Origin and evolution of pentanucleotide repeat expansions at the familial cortical myoclonic tremor with epilepsy type1 - SAMD12 locus.

Familial cortical myoclonic tremor with epilepsy type 1 (FCMTE1) is caused by (TTTTA)exp(TTTCA)exp repeat expansions in SAMD12, while pure (TTTTA)exp is polymorphic. Our investigation focused on the origin and evolution of pure (TTTTA)exp and (TTTTA)exp(TTTCA)exp at this locus. We observed a founder effect between them. The phylogenetic analysis suggested that the (TTTTA)exp(TTTCA)exp might be generated from pure (TTTTA)exp through infrequent transformation events. Long-read sequencing revealed somatic generation of (TTTTA)exp(TTTCA)exp from pure (TTTTA)exp, likely via long segment (TTTCA) repeats insertion. Our findings indicate close relationships between the non-pathogenic (TTTTA)exp and the pathogenic (TTTTA)exp(TTTCA)exp, with dynamic interconversions. This sheds light on the genesis of pathogenic repeat expansions from ancestral premutation alleles. Our results may guide future studies in detecting novel repeat expansion disorders and elucidating repeat expansion mutational processes, thereby enhancing our understanding of human genomic variation.

A novel ATP13A2 variant causing complicated hereditary spastic paraplegia.

BACKGROUND: ATP13A2 is a monogenic causative gene of Parkinson's disease, whose biallelic mutations can result in Kufor-Rakeb syndrome. Biallelic mutations in ATP13A2 have also been reported in pure or complicated hereditary spastic paraplegia (HSP). Here, we report clinical, neuroimaging, and genetic findings from a patient with a novel homozygous mutation in ATP13A2 presenting with HSP plus parkinsonism. METHODS: Whole genome sequencing was performed on the patient, a 46-year-old Chinese woman from a consanguineous family, to identify the genetic cause. Furthermore, functional studies of the identified ATP13A2 mutation were conducted. RESULTS: The patient initially presented with abnormal gait because of lower-limb spasticity and recurrent seizures. Parkinsonism (presenting as bradykinesia and rigidity) and peripheral neuropathy in lower limbs further evolved and resulted in her eventual use of a wheelchair. Symmetrically decreased dopamine transporter density was detected within the bilateral putamen and caudate nucleus in dopamine transporter-positron emission tomography. Genetic analysis revealed a novel homozygous missense mutation in ATP13A2 (c.2780 T > C, p.Leu927Pro), which was heterozygous in the patient's parents and son. Functional studies suggested that this mutation results in the reduced expression and altered subcellular localization of ATP13A2. CONCLUSIONS: Our report broadens the genetic and phenotypic spectrum of ATP13A2-related HSP. Further research is needed to fully elucidate the mechanism linking ATP13A2 variants to HSP.

Seizures and electrophysiological features in familial cortical myoclonic tremor with epilepsy 1.

OBJECTIVES: To investigate and characterize epileptic seizures and electrophysiological features of familial cortical myoclonic tremor with epilepsy (FCMTE) type 1 patients in a large Chinese cohort. METHODS: We systematically evaluated 125 FCMTEtype 1 patients carrying the pentanucleotide (TTTCA) repeat expansion in the SAMD12 gene in China. RESULTS: Among the 28 probands, epileptic seizures (96.4%, 27/28) were the most common reason for an initial clinic visit. Ninety-seven (77.6%, 97/125) patients had experienced seizures. The seizures onset age was 36.5 ± 9.0 years, which was 6.9 years later than cortical tremors. The seizures were largely rare (<1/year, 58.8%) and occasional (1-6/year, 37.1%). Prolonged prodromes were reported in 57.7% (56/97). Thirty-one patients (24.8%, 31/125) reported photosensitivity history, and 79.5% (31/39) had a photoparoxysmal response. Interictal epileptiform discharges (IEDs) were recorded in 69.1% (56/81) of patients. Thirty-three patients showed generalized IEDs and 72.7% (24/33) were occipitally dominant, while 23 patients presented with focal IEDs with 65.2% (15/23) taking place over the occipital lobe. Overnight EEG of FCMTE patients displayed paradoxical sleep-wake fluctuation, with a higher average IED index of 0.82 ± 0.88/min during wakefulness and a lower IED index of 0.04 ± 0.06/min during non-rapid eye movement sleep stages I-II. INTERPRETATION: FCMTE type 1 has a benign course of epilepsy and distinct clinical and electrophysiological features. In addition to a positive family history and cortical myoclonus tremor, the seizure prodromes, specific seizure triggers, photosensitivity, distribution of IEDs, and unique fluctuations during sleep-wake cycle are cues for proper genetic testing and an early diagnosis of FCMTE.

Retinal Thinning as a Marker of Disease Severity in Progressive Supranuclear Palsy.

OBJECTIVE: Progressive supranuclear palsy (PSP) involves a variety of visual symptoms that are thought to be partially caused by structural abnormalities of the retina. However, the relationship between retinal structural changes, disease severity, and intracranial alterations remains unknown. We investigated distinct retinal thinning patterns and their relationship with clinical severity and intracranial alterations in a PSP cohort. METHODS: We enrolled 19 patients with PSP (38 eyes) and 20 age-matched healthy controls (40 eyes). All of the participants underwent peripapillary and macular optical coherence tomography. Brain 11C-2ß-carbomethoxy-3ß-(4-fluorophenyl) tropane (11C-CFT) and 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography imaging were also performed in patients with PSP. We investigated the association between retinal thickness changes and clinical features, striatal dopamine transporter availability, and cerebral glucose metabolism. RESULTS: The peripapillary retinal nerve fiber layer (pRNFL) and macula were significantly thinner in patients with PSP than in controls. The thickness of the superior sector of the pRNFL demonstrated a significant negative relationship with the Movement Disorder Society-Unified Parkinson's Disease Rating Scale part III and Hoehn and Yahr staging scale scores. A significant negative correlation was found between outer inferior macular thickness and disease duration. Outer temporal macular thickness was positively correlated with Montreal Cognitive Assessment scores. In PSP, lower outer temporal macular thickness was also positively correlated with decreased dopamine transporter binding in the caudate. CONCLUSION: The pRNFL and macular thinning may be candidate markers for monitoring disease severity. Additionally, macular thinning may be an in vivo indicator of nigrostriatal dopaminergic cell degeneration in PSP patients.

Generation of an induced pluripotent stem cell line (ZJUi013-A) from a Familial cortical myoclonic tremor with epilepsy type 1 patient carrying (TTTCA)n insertion in the SAMD12 gene.

FCMTE1 is an autosomal dominant inherited neurodegenerative disorder characterized by myoclonic tremors and epilepsy. The cause of FCMTE1 is an abnormal (TTTCA)n insertion in intron 4 of SAMD12 gene. Fibroblasts obtained from a FCMTE1 patient were successfully transformed into induced pluripotent stem cells (iPSCs) (ZJUi013-A) using the Sendai virus. Our approach provided a resource for further pathogenesis study and drug screening of FCMTE1.

A Three-Dimensional Finger-Tapping Framework for Recognition of Patients With Mild Parkinson's Disease.

The finger tapping test is a widely-used and important examination in the Movement Disorder Society Clinical Diagnosis for Parkinson's Disease. However, finger tapping motion could be affected by age, medication, and other conditions. As a result, Parkinson's disease patients with mild sign and healthy people could be rated as similar scores on the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale, making it difficult for community doctors to perform diagnosis. We therefore propose a three-dimensional finger tapping framework to recognize mild PD patients. Specifically, we first derive the three-dimensional finger-tapping motion using a self-designed three-dimensional finger-tapping measurement system. We then propose a three-dimensional finger-tapping segmentation algorithm to segment three-dimensional finger tapping motion. We next extract three-dimensional pattern features of motor coordination, imbalance impairment, and entropy. We finally adopted the support vector machine as the classifier to recognize PD patients. We evaluated the proposed framework on 49 PD patients and 29 healthy controls and reached an accuracy of 94.9% for the right hand and 89.4% for the left hand. Moreover, the proposed framework reached an accuracy of 95.0% for the right hand and 97.8% for the left hand on 17 mild PD patients and 28 healthy controls who were both rated as 0 or 1 on the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale. The results demonstrated that the proposed framework was less sensitive to traditional features and performed well in recognizing mild PD patients by involving three-dimensional patter features.

Loss of function of CMPK2 causes mitochondria deficiency and brain calcification.

Brain calcification is a critical aging-associated pathology and can cause multifaceted neurological symptoms. Cerebral phosphate homeostasis dysregulation, blood-brain barrier defects, and immune dysregulation have been implicated as major pathological processes in familial brain calcification (FBC). Here, we analyzed two brain calcification families and identified calcification co-segregated biallelic variants in the CMPK2 gene that disrupt mitochondrial functions. Transcriptome analysis of peripheral blood mononuclear cells (PBMCs) isolated from these patients showed impaired mitochondria-associated metabolism pathways. In situ hybridization and single-cell RNA sequencing revealed robust Cmpk2 expression in neurons and vascular endothelial cells (vECs), two cell types with high energy expenditure in the brain. The neurons in Cmpk2-knockout (KO) mice have fewer mitochondrial DNA copies, down-regulated mitochondrial proteins, reduced ATP production, and elevated intracellular inorganic phosphate (Pi) level, recapitulating the mitochondrial dysfunction observed in the PBMCs isolated from the FBC patients. Morphologically, the cristae architecture of the Cmpk2-KO murine neurons was also impaired. Notably, calcification developed in a progressive manner in the homozygous Cmpk2-KO mice thalamus region as well as in the Cmpk2-knock-in mice bearing the patient mutation, thus phenocopying the calcification pathology observed in the patients. Together, our study identifies biallelic variants of CMPK2 as novel genetic factors for FBC; and demonstrates how CMPK2 deficiency alters mitochondrial structures and functions, thereby highlighting the mitochondria dysregulation as a critical pathogenic mechanism underlying brain calcification.

Aberrant visual-related networks in familial cortical myoclonic tremor with epilepsy.

INTRODUCTION: In familial cortical myoclonic tremor with epilepsy, photic stimulation can trigger visual symptoms and induce a photoparoxysmal response, or photosensitivity, on electroencephalography. However, the mechanism is poorly understood. In this study, we aimed to explore the neuroimaging changes related to visual symptoms and photosensitivity in genetically confirmed familial cortical myoclonic tremor with epilepsy type 1. METHODS: Resting-state functional magnetic resonance imaging and electroencephalography data were collected from 31 patients carrying the heterozygous pathogenic intronic pentanucleotide (TTTCA)n insertion in the sterile alpha motif domain-containing 12 gene and from 52 age- and sex-matched healthy controls. RESULTS: (1) Both regional homogeneity and degree centrality values in the bilateral calcarine sulcus were significantly increased in patients compared with healthy controls. (2) When the calcarine sulcus area with increased regional homogeneity was taken as a seed, increased functional connectivity values were observed in the right precentral gyrus, while decreased functional connectivity values were observed in the right superior frontal gyrus and right inferior parietal lobule. (3) Independent component analysis showed increased connectivity in the left calcarine sulcus inside the medial visual network. (4) Correlation analysis revealed a significant positive correlation between regional homogeneity values and frequency of seizure, and photoparoxysmal response grades were positively correlated with the severity of cortical tremor and duration of epilepsy. CONCLUSION: These findings provide strong evidence for the interpretation of visual symptoms and photosensitivity in familial cortical myoclonic tremor with epilepsy. We speculate that functional changes in the primary visual cortex may be an imaging biomarker for the disease.

White matter alterations in familial cortical myoclonic tremor with epilepsy type 1.

OBJECTIVE: Although previous imaging studies have reported cerebellar gray matter loss in patients with familial cortical myoclonic tremor with epilepsy (FCMTE), the corresponding white matter alterations remain unknown. We investigated white matter structural changes in FCMTE1 and compared them with clinical and electrophysiological features. METHODS: We enrolled 36 patients carrying heterozygous pathogenic intronic pentanucleotide insertions in the SAMD12 gene and 52 age- and sex-matched healthy controls. Diffusion tensor imaging-derived metrics, including fractional anisotropy, mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD), were calculated along with white matter voxel-based morphometry (VBM) analysis. We also examined correlations between magnetic resonance metrics and clinical and electrophysiological features. RESULTS: We detected widespread white matter reductions in MD, RD, and AD values in FCMTE1 patients, including in the commissural, projection, and association fibers. VBM analysis revealed that increases in white matter volume predominantly occurred in the right cerebellum and sagittal stratum. MD, RD, AD, and VBM analysis clearly indicated changes in the sagittal stratum. We found a positive correlation between VBM values in the right cerebellum and somatosensory-evoked potential P25-N33 amplitude. Decreased MD and AD values in the right sagittal stratum were detected in patients with versus without photophobia. SIGNIFICANCE: FCMTE is a network disorder involving a wide range of cortical and subcortical structures, including the cerebellum, thalamus, thalamocortical connections, and corticocortical connections. The right sagittal stratum is closely related with visual symptoms, especially photophobia. Our findings indicate that cerebellum and cortical hyperexcitability are closely linked, and emphasize the important role of the cerebellum in the pathophysiological mechanisms of cortical tremor.

The role of NOTCH2NLC in Parkinson's disease: A clinical, neuroimaging, and pathological study.

BACKGROUND AND PURPOSE: Recently, the pathogenic and intermediate GGC repeat expansion in NOTCH2NLC was detected in Parkinson's disease (PD). However, detailed clinical, neuroimaging, and pathological information of clinically diagnosed PD patients with pathogenic GGC repeat expansion in NOTCH2NLC remains scarce. Thus, we aimed to elucidate the clinical, neuroimaging, and pathological characteristics of PD patients carrying the pathogenic GGC repeat expansion in NOTCH2NLC. METHODS: The NOTCH2NLC GGC repeat expansion was screened in 941 sporadic PD patients and 244 unrelated probands. Comprehensive assessments were performed in three PD patients with pathogenic GGC repeat expansion in NOTCH2NLC. The repeat expansion length was estimated using CRISPR/Cas9-based targeted long-read sequencing. RESULTS: The three patients (two PD patients from Family 1 and one sporadic PD) carrying the pathogenic NOTCH2NLC expansion were reconfirmed with a diagnosis of clinically established PD. Although they lacked the typical neuronal intranuclear inclusion disease (NIID) magnetic resonance imaging (MRI) feature, the typical PD pattern of striatal dopamine transporter loss was detected. Notably, all three patients presented with systemic areflexia, and other secondary causes of polyneuropathy were excluded. Skin biopsy showed intranuclear inclusions and an absence of phosphorylated alpha-synuclein deposition in the skin nerve fibers of all three patients. CONCLUSIONS: Although these clinically diagnosed PD patients with pathogenic GGC repeat expansion in NOTCH2NLC were hardly distinguishable from idiopathic PD based on clinical course and neuroimaging features, the pathological findings indicated that their phenotype was a PD phenocopy of NIID. Systemic areflexia may be an important and unique clinical clue suggesting further genetic testing and skin biopsy examination to confirm the diagnosis of NIID in patients presenting with a PD phenocopy.

Early-onset Parkinson's disease with atypical molecular imaging abnormalities in a patient carrying the de novo PRKCG mutation.

Cerebellar ataxia and parkinsonism are two common overlapping clinical syndromes in patients with spinocerebellar ataxia. We report a case mimicking the phenotype of early-onset Parkinson's disease with a candidate novel de novo mutation (c.1151A>G, p.K384R) in PRKCG, a gene known to cause spinocerebellar ataxia type 14.

Neuronal intranuclear inclusion disease tremor-dominant subtype: A mimicker of essential tremor.

BACKGROUND AND PURPOSE: The GGC repeat expansion in the NOTCH2NLC gene has been identified as the genetic cause of neuronal intranuclear inclusion disease (NIID). Recently, this repeat expansion was also reported to be associated with essential tremor (ET). However, some patients with this repeat expansion, initially diagnosed with ET, were eventually diagnosed with NIID. Therefore, controversy remains regarding the clinical diagnosis of these expansion-positive patients presenting with tremor-dominant symptoms. This study aimed to clarify the clinical phenotype in tremor-dominant patients who have the GGC repeat expansion in the NOTCH2NLC gene. METHODS: We screened for pathogenic GGC repeat expansions in 602 patients initially diagnosed with ET and systematically re-evaluated the clinical features of the expansion-positive probands and their family members. RESULTS: Pathogenic GGC repeat expansion in the NOTCH2NLC gene was detected in 10 probands (1.66%). Seven of these probands were re-evaluated and found to have systemic areflexia, cognitive impairment, and abnormal nerve conduction, which prompted a change of diagnosis from ET to NIID. Three of the probands had typical hyperintensity in the corticomedullary junction on diffusion-weighted imaging. Intranuclear inclusions were detected in all four probands who underwent skin biopsy. CONCLUSIONS: The NIID tremor-dominant subtype can be easily misdiagnosed as ET. We should take NIID into account for differential diagnosis of ET. Systemic areflexia could be an important clinical clue suggesting that cranial magnetic resonance imaging examination, or even further genetic testing and skin biopsy examination, should be used to confirm the diagnosis of NIID.

Cardiovascular autonomic dysfunction is associated with executive dysfunction and poorer quality of life in progressive supranuclear palsy-Richardson's syndrome.

BACKGROUND: Autonomic dysfunction in progressive supranuclear palsy (PSP) is not uncommon but is easily neglected. OBJECTIVE: We evaluated blood pressure (BP) profiles in PSP patients and aimed to determine the associations between BP variability and cognition and quality of life. METHODS: Consecutive patients diagnosed with PSP were enrolled in this cross-sectional study. All patients underwent 24-hour ambulatory blood pressure monitoring, office blood pressure measurements, and comprehensive clinical assessments. RESULTS: We enrolled 31 PSP patients. Ten (32.3%) patients presented with reverse dipping, 10 (32.3%) presented with reduced dipping, and 11 (35.5%) presented with normal dipping. Additionally, 19 (61.3%) patients had supine hypertension, and no patients had orthostatic hypotension. In the entire PSP cohort, the Movement Disorder Society-Unified Parkinson's Disease Rating Scale part III (MDS-UPDRS III) score, Scales for Outcomes in Parkinson's Disease-Autonomic (SCOPA-AUT) score, and daytime systolic BP (SBP) standard deviation explained 61.5% (adjusted R2) of the variance in Parkinson's Disease Questionnaire-39 (PDQ-39) scores. In the PSP with Richardson's syndrome group, the daytime SBP coefficient of variation and Mini-Mental State Examination score accounted for 33.9% of the variance in Frontal Assessment Battery scores. The MDS-UPDRS III score, 24-hour SBP coefficient of variation, and SCOPA-AUT score explained 77.6% of the variance in PDQ-39 scores. CONCLUSIONS: Greater BP variability was associated with executive dysfunction and poorer quality of life in patients with PSP. A high prevalence of abnormal dipping patterns indicated circadian disruption in patients with PSP.

The link between lateral trunk flexion in Parkinson's disease and vestibular dysfunction: a clinical study.

INTRODUCTION: Lateral trunk flexion (LTF) is a common postural deformity in Parkinson's disease (PD). Postural control is known to depend on visual, vestibular, and somatosensory information. OBJECTIVES: This study aimed to investigate the relationship between vestibular dysfunction and postural abnormalities in PD patients with LTF. METHODS: We enrolled a total of 19 PD patients with LTF (PD-LTF+) and 19 age- and sex-matched PD patients without LTF (PD-LTF-). All patients underwent vestibular tests, including spontaneous nystagmus, gaze-evoked nystagmus, ocular movements, optokinetic eye test, fast positioning maneuvers, and the bithermal caloric test. RESULTS: Most of the PD-LTF + patients had abnormal vestibular function (11/19), while there were fewer vestibular function injuries in the control group (3/19). In PD-LTF + group, there were 5 patients (5/11, 45.5%) of peripheral vestibular dysfunction, 2 patients (2/11, 18.2%) of central vestibular damage, and 4 patients (4/11, 36.4%) of mixed injuries. The peripheral vestibular deficiencies could be either bilateral (4/9, 44.4%) or unilateral (5/9, 55.6%). The unilateral vestibular dysfunction was ipsilateral to the leaning side in 2 patients and contralateral to the leaning side in the other 3 patients. CONCLUSION: Vestibular dysfunction may be an independent risk factor for LTF in PD patients.

Three-Dimensional Pattern Features in Finger Tapping Test for Patients with Parkinson's disease.

Finger tapping test is an important neuropsychological test to evaluate human motor function. Most recent researches simplified the finger tapping motion as a scissors-like motion, though the rotation axis of the thumb was different from that of the forefinger. In this paper, we proposed a three-dimensional (3-D) finger tapping measurement system to obtain 3-D pattern features in finger tapping test for patients with Parkinson's disease (PD). The proposed system collected the motion of the thumb and the forefinger by nine-degrees-freedom sensors and calculated 3-D motion of finger tapping by an orientation estimation method and a 3-D finger-tapping kinematic model. We further extracted 3-D pattern features, i.e. motor coordination and relative thumb motion, from 3-D Finger Tapping motion. Moreover, we used the proposed system to collect the finger-tapping motion of 43 PD patients and 30 healthy controls in horizontal tasks and vertical tasks. The results indicated that 3-D pattern features showed a better performance than one-dimensional features in the identification of mild PD patients.Clinical Relevance- These three-dimensional pattern features could be used to evaluate finger tapping motion in a novel way, which could be used to better identify mild Parkinson's disease patients. Furthermore, the results showed that a combination of horizontal tasks and vertical tasks might be a better way to identify mild Parkinson's disease patients.

Altered Cerebello-Motor Network in Familial Cortical Myoclonic Tremor With Epilepsy Type 1.

BACKGROUND: Intronic pentanucleotide insertion in the sterile alpha motif domain-containing 12 gene was recently identified as the genetic cause of familial cortical myoclonic tremor with epilepsy type 1. OBJECTIVES: We thereafter conducted a multimodal MRI research to further understand familial cortical myoclonic tremor with epilepsy type 1. METHODS: We enrolled 31 patients carrying heterozygous pathogenic intronic pentanucleotide insertion in the sterile alpha motif domain-containing 12 gene and 31 age- and sex-matched healthy controls. We compared multimodal MRI metrics, including voxel-based morphometry, fractional anisotropy of diffuse tensor imaging, frequency-dependent percent amplitude fluctuation, and seed-based functional connectivity of resting-state functional MRI. RESULTS: Significant decreased gray matter volume was found in the cerebellum. Percent amplitude fluctuation analysis showed significant interaction effect of "Frequency by Group" in three regions, including the vermis VIII, left cerebellar lobule VIII, and left precentral gyrus. Specifically, the lowest-frequency band exhibited significant increased percent amplitude fluctuation in patients in the two cerebellar subregions, whereas the highest-frequency band exhibited decreased percent amplitude fluctuation in the precentral gyrus in patients. Discriminative analysis by support vector machine showed a mean accuracy of 82% (P = 1.0-5 ). An increased functional connectivity between vermis VIII and the left precentral gyrus was found in patients with familial cortical myoclonic tremor with epilepsy type 1. A positive correlation between the percent amplitude fluctuation in the left cerebellar lobule VIII and duration of cortical tremor was also found. CONCLUSION: The cerebellum showed both structural and functional damages. The distinct change of spontaneous brain activity, that is, increased ultra-low-frequency amplitude in the cerebellum and the decreased higher-frequency amplitude in the motor cortex, might be a pathophysiological feature of familial cortical myoclonic tremor with epilepsy type 1. © 2020 International Parkinson and Movement Disorder Society.

MYORG Mutation Heterozygosity Is Associated With Brain Calcification.

BACKGROUND: Biallelic mutations in the MYORG gene were first identified as the cause of recessively inherited primary familial brain calcification. Interestingly, some heterozygous carriers also exhibited brain calcifications. OBJECTIVES: To further investigate the role of single heterozygous MYORG mutations in the development of brain calcifications. METHODS: A nation-wide cohort of Chinese primary familial brain calcification probands was enrolled from March 2016 through September 2019. Mutational analysis of MYORG was performed in 435 primary familial brain calcification probands who were negative for mutations in the other four known primary familial brain calcification-causative genes (SLC20A2, PDGFRB, PDGFB, and XPR1). RESULTS: Biallelic MYORG mutations were identified in 14 primary familial brain calcification patients from 10 unrelated families. Interestingly, 12 heterozygous carriers from seven of these families also exhibited mild-to-moderate brain calcifications. Moreover, single heterozygous mutations were detected in an additional 9 probands and in 7 of their family members affected with brain calcifications. In our cohort, clinical and imaging penetrance of individuals with biallelic mutations were 100%, whereas among individuals with heterozygous mutations, penetrance of imaging phenotype was reduced to 73.7% (28 of 38) and clinical penetrance was much lower. Most (34 of 38) remained asymptomatic whereas 4 carriers had symptoms of uncertain clinical significance (nonspecific depression, epilepsy and late-onset parkinsonism). Compared with individuals with biallelic MYORG mutations, individuals with heterozygous mutations had brain calcifications with much lower calcification scores (P < 2e-16). CONCLUSIONS: Presence of brain calcifications in individuals with heterozygous MYORG mutations suggested a semidominant inheritance pattern with incomplete penetrance. This finding further expanded the genotype-phenotype correlations of MYORG-related primary familial brain calcification. © 2020 International Parkinson and Movement Disorder Society.