After plasma membrane permeabilization, MSTO1 is released from the cells. ...an MSTO1 loss-of-function mutation is associated with a human disorder showing mitochondrial involvement. ...we have also ...studied an ADOA-associated OPA1 mutation (c.984) that caused a lesser decrease in the fusion activity (30%) than the present MSTO1 mutations. ...the MSTO1-associated fusion decrease is in the range of the OPA1-associated ones.” The cDNA sequencing confirmed the heterozygous V8M, while in the genomic DNA, no exon loss or multiplication was found in this gene. ...the Hungarian patients seem to have one impaired and one normal MSTO1 allele, which results in a partial decrease in MSTO1 mRNA and protein levels. The following text on page 980 has been removed: “The cause–effect relationship between MSTO1 decrease and fusion inhibition was validated by genetic rescue studies in the patient fibroblasts (Fig 4).” “Since a loss of function mutation in MSTO1 is associated with impaired mitochondrial dynamics and several symptoms characteristic to mitochondrial disease patients, MSTO1 might be a factor in diseases that have a mitochondrial component.”
We present a male patient carrying a pathogenic MECP2 p. Arg179Trp variant with predominant negative psychiatric features and multilevel evidence of mitochondrial dysfunction who responded to the ...cariprazine treatment. He had delayed speech development and later experienced severe social anxiety, learning disabilities, cognitive slowing, and predominant negative psychiatric symptoms associated with rigidity. Clinical examinations showed multisystemic involvement. Together with elevated ergometric lactate levels, the clinical picture suggested mitochondrial disease, which was also supported by muscle histopathology. Exploratory transcriptome analysis also revealed the involvement of metabolic and oxidative phosphorylation pathways. Whole-exome sequencing identified a pathogenic MECP2 variant, which can explain both the dopamine imbalance and mitochondrial dysfunction in this patient. Mitochondrial dysfunction was previously suggested in classical Rett syndrome, and we detected related phenotype evidence on multiple consistent levels for the first time in a MECP2 variant carrier male. This study further supports the importance of the MECP2 gene in the mitochondrial pathways, which can open the gate for more personalized therapeutic interventions. Good cariprazine response highlights the role of dopamine dysfunction in the complex psychiatric symptoms of Rett syndrome. This can help identify the optimal treatment strategy from a transdiagnostic perspective instead of a classical diagnostic category.
Introduction:
Wernicke encephalopathy (WE) and Wernicke–Korsakoff syndrome (WKS) are well-known disorders caused by thiamine deficiency. In addition to the classical concept of these diseases, some ...literature data suggest a connection between mitochondrial dysfunction and WE/WKS. Psychotic disorders and WKS seem to run in families, as the deficiency of the oxidative phosphorylation can be a trigger factor in psychotic events and WE/WKS as well. We present a patient harbouring the m.A3243G mtDNA mutation with the clinical and magnetic resonance imaging (MRI) findings of WKS who developed schizophrenia with predominantly negative symptoms some years later.
Case presentation:
A 27-year-old woman was referred to our clinic with severe weight loss after severe vomiting episodes, memory dysfunction and gait ataxia. Family history, as well as clinical, imaging and laboratory findings suggested a mitochondrial aetiology of her symptoms. Brain MRI detected bilateral mild thalamic lesions and loss of corpus mammillae, indicating Wernicke encephalopathy. Genetic testing detected an m.A3243G mtDNA mutation, which has been frequently associated with mitochondrial encephalopathy with lactic acidosis and stroke-like episodes. High-dose vitamin B1 supplementation with supportive antioxidant therapy improved the patient’s memory and learning disturbance; however, some months later she developed psychosis with predominantly negative symptoms and her cognitive functions deteriorated again. Both cognitive and negative symptoms responded well to cariprazine monotherapy.
Discussion:
Mitochondrial disease due to mtDNA alteration can be a rare cause of WE. In addition to vitamin B1 supplementation, cariprazine with significant dopamine D3 receptor binding can be useful to treat the predominantly negative symptoms and cognitive dysfunction in patients with mitochondrial dysfunction.
Conclusion:
We assume that patients with a mitochondrial disorder might be prone to develop WE/WKS and therefore need tailored supportive therapy during metabolic crisis as well as symptom-based personalized antipsychotic treatment.
Phospholipase A2-associated Neurodegeneration (PLAN) is a group of neurodegenerative diseases associated with the alterations of PLA2G6. Some phenotype-genotype association are well known but there ...is no clear explanation why some cases can be classified into distinct subgroups, while others follow a continuous clinical spectrum.
Long-term neurological, and psychiatric follow-up, neuropathological, radiological, and genetic examinations, were performed in three affected girls and their family.
Two 24-years old twins and their 22-years old sister harbored the p.P622S, and p.R600W mutation in PLA2G6. The age of onset and the most prominent presenting symptoms (gaze palsy, ataxia, dystonia, psychomotor regression indicated atypical neuroaxonal dystrophy (ANAD), however, optic atrophy, severe tetraparesis would fit into infantile neuroaxonal dystrophy (INAD). All siblings had hyperintensity in the globi pallidi and substantiae nigrae which is reported in ANAD, whereas it is considered a later neuroradiological marker in INAD. The slow progression, rigidity, bradykinesis, and the prominent psychiatric symptoms indicate PLA2G6-related dystonia-parkinsonism. Abnormal mitochondria, lipid accumulation and axonal spheroids were observed in the muscle and nerve tissue. Brain deposition appeared 6 years following the initial cerebellar atrophy. Mild MRI alterations were detected in the asymptomatic carrier parents.
The colorful clinical symptoms, the slightly discordant phenotype, and the neuroimaging data in the family supports the view that despite the distinct definition of age-related phenotypes in PLAN, these are not strict disease categories, but rather a continuous phenotypic spectrum. The mild MRI alterations of the parents and the family history suggest that even heterozygous pathogenic variants might be associated with clinical symptoms, although systematic study is needed to prove this.
The aim of our study was to assess psychiatric symptoms in patients with genetically proven primary mutation of the mitochondrial DNA.
19 adults with known mitochondrial mutation (MT) have been ...assessed with the Stanford Health Assessment Questionnaire 20-item Disability Index (HAQ-DI), the Symptom Check List-90-Revised (SCL-90-R), the Beck Depression Inventory-Short Form (BDI-SF), the Hamilton Depression Rating Scale (HDRS) and the clinical version of the Structured Clinical Interview for the the DSM-IV (SCID-I and SCID-II) As control, 10 patients with hereditary sensorimotor neuropathy (HN), harboring the peripheral myelin protein-22 (PMP22) mutation were examined with the same tools.
The two groups did not differ significantly in gender, age or education. Mean HAQ-DI score was 0.82 in the MT (range: 0-1.625) and 0.71 in the HN group (range: 0-1.625). Level of disability between the two groups did not differ significantly (p = 0.6076). MT patients scored significantly higher on the BDI-SF and HDRS than HN patients (12.85 versus 4.40, p = 0.031, and 15.62 vs 7.30, p = 0.043, respectively). The Global Severity Index (GSI) of SCL-90-R also showed significant difference (1.44 vs 0.46, p = 0.013) as well as the subscales except for somatization. SCID-I interview yielded a variety of mood disorders in both groups. Eight MT patient (42%) had past, 6 (31%) had current, 5 (26%) had both past and current psychiatric diagnosis, yielding a lifetime prevalence of 9/19 (47%) in the MT group. In the HN group, 3 patients had both past and current diagnosis showing a lifetime prevalence of 3/10 (30%) in this group. SCID-II detected personality disorder in 8 MT cases (42%), yielding 3 avoidant, 2 obsessive-compulsive and 3 personality disorder not otherwise specified (NOS) diagnosis. No personality disorder was identified in the HN group.
Clinicians should be aware of the high prevalence of psychiatric symptoms in patients with mitochondrial mutation which has both etiologic and therapeutic relevance.
Pompe disease is caused by the accumulation of glycogen in the lysosomes due to a deficiency of the lysosomal acid-α-glucosidase (GAA) enzyme. Depending on residual enzyme activity, the disease ...manifests two distinct phenotypes. In this study, we assess an enzymatic and genetic analysis of Hungarian patients with Pompe disease. Twenty-four patients diagnosed with Pompe disease were included. Enzyme activity of acid-α-glucosidase was measured by mass spectrometry. Sanger sequencing and an MLPA of the GAA gene were performed in all patients. Twenty (83.33%) patients were classified as having late-onset Pompe disease and four (16.66%) had infantile-onset Pompe disease. Fifteen different pathogenic GAA variants were detected. The most common finding was the c.-32-13 T > G splice site alteration. Comparing the α-glucosidase enzyme activity of homozygous cases to the compound heterozygous cases of the c.-32-13 T > G disease-causing variant, the mean GAA activity in homozygous cases was significantly higher. The lowest enzyme activity was found in cases where the c.-32-13 T > G variant was not present. The localization of the identified sequence variations in regions encoding the crucial protein domains of GAA correlates with severe effects on enzyme activity. A better understanding of the impact of pathogenic gene variations may help earlier initiation of enzyme replacement therapy (ERT) if subtle symptoms occur. Further information on the effect of GAA gene variation on the efficacy of treatment and the extent of immune response to ERT would be of importance for optimal disease management and designing effective treatment plans.
The protein MSTO1 has been localized to mitochondria and linked to mitochondrial morphology, but its specific role has remained unclear. Lactate stress test and myopathological results suggest ...mitochondrial dysfunction. In patient fibroblasts, MSTO1 mRNA and protein abundance are decreased, mitochondria display fragmentation, aggregation, and decreased network continuity and fusion activity. Short-term silencing of MSTO1 in HeLa cells reproduced the impairment of mitochondrial morphology and dynamics observed in the fibroblasts without damaging bioenergetics. At variance with a previous report, we find MSTO1 to be localized in the cytoplasmic area with limited colocalization with mitochondria. MSTO1 interacts with the fusion machinery as a soluble factor at the cytoplasm-mitochondrial outer membrane interface. After plasma membrane permeabilization, MSTO1 is released from the cells. MSTO1 likely has a physiologically relevant role in mitochondrial morphogenesis by supporting mitochondrial fusion.§
The protein product of the nuclear-encoded POLG gene plays a key role in the maintenance of mitochondrial DNA replication, and its failure causes multi-system diseases with varying severity. The ...clinical spectrum is extremely wide, and the most common symptoms include ptosis, myoclonus, epilepsy, myopathy, sensory ataxia, parkinsonism, cognitive decline and infertility. Now, it is known that mitochondrial dysfunction in Parkinson's disease plays a key role in the loss of dopaminergic neurons in the substantia nigra. Therefore, changes in the POLG gene may influence the development of various hereditary neurodegenerative diseases, including monogenic parkinsonism. However, only limited information is available on the relationship between Parkinson's disease and POLG gene and until now, there are no available data about the Hungarian population. In our study, we performed a next-generation sequencing study of 67 Hungarian patients with parkinsonism and analyzed the potentially damaging alterations in the POLG gene. 3 patients have been identified with a potential pathogen variant. In this study, we would like to call attention to the fact that during the differential diagnosis of parkinsonism, the possible involvement of POLG gene should be kept in mind. Especially in the presence of additional symptoms, such as ophthalmoparesis, non-vascular white matter lesions, psychiatric comorbidity, and relatively early age of onset, the POLG gene should be taken into consideration. Based on previous data from the literature and our own experience, we have summarized a possible diagnostic approach for POLG-associated parkinsonism. Orv Hetil. 2020; 161(20): 821-828.
The anti-apoptotic gene replacements could be an option in preventing hypoxia-induced neuronal loss. In this paper we tested the effect of anti-apoptosis (bcl-2 and bcl-XL) gene transfer on cell ...plasticity. Nestin, synapsin-1 and c-fos genes and proteins expression were measured in PC12 cells in normal condition, and after hypoxia/re-oxygenation. Gene delivery results a significant increase in both bcl-2 and bcl-XL gene expression. Hypoxia (1h)/re-oxygenation (24h) have a detrimental effect upon cultured cells by increasing the pro-apoptotic, bax gene and protein expression. Bcl-2 or bcl-XL gene delivery resulted in a significant increase in and the cellular levels of the corresponding mRNAs and proteins. Bcl-2 gene augmented the nestin gene and protein expression which has been compromised previously by the hypoxic event. Similarly c-fos mRNA and protein expression decreased significantly after hypoxia, while the anti-apoptotic gene treatment normalized c-fos expression. Synapsin-1 gene or protein expression remained about on the same level under normoxic conditions or following hypoxia after gene treatment.
We can conclude that anti-apoptotic gene transfers activate neuronal plasticity proteins nestin and c-fos. This link on anti-apoptotic proteins and cell plasticity is a new finding.
Abstract Autoimmune myasthenia gravis is a disorder with a complex pathomechanism in which sex hormones, in particular oestrogen, have long been considered to play a role. Here we report the result ...of a case-control study which evaluated the association of two oestrogen receptor alpha gene polymorphisms with myasthenia gravis in Caucasian patients. PvuII (rs2234693) and XbaI (rs9340799) restriction fragment polymorphisms of the oestrogen receptor alpha gene were analyzed in 113 female myasthenia patients and 184 female controls. Distribution of these polymorphisms was compared with PCR-RFLP. Patients were divided into groups according to their oestrogen receptor alpha genotypes, and acetylcholine receptor antibody status and age of onset were compared between the groups. We found no significant difference between any of the groups implying that these two polymorphisms probably do not play a role in the pathomechanism of myasthenia gravis in Caucasian women.
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