Primary brain calcification due to a homozygous MYORG mutation causing isolated paroxysmal kinesigenic dyskinesia

Sir, Mutations in the PRRT2 gene are the most common definable cause of paroxysmal kinesigenic dyskinesia (PKD) (Chen et al., 2011; Ebrahimi-Fakhari et al., 2015). Rarely, there are acquired causes of PKD, which include diffuse brain calcification (Erro and Bhatia, 2018). Primary familial brain calcification (PFBC), previously known as idiopathic basal ganglia calcification (IBGC) or Fahr’s disease, is a genetic disorder characterized by calcium deposits in multiple areas of the brain, which can present with neuropsychiatric symptoms, cognitive dysfunction or a variety of movement disorders (Westenberger et al., 2019). At present, pathogenic variants in six genes are known to cause PFBC: SLC20A2, PDGFB, PDGFRB, XPR1, MYORG, and JAM2 (Wang et al., 2012; Keller et al., 2013; Nicolas et al., 2013; Legati et al., 2015; Yao et al., 2018; Cen et al., 2020). All these PFBC forms but the last two are inherited in an autosomal dominant pattern. Grangeon et al. (2019) extensively studied the clinical and radiological features of six pathogenic and 11 likely pathogenic biallelic variants in MYORG, one of which is rs536187898; c.1831C>T; p.Arg611Trp that was found to be pathogenic in the compound heterozygous state. The same variant in the heterozygous state was also found in a patient in a recently reported cohort (Chen et al., 2020). We describe here a patient homozygous for this MYORG variant presenting only with PKD associated with PFBC. Our data complement recent findings, and further expand the phenotypic spectrum of MYORG-associated PFBC. A 26-year-old female patient from Canada was born to healthy non-consanguineous parents who come from different provinces of China. Her birth, perinatal and developmental histories were unremarkable. At 8 years of age, she began to have periodic involuntary posturing of her limbs, most notably in the left leg. The attacks lasted for a few seconds only and were almost always triggered by sudden or increased pace of movements (Supplementary Video 1). These were never associated with pain, loss of consciousness, upward rolling of the eyes, urinary incontinence, or post-ictal confusion. The paroxysmal events became more frequent in her teenage years with a maximum of 10 attacks in a day. Paroxysms could also be triggered by extended hyperventilation. Interictally, she has been asymptomatic and general physical and neurological examinations, including stature and cognitive function, were normal. She has had two full-term pregnancies and two miscarriages; in two of her pregnancies, the placentae were reportedly noted to have widespread calcification. During her pregnancies, regardless of the outcome, she reported a complete absence of attacks. To date, she has declined symptomatic treatment because her attacks were only mild and non-disabling, and she was concerned about the possible teratogenic effects of the medication should she conceive again. The patient has had extensive negative genetic and metabolic work-up including testing for PRRT2 mutations. Secondary causes of PKD were also investigated including (i) metabolic; (ii) immune; and (iii) structural causes. Pseudopseudohypoparathyroidism (Albright’s hereditary osteodystrophy) was initially suspected because of a possible shortened fourth metacarpal bone on X-ray. However, calcium, phosphate, and parathyroid hormone levels were normal, and testing for the genes known to cause pseudopseudohypoparathyroidism, GNAS and STX16, were unremarkable. Immune causes were considered because of the recurrent miscarriages. Her antinuclear antibody level has always been normal. Lupus anticoagulant has been persistently mildly elevated but she has never met the criteria for systemic lupus erythematosus or antiphospholipid antibody syndrome. Neuroimaging showed florid symmetrical bilateral calcifications involving the cerebellum, basal ganglia, thalamus, midbrain and the frontal and occipital cortical and subcortical areas (Fig. 1). Screening cranial CT of the patient’s father and sister were unremarkable. Clinically, her parents and her sister are not known to have any neurological symptoms. Initial genetic testing for SLC20A2, XPR1, PDGFB, and PDGFRB were negative. Subsequent sequencing of the MYORG gene revealed that the patient was homozygous for a missense variant (rs536187898; c.1831C>T; p.Arg611Trp). Targeted sequencing of the mutated region in the patient’s parents confirmed their heterozygous carrier state while the patient’s sister does not carry this change at all (Fig. 2). Neuroimaging findings. Cranial CT showing florid symmetrical bilateral calcifications in the cerebellum (A), midbrain (B), thalamus (C), basal ganglia (B and C), and in the frontal and occipital cortical and subcortical areas (C and D). Cranial MRI (gradient echo sequence) showed hypointensities in the cerebellum (E), thalamus and basal ganglia (F). Sagittal T1-weighted sequence showed normal cerebellar volume (G). Pedigree of the patient’s family. The index patient (II-1) is marked by an arrow. Black symbols indicate bilateral calcifications in combination with PKD. White symbols indicate no disease phenotype. Wild-type allele of MYORG is depicted by the minus sign and rs536187898; c.1831C>T; p.Arg611Trp by the plus symbol. The results of our study further support the pathogenicity of the c.1831C>T; p.Arg611Trp missense mutation, but in the homozygous state. The patient’s father, who is a heterozygous carrier, does not have brain calcification. To date, 44 heterozygous carriers from 15 families of different MYORG mutations have shown heterogeneous neuroimaging findings (Chen et al., 2020). Among those with available neuroimaging findings, 26 have unremarkable cranial CT findings, four have punctate calcification limited to the lentiform nuclei, while three have diffuse calcification. All heterozygous carriers are reported to be healthy, except for one with very mild postural tremor, and one with depression and cognitive impairment. The presence of calcification among heterozygous carriers of MYORG mutations is thought to be related to a dosage effect (Chen et al., 2020). Concerning the phenotype, our patient’s presentation is interesting in that her only symptom is PKD, without the other known common symptoms of PFBC. This is quite different from the phenotype of the patient reported with the same MYORG variant (as part of a compound heterozygous state) who presented with dysarthria, cerebellar dysfunction, pyramidal signs, akinetic-rigid syndrome, and tremor (Grangeon et al., 2019). In addition, our patient does not fulfill the full triad reported as highly specific for MYORG mutation as she only has extensive brain calcification, but not profound motor symptoms, and cerebellar atrophy (Nicolas et al., 2019). Our patient, currently 36 years old with isolated PKD, demonstrates the mildest phenotype of all published cases of MYORG with PFBC. Further, the onset in childhood, the relative increased frequency in her teenage years, and the lack of attacks during pregnancy are also worth noting as these are more characteristic of primary PKD (Bruno et al., 2004; Fabbri et al., 2013). To our knowledge, this patient has the earliest age at onset among all known cases of MYORG mutations, with 52 years as the median age at onset in the largest published cohort (range: 21–62) (Grangeon et al., 2019). PFBC cases presenting with isolated PKD or PKD as the main phenotype are rare (Chen et al., 2013; Yamada et al., 2014; Zhu et al., 2014; Takeuchi et al., 2016; Wang et al., 2017; Ramos et al., 2018; Zhan et al., 2020). Among all reported cases, mutations in SLC20A2, PDGFB, and PDGFRB have been described (Supplementary Table 1). In comparison, our patient has the youngest age at onset and is the only, to date, with a confirmed MYORG mutation. Further studies are also needed to establish the role of MYORG with regards to coagulation and microvascular integrity in other organs, as this may also be the cause of her recurrent miscarriages. Interestingly, in two of her pregnancies, the placentae were noted to have widespread calcification. Mutations in SLC20A2 and PDGFB are known to cause placental calcification due to impaired pericyte organization (Bjarnegård et al., 2004; Wallingford et al., 2016; Zarb et al., 2019). MYORG expression in animal models, however, was only seen in astrocytes and not in pericytes and other endothelial cells (Yao et al., 2018). In summary, this report highlights a patient with a homozygous pathogenic missense variant in the MYORG gene as the probable cause of primary brain calcification presenting with PKD. Our study expands the phenotypic spectrum of MYORG-associated PFBC and further demonstrates heterogeneity of the neuroimaging findings among heterozygous carriers of MYORG mutations. The data that support the findings of this study are available from the corresponding author, upon reasonable request. The authors would like to thank the patient and her family for their cooperation, Ms Patricia Williams for helping in the collection of blood samples and to Dr Jessalyn Nicole for her cooperation. This study was supported in part by the Parkinson’s Foundation through its support of the fellowship training of G.S. C.K. and A.W. are supported by the German Research Fondation (DFG FOR 2488). The authors report no competing interests.

Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.