Expanded-Access Use of Elamipretide Improves Quality of Life in Patients With Rare Mitochondrial Disorders Characterized by Ophthalmic Symptoms: A Case Series.

This case series presents the use of elamipretide in two patients with different progressive mitochondrial disorders (chronic progressive external ophthalmoplegia [CPEO] plus and neuropathy, ataxia, and retinitis pigmentosa [NARP] syndrome) characterized by ophthalmic traits. Elamipretide was well tolerated and both patients demonstrated improvement in symptoms while on therapy.

Safety and efficacy of intra-erythrocyte dexamethasone sodium phosphate in children with ataxia telangiectasia (ATTeST): a multicentre, randomised, double-blind, placebo-controlled phase 3 trial.

Background: Ataxia telangiectasia is a multisystem disorder with progressive neurodegeneration. Corticosteroids can improve neurological functioning in patients with the disorder but adrenal suppression and symptom recurrence on treatment discontinuation has limited their use, prompting the development of novel steroid delivery systems. The aim of the ATTeST study was to evaluate the efficacy and safety of intra-erythrocyte delivery of dexamethasone sodium phosphate compared with placebo in children with ataxia telangiectasia.

Expanded-access use of elamipretide in a patient with membrane protein-associated neurodegeneration.

This case report presents a progressively declining 17-year-old patient with membrane protein-associated neurodegeneration who demonstrated symptomatic improvements in her dysarthria, dysphagia, and gait, and objective improvements in her 6-minute walk test and 5 times sit-to-stand test during elamipretide treatment.

Early Treatment with Vigabatrin Does Not Decrease Focal Seizures or Improve Cognition in Tuberous Sclerosis Complex: The PREVeNT Trial.

Objective: This study was undertaken to test the hypothesis that early vigabatrin treatment in tuberous sclerosis complex (TSC) infants improves neurocognitive outcome at 24 months of age.

Methods: A phase IIb multicenter randomized double-blind placebo-controlled trial was conducted of vigabatrin at first epileptiform electroencephalogram (EEG) versus vigabatrin at seizure onset in infants with TSC. Primary outcome was Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) cognitive assessment score at 24 months.

Efficacy and Safety of Elamipretide in Individuals With Primary Mitochondrial Myopathy: The MMPOWER-3 Randomized Clinical Trial.

Background And Objectives: Primary mitochondrial myopathies (PMMs) encompass a group of genetic disorders that impair mitochondrial oxidative phosphorylation, adversely affecting physical function, exercise capacity, and quality of life (QoL). Current PMM standards of care address symptoms, with limited clinical impact, constituting a significant therapeutic unmet need. We present data from MMPOWER-3, a pivotal, phase-3, randomized, double-blind, placebo-controlled clinical trial that evaluated the efficacy and safety of elamipretide in participants with genetically confirmed PMM.

Development of cancer surveillance guidelines in ataxia telangiectasia: A Delphi-based consensus survey of international experts.

Background/objectives: Ataxia telangiectasia (A-T) is a multiorgan disorder with increased vulnerability to cancer. Despite this increased cancer risk, there are no widely accepted guidelines for cancer surveillance in people affected by A-T. We aimed to understand the current international practice regarding cancer surveillance in A-T and agreed-upon approaches to develop cancer surveillance in A-T.

Corrigendum to "A new pathogenic POLG variant" [Molecular Genetics and Metabolism Reports 32 (2022) 100890].

[This corrects the article DOI: 10.1016/j.ymgmr.

Use of Elamipretide in patients assigned treatment in the compassionate use program: Case series in pediatric patients with rare orphan diseases.

Several mitochondrial diseases are caused by pathogenic variants that impair membrane phospholipid remodeling, with no FDA-approved therapies. Elamipretide targets the inner mitochondrial membrane where it binds to cardiolipin, resulting in improved membrane stability, cellular respiration, and ATP production. In clinical trials, elamipretide produced clinical and functional improvements in adults and adolescents with mitochondrial disorders, such as primary mitochondrial myopathy and Barth syndrome; however, experience in younger patients is limited and to our knowledge, these are the first case reports on the safety and efficacy of elamipretide treatment in children under 12 years of age.

A new pathogenic POLG variant.

gene mutations are the most common causes of inherited mitochondrial disorders. The enzyme produced by this gene is responsible for the replication and repair of mitochondrial DNA. To date, around 300 pathogenic variants have been described in this gene.

Phenotypic and genetic spectrum of ATP6V1A encephalopathy: a disorder of lysosomal homeostasis.

Vacuolar-type H+-ATPase (V-ATPase) is a multimeric complex present in a variety of cellular membranes that acts as an ATP-dependent proton pump and plays a key role in pH homeostasis and intracellular signalling pathways. In humans, 22 autosomal genes encode for a redundant set of subunits allowing the composition of diverse V-ATPase complexes with specific properties and expression. Sixteen subunits have been linked to human disease.

A randomized, double-blind trial of triheptanoin for drug-resistant epilepsy in glucose transporter 1 deficiency syndrome.

Objective: This study was undertaken to evaluate efficacy and long-term safety of triheptanoin in patients >1 year old, not on a ketogenic diet, with drug-resistant seizures associated with glucose transporter 1 deficiency syndrome (Glut1DS).

Methods: UX007G-CL201 was a randomized, double-blind, placebo-controlled trial. Following a 6-week baseline period, eligible patients were randomized 3:1 to triheptanoin or placebo.

Adult phenotype of encephalopathy.

Background: Pathogenic variants are a frequent cause of developmental and epileptic encephalopathy.

Methods: We recruited 13 adults (between 18 years and 45 years of age) with encephalopathy and reviewed their clinical, EEG, neuroimaging and treatment history.

Results: While most patients had daily seizures at seizure onset, seizure frequency declined or remitted during childhood and adulthood.

Hypoglycemia in mitochondrial disorders.

Diabetes and hyperglycemia are common features of mitochondrial disorders. This study investigates the frequency of non-iatrogenic hypoglycemia in individuals with these disorders. Of 116 patients, 22 (18.

Leigh Syndrome as a Phenotype of Near-Homoplasmic m.8344 A>G Variant in Children.

In the field of mitochondrial medicine, correlation of clinical phenotype with mutation heteroplasmy remains an outstanding question with few, if any, clear thresholds corresponding to a given phenotype. The m.8344A>G mutation is most commonly associated with myoclonus epilepsy and ragged red fiber syndrome (MERRF) at varying levels of heteroplasmy.

Two different genetic etiologies for tuberous sclerosis complex (TSC) in a single family.

Background: Tuberous sclerosis complex (TSC) is an autosomal dominant genetic condition that involves abnormalities of the skin, hamartomas in the heart, brain, and kidneys, seizures, as well as TSC-associated neuropsychiatric disorders (TAND). About 90%-95% of individuals with TSC will have an identifiable pathogenic variant in either TSC1 or TSC2. We present here two family members with clinical diagnoses of TSC that were later determined to be due to two different genetic etiologies.

Fatigue in primary genetic mitochondrial disease: No rest for the weary.

Rates of perceived fatigue, anxiety, depression, sleepiness and mitochondrial disease severity were assessed prospectively in 2017-2018 using established validated questionnaires in 48 adult patients with genetically confirmed primary mitochondrial disease. Fatigue was found to be very common among patients with primary mitochondrial disease, with 34 to 48 (71-100%) patients reporting fatigue depending on the measure used, and the severity of fatigue correlating with the severity of disease. Moderate-to-severe depression (10/48; 20.

Partial Loss of USP9X Function Leads to a Male Neurodevelopmental and Behavioral Disorder Converging on Transforming Growth Factor β Signaling.

Background: The X-chromosome gene USP9X encodes a deubiquitylating enzyme that has been associated with neurodevelopmental disorders primarily in female subjects. USP9X escapes X inactivation, and in female subjects de novo heterozygous copy number loss or truncating mutations cause haploinsufficiency culminating in a recognizable syndrome with intellectual disability and signature brain and congenital abnormalities. In contrast, the involvement of USP9X in male neurodevelopmental disorders remains tentative.

Encephalopathies with KCNC1 variants: genotype-phenotype-functional correlations.

Objective: To analyze clinical phenotypes associated with KCNC1 variants other than the Progressive Myoclonus Epilepsy-causing variant p.Arg320His, determine the electrophysiological functional impact of identified variants and explore genotype-phenotype-physiological correlations.

Methods: Ten cases with putative pathogenic variants in KCNC1 were studied.