Polymicrogyria With Or Without Vascular-Type Ehlers-Danlos Syndrome
A number sign (#) is used with this entry because of evidence that polymicrogyria with or without vascular-type Ehlers-Danlos syndrome (PMGEDSV) is caused by homozygous or compound heterozygous mutation in the COL3A1 gene (120180) on chromosome 2q32.
Heterozygous mutation in the COL3A1 gene causes the vascular type of Ehlers-Danlos syndrome (EDSVASC; 130050), which is an autosomal dominant disorder.
DescriptionPolymicrogyria with or without vascular-type Ehlers-Danlos syndrome is an autosomal recessive disorder with a highly variable phenotype. Although all patients have polymicrogyria and other variable structural brain anomalies on imaging, only some show developmental delay and/or seizures. Similarly, only some patients have connective tissue defects that particularly affect the vascular system and can result in early death (summary by Vandervore et al., 2017).
Clinical FeaturesPlancke et al. (2009) reported an 11-year-old French girl, born of consanguineous parents, who was noted to have mildly delayed motor development (walking at age 30 months) and absence seizures in early childhood. She had normal language development. Brain imaging showed diffuse cortical dysplasia and dilated ventricles. She presented at age 10 with features of EDS, including easy bruising, thin skin with scars, varicose veins, and articular hypermobility. She had a long face with upslanting palpebral fissures, flat philtrum, and thin lips. She died of complications of small bowel occlusion, necrosis, and hemorrhagic bleeding. There was no family history of a similar disorder and the parents were clinically unaffected.
Jorgensen et al. (2015) reported 2 sibs, born of unrelated parents, with a variant of vascular EDS. One died at age 15 years of vascular dissection, including dissection of the thoracic aorta and renal and femoral arteries. He had previously been noted to have clubfoot, crowded teeth, retrognathia, and long and slender fingers. At evaluations at ages 6 and 14 years, his sister had long slender fingers, small joint hypermobility, crowded teeth, prominent eyes, pinched nose, thin upper lip, and translucent skin with visible subcutaneous vessels. She later had exercise-induced connective tissue trauma. Brain imaging in the affected sister showed frontal and parietal polymicrogyria, but she had normal cognitive function and did not have seizures. Brain imaging in the deceased affected brother had not been performed. Family history revealed early death due to cerebral bleeding in the maternal grandfather, and photographs suggested the disorder. The mother of the sibs had subtle features of a connective tissue disorder, including small joint hypermobility, emphysema, aortic elasticity, and thin skin. The father had no clinical manifestations.
Horn et al. (2017) reported a 3-year-old girl (patient 1), born of consanguineous Turkish parents, with clubfoot, joint laxity, long slender fingers, camptodactyly, widely spaced and deep-set eyes, retrognathia, prominent forehead hypotonia, and hyperopia. She had global developmental delay with inability to walk, poor speech, and poor overall growth. At 22 months, she had a spontaneous intracranial hemorrhage and brain imaging also showed frontoparietal cobblestone polymicrogyria, thin corpus callosum, vermian hypoplasia, cerebellar microcysts, pontine hypoplasia, and patchy signal abnormalities of the white matter. Family history was significant for a maternal grandfather who died of an aortic aneurysm, but the parents of the proband were unaffected.
Clinical Variability
Vandervore et al. (2017) reported 2 sibs, born of unrelated parents who originated from the same mountain village in Chechnya, who presented with global developmental delay in infancy. The girl achieved walking at age 4.5 years, had severely impaired intellectual development, and was only able to speak a few words. She developed seizures at age 5. The boy developed seizures at age 26 months, and he was unable to walk or speak at age 3, showing severely delayed intellectual development. He also had strabismus, hypermetropia, impaired ocular pursuit, and central visual impairment. Brain imaging showed cobblestone cortical changes in both patients, as well as abnormal white matter, cerebellar cysts, and brainstem and/or cerebellar vermis hypoplasia. Neither patient had significant connective tissue abnormalities, but the boy had mild hypermobility ankles; there was no family history of connective tissue abnormalities. Genetic analysis identified a homozygous missense mutation in the COL3A1 gene (P49A; 120180.0039) (see MOLECULAR GENETICS). Vandervore et al. (2017) noted that COL3A1 is a ligand for GPR56 (604110), and that the phenotype in these sibs was reminiscent of the phenotype associated with mutations in the GPR56 gene (see BFPP, 606854).
Horn et al. (2017) reported 2 sibs (patients 2 and 3), born of unrelated parents from Chechnya and Ingushetia, who presented in infancy with seizures and later showed delayed motor development with walking at age 2 years and poor speech. The seizures were well-controlled and both were seizure-free at ages 5 and 3. Brain imaging in both patients showed cobblestone microgyria. Neither patient had connective tissue manifestations, except for talipes valgus in one. The parents were clinically unaffected. Genetic analysis identified the same homozygous missense mutation in the COL3A1 gene (P49A) that was identified by Vandervore et al. (2017).
InheritanceThe transmission pattern of PMGEDSV in the family reported by Plancke et al. (2009) was consistent with autosomal recessive inheritance.
Molecular GeneticsIn an 11-year-old French girl, born of consanguineous parents, with PMGEDSV, Plancke et al. (2009) identified a homozygous frameshift mutation in the COL3A1 gene (c.479dupT; 120180.0034). The patient's unaffected parents were each heterozygous for the mutation, suggesting autosomal recessive inheritance. The mutation was shown to result in nonsense-mediated decay. The lack of phenotype in the parents was discussed by Plancke et al. (2009) in light of the study by Schwarze et al. (2001), who reported a severe phenotype resulting from haploinsufficiency for COL3A1 due to truncating mutations. Plancke et al. (2009) noted that heterozygous Col3a1-null mice have no phenotype (Liu et al., 1997), similar to the parents of their French patient. Plancke et al. (2009) also noted that the nonsense-mediated mRNA process is inefficient and, in the cases of Schwarze et al. (2001), could have resulted in the production of a small amount of protein with dominant-negative effects.
In 2 sibs with PMGEDSV, Jorgensen et al. (2015) identified compound heterozygous mutations in the COL3A1 gene: a nonsense mutation (R596X; 120180.0035) and a substitution at a glycine residue (G1284E; 120180.0036). Patient fibroblasts showed a reduced amount of type III procollagen, the chains of which all had an abnormal electrophoretic mobility compared to controls, suggestive of overmodification of the protein possibly resulting from slow folding of the triple helical domain. Fibroblasts from the mother, who was heterozygous for the G1284E variant, showed a small amount of abnormal type III procollagen. The mother had subtle features of the disorder, including small joint hypermobility, aortic elasticity, emphysema, and thin, translucent skin. The father, who was heterozygous for the R596X variant, had no clinical features suggestive of EDS.
In a 3-year-old girl with PMGEDSV, Horn et al. (2017) identified compound heterozygous loss-of-function mutations in the COL3A1 gene (120180.0037 and 120180.0038). Functional studies of the variants and studies of patient cells were not performed, but the variants were predicted to cause nonsense-mediated mRNA decay and an inability to contribute to a triple helix, consistent with a complete loss of function. Each unaffected parent was heterozygous for 1 of the mutations.
In 2 sibs with polymicrogyria without vascular-type Ehlers-Danlos syndrome, who were born of unrelated parents from the same mountain village in Chechnya, Vandervore et al. (2017) identified a homozygous missense mutation in the COL3A1 gene (P49A; 120180.0039). The variant, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant is located in a von Willebrand factor C domain that may mediate interaction with GPR56 (604110) in the N terminus of the pro-COL3A1 chain; this region is usually cleaved from the intact type III collagen domain. Patient fibroblasts showed increased levels of COL3A1 mRNA, but normal amounts of the COL3A1 protein. Immunoprecipitation assays showed no significant differences in the COL3A1 interaction with GPR56, although there was a slight alteration of binding capacity. Vandervore et al. (2017) suggested that there may be tissue-specific effects of the mutation that may result in overstimulation of neuronal migration, or that the mutation may cause altered signaling patterns involved in pial basement membrane assembly.
Horn et al. (2017) identified the same homozygous P49A mutation in 2 sibs, born of unrelated parents from Chechnya and Ingushetia, with polymicrogyria without vascular-type Ehlers-Danlos syndrome. Each unaffected parent was heterozygous for the mutation. Functional studies of the variant and studies of patient cells were not performed, but the variant was classified as pathogenic or likely pathogenic according to ACMG criteria.
Animal ModelJeong et al. (2012) found that Col3a1-null mice had a cobblestone-like cortical malformation with breakdown of the pial basement membrane and marginal zone heterotopias. There was also neuronal overmigration and radial glial detachment. The defects started around embryonic day 11.5. The findings indicated an important role for collagen III in the developing brain.