Balkan Journal of Medical Genetics

MITOCHONDRIAL DNA MUTATIONS IN TWO BULGARIAN CHILDREN WITH AUTISTIC SPECTRUM DISORDERS
Avdjieva-Tzavella D1,*, Mihailova S2, Lukanov C2, Naumova E2, Simeonov E3, Tincheva R1, Toncheva D4
*Corresponding Author: Dr. Daniela Avdjieva-Tzavella, Department of Clinical Genetics, University Pediatric Hospital, 11 Ivan Geshov str., Sofia 1606, Bulgaria; Tel.: +35928154341; E-mail: davdjieva@ yahoo.com
page: 47

DISCUSSION

The autism spectrum disorders are clinically and etiologically heterogeneous developmental disorders of the brain. Many causes of autism have been proposed, but understanding of the etiology of ASDs is incomplete. The brain is strongly dependent on the ATP production of the mitochondrion, and the high energy demands of the brain and nervous system make them particularly vulnerable to impaired energy production. Recent epidemiological studies indicate that the incidence of mitochondrial disorders in children with autism could be 550 to 770 times higher than that of the general population [15]. All these facts have led several researchers to explore mitochondrial respiratory chain disorders as potential risk factors in ASDs. Multiple studies have confirmed the role of mitochondrial dysfunctions in ASDs [4-6,15,16]. For most individuals with defects of oxidative phosphorylation, the diagnosis is made through the determination of the activities of the enzyme complexes of the electron transport chain but an underlying mitochondrial mutation (including mtDNA depletion, mutations and deletions) can rarely be identified [7-10,17]. The present study aimed to explore the roles of mtDNA mutations in ASDs and find more evidence to support the relationship between these two disorders. In an ongoing survey, we screened 21 autistic children for mtDNA mutations. Sequencing of mtDNA showed a number of polymorphisms and two mutations, presented in the homoplasmic state, which have never been reported before in autistic patients (Table 1). Patient 10 had the G6852A mutation that replaces glycine with serine in protein-coding regions (COI) documented in blood (Figure 1). This mutation was reported previously by Taylor et al. [18]. They examined colonic crypt stem cells derived from a 75-year-old patient undergoing resection for a colonic tumor and found the G6852A mutation in the heteroplasmic (60.0%) state. Probably, the variability of phenotypes associated with this mutation, is according to the existence of environmental or genetic factors in addition to the mtDNA mutation that contribute to the development of clinical presentations. We also identified the p.(Ile→Val) substitution (m.8033A>G) in protein COII, subunit of cytochrome c oxidase (Figure 2) in a patient with autism, moderate mental retardation, hypertrichosis and dysmorphic face. To the best of our knowledge, the same mutation has not been previously observed in a patient with autistic or non autistic behavior and mitochondrial cytopathies. Hair abnormalities and pigmented skin eruptions belong to the broad spectrum of presenting symptoms of mitochondrial disease and 10.0% of the children with mitochondrial disorders develop specific cutaneous manifestations [19]. Hypertri-chosis is one of the most frequent skin disorders associated with mitochondrial dysfunction, however, the relationship between cutaneous manifestations in our patient and the A8033G mutation is speculative. The two patients carrying mtDNA mutations had normal blood lactate levels (Table 1), however, normal lactate levels do not exclude mitochondrial disease. Biochemical markers may be abnormal only during illness and variations in blood collection techniques are well known to cause differences in lactate values. Only a few studies evaluated autistic children who had a normal lactate for mitochondrial disorders [7,9,20,21]. Using only lactate as a screening test for mitochondrial dysfunction may miss some individuals with mitochondrial diseases. The phenotypic presentation of mitochondrial disorders in ASDs is quite broad. Some investigators described autistic patients with mitochondrial dysfunction as not different from the general ASDs population [10,16,22]. Other investigators found that children with ASDs and mitochondrial disorders demonstrated significant neurological (developmental regression, seizures, motor delay) and/ or gastrointestinal (reflux, constipation) problems [10,23]. One of our patients (patient 10, Table 1) did not have any major clinical features that distinguished her from typical autism. The patient with the A8033G mutation had a dysmorphic face and hypertrichosis and might be classified as having a syndromic autism. The substantial clinical heterogeneity of individuals with cooccurring autism and mtDMA mutations and lack of classical features associated to mitochondrial diseases constitute a challenge for clinicians to diagnose these patients. The presence of mtDNA mutations observed in this study, performed on ASDs children, may indicate an etiological role of the mitochondrial dysfunction in autistic patients. The pathogenetic link is that all of these mutations impair mitochondrial protein synthesis, however, additional studies are needed to investigate whether the mitochondrial dysfunction in children with autism is primary or secondary. A plausible hypothesis is that the mitochondrial dysfunction can lead to reduced synaptic neurotransmitter release in GABAergic (neurons whose primary neurotransmitter is GAMMA-AMINO BUTYRIC) neurons during a specific developmental period between 12 and 30 months of age [24,25]. However, an imbalance in the excitatory and inhibitory neurotransmitter systems reported in ASDs could also contribute to secondary mitochondrial dysfunction through an inhibition of mitochondrial b-oxidation [26]. Mitochondrial dysfunction has been associated with other behavioral abnormalities besides autism, such as schizophrenia and depression, which are frequent psychiatric conditions in relatives of children with autism [7,27]. Our study has some limitations. First, the number of individuals in whom mtDNA mutations were assessed was relatively small, and further studies in a larger sample would be needed to determine the association between ASDs and the results of mtDNA analyses reported herein. Second, only a panel of the most common mutations in mtDNA has been tested and, therefore, a mutation elsewhere in the mitochondrial genome cannot be ruled out. Third, we tested only blood samples, and lack of detectable mutation in one tissue does not exclude the presence of a mutation in other tissues. Fourth, the fact that diagnosed variants are non synonymous and rare does not guarantee their pathogenic status. Additional analyses of mtDNA genomes could supply new findings about the etiological role of rare mutations.

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