Genetic test for Bilateral frontoparietal polymicrogyria

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Rosalind Greene
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1 Genetic test for Bilateral frontoparietal polymicrogyria Daniela Pilz, Cardiff UKGTN Genetic testing for neurological conditions; London February 26 th 2013

2 Region-specific Polymicrogyria (PMG) bilateral perisylvian PMG (BPP) most common bilateral frontal PMG (BFP) bilateral fronto-parietal PMG (BFPP) bilateral parieto-occipital PMG (BPOP) bilateral diffuse PMG (BDP)

Identification of GPR56 An autosomal recessive form of bilateral

Piao X et al; Am J Hum Genet 2002 Bilateral frontoparietal

3 Identification of GPR56 An autosomal recessive form of bilateral frontoparietal polymicrogyria maps to chromosome 16q Piao X et al; Am J Hum Genet 2002 Bilateral frontoparietal polymicrogyria: clinical and radiological features in 10 families with linkage to chromosome 16. Chang BS et al; Ann Neurol 2003 Frontoparietal predominant PMG, white matter changes, degrees of brain stem & cerebellar hypoplasia

4 G protein-coupled receptor-dependent development of human frontal cortex. Piao X et al; Science families; 9/12 consanguineous Add clinical features: mod-severe DD, hypotonia, seizures, strabismus, normocephaly GPR56 missense, frameshift and splicing mutations Gene: 14 exons, ORF 3kb Protein: 7 transmembrane domains, large extracellular N-terminal domain GPR56 is a member of the adhesion G protein-coupled receptor family. Major ligand is collagen III.

5 Cobblestone lissencephaly with normal eyes and muscle. Dobyns WB et al; Neuropediatrics 1996 Patient 1. Male. First cousin parents from Pakistan GPR56: E5-1G>C global delay, seizure, strabismus, nystagmus, normal ERGs, VEPs, normal CK Ht 50%, OFC > 98%, truncal hypotonia, limb hypertonia MRI: PMG?, dilated ventricles, prom perivascular spaces, cerebellar hypoplasia, small brain stem

6 Cerebral MRI scan UKGTN testing criteria Polymicrogyria (cobblestone-like) bilateral predominant frontoparietal AND Patchy white matter anomalies +/- small brain stem, small / dysplastic cerebellum AND Exclusion of congenital infection, where possible Indication: diagnosis, prognosis and management, prenatal testing

7 Genotype-phenotype analysis of human frontoparietal polymicrogyria syndromes. Piao X et al. Ann Neurol families (29 patients) with 11 different, homozygous mutations - consanguinity in 13/18 families - phenotype and MRI findings all very similar GPR56-related bilateral frontoparietal polymicrogyria: further evidence for an overlap with the cobblestone complex. Bahi-Buisson N et al. Brain families (14 patients & 1 fetus) with 8 different, homozygous mut. - consanguinity in 8/8 families - phenotype: severe global DD; seizures 12/14 (onset ~3y), ataxia, strabismus 10/14 (info not available in 4 patients) -MRI: BFPP or BDP with frontoparietal predominance, enlarged lat. ventricles, patchy or diffuse white matter changes, thin corpus callosum, cerebellar dysplasia with cysts, brain stem hypopl.

8 GPR56-related bilateral frontoparietal polymicrogyria: further evidence for an overlap with the cobblestone complex. Bahi-Buisson N et al. Brain 2010 Pathological findings in foetus -35 weeks gestation Macroscopic: complete agyria with cobblestone like features; vermian hypoplasia Histology: disorganised cortical layers, with normal, polymicrogyric and cobblestone-like cortex - ectopic neuronal overmigration through the pial membrane - normal corpus callosum and hippocampi - cerebellar hypoplasia; agenesis of vermis - massive neuronal overmigration through in the pons

9 Patients tested: 46 Cardiff experience 2009 to date Abnormal results: 4 (~10%) 1. Male. Unrelated parents from the same village in Turkey. Global DD, seizures (onset age 3.5 y), strabismus, OFC 25 th -50 th cen. 2. Female. Consanguineous parents from Pakistan Global DD, no seizures age 3y, strabismus, OFC 50 th -75 th centile 3. Male: Consanguineous parents from Yemen Moderate DD, no seizures age 3y, strabismus 4. Female. Unrelated European parents Global DD, seizures (onset?), strabismus

10 Conclusions GPR56 mutations are associated with BFPP / BDP with an anterior to posterior severity gradient, and a cobblestone-like cortex usually, associated with white matter +/- cerebellar / brain stem abnormalities Add: severe DD, pseudo-myopathy with normal CK, strabismus, usually normal OFC, seizures GPR56 is expressed in the developing brain with an anterior to posterior gradient in the preplate from by the first born neurons (mouse data) GPR56-collagen III interaction responsible for neuronal migration regulation Failure: Preplate neurons over migrate and pierce pial membrane

Genotype Phenotype Analysis of Human Frontoparietal Polymicrogyria Syndromes

Genotype Phenotype Analysis of Human Frontoparietal Polymicrogyria Syndromes Xianhua Piao, MD, PhD, 1 Bernard S. Chang, MD, 2 Adria Bodell, MS, 2 Katelyn Woods, BS, 1 Bruria BenZeev, MD, 3 Meral Topcu,