Az örökletes Parkinson-kór mint a POLG-gén károsodásának új klinikai megjelenési formája

A nukleárisan kódolt POLG-gén fehérjeterméke kulcsszerepet játszik a mitokondriális DNS replikációjának fenntar- tásában, és hibája különböző súlyosságú, több szervrendszert érintő betegségeket okoz. A klinikai spektrum rendkí- vül tág, a leggyakrabban előforduló tünetek közé tartozik többek között a ptosis, a myoclonus, az epilepszia, a myopathia, a szenzoros ataxia, a parkinsonizmus, a kognitív hanyatlás és az infertilitás is. Ma már ismert, hogy a Parkinson-kór kialakulása során a mitokondriális diszfunkció is nagy jelentőséggel bír a substantia nigra dopaminerg sejtjeinek elhalásában. Ezért a POLG-génben bekövetkező változások befolyásolhatják a különböző örökletes neuro- degeneratív betegségeknek, így a monogénes parkinsonizmusnak a kialakulását is. A Parkinson-kór és a POLG kap- csolatáról azonban még kevés az elérhető információ, és ez idáig a magyar populációra vonatkozó adatok sem álltak rendelkezésünkre. Vizsgálatunk során 67 magyar, a parkinsonizmus tüneteit mutató páciens esetében újgenerációs szekvenálást végeztünk, és a POLG-génben található, potenciálisan káros variánsokat elemeztük. 3 beteg esetében azonosítottunk potenciálisan kóroki eltérést. Közleményünkkel arra szeretnénk felhívni a figyelmet, hogy a parkinso- nizmus differenciáldiagnózisa során az esetleges POLG genetikai érintettségét is figyelembe kell venni. Különösen olyan plusztünetek jelenlétekor, mint az ophthalmoparesis, a nem vascularis típusú fehérállományi laesiók, a pszichi- átriai komorbiditás és a tünetek viszonylag korai indulása. Korábbi irodalmi adatok és saját tapasztalataink alapján összefoglaltuk a POLG-asszociált parkinsonizmus lehetséges diagnosztikai megközelítését is

Broadening the phenotype of the TWNK gene associated Perrault syndrome

Perrault syndrome is a genetically heterogenous, very rare disease, characterized clinically by sensorineural hearing loss, ovarian dysfunction and neurological symptoms. We present the case of a 33 years old female patient with TWNK-associated Perrault syndrome. The TWNK gene is coding the mitochondrial protein Twinkle and currently there are only two reports characterizing the phenotype of TWNK-associated Perrault syndrome. None of these publications reported about special brain MRI alterations and neuropathological changes in the muscle and peripheral nerves.Our patients with TWNK-dependent Perrault syndrome had severe bilateral hypoacusis, severe ataxia, polyneuropathy, lower limb spastic paraparesis with pyramidal signs, and gonadal dysgenesis. Psychiatric symptoms such as depression and paranoia were present as well. Brain MRI observed progressive cerebellar hyperintensive signs associated with cerebellar, medulla oblongata and cervical spinal cord atrophy. Light microscopy of the muscle biopsy detected severe neurogenic lesions. COX staining was centrally reduced in many muscle fibers. Both muscle and sural nerve electron microscopy detected slightly enlarged mitochondria with abnormal cristae surrounded by lipid vacuoles. In the sural nerve, dystrophic axons had focally uncompacted myelin lamellae present. Genetic investigation revealed multiple mtDNA deletion and compound heterozygous mutations of the TWNK gene (c.1196 A > G, c.1358 G > A).This study demonstrates that TWNK associated Perrault syndrome has a much broader phenotype as originally published. The coexistence of severe hypoacusis, spastic limb weakness, ataxia, polyneuropathy, gonadal dysgensia, hyperintense signals in the cerebellum and the presence of the mtDNA multiple deletion could indicate the impairment of the TWNK gene. This is the first report about pyramidal tract involvement and cerebellar MRI alteration associated with TWNK-related Perrault syndrome

Mitochondrial dysfunction and autism: Comprehensive genetic analyses of children with autism and mtDNA deletion

Additional file 1: Table S1. Investigated genes responsible for mtDNA maintenance (intergenomic NGS panel)

Maternálisan öröklődő diabetes mellitus, nagyothallás, krónikus progresszív ophthalmoplegia externa és myopathia mint az mtDNS A3243G-mutáció következménye = Maternally inherited diabetes mellitus, deafness, chronic progressive external ophthalmoplegia and myopathy as the result of A3243G mutation of mtDNA

A mitokondriális encephalomyopathiát, laktátacidózist, stroke-szerű epizódokat (MELAS-szindrómát) a leggyakrabban a mitokondriális genom A3243G-mutációja okozza. A mitokondriális DNS (mtDNS) A3243G-szubsztitúciója számos egyéb klinikai tünet, tünetcsoport hátterében is előfordulhat. Jelen közleményünkben egy 33 éves nő esetét ismertetjük, akinél a serdülőkori ophthalmoplegia externa, 19 éves korban, szülést követően jelentkező generalizált izomgyengeség, terhelési intolerancia, progresszív hypacusis és diabetes mellitus hátterében a szövettani vizsgálat mitokondriális betegséget igazolt. A genetikai analízis az mtDNS tRNS Leu(UUR) génjében heteroplazmikus formában A3243G-cserét talált. Esetünkben a klasszikus MELAS-fenotípus nem jelentkezett, az irodalmi adatok alapján azonban az A3243G-mutációhoz izoláltan társuló maternális öröklődésű diabetes mellitus, progresszív nagyothallás, krónikus progresszív ophthalmoplegia externa (CPEO), terhelési intolerancia és myopathia együttesen fordult elő. A családon belüli fenotípus egységes, a proband szintén A3243G-mutációt hordozó leányának is ptosisa, terhelési intoleranciája és myopathiája van. Az esetleírás kapcsán rövid áttekintést nyújtunk az A3243G-mutációkhoz társuló változatos klinikai fenotípusokról, valamint a CPEO-szindróma hátterében álló mtDNS-alterációkról. | Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome are caused mainly by the A3243G mutation of the mitochondrial genome. The A3243G substitution of mitochondrial DNA (mtDNA) is also responsible for various, other clinical phenotypes and syndromes. Here we report the case of a 33-year-old woman, with childhood onset ophthalmoplegia externa, progressive, generalised exercise intolerability, muscle weakness, hypacusis and diabetes mellitus as the symptoms of mitochondrial disease. Genetic analysis of the mitochondrial DNA revealed a heteroplasmic A to G substitution at position 3243 in the tRNS Leu(UUR) gene. In our case the classical MELAS phenotype has not yet appeared, however, some examples show in the literature that maternally inherited diabetes mellitus, progressive hypacusis, progressive ophthalmoplegia externa, exercise intolerance, and myopathy are often linked to as isolated symptoms of A3243G mutation. The phenotype in the family is consistent, the proband’s daughter has ptosis, exercise intolerance, and myopathy, too. A brief summary of the different clinical phenotypes associated with A3243G mutation, and of the different mtDNA mutations which can cause chronic progressive ophthalmoplegia externa (CPEO) will also be reviewed in this case report

Bcl-2 or bcl-XL gene therapy increases neural plasticity proteins nestin and c-fos expression in PC12 cells

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

Asian-specific mitochondrial genome polymorphism (9-bp deletion) in Hungarian patients with mitochondrial disease

A 9-bp deletion of the mtDNA is known as an anthropological marker of people with East-Asian origin. This 9-bp mtDNA deletion was analyzed in 1073 Hungarians with suspected mitochondrial disease and in 468 healthy control individuals. Fourteen cases with the 9-bp deletion were found in the cohort of mitochondrial patients, and one individual from 468 controls. In six cases the 9-bp deletion was present together with pathogenic major deletions in the mitochondrial genome. In one patient we found a frame shift mutation in the D-loop region, and in another family a pathogenic m.8322 A > G mutation in the tRNALys gene. Although the 9-bp deletion is common in the populations of the Pacific region and Asia, it is present in the Hungarian population as well. This 9-bp deletion may induce instability of the mtDNA and may provoke the introduction of other pathogenic mutations

Targeted next generation sequencing of a panel of autism-related genes identifies an EHMT1 mutation in a Kleefstra syndrome patient with autism and normal intellectual performance.

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

Genetic background of the hereditary spastic paraplegia phenotypes in Hungary - An analysis of 58 probands.

BACKGROUND: Hereditary spastic paraplegias (HSPs) are a clinically and genetically heterogeneous group of neurodegenerative diseases with progressive lower limb spasticity and weakness. The aim of this study is to determine the frequency of different SPG mutations in Hungarian patients, and to provide further genotype-phenotype correlations for the known HSP causing genes. METHODS: We carried out genetic testing for 58 probands with clinical characteristics of HSP. For historical reasons, three different approaches were followed in different patients: 1) Sanger sequencing of ATL1 and SPAST genes, 2) whole exome, and 3) targeted panel sequencing by next generation sequencing. RESULTS: Genetic diagnosis was established for 20 probands (34.5%). We detected nine previously unreported mutations with high confidence for pathogenicity. The most frequently affected gene was SPAST with pathogenic or likely pathogenic mutations in 10 probands. The most frequently detected variant in our cohort was the SPG7 p.Leu78*, observed in four probands. Altogether five probands were diagnosed with SPG7. Additional mutations were detected in SPG11, ATL1, NIPA1, and ABCD1. CONCLUSION: This is the first comprehensive genetic epidemiological study of patients with HSP in Hungary. Next generation sequencing improved the yield of genetic diagnostics in this disease group even when the phenotype was atypical. However, considering the frequency of the HSP-causing gene defects, SPG4, the most common form of the disease, should be tested first to be cost effective in this economic region