Periodontal Ehlers–Danlos syndrome is associated with leukoencephalopathy

Abstract

Here, we report brain white matter alterations in individuals clinically and genetically diagnosed with periodontal Ehlers–Danlos syndrome, a rare disease characterized by premature loss of teeth and connective tissue abnormalities. Eight individuals of two families clinically diagnosed with periodontal Ehlers–Danlos syndrome were included in the present study and underwent general physical, dental, and neurological examination. Whole exome sequencing was performed, and all patients included in the study underwent MRI of the brain. Whole exome sequencing revealed heterozygous C1R mutations c.926G>T (p.Cys309Phe, Family A) and c.149_150TC>AT (p.Val50Asp, Family B). All adult individuals (n = 7; age range 31 to 68 years) investigated by MRI had brain white matter abnormalities. The MRI of one investigated child aged 8 years was normal. The MRI pattern was suggestive of an underlying small vessel disease that is progressive with age. As observed in other leukoencephalopathies related to microangiopathies, the extent of the white matter changes was disproportionate to the neurologic features. Medical history revealed recurrent headaches or depression in some cases. Neurological examination was unremarkable in all individuals but one had mild cognitive decline and ataxia and experienced a seizure. The observation that periodontal Ehlers–Danlos syndrome caused by missense mutations in C1R is consistently associated with a leukoencephalopathy opens a new pathogenic link between the classical complement pathway, connective tissue, brain small vessels, and brain white matter abnormalities.

C1R Mutations Trigger Constitutive Complement 1 Activation in Periodontal Ehlers-Danlos Syndrome

“…A total of 16 different C1R variants from two publications (4, 16) were investigated, including one previously unpublished variant c.277G>T (p.G93C) identified in a family from Australia (Table 2). All variants are predicted to be pathogenic, and none of the variants has been found in registered control populations [ExAc database http://exac.broadinstitute.org/ (17), last accessed September 26, 2019].…”

Weighted burden analysis of exome‐sequenced late‐onset Alzheimer's cases and controls provides further evidence for a role for PSEN1 and suggests involvement of the PI3K/Akt/GSK‐3β and WNT signalling pathways

“…Heterozygous missense variants in C1R are a known cause of periodontal Ehlers–Danlos syndrome (pEDS) (Kapferer‐Seebacher et al., ) and this is potentially of interest for two reasons. One is that a recent MRI study of seven adults with pEDS and C1R mutations reported that they all had leukoencephalopathy, which appeared to be progressive with age and which was suggestive of underlying small vessel disease (Kapferer‐Seebacher et al., ). The second is that pEDS is characterised by periodontitis and it has been proposed that periodontal disease is a risk factor for LOAD, perhaps mediated either by direct infection of the brain with the key periodontal pathogen Porphyromonas gingivalis or through secondary effects of chronic inflammation, perhaps involving activation of the complement cascade (Singhrao, Harding, Poole, Kesavalu, & Crean, ).…”

Weighted burden analysis of exome-sequenced late onset Alzheimer’s cases and controls provides further evidence for a role for PSEN1 and suggests involvement of the PI3K/Akt/GSK-3β and WNT signalling pathways

“…Heterozygous missense variants in C1R are a known cause of periodontal Ehlers-Danlos syndrome (pEDS) (Kapferer-Seebacher et al, 2016) and this is potentially of interest for two reasons. One is that a recent MRI study of seven adults with pEDS and C1R mutations reported that they all had leukoencephalopathy, which appeared to be progressive with age and which was suggestive of underlying small vessel disease (Kapferer-Seebacher et al, 2019). The second is that pEDS is characterised by periodontitis and it has been proposed that periodontal disease is a risk factor for LOAD, perhaps mediated either by direct infection of brain with the key periodontal pathogen Porphyromonas gingivalis or through secondary effects of chronic inflammation, perhaps involving activation of the complement cascade (Singhrao et al, 2015).…”