Indeed, white matter is exquisitely vulnerable to ischemia and is often injured more severely than gray matter. Grey matter, which has a pinkish-grey color in the li… CNS Neurosci Ther (2015) 21(2):112–22. In the brain, FLNA is expressed at high levels in prenatal and neonatal stages and these levels diminish during adolescence to reach moderate expression in adulthood 27). J Neurochem 2004;90:173–189. Thus, the phenotype would associate a cell‐autonomous migration defect as largely proposed and an alteration of RGCs and radial glial scaffold. google_ad_client: "ca-pub-9759235379140764", Periventricular heterotopia: phenotypic heterogeneity and correlation with Filamin A mutations. Mice with mutations in the Napa gene, which encodes for the vesicle trafficking protein αSnap, also replicate the periventricular nodular heterotopia phenotype 44). Discover the signs that it’s time to switch treatment. Neuroscience . Bilateral periventricular nodular heterotopia can co-occur with cerebellar vermis hypoplasia and hypoplasia of the corpus callosum. Most males with subcortical band heterotopia have a DCX gene mutation that is not inherited and is present in only some of the body’s cells, a situation known as mosaicism. Mutations in the DCX or PAFAH1B1 gene cause subcortical band heterotopia. The symptoms of microvascular ischemic disease can range from mild to severe, depending on the extent of the damage. Hence, the burden on public health and social care is substantial (Thurman et al., 1999). Published 2017 Mar 28. doi:10.4102/sajpsychiatry.v23i0.923 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6138094, Bourgeois JA, Nisenbaum J, Drexler KG, Dobbins KM, Hall MJ. These teratogens produce damages within the proliferative neuroepithelium, affecting both the genesis of newborn neurons and their migration along the radial glial scaffold 47). In: Adam MP, Ardinger HH, Pagon RA, et al., editors. Overall, as the majority of periventricular nodular heterotopia genes are required for some forms of vesicle trafficking, it has been proposed that an overriding defect in the vesicle trafficking machinery may contribute to periventricular nodular heterotopia formation 46). Degeneration of the white matter — specifically, the myelin sheaths — can affect a person’s mood, focus, muscle strength, vision, and balance. Ann Clin Trans Neurol (2018) 5(11):1314–22. The inheritance is dominant if one copy of the altered gene in each cell is sufficient to cause the condition. Mutations in the FLNA gene, on Xq28, were found in 100% of families with X‐linked bilateral periventricular nodular heterotopia and in 26% of sporadic patients with periventricular nodular heterotopia 25). grey matter lesions (Figure 1), the causes of grey matter damage and its relationship to white matter lesions remain unclear. People with specific questions about genetic risks or genetic testing for themselves or family members should speak with a genetics professional. Dyspraxia (difficulties with coordinated movement) and problems with fine motor skills have also been found 52). FLNA-Related Periventricular Nodular Heterotopia. Gray matter heterotopia also called grey matter heterotopia, is a relatively common malformation of cortical development, where cortical cells (grey matter) are present in inappropriate locations in the brain, due to interruption in their migration … Epilepsy usually develops during the second decade of life 49). During the past decades it became clear that gray matter (GM) damage of the brain is also of major importance in patients with MS. Healthline Media does not provide medical advice, diagnosis, or treatment. Researchers believe that mutations in the FLNA or ARFGEF2 genes may also result in weakening of the attachments (adhesion) between cells that form the lining of the ventricles. Sarkisian MR, Bartley CM, Chi H, et al. Along with epilepsy, further manifestations of gray matter heterotopia are represented by mild intellectual disability, developmental delay and motor impairments and dyslexia involving impairments in reading ability, processing speed, and executive functioning 50). Parrini E, Ramazzotti A, Dobyns WB, et al. The number of neurons is clearly important, but so is the connectivity of the neuronal network. A developmental and genetic classification for malformations of cortical development: update 2012. Treatment of epilepsy generally follows principles for a seizure disorder caused by a known structural brain abnormality. Multiple sclerosis (MS) is a chronic condition of the central nervous system, which includes the brain. Filamins as integrators of cell mechanics and signalling. Early cognitive and behavioral problems in children with nodular heterotopia. White matter damage has long been a concern among premature babies, but full-term babies sometimes also display the damage—and its related symptoms. The brefeldin A‐inhibited GDP/GTP exchange factor 2, a protein involved in vesicular trafficking, interacts with the beta subunits of the GABA receptors. Individuals with periventricular gray matter heterotopia in whom ARFGEF2 gene mutations have been identified have a severe form of the disorder, including microcephaly, severe developmental delay, and seizures beginning in infancy. Neuron 1998;21:1315–1325. In most cases, periventricular gray matter heterotopia is caused by mutations in the FLNA gene. Developmental delay is common but neurological deficits are usually only seen in more severe cases of gray matter heterotopia with mild motor, sensory and visual defects being reported 51). ARFGEF2 encodes a protein called BIG2 (brefeldin A‐inhibited guanine nucleotide exchange factor 2 protein) localized along the Golgi and recycling endosomes 34). The αSnap protein is involved in SNAP receptor (SNARE)‐mediated vesicle fusion thus suggesting that it plays a role in vesicle trafficking in periventricular nodular heterotopia formation. A case of subcortical grey matter heterotopia presenting as bipolar disorder. Brain 2013;136:3378–3394. Lack of grey matter in the brain is linked to schizophrenia and bipolar disorder. 10.1176/appi.neuropsych.11110336, Blackmon K, Ben-Avi E, Wang X, Pardoe HR, Di Martino A, Halgren E, et al. Hum Mol Genet 2001;10:1775–1783. Mutations in the ARFGEF2 gene may disrupt this function, which could result in the abnormal neuronal migration seen in periventricular gray matter heterotopia. Nat Rev Mol Cell Biol 2001;2:138–145. Most survivors are young and have near-normal life expectancy (Thornhill et al., 2000). Gray matter heterotopia is characterized by the presence of small or extended portions of grey matter in areas of the brain or spinal cord that should physiologically be occupied by white matter. Nat Genet 2004;36:69–76. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1185, Band heterotopia also known as double cortex heterotopia and X-linked lissencephaly (chromosome Xq22.3), Laminar heterotopia (a problematic term variably defined), Unspecified schizophrenia spectrum disorder, Attention-deficit hyperactivity disorder (ADHD), Lack of remorse for problematic behaviour, Sexual inhibition and sexually inappropriate behavior, Vague delusions (more so than systematised delusions). People who have mild forms of microvascular ischemic disease may have no symptoms. All rights reserved. White matter damage can cause a great deal of stress and increase the energy demands on the neuron. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. J Comp Neurol 2012;520:3013–3034. Neuronal migration is essential for normal brain development and function. Shin H, Shinotsuka C, Nakayama K. Expression of BIG2 and analysis of its function in mammalian cells. Hum Mol Genet 2012;21:1004–1017. Periventricular heterotopia in 6q terminal deletion syndrome: role of the C6orf70 gene. Varying results from surgical resection of the affected area have been reported. Interestingly, although gray matter declines steadily from adolescence, white matter keeps growing until our late forties. As a consequence, animals generated with these treatments invariably have microcephaly and altered cortical structure and exhibit various types and combination of gray matter heterotopia, including periventricular nodular heterotopia, layer 1 ectopia, intracortical and subcortical heterotopia, and intrahippocampal heterotopia. Compr Psychiatry. When subcortical band heterotopia is caused by mutations in the DCX gene, it is inherited in an X-linked pattern. Periventricular nodular heterotopia has also been observed in patients with chromosomal rearrangements, such as deletions of the 5q14.3‐15 37) or 6q27 38) regions. 1998;10:351–3. Gray matter damage in multiple sclerosis: impact on clinical symptoms. Without proper neuronal migration, neurons in the developing brain can be misplaced, forming abnormal bands of tissue beneath the cerebral cortex. Information on the extent of global differences in the 3 principal supertentorial compartments is necessary for interpretation of regional effects. 10.16966/2471-4925.172. The first include mutations of the X-linked FNLA gene (Xq28), coding for the Filamin, an actin-binding protein that crosslinks actin filaments and links actin filaments to membrane glycoproteins 22). Affected individuals usually have normal intelligence, although some have mild intellectual disability. Periventricular gray matter heterotopia can have different inheritance patterns. The single most important thing in brain injury litigation is objectification of injury. AJNR Am J Neuroradiol. (adsbygoogle = window.adsbygoogle || []).push({}); (adsbygoogle = window.adsbygoogle || []).push({ NeuroImage Clin (2016) 10:36–45. Other cases may result from new mutations in the gene. Difficulty with reading and spelling (dyslexia) and movement problems have been reported in some people with periventricular gray matter heterotopia. Footnote: Magnetic resonance imaging (MRI) scan sections of the patient’s brain reporting the presence of gray matter heterotopia (indicated by arrows and circles). Altered structure or function of the proteins produced by the DCX or PAFAH1B1 gene impairs important interactions that are needed for neuronal migration. Nat Neurosci 2006;9:1099–1107. These neurons stop their migration process in areas of the brain where they are not supposed to be and form band-like clusters of tissue. If you're having memory problems or a loved one is, a doctor will need to run tests to make a diagnosis. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1213, Periventricular heterotopia. Grey:white matter ratio at diagnosis and the risk of 10-year multiple sclerosis progression. Subcortical band heterotopia is typically found when brain imaging is done following the onset of seizures, usually in adolescence or early adulthood. Gray matter heterotopia also called grey matter heterotopia, is a relatively common malformation of cortical development, where cortical cells (grey matter) are present in inappropriate locations in the brain, due to interruption in their migration to their correct location in the cerebral cortex 1). Another had experienced a recent cardiac arrest and showed subtle white matter changes on structural MR. Symptoms range from absent to profound, the more severe are seen in those with bilateral or extensive heterotopia or other brain abnormalities. Furthermore, these structural changes are greater in those that report more PCS symptoms, suggesting a neurophysiological basis for these persistent symptoms. Neuropsychiatric disease in patients with periventricular heterotopia. 2015;303:446-461. Fox JW, Lamperti ED, Eksioglu YZ, et al. (A) T2W – coronal section; (B) T1W- assial section; (C) T1W – sagittal section. The mechanism involved in the genesis of periventricular nodular heterotopia remains elusive although it is widely accepted that it results from a defective migration of neurons which remain blocked in the ventricular zone (VZ)–subventricular zone (SVZ). There is a wide spectrum of anatomic and clinical presentations of periventricular nodular heterotopia, ranging from asymptomatic small unilateral or bilateral nodules to extensive agglomerates of heterotopia lining the lateral ventricles in patients with intractable epilepsy and intellectual disabilities 13). MEKK4 signaling regulates filamin expression and neuronal migration. Symptoms of Gray and White Matter Disease “In general, white matter disease causes acute MS symptoms, like numbness and weakness," Stone … Periventricular nodular heterotopia in 22q11. This gene provides instructions for producing the protein filamin A, which helps build the network of protein filaments (cytoskeleton) that gives structure to cells and allows them to change shape and move. J Neuropsychiatry Clin Neurosci. It is not known how this duplicated genetic material results in the signs and symptoms of periventricular gray matter heterotopia. Data from several cross-sectional studies indicate that Grey Matter damage and Grey Matter loss are significantly correlated with both cognitive and physical disability 2,7,8,16-20; Clinical research has also found that Grey Matter atrophy (loss of Grey Matter in the brain) is … The white matter at the cord’s periphery contains ascending and descending tracts of myelinated sensory and motor nerve fibers. Periventricular white matter abnormalities and restricted repetitive behavior in autism spectrum disorder. Some affected individuals also have weak muscle tone (hypotonia), loss of fine motor skills such as using utensils, or behavioral problems. MS can damage white and gray matter in the brain. There is also a range of associated cerebral and systemic malformations. Epilepsy Res. 2000;55:1603–8. 1-4 Historically, researchers and clinicians focused on WM activity, yet recent evidence has made it clear that GM damage is also critically important and a major cause of disease disability. BIG2 is thought to carry out ARF‐dependent vesicle trafficking along these subcellular compartments 35). See how Hopkins clinicians are teaming to provide a better assessment of this often overlooked damage. A glial origin for periventricular nodular heterotopia caused by impaired expression of Filamin‐A. Neuropsychiatric symptoms are less well researched and possibly underrecognised 64). Abdel Razek AA, Kandell AY, Elsorogy LG, Elmongy A, Basett AA. 2013;25:26–31. Figure 2. However, the development of some clinical symptoms such as cognitive impairment cannot be fully explained by the severity of WM pathology alone. Distinct regional and subcellular localization of the actin‐binding protein filamin A in the mature rat brain. 10.1016/0925-4927(95)02573-G, Fry AE, Kerr MP, Gibbon F, Turnpenny PD, Hamandi K, Stoodley N, et al. Gray matter heterotopias can be divided macroscopically into: Gray matter heterotopia patients most commonly present with partial seizures in the second decade of life, frequently resistant to medication. 2011;22(3):523–6. Talk to your doctor to learn more about the potential effects of MS, as well as your treatment options. Many medications and other treatments are also available to treat symptoms of the condition. Among epigenetic factors, perinatal stressors, such as hypoxic-ischemic events occurring during migration of neuroblasts, at 7-16 weeks of fetal development, may play a crucial role in the etiopathogenesis of gray matter heterotopia 24). Seattle (WA): University of Washington, Seattle; 1993-2020. Brains are made up of both white matter and grey matter. In a few cases, periventricular gray matter heterotopia has been associated with abnormalities in chromosome 5. 10.1016/j.nicl.2015.10.017, Nopoulos P, Berg S, Castellenos FX, Delgado A, Andreasen NC, Rapoport JL. Five different groups of periventricular nodular heterotopia have been distinguished 16): (1) bilateral and symmetrical; (2) bilateral single-noduled; (3) bilateral and asymmetrical; (4) unilateral; and (5) unilateral with extension to neocortex. In a study of 16 patients who were being evaluated for intractable epilepsy, all of them were found to have gray matter heterotopia – both laminar and nodular forms were discovered 7). 2 deletion and frontal lobe migration. During the past decades it became clear that gray matter (GM) damage of the brain is also of major importance in patients with MS. … 2014 Mar;108(3):547-54. https://doi.org/10.1016/j.eplepsyres.2014.01.009, Hehr U, Uyanik G, Aigner L, et al. Grey matter heterotopias are believed to be due interruption of the normal migration of neurons from the periventricular telencephalic germinal matrix to the cortex and may be due to either genetic abnormalities or infection/trauma 2). Gray matter is not the sole arbiter of ability and knowledge, of course. In each case, the affected individual had extra genetic material caused by an abnormal duplication of part of this chromosome. Additionally, and depending on the extent, children may demonstrate developmental delay or intellectual disability, although symptoms range from absent to profound 3). Front Psychiatry. There is evidence for both white and grey matter damage in participants with mTBI over 1 year after injury. Over time, this can cause physical and cognitive symptoms — but early treatment may make a difference. In normal brain development, neurons form in the periventricular region, located around fluid-filled cavities (ventricles) near the center of the brain. Read on to learn more about the different types of brain tissue and how MS can affect them. Heterozygous females have normal to borderline intelligence and epilepsy 29). Dr. Alhilali began looking at the white matter of the brain because she wanted to understand why symptoms vary widely in concussion patients. 2002 Oct 8 [Updated 2015 Sep 17]. Periventricular heterotopia: shuttling of proteins through vesicles and actin in cortical development and disease. A. J. Barkovich, R. I. Kuzniecky, G. D. Jackson, R. Guerrini and W. B. Dobyns. Finally, it has been shown that deletion of the RhoGTPase Cdc42 gene in mouse disrupts the neuroependymal lining, local adherens junctions, and proliferation of basal progenitors, which may lead to neuronal heterotopia 45). Normally, the neurons that make up the outer surface of the brain (cerebral cortex) are distributed in a well-organized and multi-layered way. In X-linked periventricular gray matter heterotopia, males experience much more severe symptoms of the disorder than females, and in most cases die before birth. Incidence of ectopic gray matter in patients with schizophrenia and healthy control subjects studied with MRI. PAFAH1B1 gene mutations that occur in all of the body’s cells (germline mutations) usually cause isolated lissencephaly sequence. Experts have long known that MS affects white matter in the brain, but recent research suggests that it affects gray matter, too. Footnote: A and B, Coronal T1-weighted images show a few small periventricular nodules, isointense to the gray matter, along the lateral ventricular wall. Seattle (WA): University of Washington, Seattle; 1993-2020. 10.1176/jnp.10.3.351. The nodules around the ventricles are then typically discovered when magnetic resonance imaging (MRI) studies are done. Everyone is different and symptoms will vary in individual cases. There is a female predominance in cases of bilateral periventricular nodular heterotopia. Classification system for malformations of cortical development: Update 2001. Gray matter heterotopia. Periventricular gray matter heterotopia caused by mutations in the ARFGEF2 gene is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. Mutations in this gene reduce the protein’s function. 10.1176/appi.neuropsych.11110336, Lippi G. Neuropsychiatric symptoms and diagnosis of grey matter heterotopia: a case-based reflection. The development of all these symptoms can be independent of epilepsy because they were found to be present before the onset of seizures in many children with gray matter heterotopia 65). The primary form of white matter brain disease is multiple sclerosis, which results in the destruction of the myelin sheath 2.In multiple sclerosis, there is defective formation or maintenance of the myelin because of dysfunction of the oligodendrocytes, a type of glial cell 2. Other studies have shown that mice mutant for MEKK4, a MAP kinase that regulates the CSBP2 and JNK‐MAPK pathways, showed a periventricular nodular heterotopia phenotype 43). Cog Fog: How to Deal with This Frequent MS Symptom, MS: Exercises for Better Balance and Coordination, 7 Daily Tips for Managing Multiple Sclerosis, How to Keep Your Brain Healthy with MS: A Guide, These Dogs Know When Their Owners Are About to Have an MS Flare, RRMS: What You Need to Know About Switching Medications. Moreover, because of the potentially disruptive impact of heterotopic neuronal migration, a number of neurodevelopmental disorders, such as autism 54) and ADHD 55), are associated with gray matter heterotopia. Curr Opin Genet Dev 2005;15:301–307. The third had no clear encephalopathy or recent cardiac arrest. Dev Neurosci 1997;19:521–528. GeneReviews® [Internet]. Behavioral disorders and psychological symptoms (BPSD) in Alzheimer's disease (AD) are known to correlate with grey matter (GM) atrophy and, as shown recently, also with white matter (WM) damage. Interestingly, phosphorylation of FLNA at serine 2152 depends on MEKK4 signaling and phosphorylation at this site regulates FLNA localization at the cell membrane. However, the choice of antiepileptic drug may be selected based on side effects, tolerability, and efficacy 68). Display the damage—and its related symptoms disease results in the ARFGEF2 gene the germinal matrix between and! With fine motor skills have also been found 52 ) than gray matter heterotopia when brain imaging is done the. Bands are located beneath the cerebral cortex do not reach it can not reverse developmental disabilities, it is in! Been described but for the majority of them the etiology remains unknown 14 ) known this! 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Halgren E, Ramazzotti a, Dobyns WB is associated with 5q14.3‐q15 deletion Swayze VW, M. Apical surface big2 is thought to carry out ARF‐dependent vesicle trafficking along these compartments...