bims-curels 2024-12-29 papers

bims-curels

Biomed News

on Leigh syndrome

Issue of 2024–12–29
eight papers selected by
Cure Mito Foundation

Ndufs4 inactivation in glutamatergic neurons reveals swallow-breathing discoordination in a mouse model of Leigh syndrome.
Biallelic variants in the NDUFAF6 cause mitochondrial respiratory complex assembly defects associated with Leigh syndrome in probands.
Mitochondrial tRNA modifications: functions, diseases caused by their loss, and treatment strategies.
Aging through the lens of mitochondrial DNA mutations and inheritance paradoxes.
Multisystem clinicopathologic and genetic analysis of MELAS.
Optimizing regulatory frameworks for gene therapies in rare diseases: Challenges and solutions.
Visual Functions in Patients With Leber Hereditary Optic Neuropathy (LHON).
Impact of genetic testing in developmental and epileptic encephalopathy- parents' perspective.

Exp Neurol. 2024 Dec 20. pii: S0014-4886(24)00449-7. [Epub ahead of print]385 115123

Ndufs4 inactivation in glutamatergic neurons reveals swallow-breathing discoordination in a mouse model of Leigh syndrome.

Alyssa Huff, Luiz Marcelo Oliveira, Marlusa Karlen-Amarante, Favour Ebiala, Jan Marino Ramirez, Franck Kalume.

  Swallowing, both nutritive and non-nutritive, is highly dysfunctional in children with Leigh Syndrome (LS) and contributes to the need for both gastrostomy and tracheostomy tube placement. Without these interventions aspiration of food, liquid, and mucus occur resulting in repeated bouts of respiratory infection. No study has investigated whether mouse models of LS, a neurometabolic disorder, exhibit dysfunctions in neuromuscular activity of swallow and breathing integration. We used a genetic mouse model of LS in which the NDUFS4 gene is knocked out (KO) specifically in Vglut2 or Gad2 neurons. We found increased variability of the swallow motor pattern, disruption in breathing regeneration post swallow, and water-induced apneas only in Vglut2 KO mice. These physiological changes likely contribute to weight loss and premature death seen in this mouse model. Following chronic hypoxia (CH) exposure, there was no difference in swallow motor pattern, breathing regeneration, weight, and life expectancy in the Vglut2-Ndufs4-KO CH mice compared to control CH, indicating a phenotypic rescue or prevention. These findings show that like patients with LS, Ndufs4 mouse models of LS exhibit swallow impairments as well as swallow-breathing discoordination alongside the other phenotypic traits described in previous studies. Understanding this aspect of LS will open roads for the development of future more efficacious therapeutic intervention for this illness.

Keywords:  Airway protection; Dysphagia; Hypoxia; Mitochondrial disease

DOI:  https://doi.org/10.1016/j.expneurol.2024.115123
Mol Genet Metab Rep. 2024 Dec;41 101168

Biallelic variants in the NDUFAF6 cause mitochondrial respiratory complex assembly defects associated with Leigh syndrome in probands.

Yuwei Zhou, Xiaofei Zeng, Luyi Zhang, Xiaojie Yin, Xue Ma, Keyi Li, Peijing Qiu, Xiaoting Lou, Liqin Jin, Ya Wang, Yanling Yang, Ting Shen.

   Background: Variants in NDUFAF6 have been reported to be associated with Leigh syndrome. However, further expansion of the NDUFAF6-phenotype and variants spectrum of NDUFAF6-related Leigh syndrome are still required.
Methods: Two patients diagnosed with Leigh syndrome were recruited, and whole-exome sequencing was performed to identify the genetic variants responsible for the abnormal gait, dystonia, and bilateral basal ganglia lesions, followed by validation using Sanger sequencing. Detailed medical records of the patients were collected and reviewed. Patient-derived immortalized B lymphocytes were generalized for functional assays. The clinical manifestations of the patients in this study and previously reported studies are summarized.
Results: Two patients developed gait dystonia followed by rapid progression to generalized dystonia and psychomotor regression. Brain magnetic resonance images showed lesions in bilateral symmetric basal ganglia. We identified that patient 1 and patient 2 had two missense changes (NM_152416 c.371 T > C, c.923 T > C and c.371 T > C, c.920 A > T) in NDUFAF6, respectively. The deficiency of mature super complex of complex I was confirmed in patient-derived immortalized B lymphocytes. Meanwhile, cellular ATP production was decreased, and mitochondrial ROS was increased. A literature review of 18 patients carrying variants in NDUFAF6 was conducted, focusing on neurological presentation.
Conclusions: NDUFAF6-related Leigh syndrome is a relevant cause of initial symptoms with abnormal gait, dystonia, and bilateral basal ganglia lesions. Two novel genetic variants, c.923 T > C and c.920 A > T were reported, which expands NDUFAF6-related Leigh syndrome and is advantageous for genetic counseling.

Keywords:  Complex I deficiency; Leigh syndrome; Mitochondrial disease; NDUFAF6

DOI:  https://doi.org/10.1016/j.ymgmr.2024.101168
RNA. 2024 Dec 24. pii: rna.080257.124. [Epub ahead of print]

Mitochondrial tRNA modifications: functions, diseases caused by their loss, and treatment strategies.

Takeshi Chujo, Kazuhito Tomizawa.

  Mitochondrial tRNA (mt-tRNA) modifications play pivotal roles in decoding and sustaining tRNA stability, thereby enabling synthesis of essential respiratory complex proteins in mitochondria. Consequently, loss of human mt-tRNA modifications caused by mutations in the mitochondrial or nuclear genome can cause life-threatening mitochondrial diseases such as encephalopathy and cardiomyopathy. In this article, we first provide a comprehensive overview of the functions of mt-tRNA modifications, the responsible modification enzymes, and the diseases caused by loss of mt-tRNA modifications. We then discuss progress and potential strategies to treat these diseases, including taurine supplementation for MELAS patients, targeted deletion of mtDNA variants, and overexpression of modification-related proteins. Finally, we discuss factors that need to be overcome to cure 'mitochondrial tRNA modopathies'.

Keywords:  MELAS; mitoTALEN; mitochondrial disease; tRNA modification; tRNA modopathy

DOI:  https://doi.org/10.1261/rna.080257.124
Biogerontology. 2024 Dec 27. 26(1): 33

Aging through the lens of mitochondrial DNA mutations and inheritance paradoxes.

Jia Chen, Hongyu Li, Runyu Liang, Yongyin Huang, Qiang Tang.

  Mitochondrial DNA encodes essential components of the respiratory chain complexes, serving as the foundation of mitochondrial respiratory function. Mutations in mtDNA primarily impair energy metabolism, exerting far-reaching effects on cellular physiology, particularly in the context of aging. The intrinsic vulnerability of mtDNA is increasingly recognized as a key driver in the initiation of aging and the progression of its related diseases. In the field of aging research, it is critical to unravel the intricate mechanisms underpinning mtDNA mutations in living organisms and to elucidate the pathological consequences they trigger. Interestingly, certain effects, such as oxidative stress and apoptosis, may not universally accelerate aging as traditionally perceived. These phenomena demand deeper investigation and a more nuanced reinterpretation of current findings to address persistent scientific uncertainties. By synthesizing recent insights, this review seeks to clarify how pathogenic mtDNA mutations drive cellular senescence and systemic health deterioration, while also exploring the complex dynamics of mtDNA inheritance that may propagate these mutations. Such a comprehensive understanding could ultimately inform the development of innovative therapeutic strategies to counteract mitochondrial dysfunctions associated with aging.

Keywords:  Aging; Evolutionary selection; Genetic bottleneck; Mitochondrial DNA mutations; Mother’s curse

DOI:  https://doi.org/10.1007/s10522-024-10175-x
Orphanet J Rare Dis. 2024 Dec 24. 19(1): 487

Multisystem clinicopathologic and genetic analysis of MELAS.

Shuai Xu, Jialiu Jiang, Leilei Chang, Biao Zhang, Xiaolei Zhu, Fengnan Niu.

   BACKGROUND AND OBJECTIVES: Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome is a maternally inherited mitochondrial disorder that mostly affects the central nervous system and skeletal muscle. This study provides a comprehensive summary of the clinical symptoms, multisystemic pathogenesis, and genetic characteristics of MELAS syndrome. The aim was to improve comprehension of clinical practice and gain a deeper understanding of the latest pathophysiological theories.
METHODS: The present investigation involved a cohort of patients diagnosed with MELAS at Nanjing Drum Tower Hospital between January 2014 and December 2022. Multisystem symptoms, magnetic resonance imaging/spectroscopy (MRI/MRS), muscle biopsy, and mitochondrial DNA (mtDNA) data were summarized and subsequently analysed.
RESULTS: This retrospective study included a cohort of 29 MELAS patients who predominantly presented symptoms such as stroke-like episodes, proximal muscle weakness, and exercise intolerance. MRI scans revealed very small infarcts beneath the deep cortex during stroke-like episodes, indicating nonvascular brain damage. Pathology analyses of the brain also showed neuronal degeneration and glial cell proliferation in the cerebral parenchyma. Proton magnetic resonance spectroscopy (1H-MRS) analysis revealed an increase in the lactate peak and a reduction in the N-acetylaspartate (NAA) level. Similarly, the phosphorus magnetic resonance spectroscopy (31P-MRS) analysis revealed an abnormal ratio of inorganic phosphate (Pi) to phosphocreatine (PCr). Muscle biopsy revealed the presence of ragged red fibres (RRFs) and cytochrome c oxidase (COX) enzyme-defective cells. These abnormalities indicate structural abnormalities in the mitochondria and deficiencies in oxidative phosphorylation, respectively. In addition to the common m.3243A > G variant, other prevalent variants, including m.5628 T > C, m.6352-13952del, and a 9-bp small deletion combined with m.3243A > G, exist.
CONCLUSIONS: MELAS is a rare mitochondrial syndrome characterized by clinical heterogeneity and genetic heteroplasmy. Abnormalities in mitochondrial metabolic function and impairments in enzyme activity are the pathogenic processes underlying MELAS. Mitochondrial vasculopathy and mitochondrial neuropathy may provide a partial explanation for the unique aetiology of stroke-like episodes.

Keywords:  COX enzyme defects; MELAS; MRS; RRFs; Stroke-like episodes

DOI:  https://doi.org/10.1186/s13023-024-03511-4
Mol Ther Methods Clin Dev. 2024 Dec 12. 32(4): 101386

Optimizing regulatory frameworks for gene therapies in rare diseases: Challenges and solutions.

Diane Berry, Kate Donigan, Lisa Kahlman, James Long, Christina Markus, Caitlin K McCombs.

The advent of genetic medicines and advanced diagnostics has revolutionized the treatment landscape for rare diseases and, with over 10,000 identified conditions affecting millions globally, has the potential to improve many lives. Despite this progress, only 5% of rare diseases have FDA-approved therapies, highlighting a significant unmet need. This article examines the critical need for optimizing the regulatory environment to support the development and approval of gene therapies for rare and ultrarare diseases, which often face unique challenges due to their complexity in the midst of a rapidly evolving field. Key issues discussed include the mismatch between traditional regulatory paradigms and the nature of gene therapies, the need for innovative clinical trial designs, and the importance of flexible manufacturing processes. The article proposes targeted reforms to align regulatory frameworks with the needs of patients with rare diseases and the pace of science, emphasizing the value of a holistic evidence approach, platform technologies, and iterative manufacturing evaluations. By addressing these challenges, we can accelerate the development of life-changing therapies in order to realize the opportunity to provide treatments to patients with rare genetic disorders in their lifetime.

DOI: https://doi.org/10.1016/j.omtm.2024.101386
J Neuroophthalmol. 2024 Dec 24.

Visual Functions in Patients With Leber Hereditary Optic Neuropathy (LHON).

Robin Francomme, Quentin Lenoble, Vasily Smirnov, Muriel Boucart.

BACKGROUND: Most of the data on visual functions in Leber hereditary optic neuropathy (LHON) is based on patient questionnaires. Our study assessed the impact of LHON on visual function by testing facial recognition and execution of purposeful actions.
METHODS: Twelve participants with LHON with central scotoma ranging from 5° to 20° and 12 unaffected age-matched controls were involved in our study. In the face recognition test, participants were asked to recognize the sex and the facial expression of photographs of faces increasing in size to simulate approaching faces. In the purposeful action test, they were asked to manipulate real objects while their eye movements were recorded.
RESULTS: Although most patients were able to recognize the correct sex of a face at a size corresponding to a 1-m viewing distance, recognition of facial expressions was severely impaired. Patients were slower than control subjects in executing purposeful tasks. A dynamic strategy to sample information needed for the execution of a task was documented in a longer scanpath and in higher frequency of saccades and fixation eye movements in patients than in control subjects.
CONCLUSIONS: Face perception is strongly impaired in patients with LHON. In addition, although the selection and manipulation of real objects to execute a task are slowed, they can be performed efficiently using peripheral vision.

DOI: https://doi.org/10.1097/WNO.0000000000002237
Epilepsy Behav. 2024 Dec 21. pii: S1525-5050(24)00556-0. [Epub ahead of print]163 110174

Impact of genetic testing in developmental and epileptic encephalopathy- parents' perspective.

Ida Stenshorne, Marte Roa Syvertsen, Anette Ramm-Pettersen, Kaja K Selmer, Jeanette Koht, Mari Wold Henriksen.

   BACKGROUND: Developmental and epileptic encephalopathies (DEEs) are a group of severe and heterogeneous epilepsies. Most of the affected patients have treatment refractory seizures, intellectual disability (ID), and multiple comorbidities. The condition has a negative impact on quality of life, both for the patients and their families. In recent decades, genetic testing has become an important part of the diagnostic routine investigation of patients with DEE. However, there are few quantitative studies on parental experiences and their perspectives on the genetic testing of their children. The aim of the present study was to describe parental experiences and perspectives concerning genetic testing, to investigate the importance of receiving an etiologic diagnosis, and consider the emotional impact of test results on parents.
METHODS: Based on a systematic literature search, a semi-quantitative questionnaire was designed to investigate the experiences of caregivers of patients with DEE, focusing on the period of genetic investigation. Eligible participants were caregivers of patients with epilepsy and intellectual disability or psychomotor delay (DEE) who had been through genetic investigation. Participants were consecutively recruited at Drammen Hospital (Norway) and through online recruitment in 2022-2023. The study was explorative and descriptive, and statistical analyses were performed with STATA.
RESULTS: Among the 60 responding caregivers, 59 were biological parents (32-75 years old) of children with DEE (1-43 years old) and were included in the statistical analyses. Among them, 67 % had a child with a genetic diagnosis. Knowing the etiology of the child's DEE was important for 91 %. Prior to genetic diagnostics, 62 % thought that knowing the cause of disease would make it easier to handle the epilepsy and other medical challenges. A large proportion (71 %) reported having had concerns about the cause of their child's disease before a potential genetic diagnosis was established, and, among these, 67 % suspected that something had happened during pregnancy or birth. The result of the genetic test led to a significantly higher degree of self-reported relief, grief, sadness, loneliness, and despair for the parents of a child that received a specific genetic diagnosis, compared to those who did not receive a diagnosis. While 24 % of parents had felt guilt concerning their child's epileptic condition (at any time), only 8,6% reported feeling guilt when receiving the result of the genetic test.
CONCLUSIONS: This study provides insight into the parental experiences of genetic testing in children with DEE. It is important for the parents of a child with DEE to know the cause of disease. Parents of children with DEE who received a genetic diagnosis experienced relief, but also negative feelings associated with receiving the result of the genetic test. Support and follow-up after a conclusive diagnostic test should therefore be prioritized.

Keywords:  Caregiver; DEE; Developmental and epileptic encephalopathy; Genetic testing; Parent

DOI:  https://doi.org/10.1016/j.yebeh.2024.110174