Manual Mitochondrial Disorders: From Pathophysiology to Acquired Defects

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This means that each parent has inherited a defective gene but do not show symptoms of the disease. However, "carriers" are able to pass the defective gene onto their children. One out of the four children would inherit the defective gene and develop a mitochondrial disease and show symptoms. Two out of the four children will be genetic carriers of a mitochondrial disease, just like their parents.

The remaining child would be genetically "typical. Even though these disorders are long term and incurable, treatments are available. Early treatment of symptoms can reduce symptoms or slow the decline in health. Avoiding certain medications and medical stressors that worsen symptoms is also helpful. Certain medications and supplements may improve mitochondrial disease-related symptoms -- just as they do for other incurable diseases -- such as diabetes and emphysema.

Although all U. In some patients, the diagnosis can be made based on clinical symptoms and a positive blood test identifying a genetic mutation or a combination of clinical findings and other non-invasive testing. In either case, a muscle biopsy is not necessary. Finally, since biopsy results usually do not alter the long-term outcome or treatment considerations, some specialists and patients choose to treat without the need for a muscle biopsy. There is no clear evidence that immunizations themselves hurt patients with mitochondrial or metabolic disorders.

Medical stress fever, dehydration, illness, revving up the immune system may bring out or worsen metabolic disorders. Thus, there have been some patients where the fever after an immunization led to symptom onset or worsening. In these individuals, it was not the immunization itself that caused these problems.

It is generally believed that patients should get their immunizations. Still, for individuals whose symptoms emerge or worsen when under medical stress, spacing out immunizations and tight fever-control may help. This approach is not based in medical science. Acronyms were commonly used when these disorders were first described. Today, the naming of mitochondrial disorders is evolving. Mitochondrial disorders are currently named by any of the following methods:. It is important to note that the labels given this disorder do not, in and of themselves, predict the long-term outcome or alter treatment.

Cleveland Clinic is a non-profit academic medical center. Advertising on our site helps support our mission. We do not endorse non-Cleveland Clinic products or services. The co-occurrence of these symptoms is an indicator for MD according to mitochondrial disease criteria MDC [ 36 ]. The distribution of symptoms which are common in mitochondrial disorders in the patients with mtdel-ASD and in ASD without mtdel.

Minor physical anomalies were identified in 44 children. Mitochondrial deletions were identified in Two children had multiple deletions, whereas a single major deletion was detected in the range of 2.

Mitochondrial diseases: advances and issues

An evaluation of clinical phenotype, family history, and laboratory data suggested MD in seven cases with mtDNA deletion. None of the investigated families had a previous diagnosis of primary MD. In the 60 healthy control individuals, a mtDNA deletion was found in two cases. In this subgroup, we found one rare likely pathogenic variant and one variant with uncertain significance VUS. In one patient the compound heterozygous state of one pathogenic and one VUS in C10orf2 gene were detected. A heterozygous pathogenic mutation in chromodomain helicase DNA-binding protein 7 CHD7 was found in this patient as well as a heterozygous mutation of uncertain significance in tuberin TSC2.

In Patient 8 P8 , we found a pathogenic nonsense mutation in 7-dehydrocholesterol reductase DHCR7 , which was present in only one allele. The significance of the missense mutation identified in our study is uncertain; during segregation analysis the same mutation was present in the healthy mother, however we do not know exactly the penetrance of the genetic defects of AUTS2.

Aside from his developmental abnormalities, neurological investigation detected pes varus, severe visual impairment, bilateral ptosis, chewing difficulties, mild atrophy and weakness in the distal muscles of the extremities, and truncal ataxia. High lactate levels were detected in both serum and cerebrospinal fluid, and decreased levels of serum melatonin, calcium, and vitamin D3 were measured. A brain MRI detected hypoplastic vermis and transverse sinus on the right side. Brainstem auditory evoked potentials was normal. Family history identified arrhythmia, diabetes mellitus, and colon polypomatosis on the maternal side, and diabetes mellitus, arrhythmia, and dementia on the paternal side.

Evidence of prolonged neonatal jaundice, highly elevated liver enzymes, low prothrombin level, and high IgM and IgG type anti-cytomegalovirus CMV antibodies led to the diagnosis of a congenital CMV infection-induced hepatic lesion. She had congenital sensorineural hearing loss, mild myopathic facies, mild ptosis, and atopic facial dermatitis. The healthy mother also harbours the detected heterozygous mutation. Cholesterol and 7-dehydrocholesterol levels of the child are in the normal range. However, human CMV infection may lead to altered mitochondrial biogenesis [ 40 ]. We believe that this case demonstrates a direct interaction between genetic and environmental risk factors in some forms of ASD.

In this study, we provide for the first time a comprehensive genetic analysis of patients with ASD that investigates co-occurrence of the most frequent mtDNA alterations, intergenomic communication disturbances 51 genes , and genes previously associated with ASD. We found co-occurrence of mtDNA deletions with ASD-associated genetic alterations, which supports the previous observation that mitochondrial alterations are frequently associated with ASD. These genetic alterations in P3 were also accompanied by a TSC2 mutation of uncertain significance.

Based on the phenotype, we conclude that the driving genetic alteration in this patient is the CHD7 mutation, and the mitochondrial gene defect may not be the true causative factor in the etiology of the disease; however, CHD7 function is strongly ATP-dependent [ 41 ]. In addition, the associated heterozygous TSC2 mutation is likely a modifying gene. CHD7 is a member of the chromo-domain helicase DNA-binding CHD protein family and plays a role in transcription regulation through chromatin remodelling. Mutations in TSC2 are known to cause one syndromic form of ASD; however, our patient did not develop the classic symptoms of tuberous sclerosis until recently.

Furthermore, a high 7-dehydrocholesterol level results in mitochondrial dysfunction [ 43 ]. However, the significance of a heterozygous mutation in this gene is not known. We hypothesize that in the case presented here the co-occurrence of the DHCR7 heterozygous mutation and CMV infection may play a role in changes of mitochondrial biogenesis and in the pathogenesis of autistic features.

Currently, it is the most common metabolic abnormality known in ASD with a prevalence of 7. Therefore, the possibility of secondary damage to mitochondria cannot be excluded. A small pilot study examining 12 patients with ASD described 8 mitochondrial deletions [ 21 ], which could be the result of intergenomic communication disturbances, environmental factors, or other gene—gene interactions. As is the case for many other disorders, it is still not clear whether the detected mitochondrial dysfunction in ASD is a primary or secondary event either having a key role in disease pathogenesis or is simply a downstream effect.

In our study, mtDNA deletions were identified in The importance of the presence of heterozygous mutations is not well understood. It is known in some genes responsible for intergenomic communications heterozygous mutations may result in a less severe phenotype than that found with the homozygous form [ 45 ]. The question has also been raised whether patients with MD and ASD symptoms have special characteristics.

Significant difference between mtdel-ASD and non-mtdel-ASD group was found regarding clinical phenotypes developmental regression, muscle hypotonia, additional neurological signs and multisystemic alterations were more common in cases mt-delASD. Interestingly, the phenotypes of classic mitochondrial deletion syndromes, such as Pearson syndrome, progressive ophthalmoplegia externa, and Kearns—Sayre syndrome, were not detected in any of our patients. The family histories of mtdel-ASD children in our cohort differed from the family histories of the ASD cohort without a mtDNA deletion, since various psychiatric disorders were common among family members of mtdel-ASD cases both on maternal and paternal side.

However none of the parents reached the MDC scoring cut-off value for definitive MD, which could not be independently verified because none of the family members agreed to perform muscle biopsy. MtDNA disorders are usually inherited maternally, however single mtDNA deletions are considered sporadic events with low inheritance risk, whereas multiple mtDNA deletions are the result of primary nuclear defects in genes responsible for mtDNA maintenance or nucleoside metabolism and follow Mendelian inheritance patterns [ 46 ].

Mitochondrial haplogroups were also investigated in association with ASD. Chalkia et al. In Hungary it is not rare that a person has ancient European haplotype such as T, K, and U haplotype, and rarely Asian haplotype such as B can occur as well. In some Hungarian patients the mtDNA deletion was coexisting with ancient haplotype [ 48 ]. A rare mutation was detected in AUTS2 in which deletions are inherited in an autosomal dominant manner and are associated with neurological symptoms including intellectual disability and developmental delay [ 49 ].

In a modest study of 13 cases of ASD associated with AUTS2 alterations, only one patient had a nonsense mutation; all the other patients had a deletion [ 49 ]. The significance of the missense mutation identified in our study is uncertain her mother harbours the mutation as well ; however, clinical symptoms of the patient correlate with the phenotype of previously published AUTS2 mutations.

The gene—gene interaction of these two alterations are hypothesized. Most of these genes play a role in cell regulation, signal transduction, and various signalling pathways, which could influence mitochondrial function. FOXP2 is an evolutionarily conserved transcription factor that regulates the expression of a variety of genes.

Mutations in this gene cause speech-language disorder 1 OMIM , which is also known as autosomal dominant speech and language disorder with orofacial dyspraxia [ 50 ]. RAI1 acts as a transcriptional regulator of chromatin remodelling by interacting with basic transcriptional machinery [ 51 ]. RAI1 deletion is associated with Smith—Magenis syndrome, whereas duplications are associated with Potocki—Lupski syndrome [ 52 ]. Several heterozygous mutations are also associated with Smith—Magenis syndrome [ 53 ].

In our case, we found that the typical symptoms of Smith—Magenis syndrome were not present. Mutations in PDE10A can affect cyclic nucleotide concentrations. The phosphodiesterase family of proteins regulates cellular levels, localization, and duration of action of these second messengers by controlling the rate of their degradation. In addition, phosphodiesterases are involved in many signal transduction pathways and are implicated in the pathogenesis of bipolar disorder [ 54 ].

Mitochondrial dysfunction may be associated with several forms of syndromic ASD, but is also frequently related to non-syndromic cases [ 8 , 9 ]. During our comprehensive analysis, we found examples of both but in most cases we did not find the causative genetic mutation that accounts for the mitochondrial dysfunction. In the examined children from the general ASD cohort without mtDNA deletion , we found several VUS, most of which were identified in genes without previous correlation to mitochondrial dysfunction. Based on our findings, we conclude that the detected mitochondrial DNA deletions in patients with ASD in our cohort are a secondary effect.

By investigating the most common mtDNA alterations and the most common nuclear genes responsible for intergenomic communications, we did not identify the clear genetic etiology in most of our cases. Therefore, further investigation and characterization is warranted.

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We identified certain limitations in our study. We focused our investigation to analyse mutational hotspots and large mtDNA deletions and did not sequence the entire mitochondrial genome. The mtDNA mutations were analysed from blood samples; postmitotic tissue was not available. The detection of mtDNA deletion from NGS data will be in the future a new perspective, but today it is not in the everyday praxis. However, these panels do not include all currently associated genes and the number of these genes is continuously increasing.

Finally, our healthy control group was older than our ASD cohort and had different gender ratios. However, we felt that ethically it was not appropriate to obtain biomaterial from healthy children for genetic testing. Since somatic mtDNA deletion may occur in association with ageing, and we detected the mtDNA deletion less frequently in the control group it had no impact on our data. Mitobreak Database [ 55 ] supports or presumption since deletion were present mostly only aged healthy controls, otherwise they were associated or to sporadic primary mitochondrial disorders single deletion or to disorders due to intergenomial gene alterations multiple deletions.

The aim of our study was to gain a better understanding of mitochondrial dysfunction in autism. Our findings indicate a very complex pathophysiology of ASD in which mitochondrial dysfunction is not rare and can be caused by mtDNA deletion, which may be considered as de novo mutations or the consequence of the alterations of the causative culprit genes for autism or genes responsible for mtDNA maintenance.

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Introduction to mitochondrial disease

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What is Mitochondrial Disease? – UMDF

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