Observation of a Possible Successful Treatment of DEPDC5-Related Epilepsy with mTOR Inhibitor.

The mechanistic target of the rapamycin signaling pathway serves as a central regulator of cell metabolism, growth, proliferation, and survival. In its regulation, the GTPase-activating protein activity toward Rags1 complex has an inhibitory effect. Mutations in genes encoding this complex protein are among the most common abnormalities in focal epilepsies. Within these mutations, the mutations affecting the DEPDC5 gene have been associated with different autosomal dominantly inherited epilepsy types. Due to the limited data available on mTOR inhibitor therapy in nontuberous sclerosis complex epileptic patients, here we present the clinical management of a patient with intractable epilepsy, skin hypopigmentation, and a DEPDC5 variant. The patient's phenotype is compatible with a nonlesional DEPDC5-related epileptic encephalopathy. We initiated compassionate, off-label everolimus treatment as the patient's condition continuously deteriorated. Due to bilateral pneumonia occurring at the beginning of the treatment, it was temporarily discontinued, and resumed in half the dose. Follow-up examination after 18 months showed a 90% reduction in seizure frequency with moderate improvement in attention function and nutritional status. Our case report emphasizes the importance of early genetic testing in patients with epileptic encephalopathy. Clinical consequences of mammalian target of rapamycin complex 1 (mTORC1) upregulation may be amenable to tailored treatment with mTOR inhibitors. A clinical trial on an international scale would be needed to draw conclusions.

Three-Year Follow-Up after Intrauterine mTOR Inhibitor Administration for Fetus with TSC-Associated Rhabdomyoma.

Tuberous sclerosis complex (TSC) is a multisystem disorder characterized by seizures, neuropsychiatric disorders, and tumors of the heart, brain, skin, lungs, and kidneys. We present a three-year follow-up of a patient with TSC-associated rhabdomyoma detected in utero. Genetic examination of the fetus and the parents revealed a de novo variant in the TSC2 gene (c.3037delG, p.Asp1013IlefsTer3). Oral everolimus was initiated in the pregnant mother to regress the fetal tumor, which was successful. To the best of our knowledge, there is very little information regarding the use of everolimus therapy during pregnancy. West-syndrome was diagnosed when the proband was four months old. The symptoms were well-manageable, however temporarily. Therapy-resistant focal seizures were frequent. The patient had good vitals and was under regular cardiological control, showed a balanced circulation, and did not require any medication. Subependymal giant cell astrocytoma (SEGA) identified by regular neuroimaging examinations remained unchanged, which may be a consequence of early intrauterine treatment. Early detection of the pathogenic TSC2 variant, followed by in utero administration of everolimus and early vigabatrin therapy, allowed the detection of a milder developmental delay of the proband. Our study emphasizes how early genetic testing and management of epilepsy are pivotal for proper neurodevelopmental impacts and therapeutic strategies.

Investigating the genetic characteristics of the Csangos, a traditionally Hungarian speaking ethnic group residing in Romania.

Csango people are an East-Central European ethnographic group living mostly in the historical region of Moldavia, Romania. Their traditional language, the Csango is an old Hungarian dialect, which is a severely endangered language due to language shift. Their origin is still disputed among experts and there are many hypotheses since the 19th century. Previous genetic studies found connection with ethnic groups living in Hungary and provided evidence which might support their Hungarian origin. Another study found Inner Asian Altaic ancestry in their genetic makeup. The goal of this study was to analyze the genetic characteristics of the Csango people by comparing their genetic characteristics to contemporary Eurasian populations based on genome-wide autosomal marker data. Our findings suggest that genetic affinity of Csangos to Hungarians is more significant than to Romanians. They also have a detectable connection with Central-Asian and Siberian Turkic ethnic groups. Besides the presumable Middle Eastern/Central-Asian Turkic ancestry, Csangos show ~4% Turkic ancestry from Central Asia/Siberia, which makes them unique in comparison to all other East-Central European populations investigated in this study. The admixture that resulted in this Turkic ancestry could have occurred 30-40 generations ago, which date interval corresponds to Hungarian historical events regarding their migration and the conquest of the Carpathian basin.

Common functional variants of APOA5 and GCKR accumulate gradually in association with triglyceride increase in metabolic syndrome patients.

The common functional variants of the apolipoprotein A5 (APOA5) and the glucokinase regulatory protein genes (GCKR) have been shown to associate with increased fasting triglyceride (TG) levels. Albeit the basic association has been extensively investigated in several populations of different origin, less is known about quantitative traits of them. In our study accumulation rates of four APOA5 (T-1131, IVS3 + G476A, T1259C and C56G) and two GCKR (C1337T and rs780094) functional SNPs were analyzed in patients stratified into four TG quartile groups. Randomly selected 325 metabolic syndrome patients were separated into four quartile (q) groups based on the TG levels as follows q1: TG <1.38 mmol/l; q2: 1.38-1.93 mmol/l; q3: 1.94-2.83 mmol/l; and q4: TG >2.83 mmol/l. We observed significant stepwise increase of prevalence rates of minor allele frequencies in the four plasma TG quartiles for three APOA5 SNPs: -1131C (q1: 4.94%; q2: 8.64%; q3: 11.6%; q4: 12.3%), IVS3 + 476A (q1: 4.32%; q2: 7.4%; q3: 10.36%; q4: 11.1%), and 1259C (q1: 4.94%; q2: 7.41%; q3: 10.4%; q4: 11.7%). The haplotype analysis revealed, that the frequency of APOA5*2 haplotype gradually increased in q2, q3 and q4 (q1: 9.87%; q2: 14.8%; q3: 18.3%; q4: 21%). The distribution of the homozygotes of the two analyzed GCKR variants resembled to the APOA5 pattern. Contrary to the hypothetically predictable linear association coming from the current knowledge about the APOA5 and GCKR functions, the findings presented here revealed a unique, TG raise dependent gradual accumulation of the functional variants of in MS patients. Thus, the findings of the current study serve indirect evidence for the existence of rare APOA5 and GCKR haplotypes in metabolic syndrome patients with higher TG levels, which contribute to the complex lipid metabolism alteration in this disease.

[Significance of thiopurine s-methyltransferase gene test in a clinical case]. / Thiopurin s-metil-transzferáz gén vizsgálatának jelentosége egy eset kapcsán.

Thiopurine s-methyltransferase enzyme is responsible for the metabolism of immunosuppressant thiopurines, which are used in inflammatory bowel diseases, acute lymphoblastic leukemia and autoimmune diseases. Because of the relative narrow therapeutic index of thiopurines serious or life threatening side effects can occur. A total of 28 variant alleles of the gene coding for the thiopurine s-methyltransferase enzyme are responsible for altered catalytic activity of the enzyme. Patients with one non-functional (heterozygous) allele have intermediate, while those with two non-functional (homozygous) alleles have low enzyme activity. Using polymerase chain reaction/restriction fragment length polymorphism and direct DNA sequencing the authors determined the G238C, G460A and A719G polymorphisms of the thiopurine s-methyltransferase gene in a child with Crohn's disease who developed thiopurine-induced severe agranulocytosis. The presence of the G460A and A719G polymorphic alleles in homozygous forms were detected which corresponded to the *3A variant allele. This variant has been shown to be associated with lower enzyme activity and low amount of the enzyme resulting in thiopurine toxicity and agranulocytosis. These findings underline the need for genotyping of the thiopurine s-methyltransferase variants prior to thiopurine treatment.

TUBB4B gene mutation in Leber phenotype of congenital amaurosis syndrome associated with early-onset deafness.

Beta-tubulin 4B isotype is one of the subunits of microtubules encoded by TUBB4B gene on chromosome 9, which is responsible for the maintenance of microtubule stability. In humans, mutations in microtubule-encoding genes have been associated with several tubulinopathies with very heterogeneous symptoms. So far, only two missense mutations in TUBB4B gene have been found to have pathological implications in this disorder. Here we report a Hungarian family with three affected members, mother and her 12- and 14-year-old children, who suffer from ophthalmologic and hearing impairments probably due to c.1171C > T missense variant in the TUBB4B gene. The presented case is the second report, and unique in the literature because of three affected family members carrying the same mutation and the family provides evidence for a quite similar but not identical phenotype of LCAEOD in subjects carrying this mutation.

[Genetics of ischemic stroke: where are we now?]. / Ischaemiás stroke genetikai háttere: Hol tartunk most?

As stroke is the third leading cause of death after heart failure and tumors worldwide, cerebrovascular diseases reached substantial attention. In the past few years, significant progression has been seen in identification of genetic variants in the background of stroke and other cerebrovascular and cardiovascular events. Examination of these variants is a new approach to recognize pathogenesis of disorders that hopefully helps in future prevention and prospects of screening and, optimistically, it contributes to special care of patients susceptible for stroke. In the background of ischemic stroke several genetic variants have been identified, which localize in genes encoding proteins involved in hemostasis, renin-angiotensin system and lipid metabolism. The number of these variants exponentially increases permanently due to rapid spreading of genome wide association studies. The goal of this review is to summarize the results of genetic studies on ischemic stroke. Here the authors focus on genetic variants which can have major role in personalized medicine and prevention of stroke.

Xp11.2 Duplication in Females: Unique Features of a Rare Copy Number Variation.

Among the diseases with X-linked inheritance and intellectual disability, duplication of the Xp11.23p11.22 region is indeed a rare phenomenon, with less than 90 cases known in the literature. Most of them have been recognized with the routine application of array techniques, as these copy number variations (CNVs) are highly variable in size, occurring in recurrent and non-recurrent forms. Its pathogenic role is not debated anymore, but the information available about the pathomechanism, especially in affected females, is still very limited. It has been observed that the phenotype in females varies from normal to severe, which does not correlate with the size of the duplication or the genes involved, and which makes it very difficult to give an individual prognosis. Among the patients studied by the authors because of intellectual disability, epilepsy, and minor anomalies, overlapping duplications affecting the Xp11.23p11.22 region were detected in three females. Based on our detailed phenotype analysis, we concluded that Xp11.23p11.22 duplication is a neurodevelopmental disorder.

GCKR gene functional variants in type 2 diabetes and metabolic syndrome: do the rare variants associate with increased carotid intima-media thickness?

BACKGROUND: Recent studies revealed that glucokinase regulatory protein (GCKR) variants (rs780094 and rs1260326) are associated with serum triglycerides and plasma glucose levels. Here we analyzed primarily the association of these two variants with the lipid profile and plasma glucose levels in Hungarian subjects with type 2 diabetes mellitus and metabolic syndrome; and also correlated the genotypes with the carotid intima-media thickness records. METHODS: A total of 321 type 2 diabetic patients, 455 metabolic syndrome patients, and 172 healthy controls were genotyped by PCR-RFLP. RESULTS: Both GCKR variants were found to associate with serum triglycerides and with fasting plasma glucose. However, significant association with the development of type 2 diabetes mellitus and metabolic syndrome could not be observed. Analyzing the records of the patients, a positive association of prevalence the GCKR homozygous functional variants and carotid intima-media thickness was found in the metabolic syndrome patients. CONCLUSIONS: Our results support that rs780094 and rs1260326 functional variants of the GCKR gene are inversely associated with serum triglycerides and fasting plasma glucose levels, as it was already reported for diabetic and metabolic syndrome patients in some other populations. Besides this positive replication, as a novel feature, our preliminary findings also suggest a cardiovascular risk role of the GCKR minor allele carriage based on the carotid intima-media thickness association.

Gene testing in Treacher Collins syndrome / Génvizsgálat Treacher Collins-szindrómában

Összefoglaló. A Treacher Collins-szindróma a mandibulofacialis dysostosisok csoportjába tartozó kórkép. Fobb jellegzetességei a maxillaris és mandibularis dysostosis, az antimongoloid szemrések, az alsó szemhéj colobomája, illetve a vezetéses halláscsökkenés. A szindrómával járó tünetek egyénenként és családon belül is nagyon eltéroek lehetnek; legenyhébb formái csaknem észrevehetetlenek, míg a súlyosabb esetekben az életet veszélyezteto légúti szövodmények léphetnek fel. Hátterében az esetek dönto többségében a TCOF1-gén eltérései játszanak szerepet, mely eltérések autoszomális domináns módon öröklodnek. Esetbemutatásunk célja, hogy felhívjuk a figyelmet a genetikai vizsgálat elvégzésének fontosságára olyan, klinikailag jól felismerheto tünetegyüttes, mint a Treacher Collins-szindróma esetén. Bár a betegség a klinikai kép alapján diagnosztizálható, az ismétlodés kockázatát csak úgy tudjuk pontosan meghatározni, ha ismerjük a családtagok genotípusát. A bemutatott család több tagjánál kimutatható volt a TCOF1-gén mutációja, annak ellenére, hogy klinikai tünetük nem volt. A jelenség magyarázata az inkomplett penetrancia, azaz a hibás gén fenotípusosan nem kerül kifejezodésre. Orv Hetil. 2020; 161(52): 2201-2205. Summary. Treacher Collins syndrome belongs to the group of mandibulofacial dysostoses. Its main features are maxillary and mandibular dysostosis, downward-slanting palpebral fissures, coloboma of the lower eyelid and conductive hearing loss. The symptoms associated with the syndrome can vary greatly from individual to individual and within the family. In its mildest form, the syndrome is almost imperceptible, and when severe, life-threatening respiratory complication can occur. TCOF1 is the major gene involved with an autosomal dominant mode of inheritance. The purpose of our case study is to draw attention to the importance of performing genetic testing in a clinically recognizable disorder such as Treacher Collins syndrome. Although the disease can be diagnosed based on the clinical symptoms, the risk of recurrence can only be accurately determined if the genotype of the family members is known. Several members of the presented family had a mutation in the TCOF1 gene despite having no clinical symptoms. The explanation for this phenomenon is incomplete penetrance, i.e., the defective gene is not expressed in the phenotype. Orv Hetil. 2020; 161(52): 2201-2205.

Phenotypic variants of the deafness-associated mitochondrial DNA A7445G mutation.

A number of nuclear and mitochondrial mutations have been implicated in non-syndromic hearing loss. Among them, various mutations of mitochondrial Ser(UCN)-tRNA and 12S rRNA genes have been found to be associated with deafness; the A7445G mitochondrial DNA (mtDNA) in this group is unique, simultaneously affecting two different mitochondrial genes, encoding the Ser(UCN)-tRNA and the first subunit of cytochrome oxidase. Besides the hearing loss, it is mainly associated with palmoplantar keratoderma, though; different phenotypic associations have been reported. The current paper reviews the available PubMed reports on the A7445G mtDNA mutation, with special attention to the phenotypic variations. Further, a Hungarian family with the A7445G mutation is reported, in which analysis of both the affected and the non-affected members revealed the mutation in both homo- and heteroplasmic forms, independently of the hearing status of the subjects, a phenomenon previously not reported in other pedigrees. The female lineage represented a rare variant of the U4b haplogroup.

Apolipoprotein A5 gene C56G variant confers risk for the development of large-vessel associated ischemic stroke.

OBJECTIVES: Ischemic stroke is a suddenly developing temporary or often permanent damage of the brain. Several candidate genes have been shown to have an impact in the pathogenesis of stroke. The aim of our study was to investigate the possible association between the C56G variant of the apolipoprotein A5 (APOA5) gene and ischemic stroke. METHODS: PCR-RFLP assays were performed to detect the C56G alleles in 403 patients with classified stroke types and 171 controls. RESULTS: Triglyceride levels of subjects carrying 56G allele were elevated compared to the subjects with 56C allele in all stroke subgroups and in the controls. The serum total cholesterol levels did not differ between subjects with C or G alleles in each group. An accumulation of APOA5 56G allele was observed in the large-vessel associated stroke group compared to the healthy controls (10.9 vs. 5.6 %; p < 0.05), while its prevalence did not increase in any other stroke subgroups. Multivariate logistic regression analysis adjusted for differences in age, gender, BMI, serum total cholesterol levels, ischemic heart disease, hypertension, diabetes mellitus, smoking and drinking habits revealed that the APOA5 56G allele represents a susceptibility factor for large-vessel associated stroke (OR = 2.132 at 95 % CI; p < 0.05). CONCLUSION: The data presented here suggest that the 56G allele can confer risk exclusively for development of large-vessel associated stroke. Thereby, the 56G allele differs from the APOA5 T-1131C allelic variant, which has been previously identified as a risk factor for all subgroups of the stroke disease.

The combination of homozygous MTHFR 677T and angiotensin II type-1 receptor 1166C variants confers the risk of small-vessel-associated ischemic stroke.

Previous studies have suggested that both angiotensin II type-1 receptor (AT1R) 1166C and methylenetetrahydrofolate reductase (MTHFR) 677T variants can have disadvantageous effects on the small-vessel circulation under certain conditions. The purpose of this study was to analyze the possible consequences of the simultaneous distribution of these two genetic variants in different types of ischemic stroke. The genetic and clinical data on 357 ischemic stroke patients and 263 control subjects were analyzed by using univariate and logistic statistical approaches. Neither the MTHFR 677T nor the AT1R 1166C genetic variant alone conferred the risk of any subtype of ischemic stroke. The combination of the homozygous MTHFR 677TT genotype and at least one AT1R 1166C allele occurred more frequently in the ischemic stroke patients (8.68%) than in the controls (4.56%, p < 0.05). Specific subclassification of the patients revealed an accumulation of this combination in small-vessel-associated ischemic stroke (12.2%, p < 0.01); multivariate logistic regression analysis of the data confirmed this association, with an odds ratio of 2.66 (95% confidence interval, 1.28-7.89; p < 0.05). These findings suggest that the combination of these two genetic factors can contribute to the development of small-vessel cerebral infarcts. Although the exact mechanism of action is not known, addition of the unfavourable effects on the endothelial function can be presumed.

Apolipoprotein A5 T-1131C variant confers risk for metabolic syndrome.

The -1131C is a naturally occurring variant of the apolipoprotein A5 (ApoA5) gene, which has been shown to associate with increased triglyceride levels. This variant has also been shown to confer risk for development of ischemic heart disease and stroke. The gene is in linkage disequilibrium with factors known to correlate with impaired glucose homeostasis. These observations prompted us to study the prevalence of the ApoA5 -1131C allele in patients with metabolic syndrome. A total of 201 metabolic syndrome patients and 210 controls were studied. In both groups the triglyceride levels of patients with -1131C allele were significantly increased compared to the subjects with -1131T allele (3.22+/-0.43 mmol/l vs. 2.24+/-0.12 mmol/l, p<0.01 in the metabolic syndrome patients; 2.10+/-0.19 mmol/l vs. 1.22+/-0.05 mmol/l, p<0.01 in the controls). In metabolic syndrome patients the prevalence of the ApoA5 -1131C variant was increased compared to the healthy controls (11% vs. 6.20%). Multiplex regression analysis model adjusted for age, gender, serum total cholesterol levels, acute myocardial infarction and stroke events revealed that the examined ApoA5 variant confers risk for the development of metabolic syndrome: the odds ratio at 95% confidence interval was 3.622 (1.200-10.936), p=0.02. Our findings strongly suggest that this variant is a risk factor for the development of hypertriglyceridemia and metabolic syndrome.

[Mitochondrial DNA and its mutations: new advances in a new field]. / A mitokondriális DNS és mutációi: újabb ismeretek egy új területen.

The past two decades are considered as the golden age of the clinical research of mitochondrial DNA. The number of disease-associated pathologic variants is still expanding; the available knowledge about the entities caused by the abnormalities of the mitochondrial DNA is gradually increasing. The inheritance of the mitochondrial DNA exhibits maternal transmission; the properties are different from the nuclear genome in many respects. Albeit the establishment of correct diagnosis of several mitochondrial diseases still means diagnostic challenge, more and more entities can be identified due to the available molecular biology methods. Nowadays, significant progress of mitochondrial medicine can be observed in relation to several medical subspecialties; thus, mitochondrial gastroenterology, endocrinology, otology, ophthalmology, nephrology, hematology, oncology, reproductive medicine and psychiatry have been partially separated as the more or less circumscribed territory of the specific subspecialty. Besides the short overview of the general aspects of the mitochondrial medicine the present review provides an outlook to these chapters.

Marked Differences of Haplotype Tagging SNP Distribution, Linkage, and Haplotype Profile of APOA5 Gene in Roma Population Samples.

Roma people are underprivileged, neglected population worldwide, with severe healthcare problems. They have significantly increased prevalence of cardiovascular morbidity, presumably related to their poor social status, alcohol consumption and smoking habits. Assuming that genetic background also plays a role in their susceptibility for cardiovascular diseases, we hypothesized that APOA5 gene polymorphisms, an important role-player in lipid metabolism and in the development of metabolic syndrome and cardio/cerebrovascular events, may also be involved. We examined four APOA5 polymorphisms in 363 Roma and 404 Hungarian DNA samples. For rs662799, rs2266788, rs207560 and rs3135506 we found elevated plasma triglyceride levels in the risk allele carriers compared to non-carriers in both populations. At least a two-fold significant increase was detected in minor allele frequencies in Roma when compared to Hungarians, except the rs2266788 variant. Haplotype analysis revealed significant increase of APOA5*2, APOA5*4 in Roma, as opposed to the higher levels of APOA5*5 found in Hungarians. Different linkage disequilibrium was found between rs207560 and rs3135506 variants in Roma compared to Hungarians. The profound differences observed in almost all APOA5 polymorphisms in Roma require special attention, since these variants are known to associate with cardio/cerebrovascular susceptibility.

Coexistence of angiotensin II type-1 receptor A1166C and angiotensin-converting enzyme D/D polymorphism suggests susceptibility for small-vessel-associated ischemic stroke.

The renin-angiotensin system plays an important role in the maintenance of blood pressure homeostasis. The angiotensin-converting enzyme (ACE) converts angiotensin I into angiotensin II. Angiotensin II, which binds the angiotensin II type-1 receptor (AT1R), is a potent vasoconstrictor. On a pathophysiological basis, both ACE I/D and AT1R A1166C polymorphism lead to an enhanced activity of the angiotensin II-AT1R axis, thereby possibly contributing to circulatory disturbances. A mutually facilitatory effect may be presumed between the two polymorphisms. We examined whether this synergistic effect is involved in the evolution of different types of ischemic stroke. Genetic and clinical data on 308 consecutive patients with acutely developing ischemic stroke were analyzed. Atotal of 272 stroke and neuroimaging alteration-free subjects served as a control group. Univariate and logistic regression statistical approaches were used. The ACE D allele combined with the AT1R 1166C allele did not yield a risk of ischemic stroke. However, the co-occurrence of the homozygous ACE D/D and at least one AT1R 1166C allele was more frequent in the ischemic stroke group than in the control group (22.4 vs 11%, p < 0.005, OR, 2.33; 95% CI, 1.46-3.7). After specific subgroup analysis, this synergistic association was even stronger for small-vessel ischemic stroke (OR, 3.44; 95% CI, 1.9-6.24; p < 0.0005). Multivariate logistic regression analysis of the data confirmed this association (adjusted OR, 3.54, 95% CI, 1.88-7.16; p < 0.0005). Our results demonstrate that ACE D/D and AT1R 1166C polymorphism were associated with the development of small-vessel ischemic stroke through a mutually facilitatory interplay between them. Genetic interactions might contribute to the altered functional network in renin-angiotensin system in vascular disorders.

Apolipoprotein A5 gene promoter region T-1131C polymorphism associates with elevated circulating triglyceride levels and confers susceptibility for development of ischemic stroke.

The possible pathogenic role of triglycerides (TG) in the development of ischemic stroke is still under extensive investigation. Recently, apolipoprotein (apo)A5 gene promoter region T-1131C polymorphism has been shown to associate with elevated serum TG levels. In the current work, a total of 302 subjects were classified as being large vessel-associated, small vessel-associated, or belonging to a mixed group of ischemic stroke-affected patients. The level of TG was increased in all groups (p < 0.01). The apoA5-1131C allele frequency was approximately twofold in all groups of stroke patients compared with the controls (5 vs 10-12%; p < 0.05); and the apoA5-1131C allele itself was also found to associate with increased TG levels in all groups. In a multivariate logistic regression analysis model adjusted for differences in age, gender, serum cholesterol, hypertension, presence of diabetes mellitus, smoking and drinking habits, and ischemic heart disease, a significantly increased risk of developing stroke disease was found in patients carrying the apoA5-1131C allele (p < 0.05; odds ratio OR = 2.1 [1.3-4.7]); this association was also proven for all subtypes of the stroke. The results presented here suggest that the apoA5-1131C allele is an independent risk factor for the development of stroke. Being that apoA5 gene is under the control of the peroxisome proliferator-activated receptor alpha, theoretically, the current observations also can have long-term therapeutic consequences.

[Search for mitochondrial DNA T4291C mutation in Hungarian patients with metabolic syndrome]. / Mitokondriális DNS T4291C mutáció vizsgálata metabolikus szindrómában szenvedo betegekben.

INTRODUCTION: Metabolic syndrome affects 15-30 percentage of the population. It is characterized by obesity, hypertension, diabetes mellitus, insulin resistance, hypercholesterolemia and hypertriglyceridemia. AIMS: In a recent study metabolic syndrome was shown to be transmitted on maternal lineage in a large family; an uridine to cytidine transition was detected in homoplasmic form at position 4291 of the mitochondrial DNA (mtDNA) which affects the 5' neighboring nucleotide to the anticodon of the isoleucine-tRNA. METHODS: Using specific restriction analysis and direct sequencing for detection of this mutation the authors genotyped 365 DNA samples which were collected from 164 adult and 119 pediatric patients with metabolic syndrome. RESULTS AND CONCLUSIONS: The T4291C mtDNA variant could not be detected in any of these patients suggesting that this alteration is likely rare in the Hungarian metabolic syndrome population.

Maternally inherited deafness and unusual phenotypic manifestations associated with A3243G mitochondrial DNA mutation.

The mitochondrial DNA A3243G transition is a fairly common mutation which often associates with a MELAS (mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes) phenotype, however, a broad variety in the associated clinical picture has also been described. The patient reported here developed a generalized seizure at age 12, which was followed by bilateral hearing loss and occasional fatigue. The maternal inheritance pattern of hearing loss pointed to a possible mitochondrial origin, which was confirmed by molecular analysis of the mitochondrial DNA, revealing a heteroplasmic A3243G transition. Interestingly, muscle biopsy showed ragged-red fibers in the proband, which is unusual in the deafness-associated forms of this mitochondrial disorder. In addition to hearing impairment in four generations of the family, fatal cerebral embolization in the mother and fatal heart attack in the maternal grandmother (both at age 33) also occurred. On the contrary, diabetes, which usually accompanies the hearing loss variant, was specifically absent in all generations. The unusual manifestations associated with this mutation somewhat differentiate this family from the already known variants.