scholarly journals Movement Disorders in Children with a Mitochondrial Disease: A Cross-Sectional Survey from the Nationwide Italian Collaborative Network of Mitochondrial Diseases

2021 ◽  
Vol 10 (10) ◽  
pp. 2063
Author(s):  
Chiara Ticci ◽  
Daniele Orsucci ◽  
Anna Ardissone ◽  
Luca Bello ◽  
Enrico Bertini ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Movement Disorder ◽  
Movement Disorders ◽  
Age At Onset ◽  
Cerebellar Atrophy ◽  
Mitochondrial Diseases ◽  
Fine Tuning ◽  
Cerebral White Matter ◽  
Collaborative Network ◽  
Childhood Onset

Movement disorders are increasingly being recognized as a manifestation of childhood-onset mitochondrial diseases (MDs). However, the spectrum and characteristics of these conditions have not been studied in detail in the context of a well-defined cohort of patients. We retrospectively explored a cohort of individuals with childhood-onset MDs querying the Nationwide Italian Collaborative Network of Mitochondrial Diseases database. Using a customized online questionnaire, we attempted to collect data from the subgroup of patients with movement disorders. Complete information was available for 102 patients. Movement disorder was the presenting feature of MD in 45 individuals, with a mean age at onset of 11 years. Ataxia was the most common movement disorder at onset, followed by dystonia, tremor, hypokinetic disorders, chorea, and myoclonus. During the disease course, most patients (67.7%) encountered a worsening of their movement disorder. Basal ganglia involvement, cerebral white matter changes, and cerebellar atrophy were the most commonly associated neuroradiological patterns. Forty-one patients harbored point mutations in the mitochondrial DNA, 10 carried mitochondrial DNA rearrangements, and 41 cases presented mutations in nuclear-DNA-encoded genes, the latter being associated with an earlier onset and a higher impairment in activities of daily living. Among our patients, 32 individuals received pharmacological treatment; clonazepam and oral baclofen were the most commonly used drugs, whereas levodopa and intrathecal baclofen administration were the most effective. A better delineation of the movement disorders phenotypes starting in childhood may improve our diagnostic workup in MDs, fine tuning management, and treatment of affected patients.

scholarly journals Adult-onset mitochondrial movement disorders: a national picture from the Italian Network

2021 ◽  
Author(s):  
V. Montano ◽  
D. Orsucci ◽  
V. Carelli ◽  
C. La Morgia ◽  
M. L. Valentino ◽  
...  
Keyword(s):  
Movement Disorder ◽  
Movement Disorders ◽  
Cerebellar Atrophy ◽  
Mitochondrial Diseases ◽  
Daily Practice ◽  
Clinical Genetic ◽  
Mitochondrial Movement ◽  
Neurophysiological Data ◽  
Diagnostic Flowchart

Abstract Introduction Both prevalence and clinical features of the various movement disorders in adults with primary mitochondrial diseases are unknown. Methods Based on the database of the “Nation-wide Italian Collaborative Network of Mitochondrial Diseases”, we reviewed the clinical, genetic, neuroimaging and neurophysiological data of adult patients with primary mitochondrial diseases (n = 764) where ataxia, myoclonus or other movement disorders were part of the clinical phenotype. Results Ataxia, myoclonus and movement disorders were present in 105/764 adults (13.7%), with the onset coinciding or preceding the diagnosis of the mitochondrial disease in 49/105 (46.7%). Ataxia and parkinsonism were the most represented, with an overall prevalence at last follow-up of 59.1% and 30.5%, respectively. Hyperkinetic movement disorders were reported in 15.3% at last follow-up, being the less common reported movement disorders. The pathogenic m.8344A > G and POLG variants were always associated with a movement disorder, while LHON variants and mtDNA single deletions were more commonly found in the subjects who did not present a movement disorder. The most common neuroimaging features were cortical and/or cerebellar atrophy, white matter hyperintensities, basal ganglia abnormalities and nigro-striatal degeneration. Almost 70% of patients with parkinsonism responded to dopaminergic therapy, mainly levodopa, and 50% with myoclonus were successfully treated with levetiracetam. Conclusion Movement disorders, mainly ataxia and parkinsonism, are important findings in adult primary mitochondrial diseases. This study underlies the importance of looking for a mitochondrial etiology in the diagnostic flowchart of a movement disorder and may help direct genetic screening in daily practice.

Phenotypic variation in leukoencephalopathy with vanishing white matter

Neurology ◽  
1998 ◽  
Vol 51 (2) ◽  
pp. 540-547 ◽  
Author(s):  
M. S. van der Knaap ◽  
W. Kamphorst ◽  
P. G. Barth ◽  
C. L. Kraaijeveld ◽  
E. Gut ◽  
...  
Keyword(s):  
Early Childhood ◽  
White Matter ◽  
Age At Onset ◽  
Cerebral White Matter ◽  
Complete Disappearance ◽  
Childhood Onset ◽  
Primary Demyelination ◽  
Histopathologic Findings ◽  
Clinical Mri ◽  
Vanishing White Matter

Objective: The objective of this study is to describe milder and later onset variants of a recently described leukoencephalopathy with vanishing white matter.Background: The diagnostic criteria used currently for this disease include an early-childhood onset of neurologic deterioration.Methods: Clinical, MRI, and spectroscopic findings of five patients were reviewed who fulfilled all inclusion criteria for the disease of vanishing white matter, apart from the age at onset. In one patient histopathologic findings were documented.Results: Onset of the disease was in late childhood or adolescence in four patients, and one patient was still presymptomatic in his early twenties. The course of the disease tended to be milder than in the patients with early-childhood onset. MRI revealed a diffuse cerebral hemispheric leukoencephalopathy with evidence of white matter rarefaction. MRS of the abnormal white matter showed a serious decrease but not complete disappearance of all "normal" signals and, in some patients, the presence of extra signals from lactate and glucose. Changes in relative spectral peak heights were compatible with axonal damage or loss, but not with active demyelination or substantial gliosis. Autopsy in one patient confirmed the extensive rarefaction of the cerebral white matter. There was a commensurate loss of axons and myelin sheaths. Within the brainstem, pontine lesions were present, also involving the central tegmental tracts-a phenomenon previously described in early-onset patients.Conclusion: Later onset does occur in the disease of vanishing white matter, and both MRS and histopathology are compatible with a primary axonopathy rather than primary demyelination.

Sleep Exacerbations and Facial Twitching: Diagnostic Clues for ADCY5-Related Dyskinesias

2020 ◽  
Author(s):  
Margherita Nosadini ◽  
Gianluca D'Onofrio ◽  
Maria Federica Pelizza ◽  
Concetta Luisi ◽  
Davide Padrin ◽  
...  
Keyword(s):  
Movement Disorder ◽  
Developmental Delay ◽  
De Novo ◽  
Brain Magnetic Resonance Imaging ◽  
Neurological Impairment ◽  
De Novo Mutation ◽  
Oligoclonal Bands ◽  
Emotional Stimuli ◽  
Childhood Onset ◽  
Ataxic Gait

Abstract Background Mutations in the adenylate cyclase 5 (ADCY5) gene are associated with childhood-onset paroxysmal dyskinesia. Methods We report a new video-documented case of pediatric ADCY5-related dyskinesia with de novo ADCY5 mutation. Results A boy born to nonconsanguineous parents after an uneventful pregnancy had developmental delay and hypotonia. At the age of 7 months, he presented with paroxysmal jerky–choreic–dystonic involuntary movements in wakefulness involving limbs, trunk, and face, exacerbated by emotional stimuli. These episodes gradually worsened in duration and frequency: at the age of 2.5 years, they occurred up to six times per day, and appeared also during sleep in prolonged bouts; the boy also had basal choreoathetoid–dystonic movements, hyperactivity, paraparetic–ataxic gait, generalized hypotonia with brisk tendon reflexes, drooling, and language delay with intellectual disability. Brain magnetic resonance imaging, electroencephalogram, electromyogram, eye review, metabolic investigations, oligoclonal bands, and autoantibodies were normal. Extensive genetic testing had not let to a diagnosis, until a heterozygous de novo mutation c.1252C > T (p.Arg418Trp) was identified in the ADCY5 gene. Clonazepam had partial effectiveness. The boy walked at the age of 3.5 years. At the age of 5 years, the paroxysmal movement disorder has slightly improved. Conclusion ADCY5 mutations should be considered among the differential diagnoses of early-onset paroxysmal choreic–athetosic–myoclonic–dystonic movement disorder involving limbs, trunk, and face, in patients with global neurological impairment with hypotonia and developmental delay. Facial dyskinesias and exacerbation by drowsiness/sleep and emotional stimuli are important clues that may allow a timely recognition of the disorder and avoidance of unnecessary diagnostic investigations.

scholarly journals Nanoscopic quantification of sub-mitochondrial morphology, mitophagy and mitochondrial dynamics in living cells derived from patients with mitochondrial diseases

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Weiwei Zou ◽  
Qixin Chen ◽  
Jesse Slone ◽  
Li Yang ◽  
Xiaoting Lou ◽  
...  
Keyword(s):  
Oxidative Phosphorylation ◽  
Optic Atrophy ◽  
Respiratory Function ◽  
Clinical Symptoms ◽  
Mitochondrial Dynamics ◽  
Cerebellar Atrophy ◽  
Mitochondrial Diseases ◽  
Living Cells ◽  
Mitochondrial Morphology ◽  
Mitochondrial Oxidative Phosphorylation

AbstractSLC25A46 mutations have been found to lead to mitochondrial hyper-fusion and reduced mitochondrial respiratory function, which results in optic atrophy, cerebellar atrophy, and other clinical symptoms of mitochondrial disease. However, it is generally believed that mitochondrial fusion is attributable to increased mitochondrial oxidative phosphorylation (OXPHOS), which is inconsistent with the decreased OXPHOS of highly-fused mitochondria observed in previous studies. In this paper, we have used the live-cell nanoscope to observe and quantify the structure of mitochondrial cristae, and the behavior of mitochondria and lysosomes in patient-derived SLC25A46 mutant fibroblasts. The results show that the cristae have been markedly damaged in the mutant fibroblasts, but there is no corresponding increase in mitophagy. This study suggests that severely damaged mitochondrial cristae might be the predominant cause of reduced OXPHOS in SLC25A46 mutant fibroblasts. This study demonstrates the utility of nanoscope-based imaging for realizing the sub-mitochondrial morphology, mitophagy and mitochondrial dynamics in living cells, which may be particularly valuable for the quick evaluation of pathogenesis of mitochondrial morphological abnormalities.

Gamma knife radiosurgery as a lesioning technique in movement disorder surgery

1997 ◽  
Vol 2 (3) ◽  
pp. E13 ◽  
Author(s):  
Ronald F. Young ◽  
Anne Shumway-Cook ◽  
Sandra S. Vermeulen ◽  
Peter Grimm ◽  
John Blasko ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Movement Disorder ◽  
Gamma Knife ◽  
Movement Disorders ◽  
Rating Scale ◽  
Gamma Knife Radiosurgery ◽  
Magnetic Resonance Images ◽  
Maximum Deviation

Fifty-five patients underwent radiosurgical placement of lesions either in the thalamus (27 patients) or globus pallidus (28 patients) for treatment of movement disorders. Patients were evaluated pre- and postoperatively by a team of observers skilled in the assessment of gait and movement disorders who were blinded to the procedure performed. They were not associated with the surgical team and concomitantly and blindly also assessed a group of 11 control patients with Parkinson's disease who did not undergo any surgical procedures. All stereotactic lesions were made with the Leksell gamma unit using the 4-mm secondary collimator helmet and a single isocenter with dose maximums from 120 to 160 Gy. Clinical follow-up evaluation indicated that 88% of patients who underwent thalamotomy became tremor free or nearly tremor free. Statistically significant improvements in performance were noted in the independent assessments of Unified Parkinson's Disease Rating Scale (UPDRS) scores in the patients undergoing thalamotomy. Eighty-five and seven-tenths percent of patients undergoing pallidotomy who had exhibited levodopa-induced dyskinesias had total or near-total relief of that symptom. Clinical assessment indicated improvement of bradykinesia and rigidity in 64.3% of patients who underwent pallidotomy. Independent blinded assessments did not reveal statistically significant improvements in Hoehn and Yahr scores or UPDRS scores. On the other hand, 64.7% of patients showed improvements in subscores of the UPDRS, including activities of daily living (58%), total contralateral score (58%), and contralateral motor scores (47%). Ipsilateral total UPDRS and ipsilateral motor scores were both improved in 59% of patients. One (1.8%) of 55 patients experienced a homonymous hemianopsia 9 months after pallidotomy due to an unexpectedly large lesion. No other complications of any kind were seen. Follow-up neuroimaging confirmed correct lesion location in all patients, with a mean maximum deviation from the planned target of 1 mm in the vertical axis. Measurements of lesions at regular interals on postoperative magnetic resonance images demonstrated considerable variability in lesion volumes. The safety and efficacy of functional lesions made with the gamma knife appear to be similar to those made with the assistance of electrophysiological guidance with open functional stereotactic procedures. Functional lesions may be made safely and accurately using gamma knife radiosurgical techniques. The efficacy is equivalent to that reported for open techniques that use radiofrequency lesioning methods with electrophysiological guidance. Complications are very infrequent with the radiosurgical method. The use of functional radiosurgical lesioning to treat movement disorders is particularly attractive in older patients and those with major systemic diseases or coagulopathies; its use in the general movement disorder population seems reasonable as well.

scholarly journals Mitochondrial DNA Replacement Techniques to Prevent Human Mitochondrial Diseases

2021 ◽  
Vol 22 (2) ◽  
pp. 551
Author(s):  
Luis Sendra ◽  
Alfredo García-Mares ◽  
María José Herrero ◽  
Salvador F. Aliño
Keyword(s):  
Mitochondrial Dna ◽  
Nuclear Dna ◽  
Genetic Disorders ◽  
Mitochondrial Diseases ◽  
Legal Regulation ◽  
Donor Oocyte ◽  
Legal Position ◽  
Ethical And Legal Issues ◽  
Mitochondrial Replacement Techniques ◽  
Do So

Background: Mitochondrial DNA (mtDNA) diseases are a group of maternally inherited genetic disorders caused by a lack of energy production. Currently, mtDNA diseases have a poor prognosis and no known cure. The chance to have unaffected offspring with a genetic link is important for the affected families, and mitochondrial replacement techniques (MRTs) allow them to do so. MRTs consist of transferring the nuclear DNA from an oocyte with pathogenic mtDNA to an enucleated donor oocyte without pathogenic mtDNA. This paper aims to determine the efficacy, associated risks, and main ethical and legal issues related to MRTs. Methods: A bibliographic review was performed on the MEDLINE and Web of Science databases, along with searches for related clinical trials and news. Results: A total of 48 publications were included for review. Five MRT procedures were identified and their efficacy was compared. Three main risks associated with MRTs were discussed, and the ethical views and legal position of MRTs were reviewed. Conclusions: MRTs are an effective approach to minimizing the risk of transmitting mtDNA diseases, but they do not remove it entirely. Global legal regulation of MRTs is required.

Abstract P409: Cerebellar Atrophy and Its Clinical Implications in Cerebral Amyloid Angiopathy

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Mitchell J Horn ◽  
Elif Gokcal ◽  
J. A Becker ◽  
Alvin S Das ◽  
Kristin Schwab ◽  
...  
Keyword(s):  
Cerebellar Atrophy ◽  
Potential Effect ◽  
Tissue Loss ◽  
Gait Velocity ◽  
Cerebral White Matter ◽  
Clinical Implications ◽  
Amyloid Angiopathy ◽  
Cerebellar Tissue ◽  
Cerebral Amyloid ◽  
Gait Function

Background: Recent data show that cerebral amyloid angiopathy (CAA) might cause hemorrhagic lesions in cerebellar cortex as well as cerebral atrophy. However, the potential effect of CAA on cerebellar tissue loss and its clinical implications have not been investigated. Methods: We compared cerebellar volumes in 70 nondemented patients with probable CAA to 70 age-matched healthy controls (HC) and 70 age-matched Alzheimer’s disease (AD) patients. Volumetric analyses including cerebellar cortical volume (pCbll-CV), cerebellar subcortical volume (pCbll-ScV), cerebral white matter volume (pWMV), and cerebral white matter hyperintensity volume (pWMH) were calculated as percent of total intracranial volume. Gait velocity (meters/seconds) was used to investigate the potential effect of cerebellar tissue loss on gait function. Results: Patients with CAA had significantly lower pCbll-ScV and pCbll-CV compared to HC (1.49%±0.17 vs 1.71%±0.23, p<0.001 and 6.03%±0.50 vs 6.23%±0.56, p<0.027 respectively). When compared to AD, pCbll-ScV but not pCbll-CV was significantly lower in CAA (1.49%±0.17 vs 1.670.24, p<0.001). Diagnosis of CAA was independently associated with lower pCbll-ScV in a general linear model adjusting for age, sex and presence of hypertension when compared to both HCs and patients with AD (p<0.0001 for all associations, after Bonferroni correction for multiple comparisons). Lower pCbll-ScV was associated with lower gait velocity score in univariate and multivariate analysis adjusted for relevant variables (adjusted β=0.826, 95%CI 0.357-1.295, p=0.001). Conclusion: Patients with CAA show cerebellar atrophy; predominantly in the subcortical cerebellum when compared to both HC and AD patients. Cerebellar tissue loss independently correlated with worse gait function in CAA patients. Overall, this study supports the view that CAA causes cerebellar injury which might mediate gait disturbance in patients with CAA.

scholarly journals Clinical and molecular basis of hepatocerebral mitochondrial DNA depletion syndrome in Japan: Evaluation of outcomes after liver transplantation

2020 ◽  
Author(s):  
Masaru Shimura ◽  
Naomi Kuranobu ◽  
Minako Ogawa-Tominaga ◽  
Nana Akiyama ◽  
Yohei Sugiyama ◽  
...  
Keyword(s):  
Liver Transplantation ◽  
Mitochondrial Dna ◽  
Mitochondrial Diseases ◽  
Failure To Thrive ◽  
Neurological Complications ◽  
Mild Intellectual Disability ◽  
Initial Manifestation ◽  
Molecular Features ◽  
Mitochondrial Dna Depletion ◽  
Mitochondrial Dna Depletion Syndrome

Abstract Background Hepatocerebral mitochondrial DNA depletion syndrome (MTDPS) is a disease caused by defects in mitochondrial DNA maintenance and leads to liver failure and neurological complications during infancy. Liver transplantation (LT) remains controversial due to poor outcomes associated with extrahepatic symptoms. The purposes of this study were to clarify the current clinical and molecular features of hepatocerebral MTDPS and to evaluate the outcomes of LT in MTDPS patients in Japan.Results We retrospectively assessed the clinical and genetic findings, as well as the clinical courses, of 23 hepatocerebral MTDPS patients from a pool of 999 patients who were diagnosed with mitochondrial diseases between 2007 and 2019. Causative genes were identified in 19 of 23 patients: MPV17 (n = 13), DGUOK (n = 3), POLG (n = 1), and MICOS13 (n = 1). Eight MPV17-deficient patients harbored c.451dupC and all three DGUOK-deficient patients harbored c.143-307_170del335. The most common initial manifestation was failure to thrive (n = 13, 56.5%). The most frequent liver symptom was cholestasis (n = 21, 91.3%). LT was performed on 12 patients, including nine MPV17-deficient and two DGUOK-deficient patients. Among the 12 transplanted patients, five, including one with mild intellectual disability, survived; while seven who had remarkable neurological symptoms before LT died. Five of the MPV17-deficient survivors had either c.149G>A or c.293C>T. Conclusions MPV17 was the most common genetic cause of hepatocerebral MTDPS. The outcome of LT for MTDPS was not favorable, as previously reported, however, patients harboring MPV17 mutations associated with mild phenotypes such as c.149G>A or c.293C>T, and exhibiting no marked neurologic manifestations before LT, had a better prognosis after LT.

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