Biallelic MYORG mutation carriers exhibit primary brain calcification with a distinct phenotype

Lou Grangeon (1, 2) , David Wallon (3, 2) , Camille Charbonnier (2) , Olivier Quenez (2) , Anne-Claire Richard (2) , Stéphane Rousseau (2) , Clara Budowski (2) , Thibaud Lebouvier (4) , Anne-Gaëlle Corbillé (5) , Marie Vidailhet (6) , Aurélie Méneret (6) , Emmanuel Roze (6) , Mathieu Anheim (7, 8) , Christine Tranchant (7, 8) , Pascal Favrole (9) , Jean-Christophe Antoine (10) , Luc Defebvre (4) , Xavier Ayrignac (11) , Pierre Labauge (2) , Jérémie Pariente (12) , Michel Clanet (13) , David Maltête (14) , Anne Rovelet-Lecrux (14) , Anne Boland (15) , Jean-François Deleuze (16) , Thierry Frebourg (2) , Didier Hannequin (17, 2) , Dominique Campion (18, 2) , Gaël Nicolas (1, 2)

1 UNIROUEN UFR Santé - UNIROUEN - UFR Santé
2 GPMCND - Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques
3 CHU Rouen
4 Département de neurologie [Lille]
5 Service de neurologie [Nantes]
6 ICM - Institut du Cerveau = Paris Brain Institute
7 FMTS - Fédération de Médecine Translationnelle de Strasbourg
8 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
9 Service de Neurologie [Aix-en-Provence]
10 Service de Neurologie [CHU de Saint-Étienne]
11 Département de neurologie [Montpellier]
12 Neurologie Vasculaire [Toulouse]
13 CHU Toulouse - Centre Hospitalier Universitaire de Toulouse
14 DC2N - Différenciation et communication neuronale et neuroendocrine
15 JACOB - Institut de Biologie François JACOB
16 CNG - Centre National de Génotypage
17 Service de neurologie [Rouen]
18 Service de neurologie [Rouen]

Primary familial brain calcification (PFBC) is a rare neurogenetic disorder with diverse neuropsychiatric expression. Mutations in four genes cause autosomal dominant PFBC: SLC20A2, XPR1, PDGFB and PDGFRB. Recently, biallelic mutations in the MYORG gene have been reported to cause PFBC with an autosomal recessive pattern of inheritance. We screened MYORG in 29 unrelated probands negatively screened for the autosomal dominant PFBC genes and identified 11 families with a biallelic rare or novel predicted damaging variant. We studied the clinical and radiological features of 16 patients of these 11 families and compared them to that of 102 autosomal dominant PFBC patients carrying a mutation in one of the four known autosomal dominant PFBC genes. We found that MYORG patients exhibited a high clinical penetrance with a median age of onset of 52 years (range: 21–62) with motor impairment at the forefront. In particular, dysarthria was the presenting sign in 11/16 patients. In contrast to patients with autosomal dominant PFBC, 12/15 (80%) symptomatic patients eventually presented at least four of the following five symptoms: dysarthria, cerebellar syndrome, gait disorder of any origin, akinetic-hypertonic syndrome and pyramidal signs. In addition to the most severe clinical pattern, MYORG patients exhibited the most severe pattern of calcifications as compared to the patients from the four autosomal dominant PFBC gene categories. Strikingly, 12/15 presented with brainstem calcifications in addition to extensive calcifications in other brain areas (lenticular nuclei, thalamus, cerebellar hemispheres, vermis, ±cortex). Among them, eight patients exhibited pontine calcifications, which were observed in none of the autosomal dominant PFBC patients and hence appeared to be highly specific. Finally, all patients exhibited cerebellar atrophy with diverse degrees of severity on CT scans. We confirmed the existence of cerebellar atrophy by performing MRI voxel-based morphometry analyses of MYORG patients with autosomal dominant PFBC mutation carriers as a comparison group. Of note, in three families, the father carried small pallido-dentate calcifications while carrying the mutation at the heterozygous state, suggesting a putative phenotypic expression in some heterozygous carriers. In conclusion, we confirm that MYORG is a novel major PFBC causative gene and that the phenotype associated with such mutations may be recognized based on pedigree, clinical and radiological features.

Domains: Life Sciences [q-bio]

Lou Grangeon, David Wallon, Camille Charbonnier, Olivier Quenez, Anne-Claire Richard, et al.. Biallelic MYORG mutation carriers exhibit primary brain calcification with a distinct phenotype. Brain - A Journal of Neurology , 2019, 142 (6), pp.1573-1586. ⟨10.1093/brain/awz095⟩. ⟨hal-02538301⟩