First pediatric case with primary familial brain calcification due to a novel variant on the MYORG gene and review of the literature

Orgun, Leman Tekin; Beşen, Şeyda; Sangün, Özlem; Bişgin, Atıl; Alkan, Özlem; Erol, İlknur

doi:10.1016/j.braindev.2021.04.002

Cited by 6 publications

(9 citation statements)

References 17 publications

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“…Autosomal recessive-primary familial cerebral calcification (AR-PFBC) is caused by mutations in the MYORG gene, and has an age of onset between 38 and 53 years ( 1 ). The typical indications of AR-PFBC and of the MYORG variant are: verbal deficits, chronic progressive motor deficits, ataxia, cognitive deficits, and psychiatric symptoms ( 8 , 10 , 12 ). Among them, verbal impairment is often the first symptom of PFBC due to a MYORG variant ( 12 , 13 ), while cognitive impairment is usually milder in AR-PFBC than in AD-PFBC and does not lead to major neurocognitive impairment ( 8 , 14 ).…”

Section: Discussionmentioning

confidence: 99%

“…Among them, verbal impairment is often the first symptom of PFBC due to a MYORG variant ( 12 , 13 ), while cognitive impairment is usually milder in AR-PFBC than in AD-PFBC and does not lead to major neurocognitive impairment ( 8 , 14 ). Migraine as the main symptom is rare in AR-PFBC, with only one similar case having been reported in a 12-year-old Turkish girl with AR-PFBC ( 10 ). Cognitive deficits and depression have been documented as the main non-motor symptoms and signs of PFBC; instead headache is less common, and is observed in ~8% of cases ( 1 ).…”

Section: Discussionmentioning

confidence: 99%

“…By analyzing this information, we found that patients with dysphagia, verbal impairment, cognitive impairment, and dyskinesia as primary symptoms were mainly middle-aged and elderly ( 14 – 18 ). Conversely, patients with headache as the main clinical symptom are generally younger ( 10 , 19 ). Therefore, we hypothesize that earlier age of onset is associated with increased risk of headache and migraine, and that other corresponding symptoms may then develop with age.…”

Section: Discussionmentioning

confidence: 99%

“…The myogenesis-regulated glycosidase ( MYORG ) gene was first identified in 2018 ( 8 ). The typical indications of AR-PFBC are chronic progressive motor impairment, cognitive impairment, dysarthria, and cerebellar symptoms, whereas migraine presentation is rare ( 8 – 10 ). Here we report the case of a 24-year-old woman with AR-PFBC and migraine onset at the age of 16 years harboring MYORG compound heterozygous variants, one of which has not been previously reported.…”

Section: Introductionmentioning

confidence: 99%

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A novel MYORG mutation causes primary familial brain calcification with migraine: Case report and literature review

Song

Zhao

Wen³

et al. 2023

Front. Neurol.

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Primary familial brain calcification (PFBC) is a disorder in which pathologic calcification of the basal ganglia, cerebellum, or other brain regions with bilateral symmetry occurs. Common clinical symptoms include dysarthria, cerebellar symptoms, motor deficits, and cognitive impairment. Genetic factors are an important cause of the disease; however autosomal recessive (AR) inheritance is rare. In 2018, the myogenesis-regulated glycosidase (MYORG) gene was the first to be associated with AR-PFBC. The present case is a 24-year-old woman with AR-PFBC that presented with migraine at the age of 16 years. Symmetrical patchy calcifications were seen in the bilateral cerebellopontine nuclei, thalamus, basal ganglia, and radiocoronal area on computed tomography and magnetic resonance imaging. AR-PFBC with migraine as the main clinical symptom is rare. Whole-exome sequencing revealed a compound heterozygous mutation in the MYORG gene, one of which has not been previously reported. Our case highlights the pathogenic profile of the MYORG gene, and demonstrates the need for exclusion of calcium deposits in the brain for migraine patients with AR inheritance.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

A novel MYORG mutation causes primary familial brain calcification with migraine: Case report and literature review

Song

Zhao

Wen³

et al. 2023

Front. Neurol.

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“…Among the 46 known disease-associated MYORG mutations, 22 are missense mutations and these can be found widely distributed throughout its GH31 domain. That such mutations, some of which are quite conservative, such as G286S and I656T, give rise to PFBC is reminiscent of the lysosomal storage diseases, where many missense mutations have been found that impair protein maturation and proper trafficking to lysosomes [ 38 , 39 ]. Notable in this regard is that active site ligands that bind to lysosomal enzymes [ 40 ] stabilise these proteins and facilitate their proper folding and trafficking to lysosomes.…”

Section: Discussionmentioning

confidence: 99%

The primary familial brain calcification-associated protein MYORG is an α-galactosidase with restricted substrate specificity

et al. 2022

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Primary familial brain calcification (PFBC) is characterised by abnormal deposits of calcium phosphate within various regions of the brain that are associated with severe cognitive impairments, psychiatric conditions, and movement disorders. Recent studies in diverse populations have shown a link between mutations in myogenesis-regulating glycosidase (MYORG) and the development of this disease. MYORG is a member of glycoside hydrolase (GH) family 31 (GH31) and, like the other mammalian GH31 enzyme α-glucosidase II, this enzyme is found in the lumen of the endoplasmic reticulum (ER). Though presumed to act as an α-glucosidase due to its localization and sequence relatedness to α-glucosidase II, MYORG has never been shown to exhibit catalytic activity. Here, we show that MYORG is an α-galactosidase and present the high-resolution crystal structure of MYORG in complex with substrate and inhibitor. Using these structures, we map detrimental mutations that are associated with MYORG-associated brain calcification and define how these mutations may drive disease progression through loss of enzymatic activity. Finally, we also detail the thermal stabilisation of MYORG afforded by a clinically approved small molecule ligand, opening the possibility of using pharmacological chaperones to enhance the activity of mutant forms of MYORG.

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Fahr's disease linked to a novel mutation in MYORG variants manifesting as paroxysmal limb stiffness and dysarthria: Case report and literature review

Zhao,

Xu,

Liu

et al. 2023

Molec Gen & Gen Med

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BackgroundPrimary familial brain calcification (PFBC) is a rare hereditary neurodegenerative disorder associated with the MYORG gene; however, the clinical and radiological characteristics of MYORG‐PFBC remain unclear.MethodsWe present relevant medical data obtained from a patient affected by PFBC with a novel MYORG variant and conducted a mutational analysis of MYORG in her family members. We reviewed all reported PFBC cases with biallelic MYORG mutations until April 1, 2023, and summarized the associated clinical and radiological features and mutation sites.ResultsThe patient (22‐year‐old woman) exhibited paroxysmal limb stiffness and dysarthria for 3 years. Computed tomography revealed calcifications in the paraventricular white matter, basal ganglia, thalamus, and cerebellum. Whole‐exome sequencing revealed a novel homozygous frameshift variant (c.743delG: p.G248Afs*32) in exon 2 of the MYORG gene (NM_020702.5). To date, 62 families and 64 mutation sites have been reported. Among the reported biallelic MYORG mutations, 57% were homozygous and 43% were compound heterozygous. Individuals with biallelic MYORG mutations experience more severe brain calcification with approximately 100% clinical penetrance. Ten single heterozygous mutation sites are associated with significant brain calcifications.ConclusionAll patients with primary brain calcification, particularly younger patients without a family history of the disease, should be screened for MYORG mutations.

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First pediatric case with primary familial brain calcification due to a novel variant on the MYORG gene and review of the literature

Cited by 6 publications

References 17 publications

A novel MYORG mutation causes primary familial brain calcification with migraine: Case report and literature review

A novel MYORG mutation causes primary familial brain calcification with migraine: Case report and literature review

The primary familial brain calcification-associated protein MYORG is an α-galactosidase with restricted substrate specificity

Fahr's disease linked to a novel mutation in MYORG variants manifesting as paroxysmal limb stiffness and dysarthria: Case report and literature review

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