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.

Keywords: Complement 1; Ehlers–Danlos; Leukoencephalopathy; Periodontitis; Small vessel disease.

Fig. 1

Pedigrees of the families described in this study. Above each pedigree, the C1R genotype in the affected individuals is specified on nucleotide and predicted protein levels. The whole pedigree of family B has been published elsewhere; identification codes are identical with Kapferer-Seebacher et al. [1]. The arrows indicate the individuals who were available for neurological examination. All indicated individuals were investigated by MRI and had brain white matter abnormalities, except individual A:III-1 at age 7 years

Fig. 2

Pretibial discolorations in family A. Pretibial hemosiderotic plaques have been discribed in 83% of individuals affected with periodontal EDS (Kapferer-Seebacher et al. [1]). Photographs of shins (a) individual A-II-1, (b) individual A-III-2, and (c) individual A-III-1. No pretibial plaques were present in family B

Fig. 3

Oral features. a Intraoral radiograph of individual B:IV-10 at age 32 years. Notice severe periodontal bone loss in the lower jaw, especially teeth no. 44, 45, and 34, 35. b Intraoral photographs at age 34 years. Teeth no. 34 to 36 have been lost. Severe gingival recession (exposed tooth roots) and lack of attached gingiva with mucosa extending to the gingival margins is specific for periodontal EDS

Fig. 4

MRI. a Family A, (a–f) individual A:II-1 at age 57 years; (g, h) individual A:III-2 at age 31 years. The FLAIR (a, d) and T2-weighted (b, c) images in the older patient show virtually diffuse cerebral white matter signal abnormalities, including also the external and extreme capsules (c) and the anterior temporal white matter (d). Lacunar infarcts are seen in the head of the caudate nucleus on the left (arrow in b), left putamen (arrow in c), and pons (arrow in d). Numerous small areas of abnormal signal are seen in the basal ganglia and thalami (c) and the pons (d). Gradient echo images show microbleeds in the basal nuclei and dentate nucleus (arrows in e and f). The FLAIR (g, h) images in the younger patient show a thin periventricular rim as well as a few larger areas of abnormal signal in the deep cerebral white matter. b Family B, (a–d) individual B:III-10 at age 68 years (e, f); individual B:III-2 at age 56 years and (g, h) individual B:IV-10 at 43 years. In the oldest patient, the T2-weighted images show extensive and confluent periventricular and deep cerebral white matter abnormalities (a–d), as well as numerous enlarged perivascular spaces in the white matter (a–c) and basal nuclei (d). There is a mild generalized atrophy. The FLAIR images in the younger patients (e–h) show a thin periventricular rim as well as multifocal small and lager larger areas of abnormal signal in the deep cerebral white matter