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• Mitochondrial phenotype with ptosis associated with m.586 T5 > C variant. • m.5865 T > C variant classified as "pathogenic". • m.586 T5 > C variant is not associated with chronic progressive external opthalmoplegia. We describe a novel mitochondrial variant (m.5865 T > C) in a patient with decreased exercise endurance and juvenile onset slowly progressive bilateral ptosis without ophthamloparesis. The m.5865 T > C variant was seen in 82.9% of mtDNA molecules in skeletal muscle tissue and ~8% of mtDNA molecules in urine epithelium, but was not detected in blood leukocytes. The proband does not demonstrate any additional features often seen in individuals with a mitochondrial disorder (i.e., sensorineural hearing loss, type 2 diabetes, stroke-like episodes, muscle weakness, ophthalmoparesis, cardiomyopathy or cardiac arrhythmias). This case suggests that ptosis and exercise intolerance, without ophthalmoparesis, are the primary clinical features of the m.5865 T > C mtDNA variant. [ABSTRACT FROM AUTHOR]

Chronic progressive external ophthalmoplegia (CPEO) is a common presentation of mitochondrial disease. We performed a retrospective evaluation of the molecular genetic testing and genotype-phenotype correlations in a large cohort of adult-onset CPEO patients (N = 111). One hundred percent of patients tested had at least one mitochondrial DNA (mtDNA) deletion. Genetic testing of nuclear genes encoding mitochondrial proteins identified pathogenic/likely pathogenic variants likely to be associated with CPEO in 7.6% of patients. As expected, the nuclear gene most associated with DNA variation was POLG. A single likely pathogenic mitochondrial DNA variant (m.12278T>C) was identified in two unrelated patients. No significant differences were noted in the clinical phenotypes of patients with pathogenic or likely pathogenic nuclear variants in comparison to those with negative nuclear gene testing. Analysis of deletion size and heteroplasmy in muscle-derived mtDNA showed significant correlations with age of symptom onset but not disease severity (number of canonical CPEO features). Results suggest that smaller mtDNA deletions (p = 0.0127, r2 = 0.1201) and higher heteroplasmy of single mtDNA deletions (p = 0.0112, r2 = 0.2483) are associated with an earlier age of onset in CPEO patients. • Higher heteroplasmy of mtDNA deletions associated with earlier age of onset. • Hereditary nuclear cause of CPEO identified in 7.6% of patients. • LRPCR/NGS can be discrepant in number of deletions in muscle-derived mtDNA. [ABSTRACT FROM AUTHOR]

Abstract Mitochondrial DNA (mtDNA) mutations have been implicated in a wide variety of neurological conditions and are maternally inherited through a complex process which is not fully understood. Genetic counselling for mitochondrial conditions secondary to a mtDNA mutation can be challenging as it is not currently possible to accurately predict the mutational load/heteroplasmy of the mutation which could be passed to the offspring. In general, one expects that the higher the level of heteroplasmy the more likely that the same mtDNA mutation will be seen in the offspring. We report here a family which places a caveat on genetic counselling for mtDNA disorders. The proband is a 63 year old woman with m.14459G>A associated dystonia/spasticity/ataxia. The m.14459G>A mutation was detected at homoplasmic/near homoplasmic levels in her muscle tissue and fibroblasts, but did not appear to have been passed on to any of her offspring. To our knowledge, this is the first report of complete selection against a homoplasmic variant within maternally transmitted mtDNA. It is not clear if this novel phenomenon occurred by random chance or by another method of mitochondrial selection. Highlights • Family with female proband with m.14459G>A associated dystonia/spasticity/ataxia. • m.14459G>A was detected at homoplasmic levels in muscle tissue and fibroblasts • m.14459G>A mutation not passed to her offspring • We report complete selection against a homoplasmic mtDNA variant in a single generation [ABSTRACT FROM AUTHOR]

Abstract Chronic progressive external ophthalmoplegia (CPEO) is a common mitochondrial disease. We evaluated the impact of sex and smoking status upon knee extension strength and the phenotypic spectrum of disease in a large cohort of adult-onset CPEO patients (N = 116) using retrospective chart analysis. The CPEO patients showed significantly lower knee extension strength as compared to the age- and sex-matched control population (− 37%, P < 0.05). Smoking also negatively impacted knee extension strength only in women with CPEO (− 26%, P < 0.05). We conclude that smoking and female sex interact negatively in CPEO patients. [ABSTRACT FROM AUTHOR]

Background: Ogden syndrome is a rare X-linked disorder caused by pathogenic variants in the NAA10 gene. This syndrome, reported in just over 20 children, has been associated with dysmorphic features, failure to thrive, developmental impairments, hypotonia, and cardiac arrhythmias.Patient Description: We describe a 14-year-old girl who presented in infancy with hypotonia, global developmental delay, and dysmorphic features. She later developed autism spectrum disorder, epileptic encephalopathy, extrapyramidal signs, early morning lethargy with hypersomnolence, and hypertension with left ventricular hypertrophy. Magnetic resonance imaging showed a thin corpus callosum and progressive white matter loss. Whole exome sequencing identified a de novo pathogenic variant in the NAA10 gene (c.247C>T, p.R83C). Much of her early presentation was in keeping with what has been previously described with Ogden syndrome.Conclusions: We have identified additional evolving neurological impairments in this, to date, oldest documented girl with Ogden syndrome. We recommend screening patients with Ogden syndrome for these newly identified features of early life trajectories to guide management. [ABSTRACT FROM AUTHOR]

Background: This communication examines the expanding phenotypes of the MECP2 C-terminal atypical Rett syndromes in males and their affected carrier mothers.Descriptions: We describe three males with normal karyotypes who presented with congenital evolving complex neurodevelopmental encephalopathies with multifaceted symptomatology of hypotonia, epilepsy, ataxia, spasticity, movement disorders, behavioral issues, severe intellectual impairment, and communication skills, and a protracted regression phase followed by stabilization. These phenotypes did not prompt us to identify atypical Rett syndrome early in childhood.Results: Genetic analysis identified the two brothers with C-terminal truncation and the third male with C-terminal missense mutations. These mutations were inherited from their mothers, both of whom had incompletely characterized modest intellectual, mental health, social, and gastrointestinal impairments. Neither was independently able to care properly for their son(s).Conclusions: Mutations of the MECP2 gene should be considered early in males with hypotonia, developmental delay, profound intellectual impairment, and seizures, associated with a mother with psychosocial, cognitive, and gastrointestinal impairments. Counseling and supporting mildly affected mothers requires both medical and social efforts. [ABSTRACT FROM AUTHOR]

We describe here two novel mitochondrial mutations associated with a complex mitochondrial encephalopathy. An A to G transition at position 7495 ( MT-TS1 (MT-tRNSer(UCN))) was identified at 83% heteroplasmy in the muscle of a four year old female with ptosis, hypotonia, seizures, and dilated cardiomyopathy (Case 1). A homoplasmic C to T transition at position 5577 ( MT-TW (MT-tRNATrp)) was found in a twenty-four year old woman with exercise intolerance, mild muscle weakness, hearing loss, seizures, and cognitive decline (Case 2). The phenotypic information provided here will assist in phenotype-genotype correlations should additional patients be reported in the future. The mutations can be added to the database of mitochondrial DNA variations in conserved regions which result in clinically diverse phenotypes with the shared markers of mitochondrial disease. [ABSTRACT FROM AUTHOR]

Objectives We studied a population of individuals who experienced an acute coronary syndrome (ACS) event while traveling abroad and required nonurgent commercial air travel to the home region. Methods This retrospective study gathered data from 288 patients enrolled in a travel-based medical assistance program. Interventions, complications, and travel home were assessed for trends. Descriptive and comparison statistical analyses were performed. Results Two hundred eighty-eight patients were identified and entered into the review. Of the patients in this study, 77.1% were male with an average age of 67.7 years. One hundred sixteen (40.3%) patients were diagnosed with unstable angina pectoris (USAP), whereas the remaining 172 (59.7%) patients experienced acute myocardial infarction (AMI). Regarding inpatient complications during the initial admission, 121 (42.0%) patients experienced 1 or more adverse event. The average number of days after an ACS event that a patient began to travel home was 10.5 days for the entire patient population (USAP patients = 8.8 days, AMI patients = 11.8 days). Two hundred twenty (76.4%) patients traveled with a medical escort, and 48 (16.7%) patients received supplemental oxygen during air travel. Four (1.4%) in-flight adverse events occurred in the following ACS diagnostic groups: 2 in the complicated AMI group, 1 in the uncomplicated USAP group, and 1 in the uncomplicated AMI group. No in-flight deaths occurred. Nine (3.1%) deaths were noted within 2 weeks after returning to the home region. The deaths after returning to the home region occurred in the following ACS diagnostic groups: 2 in the complicated USAP group, 1 in the uncomplicated USAP group, and 6 in the complicated AMI group. None of the patients who experienced in-flight events died after returning to their home region. Conclusions Upon discharge, the vast majority of ACS patients who travel to their home region via commercial air do not experience adverse events in-flight; when such adverse events occur in-flight, these events do not result in a poor outcome. No in-flight deaths occurred; death occurred in a minority of patients after returning to their home region, particularly in the complicated USAP and AMI groups, who were planned readmissions to the hospital. [ABSTRACT FROM AUTHOR]

Summary: RNA sequences are expected to be identical to their corresponding DNA sequences. Here, we found all 12 types of RNA-DNA sequence differences (RDDs) in nascent RNA. Our results show that RDDs begin to occur in RNA chains ∼55 nt from the RNA polymerase II (Pol II) active site. These RDDs occur so soon after transcription that they are incompatible with known deaminase-mediated RNA-editing mechanisms. Moreover, the 55 nt delay in appearance indicates that they do not arise during RNA synthesis by Pol II or as a direct consequence of modified base incorporation. Preliminary data suggest that RDD and R-loop formations may be coupled. These findings identify sequence substitution as an early step in cotranscriptional RNA processing. [Copyright &y& Elsevier]

We report here on a patient who presented with myasthenia gravis type symptoms (fatigable ptosis, increased jitter on single fiber EMG, and a thymic mass) who was subsequently diagnosed with a mitochondrial myopathy. Sequencing of the mitochondrial genome (mtDNA) identified a transition variant in the tRNA asparagine gene (MT-TN) (m.5728T>C) at in 41% of mtDNA molecules in muscle tissue. The variant was not detectable in blood. The m.5728T>C variant has been reported previously in a ten year old male with global developmental delays, failure to thrive, ataxia, weakness, cognitive regression, seizures, and glomerulosclerosis. The variant was seen in 97% of mtDNA molecules in muscle and 50% in blood. This case report supports the pathogenicity of the m.5728T>C and helps to establish the phenotypic spectrum of this condition at a lower heteroplasmy. • Mitochondrial myopathy with myasthenic features associated with m.5728 T > C mutation • Overview of milder symptoms associated with lower heteroplasmy m.5728 T > C mutation • Report supports pathogenicity of previously reported m.5728 T > C mutation [ABSTRACT FROM AUTHOR]

• CMT2 is an autosomal dominant highly variable peripheral neuropathy. • A novel VCP mutation is identified in this CMT2 family with phenotypic variability. • This novel phenotype reflects a combined ALS-like and CMT2-like phenomena. Charcot-Marie-Tooth (CMT) disease, a hereditary motor and sensory neuropathy, has subtypes with varied inheritance patterns and phenotypic presentation. Subtypes additionally vary by genetic variants in a number of genes. Pathogenic variants in the VCP gene have newly been associated with CMT type 2. We present a family with CMT type 2 with a novel heterozygous VCP variant and phenotypic variability between the proband, his brother, and father. [ABSTRACT FROM AUTHOR]

Background: Congenital ataxias associated with cerebellar atrophy are clinically heterogeneous conditions with a variable age of onset and a diverse molecular basis. The hypothesis-free approach of genomic sequencing has led to the discovery of new genes implicated in these disorders and the identification of unexpected genotype-phenotype correlations. Although a recurrent heterozygous mutation (p.Arg1715His) in CACNA1G is known to cause adult-onset spinocerebellar ataxia 42 (SCA42*616795), gain-of-function mutations in this gene have recently been identified by whole exome sequencing (WES) in four children with cerebellar atrophy and ataxia, psychomotor delay, and other variable features.Methods: We describe four children from unrelated families with cerebellar anomalies on magnetic resonance imaging (atrophy or hypoplasia of the cerebellar vermis), hypertonia, psychomotor and speech delay, severe intellectual disability, ophthalmologic features and peculiar dysmorphic traits. All patients underwent a trio-based WES analysis. Clinical records were used to characterize the clinical profile of this newly recognized disorder.Results: Two previously reported de novo disease-causing mutations in CACNA1G (c.2881G>A, p.Ala961Thr and c.4591A>G, p.Met1531Val) were identified in these patients, providing further evidence of the specific impact of these variants. All four patients exhibit distinctive dysmorphic and ectodermal features which overlap those of the previously reported patients, allowing us to define the major features characterizing this homogeneous neurodevelopmental syndromic disorder associated with upregulated CACNA1G function.Conclusion: Our findings confirm the specific association between a narrow spectrum of missense mutations in CACNA1G and a novel syndrome with infantile-onset cerebellar ataxiaand provide a dysmorphologic delineation of this novel neurodevelopmental trait. [ABSTRACT FROM AUTHOR]

Two patients with an m.8340G>A mitochondrial DNA variant have been reported with one patient showing ptosis, ophthalmoparesis and myopathy at 53% heteroplasmy and another with pigmentary retinopathy, cataracts and sensory neural deafness and slightly higher heteroplasmy (65%). Here we report that higher muscle mutant heteroplasmy (93%) for m.8340G>A is associated with ptosis, ophthalmoparesis and mitochondrial myopathy, thus confirming the initial phenotypic association and showing that heteroplasmy per se does not explain the phenotypic spectrum of disease associated with the m.8340G>A mutation. • The m.8340G>A mitochondrial DNA variant can cause a CPEO phenotype • The percentage of mutant heteroplasmy does not fully predict the phenotypic expression in the three reported cases. • Our data supports two earlier reports and confirms pathogenicity of the m.8340G>A mtDNA variant [ABSTRACT FROM AUTHOR]