| differential = Other forms of [[polymicrogyria]], [[lissencephaly]], [[cerebral palsy]]
| prevention =
| prevention = Genetic counseling for at-risk families
| treatment =
| treatment = Supportive care, physical and speech therapy, seizure control
| medication =
| medication = [[Antiepileptic drugs]] for seizures
| prognosis =
| prognosis = Varies; developmental and neurological outcomes differ by severity
| frequency =
| frequency = Very rare
| deaths =
| deaths = Depends on severity; not typically fatal
}}
}}
[[File:Lissencephaly.png|thumb|left|Lissencephaly:Brain MRI, T1 weighted, transverse plane, that shows lyssencephaly, manifested as scarce and wide circumvolutions, mostly in the occipital, parietal and temporal lobes. As aggregated findings, there is ventriculomegaly, no true Sylvian cissure, too thick gray matter and ectopic gray matter in the white matter.|left]]
'''Bilateral frontoparietal polymicrogyria''' (BFPP) is a rare [[neurological disorder]] characterized by abnormal development of the [[cerebral cortex]], specifically affecting the [[frontal lobe|frontal]] and [[parietal lobe|parietal]] lobes of the [[brain]]. This condition is a form of [[polymicrogyria]], which involves the presence of an excessive number of small, irregularly formed [[gyri]] on the surface of the brain.
'''Bilateral frontoparietal polymicrogyria''' is a genetic disorder with [[autosomal recessive]] inheritance that causes a cortical malformation. Our brain has folds in the [[Cerebral cortex|cortex]] to increase surface area called [[Gyrus|gyri]] and patients with polymicrogyri have an increase number of folds and smaller folds than usual.<ref>"Bilateral Frontoparietal Polymicrogyria (BFPP)." Welcome to the Research View. N.p., n.d. Web. 05 Nov. 2012. <http://www.neuroscienceandgenetics.it/syndrome/bilateral-frontoparietal-polymicrogyria-bfpp>.</ref> Polymicrogyria is defined as a cerebral malformation of cortical development in which the normal gyral pattern of the surface of the brain is replaced by an excessive number of small, fused gyri separated by shallow [[Sulcus (neuroanatomy)|sulci]] and abnormal cortical lamination. From ongoing research, mutation in GPR56, a member of the adhesion G protein-coupled receptor (GPCR) family, results in BFPP. These mutations are located in different regions of the protein without any evidence of a relationship between the position of the mutation and phenotypic severity.<ref>Bahi-Buisson, N., K. Poirier, N. Boddaert, C. Fallet-Bianco, N. Specchio, E. Bertini, O. Caglayan, K. Lascelles, C. Elie, J. Rambaud, M. Baulac, I. An, P. Dias, V. Des Portes, M. L. Moutard, C. Soufflet, M. El Maleh, C. Beldjord, L. Villard, and J. Chelly. "GPR56-related Bilateral Frontoparietal Polymicrogyria: Further Evidence for an Overlap with the Cobblestone Complex." Brain 133.11 (2010): 3194-209. Print</ref> It is also found that GPR56 plays a role in cortical pattering.<ref>Piao, Xianhua, and Christopher A. Walsh. "A Novel Signaling Mechanism in Brain Development." Pediatric Research 56.3 (2004): 309-10. Print.</ref>
==Pathophysiology==
==Presentation==
Polymicrogyria results from abnormal neuronal migration during [[embryonic development]], leading to the formation of multiple small gyri. In BFPP, this malformation is bilateral and predominantly affects the frontoparietal regions. The abnormal cortical development can disrupt normal brain function, leading to a variety of neurological symptoms.
*'''Symptoms''': Developmental delay, [[Psychomotor learning|Psychomotor]] delay, Mental retardation - moderate to severe, Exaggerated reflexes and Seizures (epilepsy)
=== Associated conditions ===
BFPP is a cobblestone-like cortical malformation of the brain. Disruptions of cerebral cortical development due to abnormal neuronal migration and positioning usually lead to cortical disorders, which includes '''cobblestone lissencephaly'''. Cobblestone lissencephaly is typically seen in three different human congenital muscular dystrophy syndromes: '''[[Fukuyama congenital muscular dystrophy]]''', '''[[Walker-Warburg syndrome]]''', and '''muscle-eye-brain disease'''.<ref>Lin, Dr. Hsi-Hsien. Personal Interview. 29 October 2012.</ref> In cobblestone lissencephaly, the brain surface actually has a bumpy contour caused by the presence of collections of misplaced neurons and [[glial cell]]s that have migrated beyond the normal surface boundaries of the brain. Sometimes regions populated by these misplaced cells have caused a radiologic misdiagnosis of polymicrogyria. However, the presence of other abnormalities in these cobblestone lissencephaly syndromes, including ocular anomalies, congenital muscular dystrophy, [[ventriculomegaly]], and cerebellar dysplasia, usually distinguishes these disorders from polymicrogyria.<ref name="chang"/> There are no anatomopathologic studies that have characterized the pattern of cortical laminar alterations in patients with GPR56 gene mutations, but it has been suggested that the imaging characteristics of BFPP, including [[myelination]] defects and cerebellar cortical [[dysplasia]], are reminiscent of those of the so-called cobblestone malformations (muscle-eye-brain disease and Fukuyama congenital muscular dystrophy) that are also associated with N-glycosylation defects in the developing brain.<ref>Parrini, Elena, Anna Rita Ferrari, Thomas Dorn, Christopher A. Walsh, and Renzo Guerrini. "Bilateral Frontoparietal Polymicrogyria, Lennox-Gastaut Syndrome, Andgene Mutations." Epilepsia 50.6 (2009): 1344-353. Print.</ref>
'''Lissencephaly''' ("smooth brain") is the extreme form of pachygyria. In lissencephaly, few or no sulci are seen on the cortical surface, resulting in a broad, smooth appearance to the entire brain. Lissencephaly can be radiologically confused with polymicrogyria, particularly with low-resolution imaging, but the smoothness and lack of irregularity in the gray-white junction, along with markedly increased cortical thickness, distinguishes lissencephaly.
GPR56 mutation also can cause a severe encelphalopathy which is associated with electro clinical features of the '''Lennox-Gastaut syndrome'''. [[Lennox-Gastaut syndrome]] can be cryptogenic or symptomatic, but the symptomatic forms have been associated with multiple etiologies and abnormal cortical development. BFPP caused by GPR56 mutations is a representation of a malformation of cortical development that causes Lennox-Gastaut Syndrome.<ref>Parriniy, E., Ferrariz A.R., Dorn T., Walsh C.A., Guerrini, R., Bilateral frontoparietal polymicrogyria, Lennox-Gastaut syndrome, and GPR56 gene mutations, Epilepsia, Volume 50 Issue 6, Pages 1344–1353, 2009.</ref>
Polymicrogyria usually gets misdiagnose with pacygyria so therefore it needs to be distinguished from pachygyria. '''[[Pachygyria]]''' is a distinct brain malformation in which the surface folds are excessively broad and sparse. Pachygyria and polymicrogyria may look similar on low-resolution neuroimaging such as CT because the cortical thickness can appear to be increased and the gyri can appear to be broad and smooth in both conditions. This is why higher resolution neuroimaging are needed such as an MRI.<ref name="chang"/>
[[File:Lissencephaly.png|thumb|left|Lissencephaly:Brain MRI, T1 weighted, transverse plane, that shows lyssencephaly, manifested as scarce and wide circumvolutions, mostly in the occipital, parietal and temporal lobes. As aggregated findings, there is ventriculomegaly, no true Sylvian cissure, too thick gray matter and ectopic gray matter in the white matter.]]
==Genetics==
==Genetics==
The GPR56 is grouped in the B family of GPCRs. This GPCR group have long N termini characterized by an extracellular “cysteine box” and hydrophilic, potentially [[mucin]]-rich. The cysteine box contains four conserved [[cysteine]]s and two [[tryptophan]]s arranged in a specific fashion (C-x2-W-x6-16-W-x4-C-x10-22-C-x-C) just before the first transmembrane domain and serves as a cleavage site in some members of this group of G protein–coupled receptors.<ref>Piao, X., Chang, B. S., Bodell, A., Woods, K., BenZeev, B., Topcu, M., Guerrini, R., Goldberg-Stern, H., Sztriha, L., Dobyns, W. B., Barkovich, A. J. and Walsh, C. A. (2005), Genotype–phenotype analysis of human frontoparietal polymicrogyria syndromes. Ann Neurol., 58: 680–687. doi: 10.1002/ana.20616</ref> Although, the molecular and cellular mechanisms of how GPR56 regulates brain development remain largely unknown.<ref>Luo, R., S.-J. Jeong, Z. Jin, N. Strokes, S. Li, and X. Piao. "G Protein-coupled Receptor 56 and Collagen III, a Receptor-ligand Pair, Regulates Cortical Development and Lamination." Proceedings of the National Academy of Sciences 108.31 (2011): 12925-2930. Print.</ref> These types of receptors play an essential role in biological processes including embryonic development, central nervous system (CNS), immune system, and [[tumorigenesis]].<ref>Chiang NY, Hsiao CC, Huang YS, Chen HY, Hsieh IJ, et al. Disease-associated GPR56 mutations cause bilateral frontoparietal polymicrogyria via multiple mechanisms. J Biol Chem. 2011;286:14215–14225</ref>
BFPP is often associated with mutations in the ''GPR56'' gene, which plays a crucial role in brain development. This gene provides instructions for making a protein involved in the regulation of [[cell adhesion]] and [[cell signaling]], processes essential for the proper formation of the cerebral cortex. The condition is typically inherited in an [[autosomal recessive]] pattern, meaning that both copies of the gene in each cell have mutations.
:::::::::::*The parents of an affected individual are obligate heterozygotes and therefore carry one [[mutant]] allele.
==Clinical Features==
:::::::::::*Heterozygotes (carriers) are asymptomatic.
Individuals with BFPP may present with a range of neurological symptoms, including:
* [[Developmental delay]]
* [[Intellectual disability]]
* [[Seizures]]
* [[Spasticity]]
* [[Hypotonia]]
* [[Cerebellar ataxia]]
'''Sibs of a proband'''
The severity of symptoms can vary widely among affected individuals, even within the same family.
:::::::::::*At conception, each sibling of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
==Diagnosis==
:::::::::::*Once an at-risk sibling is known to be unaffected, the risk of his/her being a carrier is 2/3.
The diagnosis of BFPP is typically made through a combination of clinical evaluation, [[neuroimaging]], and genetic testing. [[Magnetic resonance imaging]] (MRI) of the brain is used to identify the characteristic pattern of polymicrogyria in the frontoparietal regions. Genetic testing can confirm mutations in the ''GPR56'' gene.
:::::::::::*Heterozygotes (carriers) are [[asymptomatic]].
'''Offspring of a proband'''
==Management==
There is currently no cure for BFPP, and treatment is primarily supportive and symptomatic. Management strategies may include:
* [[Anticonvulsant]] medications to control seizures
* [[Physical therapy]] to improve motor function
* [[Occupational therapy]] to enhance daily living skills
* [[Speech therapy]] to address communication difficulties
:::::::::::*Offspring of a proband are obligate heterozygotes and will therefore carry one mutant allele.
:::::::::::*In populations with a high rate of consanguinity, the offspring of a person with GPR56-related BFPP and a reproductive partner who is a carrier of GPR56-related BFPP have a 50% chance of inheriting two GPR56 disease-causing alleles and having BFPP and a 50% chance of being carriers.
'''Other family members of a [[proband]]'''.
:::::::::::*Each sibling of the proband's parents is at a 50% risk of being a carrier<ref name="chang"/>
== Diagnosis ==
Diagnostic criteria for a BFPP patient entails a [[heterozygous]] genotype for a deletion of chromosome 16q12.1-q21 region,
including GPR56 gene.<ref>Borgatti, Renato, Susan Marelli, Laura Bernardini, Antonio Novelli, Anna Cavallini, Alessandra Tonelli, Maria Teresa Bassi, and Bruno Dallapiccola. "Bilateral Frontoparietal Polymicrogyria (BFPP) Syndrome Secondary to a 16q12.1-q21 Chromosome Deletion Involving GPR56 Gene." Clinical Genetics 79 (2009): 573-76. Print.</ref> To date the only gene known to be associated with polymicrogyria is GPR56. Testing for GPR56-related bilateral frontoparietal polymicrogyria is available clinically. Mutations in GPR56 hinders Collagen III, its specific [[ligand]], to bind in a developing brain. To date, a total of fourteen BFPP-associated mutations have been identified, including one deletion, two splicing, and eleven [[missense mutation]]s. Two mutations in the GPCR proteolytic site (GPS) domain, C346S and W349S, cause a brain malformation through trapping the mutated proteins in the [[endoplasmic reticulum]].<ref>Singer K, Luo R, Jeong S, Piao X. "GPR56 and the Developing Cerebral Cortex: Cells, Matrix, and Neuronal Migration." Molecular Neurobiology 2012. doi:10.1007/s12035-012-8343-0</ref>
GPR56 are a part of the B class of the [[GPCR]] family, the largest cell surface gene family in the human [[genome]]. Within this family there are different types of bio-active molecules that transduce their signal to the [[intracellular]] compartment via interaction with this type of receptor. Children often present with developmental delay, spasticity, or seizures; they are also often [[microcephalic]]. Some patients with polymicrogyria go undiagnosed until they produce children with the disorder who have more severe manifestations. Retrospectively, these patients will often report some difficulty in their medical or educational history.<ref>"Polymicrogyria." MedLink. N.p., 1 May 2011. Web. 28 Nov. 2012. <http://www.medlink.com/medlinkcontent.asp></ref> BFPP patients demonstrate mental retardation, language impairment, motor developmental delay, and seizure disorders such as epilepsy.<ref>Jeong, S.-J., Luo, R., Li, S., Strokes, N. and Piao, X. (2012), Characterization of G protein-coupled receptor 56 protein expression in the mouse developing neocortex. J. Comp. Neurol., 520: 2930–2940. doi: 10.1002/cne.23076</ref> The association of epilepsy is in approximately 50% to 85% of affected BFPP patients.
The clinical manifestations of polymicrogyria are stable neurologic deficits:
In the '''mildest form''', polymicrogyria is [[unilateral]] with only one small region of the brain involved; neurologic problems may not be evident.
In '''more severe forms''', focal motor, sensory, visual, or cognitive problems may be present, depending on the location of the brain region affected.
In the '''most severe forms''', polymicrogyria is [[wikt:bilateral|bilateral]] and generalized, resulting in severe intellectual disability, cerebral palsy, and refractory epilepsy.
Individuals with the milder forms of polymicrogyria survive into adulthood, while those with the most severe forms, such as BFPP, may die at a young age as a result of such complications as seizures or pneumonia.<ref name="chang"/>
The prevalence of isolated polymicrogyria is unknown. Researchers believe that it may be relatively common overall, although BFPP is probably rare.<ref>"Polymicrogyria." Genetics Home Reference. N.p., 12 Nov. 2012. Web. 18 Nov. 2012. <http://ghr.nlm.nih.gov/condition/polymicrogyria>.</ref>
*'''Radiological findings''' (MRI) demonstrated symmetric generalized polymicrogyria with decreasing anterior-posterior gradient, most prominent in frontoparietal cortex.<ref name="chang"/>
*Numerous gyrus on the cortex
*Small gyri and sulci
*Thin cortex
===Methods/tests===
[[File:Polymicrogyria arrows.JPG|thumb|This child presented with seizures. The coronal true inversion recovery sequence shows thickened and disordered cortex in superior frontal and cingulate gyri bilaterally (arrow). There are small convolutions visible at the corticomedullary junction. The appearance is that of cortical dysplasia, with polymicrogyria more likely than pachygyria due to the small convolutions visible. There are also small foci of grey matter signal in the corpus callosum, deep to the dysplastic cortex (double arrows). These probably represent areas of grey matter heterotopia.]]
There are different tests or methods used to determine [[GPR56]] expression or visuals of the brain to analyze the specific sections that are affected. These tests for example, using animals such as mice, [[RNAi]], Behavioral assay, Electron microscopy, CT scan, or MRI demonstrate different results that concludes an affected BFPP patient.<ref>Koirala, S., Z. Jin, X. Piao, and G. Corfas. "GPR56-Regulated Granule Cell Adhesion Is Essential for Rostral Cerebellar Development." Journal of Neuroscience 29.23 (2009): 7439-449</ref> MRI's reveal either irregularity to the cortical surface suggestive of multiple small folds or an irregular, scalloped appearance of the gray matter-white matter junction.
'''Neuroimaging''' The diagnosis of [[polymicrogyria]] is typically made by magnetic resonance imaging (MRI) since computed tomography (CT) and other imaging methods generally do not have high enough [[Image resolution|resolution]] or adequate contrast to identify the small folds that define the condition. The cerebral cortex often appears abnormally thick as well because the multiple small gyri are fused, infolded, and superimposed in appearance.<ref name="chang"/>
'''Neuropathology''' Gross neuropathologic examination reveals a pattern of complex [[convolution]]s to the cerebral cortex, with miniature gyri fused and superimposed together, often resulting in an irregular brain surface. The cortical ribbon can appear excessively thick as a result of the infolding and fusion of multiple small gyri.<ref name="chang">Chang B, Walsh CA, Apse K, et al. Polymicrogyria Overview. 2005 Apr 18 [Updated 2007 Aug 6]. In: Pagon RA, Bird TD, Dolan CR, et al., editors. GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1329/</ref>
Microscopic examination demonstrates that the cerebral cortex is in fact abnormally thin and has abnormal lamination; typically the cortex is unlayered or has four layers, in contrast to the normal six layers. The most superficial layers between adjacent small gyri appear fused, with the pia (layer of the meninges) bridging across multiple gyri. [[Prenatal]] diagnosis for BFPP is also available for pregnancies at risk if the GPR56 mutations have been identified in an affected family member.<ref name="chang"/>
== Treatment ==
Treatment plans will vary depending on the severity of the condition and its evidences in each patient.
Areas that will probably need to be evaluated and assessed include speech, vision, hearing and [[EEG]]. Treatment measures may include physical therapy, occupational therapy, Speech therapy, anti-seizure drugs and orthotic devices. Surgery may be needed to assuage spastic motor problems. Various supportive measures such as joint contractures that could prevent complications.
Genetic counseling may also be recommended<ref>Guerrini, R., W. Dobyns, and A. Barkovich. "Abnormal Development of the Human Cerebral Cortex: Genetics, Functional Consequences and Treatment Options." Trends in Neurosciences 31.3 (2008): 154-62. Print.</ref>
==Prognosis==
==Prognosis==
Once the diagnosis of polymicrogyria has been established in an individual, the following approach can be used for discussion of prognosis:
The prognosis for individuals with BFPP varies depending on the severity of the condition and the presence of associated complications. Early intervention and supportive therapies can improve quality of life and functional outcomes.
A pregnancy history should be sought, with particular regard to infections, trauma, multiple gestations, and other documented problems. Screening for the common [[congenital]] infections associated with polymicrogyria with standard TORCH testing may be appropriate. Other specific tests targeting individual neurometabolic disorders can be obtained if clinically suggested.
The following may help in determining a genetic etiology:
'''Family history'''
It is important to ask for the presence of neurologic problems in family members, including seizures, cognitive delay, motor impairment, [[pseudobulbar]] signs, and focal weakness because many affected family members, particularly those who are older, may not have had MRI performed, even if these problems came to medical attention. In addition, although most individuals with polymicrogyria do present with neurologic difficulties in infancy, childhood, or adulthood, those with mild forms may have no obvious deficit or only minor manifestations, such as a simple lisp or isolated learning disability. Therefore, if a familial polymicrogyria syndrome is suspected, it may be reasonable to perform MRI on relatives who are asymptomatic or have what appear to be minor findings. The presence of consanguinity in a child's parents may suggest an autosomal recessive familial polymicrogyria syndrome.
'''Physical examination'''
A general physical examination of the proband may identify associated [[craniofacial]], musculoskeletal, or [[visceral]] malformations that could indicate a particular syndrome. Neurologic examination should assess cognitive and mental abilities, cranial nerve function, motor function, deep tendon reflexes, sensory function, coordination, and gait (if appropriate).<ref name="chang"/>
Varies; developmental and neurological outcomes differ by severity
Frequency
Very rare
Deaths
Depends on severity; not typically fatal
Lissencephaly:Brain MRI, T1 weighted, transverse plane, that shows lyssencephaly, manifested as scarce and wide circumvolutions, mostly in the occipital, parietal and temporal lobes. As aggregated findings, there is ventriculomegaly, no true Sylvian cissure, too thick gray matter and ectopic gray matter in the white matter.GPCR classification
Bilateral frontoparietal polymicrogyria (BFPP) is a rare neurological disorder characterized by abnormal development of the cerebral cortex, specifically affecting the frontal and parietal lobes of the brain. This condition is a form of polymicrogyria, which involves the presence of an excessive number of small, irregularly formed gyri on the surface of the brain.
Polymicrogyria results from abnormal neuronal migration during embryonic development, leading to the formation of multiple small gyri. In BFPP, this malformation is bilateral and predominantly affects the frontoparietal regions. The abnormal cortical development can disrupt normal brain function, leading to a variety of neurological symptoms.
BFPP is often associated with mutations in the GPR56 gene, which plays a crucial role in brain development. This gene provides instructions for making a protein involved in the regulation of cell adhesion and cell signaling, processes essential for the proper formation of the cerebral cortex. The condition is typically inherited in an autosomal recessive pattern, meaning that both copies of the gene in each cell have mutations.
The diagnosis of BFPP is typically made through a combination of clinical evaluation, neuroimaging, and genetic testing. Magnetic resonance imaging (MRI) of the brain is used to identify the characteristic pattern of polymicrogyria in the frontoparietal regions. Genetic testing can confirm mutations in the GPR56 gene.
The prognosis for individuals with BFPP varies depending on the severity of the condition and the presence of associated complications. Early intervention and supportive therapies can improve quality of life and functional outcomes.
