1H and 31P magnetic resonance spectroscopy reveals potential pathogenic and biomarker metabolite alterations in Lafora disease.

Lafora disease is a fatal teenage-onset progressive myoclonus epilepsy and neurodegenerative disease associated with polyglucosan bodies. Polyglucosans are long-branched and as a result precipitation- and aggregation-prone glycogen. In mouse models, downregulation of glycogen synthase, the enzyme that elongates glycogen branches, prevents polyglucosan formation and rescues Lafora disease. Mouse work, however, has not yet revealed the mechanisms of polyglucosan generation, and few in vivo human studies have been performed. Here, non-invasive in vivo magnetic resonance spectroscopy (1H and 31P) was applied to test scan feasibility and assess neurotransmitter balance and energy metabolism in Lafora disease towards a better understanding of pathogenesis. Macromolecule-suppressed gamma-aminobutyric acid (GABA)-edited 1H magnetic resonance spectroscopy and 31P magnetic resonance spectroscopy at 3 and 7 tesla, respectively, were performed in 4 Lafora disease patients and a total of 21 healthy controls (12 for the 1H magnetic resonance spectroscopy and 9 for the 31PMRS). Spectra were processed using in-house software and fit to extract metabolite concentrations. From the 1H spectra, we found 33% lower GABA concentrations (P = 0.013), 34% higher glutamate + glutamine concentrations (P = 0.011) and 24% lower N-acetylaspartate concentrations (P = 0.0043) in Lafora disease patients compared with controls. From the 31P spectra, we found 34% higher phosphoethanolamine concentrations (P = 0.016), 23% lower nicotinamide adenine dinucleotide concentrations (P = 0.003), 50% higher uridine diphosphate glucose concentrations (P = 0.004) and 225% higher glucose 6-phosphate concentrations in Lafora disease patients versus controls (P = 0.004). Uridine diphosphate glucose is the substrate of glycogen synthase, and glucose 6-phosphate is its extremely potent allosteric activator. The observed elevated uridine diphosphate glucose and glucose 6-phosphate levels are expected to hyperactivate glycogen synthase and may underlie the generation of polyglucosans in Lafora disease. The increased glutamate + glutamine and reduced GABA indicate altered neurotransmission and energy metabolism, which may contribute to the disease's intractable epilepsy. These results suggest a possible basis of polyglucosan formation and potential contributions to the epilepsy of Lafora disease. If confirmed in larger human and animal model studies, measurements of the dysregulated metabolites by magnetic resonance spectroscopy could be developed into non-invasive biomarkers for clinical trials.

Mitochondrial encephalopathies and myopathies: Our tertiary center's experience.

Mitochondrial diseases have a heterogeneous phenotype and can result from mutations in the mitochondrial or nuclear genomes, constituting a diagnostically and therapeutically challenging group of disorders. We report our center's experience with mitochondrial encephalopathies and myopathies with a cohort of 50 genetically and phenotypically diverse patients followed in the Neurology clinic over the last ten years. Seventeen patients had mitochondrial DNA mutations, presented over a wide range of ages with seizures, feeding difficulties, extraocular movements abnormalities, and had high rates of stroke-like episodes and regression. Twenty-seven patients had nuclear DNA mutations, presented early in life with feeding difficulty, failure-to-thrive, and seizures, and had high proportions of developmental delay, wheelchair dependence, spine abnormalities and dystonia. In six patients, a mutation could not be identified, but they were included for having mitochondrial disease confirmed by histopathology, enzyme analysis and clinical features. These patients had similar characteristics to patients with nuclear DNA mutations, suggesting missed underlying mutations in the nuclear genome. Management was variable among patients, but outcomes were universally poor with severe disability in all cases. Therapeutic entryways through elucidation of disease pathways and remaining unknown genes are acutely needed.

Neuropsychological assessment in rare pediatric neurogenetic disorders: considerations for cross-cultural clinical research.

Neuropsychological assessment in rare neurodevelopmental disorders has provided clinicians and researchers with a more comprehensive view of natural history as well as opportunities for additional endpoints in treatment trials. While challenges to protocol development have been addressed in the literature, cultural considerations have been overly broad resulting in limited utility when including mixed international samples. Using experiences over the past five years with the development of ten different protocols for neurogenetic rare diseases, this paper presents further considerations for protocol development that are culturally sensitive to international samples. Recommendations are offered across areas including participants from multiple countries; cognitive, sensory and motor impairments; psychometrics; and assessment logistics. A neuropsychological assessment selection checklist that guides researchers and clinicians through considerations and a standard operating procedure that provides guidance on thinking through the assessment process are offered.

Leigh syndrome global patient registry: uniting patients and researchers worldwide.

BACKGROUND: Leigh Syndrome (LS) is a rare genetic neurometabolic disorder, that leads to the degeneration of the central nervous system and subsequently, early death. LS can be caused by over 80 mutations in mitochondrial or nuclear DNA. Patient registries are important for many reasons, such as studying the natural history of the disease, improving the quality of care, and understanding the healthcare burden. For rare diseases, patient registries are significantly important as patient numbers are small, and funding is limited. Cure Mito Foundation started a global patient registry for LS in September 2021 to identify and learn about the LS patient population, facilitate clinical trial recruitment, and unite international patients and researchers. Priorities were to allow researchers and industry partners to access data at no cost through a clear and transparent process, active patient engagement, and sharing of results back to the community. RESULTS: Patient registry platform, survey design, data analysis process, and patient recruitment strategies are described. Reported results include demographics, diagnostic information, symptom history, loss of milestones, disease management, healthcare utilization, quality of life, and caregiver burden for 116 participants. Results show a high disease burden, but a relatively short time to diagnosis. Despite the challenges faced by families impacted by Leigh syndrome, participants, in general, are described as having a good quality of life and caregivers are overall resilient, while also reporting a significant amount of stress. CONCLUSION: This registry provides a straightforward, no-cost mechanism for data sharing and contacting patients for clinical trials or research participation, which is important given the recruitment challenges for clinical trials for rare diseases. This is the first publication to present results from a global patient registry for Leigh Syndrome, with details on a variety of patient-specific and caregiver outcomes reported for the first time. Additionally, this registry is the first for any mitochondrial disease with nearly 70% of participants residing outside of the United States. Future efforts include continued publication of results and further collaboration with patients, industry partners, and researchers.

Natural History of SURF1 Deficiency: A Retrospective Chart Review.

BACKGROUND: This retrospective chart review evaluated the clinical characteristics of SURF1-related neurological disease spectrum to better characterize the phenotypes. METHODS: Patient demographics, magnetic resonance imaging abnormalities, neurological events, motor abnormalities, and gastrointestinal and respiratory assistance were evaluated in 27 patients with genetically diagnosed SURF1 deficiency. RESULTS: The mean (S.D.) age of symptom onset collected from 13 patients was 19.7 (11.8) months. Mean (S.D.) age of diagnosis collected from 24 patients was 44.0 (45.1) months. The most common symptoms were gross motor delay (14 of 14), fine motor delay (10 of 11), verbal delay (9 of 10), and intellectual and learning disability (14 of 19). Neurological symptoms included ataxia (14 of 15), other abnormal movements (8 of 9), hypotonia (9 of 11), and dystonia (6 of 9). Three of nine reporting patients (33.3%) had a history of seizure, and 84.6% (11 of 13) had a history of regression/loss of acquired skills. Extraneurological clinical features included pulmonary complications (10 of 11) and feeding difficulties (13 of 13); cardiac complications were noted in three patients. Brainstem is frequently involved with the medulla and midbrain being the most common sites. As of July 2021, three patients were deceased. CONCLUSIONS: The most common clinical symptoms were motor delay, verbal delay, intellectual and learning disability, dysphagia, feeding difficulties, and reflux. Neurological presentations include ataxia, hypotonia, visual/ocular abnormalities, dystonia, and imaging abnormalities include basal ganglia and brainstem lesions. Although heterogeneous, SURF1 deficiency should be considered with these clinical and imaging presentations and may support earlier identification.

Long-term progression of retinal degeneration in a preclinical model of CLN7 Batten disease as a baseline for testing clinical therapeutics.

BACKGROUND: Batten disease is characterized by cognitive and motor impairment, retinal degeneration, and seizures leading to premature death. Recent studies have shown efficacy for a gene therapy approach for CLN7 Batten disease. This gene therapy approach is promising to treat cognitive and motor impairment, but is not likely to delay vision loss. Additionally, the natural progression of retinal degeneration in CLN7 Batten disease patients is not well-known. METHODS: We performed visual examinations on five patients with CLN7 Batten disease and found that patients were far progressed in degeneration within their first five years of life. To better understand the disease progression, we characterized the retina of a preclinical mouse model of CLN7 Batten disease, through the age at which mice present with paralysis and premature death. FINDINGS: We found that this preclinical model shows signs of photoreceptor to bipolar synaptic defects early, and displays rod-cone dystrophy with late loss of bipolar cells. This vision loss could be followed not only via histology, but using clinical live imaging similar to that used in human patients. INTERPRETATION: Natural history studies of rare paediatric neurodegenerative conditions are complicated by the rapid degeneration and limited availability of patients. Characterization of degeneration in the preclinical model allows for future experiments to better understand the mechanisms underlying the retinal disease progression in order to find therapeutics to treat patients, as well as to evaluate these therapeutic options for future human clinical trials. FUNDING: Van Sickle Family Foundation Inc., NIHP30EY030413, Morton Fichtenbaum Charitable Trust and 5T32GM131945-03.

ECHS1 deficiency and its biochemical and clinical phenotype.

ECHS1 gene encodes a mitochondrial enzyme, short-chain enoyl-CoA hydratase (SCEH). SCEH is involved in fatty acid oxidation ([Sharpe and McKenzie (2018); Mitochondrial fatty acid oxidation disorders associated with short-chain enoyl-CoA hydratase (ECHS1) deficiency, 7: 46]) and valine catabolism ([Fong and Schulz (1977); Purification and properties of pig heart crotonase and the presence of short chain and long chain enoyl coenzyme A hydratases in pig and guinea pig tissues, 252: 542-547]; [Wanders et al. (2012); Enzymology of the branched-chain amino acid oxidation disorders: The valine pathway, 35: 5-12]), and the dysfunction of SCEH leads to a severe Leigh or Leigh-like Syndrome phenotype in patients ([Haack et al. (2015); Deficiency of ECHS1 causes mitochondrial encephalopathy with cardiac involvement, 2: 492-509]; [Peters et al. (2014); ECHS1 mutations in Leigh disease: A new inborn error of metabolism affecting valine metabolism, 137: 2903-2908]; [Sakai et al. (2015); ECHS1 mutations cause combined respiratory chain deficiency resulting in Leigh syndrome, 36: 232-239]; [Tetreault et al. (2015); Whole-exome sequencing identifies novel ECHS1 mutations in Leigh, 134: 981-991]). This study aims to further describe the ECHS1 deficiency phenotype using medical history questionnaires and standardized tools assessing quality of life and adaptive skills. Our findings in this largest sample of ECHS1 patients in literature to date (n = 13) illustrate a severely disabling condition causing severe developmental delays (n = 11), regression (n = 10), dystonia/hypotonia and movement disorders (n = 13), commonly with symptom onset in infancy (n = 10), classical MRI findings involving the basal ganglia (n = 11), and variability in biochemical profile. Congruent with the medical history, our patients had significantly low composite and domain scores on Vineland Adaptive Behavior Scales, Third Edition. We believe there is an increasing need for better understanding of ECHS1 deficiency with an aim to support the development of transformative genetic-based therapies, driven by the unmet need for therapies for patients with this genetic disease.