Monday, February 8, 2016

GPR56 polymicrogyria

Desai NA, Udani V. GPR56-Related Polymicrogyria: Clinicoradiologic Profile of 4 Patients. J Child Neurol. 2015 Nov;30(13):1819-23.


Bilateral frontoparietal polymicrogyria is an autosomal recessive cortical malformation associated with abnormalities of neuronal migration, white matter changes, and mild brainstem and cerebellar abnormalities. Affected patients present with delayed milestones, intellectual disability, epilepsy, ataxia, and eye movement abnormalities. The clinicoradiologic profile resembles congenital muscular dystrophy. However, no muscle disease or characteristic eye abnormalities of congenial muscular dystrophy are detected in these children. GPR56 is the only confirmed gene associated with bilateral frontoparietal polymicrogyria. Antenatal diagnosis is possible if the index case is genetically confirmed. Four patients from different Indian families with a distinct clinicoradiologic profile resembling congenital muscular dystrophy with mutations in the GPR56 gene are described.

Santos-Silva R, Passas A, Rocha C, Figueiredo R, Mendes-Ribeiro J, Fernandes S, Biskup S, Leão M. Bilateral frontoparietal polymicrogyria: a novel GPR56 mutation and an unusual phenotype. Neuropediatrics. 2015 Apr;46(2):134-8.


Loss of function of GPR56 causes a specific brain malformation called the bilateral frontoparietal polymicrogyria (BFPP), which has typical clinical and neuroradiological findings. So far, 35 families and 26 independent mutations have been described.We present a Portuguese 5-year-old boy, born from nonconsanguineous parents, with BFPP. This patient has a novel GPR56 mutation (R271X) and an unusual phenotype, because he presents hot water epilepsy.To the best of our knowledge, this is the first reported case of BFPP evolving hot water epilepsy.

Fujii Y, Ishikawa N, Kobayashi Y, Kobayashi M, Kato M. Compound heterozygosity
in GPR56 with bilateral frontoparietal polymicrogyria. Brain Dev. 2014

Polymicrogyria is caused by a diverse etiology, one of which is gene mutation. At present, only one gene (GPR56) is known to cause polymicrogyria, which leads to a distinctive phenotype termed bilateral frontoparietal polymicrogyria (BFPP). BFPP is an autosomal recessive inherited human brain malformation with abnormal cortical lamination. Here, we identified compound heterozygous GPR56 mutations in a patient with BFPP. The proband was a Japanese female born from non-consanguineous parents. She presented with mental retardation, developmental motor delay, epilepsy exhibiting the feature of Lennox-Gastaut syndrome, exotropia, bilateral polymicrogyria with a relatively spared perisylvian region, bilateral patchy-white-matter MRI signal changes, and hypoplastic pontine basis. GPR56 sequence analysis revealed a c.107G>A substitution leading to a p.S36N, and a c.113G>A leading to a p.R38Q. Although affected individuals with compound heterozygosity in GPR56 have not been previously described, we presume that compound heterozygosity of these two mutations in a ligand binding domain within the extracellular N-terminus of protein could result in BFPP. In addition, we observed unusually less involvement of perisylvian cortex for polymicrogyria, and Lennox-Gastaut syndrome for epilepsy, which are likely common features in patients with BFPP caused by GPR56 mutations.

Singer K, Luo R, Jeong SJ, Piao X. GPR56 and the developing cerebral cortex:
cells, matrix, and neuronal migration. Mol Neurobiol. 2013 Feb;47(1):186-96.


GPR56, a member of the adhesion G protein-coupled receptor (GPCR) family, is integral to the development of the cortex, as mutations in GPR56 cause bilateral frontoparietal polymicrogyria (BFPP). BFPP is a cobblestone-like cortical malformation, characterized by overmigrating neurons and the formation of neuronal ectopias on the surface of the brain. Since its original cloning a decade ago, GPR56 has emerged from an orphaned and uncharacterized protein to an increasingly well-understood receptor, both in terms of its signaling and function. Collagen III is the ligand of GPR56 in the developing brain. Upon binding to collagen III, GPR56 activates RhoA via coupling to Gα(12/13). This pathway appears to be particularly critical in the preplate neurons, which are the earliest born neurons in the cortex, as the expression pattern of GPR56 in these neurons mimics the anterior to posterior gradient of malformation associated with loss of GPR56 in both humans and mice. Further characterizing the role of GPR56 in the preplate will shed light on the mechanism of cortical development and patterning.

Inspired by a patient at our institution. 

1 comment:

  1. In our patient, MRI shows diffuse polymicrogyria involving bilateral cerebral hemispheres, with generalized thickening of the cortical gray matter, and extensive confluent T2 hyperintensity involving the subcortical and periventricular white matter in bilateral cerebral hemispheres, without involvement of the basal ganglia or cortical gray matter. Dilated perivascular spaces are noted within the white matter bilaterally. There are several small chronic appearing lacunar infarcts within the central semiovale bilaterally and within the forceps major immediately posterior to the lateral ventricle margin. Ventriculomegaly noted. Calcification noted in the left choroid plexus. Corpus callosum, brainstem and sella are normally formed. Cerebellar vermis blunted along superior margin, with slight enlargement of arachnoid space at the posterior fossa representing a small mega cisterna magna.