neurology Unit and Laboratories, Children's Hospital A Meyer-University of Florence, Firenze, Italy.
Neurology (Impact Factor: 8.29). 03/2009; 72(9):784-92. DOI: 10.1212/01.wnl.0000336339.08878.2d
Source: PubMed


Periventricular heterotopia (PH) is an etiologically heterogeneous disorder characterized by nodules of neurons ectopically placed along the lateral ventricles. Most affected patients have seizures and their cognitive level varies from normal to severely impaired. At present, two genes have been identified to cause PH when mutated. Mutations in FLNA (Xq28) and ARFGEF2 (20q13) are responsible for X-linked bilateral PH and a rare autosomal recessive form of PH with microcephaly. Chromosomal rearrangements involving the 1p36, 5p15, and 7q11 regions have also been reported in association with PH but the genes implicated remain unknown. Fourteen additional distinct anatomoclinical PH syndromes have been described, but no genetic insights into their causes have been gleaned.
We report the clinical and imaging features of three unrelated patients with epilepsy, mental retardation, and bilateral PH in the walls of the temporal horns of the lateral ventricles, associated with a de novo deletion of the 5q14.3-15 region. We used microarray-based comparative genomic hybridization to define the boundaries of the deletions.
The three patients shared a common deleted region spanning 5.8 Mb and containing 14 candidate genes.
We identified a new syndrome featuring bilateral periventricular heterotopia (PH), mental retardation, and epilepsy, mapping to chromosome 5q14.3-q15. This observation reinforces the extreme clinical and genetic heterogeneity of PH. Array comparative genomic hybridization is a powerful diagnostic tool for characterizing causative chromosomal rearrangements of limited size, identifying potential candidate genes for, and improving genetic counseling in, malformations of cortical development.

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Available from: Carlos Cardoso
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    • "Due to its versatile function in regulating cell motility and signaling, defects in the FLNA gene have been demonstrated as the cause for a wide range of developmental malformations involving the brain, bone, limbs, and heart [10,19]. Periventricular nodular heterotopia (PNH) is a well characterized neuron development disorder, mainly caused by loss-of-function mutations in FLNA gene [20-25], while other possible genetic contributions cannot be excluded [26-29]. In patients affected by PNH, clusters of grey matter along the ventricles consisting of neurons fail to migrate to the cortex during prenatal development. "
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    ABSTRACT: Filamin-A (FLNA), also called actin-binding protein 280 (ABP-280), was originally identified as a non-muscle actin binding protein, which organizes filamentous actin into orthogonal networks and stress fibers. Filamin-A also anchors various transmembrane proteins to the actin cytoskeleton and provides a scaffold for a wide range of cytoplasmic and nuclear signaling proteins. Intriguingly, several studies have revealed that filamin-A associates with multiple non-cytoskeletal proteins of diverse function and is involved in several unrelated pathways. Mutations and aberrant expression of filamin-A have been reported in human genetic diseases and several types of cancer. In this review, we discuss the implications of filamin-A in cancer progression, including metastasis and DNA damage response.
    Full-text · Article · Feb 2013 · Cell and Bioscience
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    • "Deletion of chromosome 1p36 gives rise to PH and agenesis of the corpus callosum [40]. Genomic deletions leading to PH have also been reported to localize to 4p15, 5q14 [41, 42]. Finally, triplet CGG nucleotide repeat expansion of the FMR1 gene can lead to PH in Fragile X [43], as can mutations in the polyglutamine repeat binding protein PQBP1 [44]. "
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    ABSTRACT: During cortical development, proliferating neural progenitors exhibit polarized apical and basolateral membranes that are maintained by tightly controlled and membrane-specific vesicular trafficking pathways. Disruption of polarity through impaired delivery of proteins can alter cell fate decisions and consequent expansion of the progenitor pool, as well as impact the integrity of the neuroependymal lining. Loss of neuroependymal integrity disrupts radial glial scaffolding and alters initial neuronal migration from the ventricular zone. Vesicle trafficking is also required for maintenance of lipid and protein cycling within the leading and trailing edge of migratory neurons, as well as dendrites and synapses of mature neurons. Defects in this transport machinery disrupt neuronal identity, migration, and connectivity and give rise to a malformation of cortical development termed as periventricular heterotopia (PH). PH is characterized by a reduction in brain size, ectopic clusters of neurons localized along the lateral ventricle, and epilepsy and dyslexia. These anatomical anomalies correlate with developmental impairments in neural progenitor proliferation and specification, migration from loss of neuroependymal integrity and neuronal motility, and aberrant neuronal process extension. Genes causal for PH regulate vesicle-mediated endocytosis along an actin cytoskeletal network. This paper explores the role of these dynamic processes in cortical development and disease.
    Full-text · Article · Oct 2012
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    • "Mild to severe hypotonia was reported in 17 of 19 patients with larger deletions and in 6 of 9 patients with MEF2C defects. The ability to walk independently was reported only in the following few patients: at the age of 2 years 8 months in a boy with p.E34X mutation [Zweier et al., 2010], at the age of 3 years in a girl with p.S228X mutation [Le Meur et al., 2010], at the ages of 5 and 3 years, respectively, in 2 patients with larger deletions distally to MEF2C [Cardoso et al., 2009], and at the age of 11 years in a girl with a 1.15-Mb deletion including MEF2C and TMEM161B [Berland and Houge, 2010]. Developmental milestones of the exceptionally mildly affected patient with the 21-Mb deletion were within the normal range [Tonk et al., 2011]. "
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    ABSTRACT: Disorders related to the autosomal transcription factor MEF2C located in 5q14.3 were first described in 2009 and have since evolved to one of the more common microdeletion syndromes. Mutational screening in a larger cohort revealed heterozygous de novo mutations of MEF2C in about 1% of patients with moderate to severe intellectual disability, and the phenotype is similar in patients with intragenic deletions and multigenic microdeletions. Clinically, MEF2C-related disorders are characterized by severe intellectual disability with absent speech and limited walking abilities, hypotonia, seizures, and a variety of minor brain anomalies. The majority of patients show a similar facial gestalt with broad forehead, flat nasal bridge, hypotonic mouth, and small chin, as well as strabismus, but this phenotype is clinically not well recognized. The course of the disease is generally quite uniform, but patients with point mutations and smaller deletions seem to have a higher chance of walking skills and a lower risk of refractory seizures. Patients in whom the microdeletion also includes the RASA1 gene show features of the respective capillary and arterio-venous malformations and fistula syndrome. The phenotypic overlap with Rett syndrome is explained by a shared pathway and, accordingly, diminished MECP2 and CDKL5 expression is measureable in patients with MEF2C defects. Further research of this pathway may therefore eventually lead to a common therapeutic target.
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