The etiology of autism spectrum disorders (ASD) is very heterogeneous. Mitochondrial dysfunction has been described in ASD; however, primary mitochondrial disease has been genetically proven in a ...small subset of patients. The main goal of the present study was to investigate correlations between mitochondrial DNA (mtDNA) changes and alterations of genes associated with mtDNA maintenance or ASD.
Sixty patients with ASD and sixty healthy individuals were screened for common mtDNA mutations. Next generation sequencing was performed on patients with major mtDNA deletions (mtdel-ASD) using two gene panels to investigate nuclear genes that are associated with ASD or are responsible for mtDNA maintenance. Cohorts of healthy controls, ASD patients without mtDNA alterations, and patients with mitochondrial disorders (non-ASD) harbouring mtDNA deletions served as comparison groups.
MtDNA deletions were confirmed in 16.6% (10/60) of patients with ASD (mtdel-ASD). In 90% of this mtdel-ASD children we found rare SNVs in ASD-associated genes (one of those was pathogenic). In the intergenomic panel of this cohort one likely pathogenic variant was present. In patients with mitochondrial disease in genes responsible for mtDNA maintenance pathogenic mutations and variants of uncertain significance (VUS) were detected more frequently than those found in patients from the mtdel-ASD or other comparison groups. In healthy controls and in patients without a mtDNA deletion, only VUS were detected in both panel.
MtDNA alterations are more common in patients with ASD than in control individuals. MtDNA deletions are not isolated genetic alterations found in ASD; they coexist either with other ASD-associated genetic risk factors or with alterations in genes responsible for intergenomic communication. These findings indicate that mitochondrial dysfunction is not rare in ASD. The occurring mtDNA deletions in ASD may be mostly a consequence of the alterations of the causative culprit genes for autism or genes responsible for mtDNA maintenance, or because of the harmful effect of environmental factors.
Parkinsonism is a complex multifactorial neurodegenerative disorder, in which genetic and environmental risk factors may both play a role. Among environmental risk factors cocaine was earlier ...ambiguously linked to Parkinsonism. Former single case reports described Parkinsonism in chronic cocaine users, but an epidemiological study did not confirm an increased risk of Parkinson's disease. Here we report a patient, who developed Parkinsonism in young age after chronic cocaine use, in whom a homozygous LRRK2 risk variant was also detected.
The patient was investigated because of hand tremor, which started after a 1.5-year period of cocaine abuse. Neurological examination suggested Parkinsonism, and asymmetrical pathology was confirmed by the dopamine transporter imaging study. The genetic investigations revealed a homozygous risk allele in the LRRK2 gene. After a period of cocaine abstinence, the patient's symptoms spontaneously regressed, and the dopamine transporter imaging also returned to near-normal.
This case report suggests that cocaine abuse indeed might be linked to secondary Parkinsonism and serves as an example of a potential gene-environmental interaction between the detected LRRK2 risk variant and cocaine abuse. The reversible nature of the DaTscan pathology is a unique feature of this case, and needs further evaluation, whether this is incidental or can be a feature of cocaine related Parkinsonism.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The genetic analysis of early-onset Parkinsonian disorder (EOPD) is part of the clinical diagnostics. Several genes have been implicated in the genetic background of Parkinsonism, which is clinically ...indistinguishable from idiopathic Parkinson’s disease. The identification of patient’s genotype could support clinical decision-making process and also track and analyse outcomes in a comprehensive fashion. The aim of our study was to analyse the genetic background of EOPD in a Hungarian cohort and to evaluate the clinical usefulness of different genetic investigations. The age of onset was between 25 and 50 years. To identify genetic alterations, multiplex ligation-dependent probe amplification (n = 142), Sanger sequencing of the most common PD-associated genes (n = 142), and next-generation sequencing (n = 54) of 127 genes which were previously associated to neurodegenerative disorders were carried out. The genetic analysis identified several heterozygous damaging substitutions in PD-associated genes (
C19orf12
,
DNAJC6
,
DNAJC13
,
EIF4G1
,
LRRK2
,
PRKN
,
PINK1
,
PLA2G6
,
SYNJ1
). CNVs in
PRKN
and
SNCA
genes were found in five patients. In our cohort, nine previously published genetic risk factors were detected in three genes (
GBA
,
LRRK2
, and
PINK1
). In nine cases, two or three coexisting pathogenic mutations and risk variants were identified. Advances of sequencing technologies make it possible to aid diagnostics of PD by widening the scope of analysis to genes which were previously linked to other neurodegenerative disorders. Our data suggested that rare damaging variants are enriched versus neutral variants, among PD patients in the Hungarian population, which raise the possibility of an oligogenic effect. Heterozygous mutations of multiple recessive genes involved in the same pathway may perturb the molecular process linked to PD pathogenesis. Comprehensive genetic assessment of individual patients can rarely reveal monogenic cause in EOPD, although it may identify the involvement of multiple PD-associated genes in the background of the disease and may facilitate the better understanding of clinically distinct phenocopies. Due to the genetic complexity of the disease, genetic counselling and management is getting more challenging. Clinical geneticist should be prepared for counselling of patients with coexisting disease-causing mutations and susceptibility factors. At the same time, genomic-based stratification has increasing importance in future clinical trials.
Introduction
Parkinson’s disease (PD) has a complex genetic background involving both rare and common genetic variants. Although a small percentage of cases show a clear Mendelian inheritance ...pattern, it is much more relevant to identify patients who present with a complex genetic profile of risk variants with different severity. The ß-glucocerebrosidase coding gene (
GBA1
) is recognized as the most frequent genetic risk factor for PD and Lewy body dementia, irrespective of reduction of the enzyme activity due to genetic variants.
Methods
In a selected cohort of 190 Hungarian patients with clinical signs of PD and suspected genetic risk, we performed the genetic testing of the
GBA1
gene. As other genetic hits can modify clinical features, we also screened for additional rare variants in other neurodegenerative genes and assessed the APOE-ε genotype of the patients.
Results
In our cohort, we identified 29
GBA1
rare variant (RV) carriers. Out of the six different detected RVs, the highly debated E365K and T408M variants are composed of the majority of them (22 out of 32). Three patients carried two
GBA1
variants, and an additional three patients carried rare variants in other neurodegenerative genes (
SMPD1
,
SPG11
, and
SNCA
). We did not observe differences in age at onset or other clinical features of the patients carrying two
GBA1
variants or patients carrying heterozygous APOE-ε4 allele.
Conclusion
We need further studies to better understand the drivers of clinical differences in these patients, as this could have important therapeutic implications.
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.”
Autism spectrum disorder (ASD) is genetically and phenotypically heterogeneous. Former genetic studies suggested that both common and rare genetic variants play a role in the etiology. In this study, ...we aimed to analyze rare variants detected by next generation sequencing (NGS) in an autism cohort from Hungary.
We investigated the yield of NGS panel sequencing of an unselected ASD cohort (
= 174 ) for the detection of ASD associated syndromes. Besides, we analyzed rare variants in a common disease-rare variant framework and performed rare variant burden analysis and gene enrichment analysis in phenotype based clusters.
We have diagnosed 13 molecularly proven syndromic autism cases. Strongest indicators of syndromic autism were intellectual disability, epilepsy or other neurological plus symptoms. Rare variant analysis on a cohort level confirmed the association of five genes with autism (
,
,
,
, and
). We found no correlation between rare variant burden and number of minor malformation or autism severity. We identified four phenotypic clusters, but no specific gene was enriched in a given cluster.
Our study indicates that NGS panel gene sequencing can be useful, where the clinical picture suggests a clinically defined syndromic autism. In this group, targeted panel sequencing may provide reasonable diagnostic yield. Unselected NGS panel screening in the clinic remains controversial, because of uncertain utility, and difficulties of the variant interpretation. However, the detected rare variants may still significantly influence autism risk and subphenotypes in a polygenic model, but to detect the effects of these variants larger cohorts are needed.
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.
related disorders (also known as brain-lung-thyroid syndrome or benign hereditary chorea 1) are associated with a wide spectrum of symptoms. The core features are various movement disorders, ...characteristically chorea, less frequently myoclonus, dystonia, ataxia; thyroid disease; and lung involvement. The full triad is present in 50% of affected individuals. Numerous additional symptoms may be associated, although many of these were reported only in single cases. Pituitary dysfunction was ambiguously linked to
haploinsufficiency previously.
We examined two members of a family with motor developmental delay, mixed movement disorder (myoclonus, dystonia and chorea) and endocrinological abnormalities (peripheric thyroid disease, and pituitary hormone deficiencies). Dystonia predominated at the father, and myoclonus at the daughter. The father had hypogonadotropic hypogonadism, while the daughter was treated with growth hormone deficiency. Both patients had empty sella on MRI. Candidate gene analyses were negative. Exome sequencing detected a pathogenic stop variation (NM_003317:c.338G>A, p.Trp113
) in the
gene.
This case study has two highlights. (1) It draws attention to possible pituitary dysfunction in brain-lung-thyroid syndrome, and provide further evidences that this might be linked to loss of function of the
gene. (2) It underscores the importance of considering
related disorders in the differential diagnosis of myoclonus dystonia.
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with unknown genetic and environmental causation in most of the affected individuals. On the other hand, there are a growing ...number of ASD-associated syndromes, where the exact genetic origin can be revealed. Here we report a method, which included the targeted next generation sequencing (NGS) and filtering of 101 ASD associated genes, followed by database search. Next, RNA sequencing was used to study the region of interest at the transcriptional level. Using this workflow, we identified a de novo mutation in the euchromatic histone-lysine N-methyltransferase 1 gene (EHMT1) of an autistic patient with dysmorphisms. Sequencing of EHMT1 transcripts showed that the premature termination codon (Trp1138Ter) created by a single nucleotide change elicited nonsense-mediated mRNA decay, which led to haploinsufficiency already at the transcriptional level. Database and literature search provided evidence that this mutation caused Kleefstra syndrome (KS), which was confirmed by the presence of the disorder-specific phenotype in the patient. We provide a proof of principle that the implemented method is capable to elucidate the genetic etiology of individuals with syndromic autism. The novel mutation detected in the EHMT1 gene is responsible for KS's symptoms. In addition, further genetic factors might be involved in the ASD pathogenesis of the patient including a missense DPP6 mutation (Arg322Cys), which segregated with the autistic phenotype within the family.
•We developed a NGS-based workflow to screen for syndromic causes of autism.•A pathogenic, de novo mutation was found in an autistic patient with dysmorphisms.•The mutation leads haploinsufficiency of EHMT1 mRNA and causes Kleefstra syndrome.•A DPP6 missense variant segregated with the autism within the patient's family•Multiple genetic factors might contribute to autistic syndromes of KS patients.
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.
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