Investigations of Carnitine Transporters in Primay Carnitine Deficiency and Multifactorial Disease

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Deletion of 4q28.3-31.23 in the background of multiple malformations with pulmonary hypertension

The 4q deletion syndrome shows a broad spectrum of clinical manifestations consisting of key features comprising growth failure, developmental delay, craniofacial dysmorphism, digital anomalies, and cardiac and skeletal defects. We have identified a de novo interstitial distal deletion in a 9 month-old girl with growth failure, developmental delay, ventricular septum defect in the subaortic region, patent foramen ovale and patent ductus arteriosus, vascular malformation of the lung, dysgenesis of the corpus callosum and craniofacial dysmorphism using array-comparative genomic hybridization. This de novo deletion is located at 4q28.3-31.23 (136,127,048 - 150,690,325), its size is 14.56 Mb,and contains 8 relevant genes (PCDH18, SETD7, ELMOD2, IL15, GAB1, HHIP, SMAD1, NR3C2) with possible contributions to the phenotype. Among other functions, a role in lung morphogenesis and tubulogenesis can be attributed to the deleted genes in our patient, which may explain the unique feature of vascular malformation of the lung leading to pulmonary hypertension. With the detailed molecular characterization of our case with 4q- syndrome we hope to contribute to the elucidation of the genetic spectrum of this disorder

The role of next-generation sequencing in the diagnosis of lysosomal storage disorders

Next-generation sequencing (NGS) panels are used widely in clinical diagnostics to identify genetic causes of various monogenic disease groups including neurometabolic disorders and, more recently, lysosomal storage disorders. Many new challenges have been introduced through these new technologies, both at the laboratory level and at the bioinformatics level, with consequences including new requirements for interpretation of results, and for genetic counseling. We review some recent examples of the application of NGS technologies, with purely diagnostic and with both diagnostic and research aims, for establishing a rapid genetic diagnosis in lysosomal storage disorders. Given that NGS can be applied in a way that takes into account the many issues raised by international consensus guidelines, it can have a significant role even early in the course of the diagnostic process, in combination with biochemical and clinical data. Besides decreasing the delay in diagnosis for many patients, a precise molecular diagnosis is extremely important as new therapies are becoming available within the LSD disease spectrum for patients who share specific types of mutations. A genetic diagnosis is also the prerequisite for genetic counseling, family planning and the individual choice of reproductive options in affected families

A karnitin észterek profilszerű meghatározásának jelentősége a humán karnitin metabolizmus vizsgálatában = Determination of the carnitine ester profiles as a tool in study of human carnitine metabolism

Primer karnitin hiányban megfigyeltük, hogy a drámaian csökkent karnitin észter szintek a karnitin kezelés hatására csak mérsékelten emelkedtek. Heterozigóta családtagokban egy közel proporcionális csökkenés volt az észterekben. Az SLC22 TC haplotípust nem találtuk hajlamosító tényezőnek. Vizsgáltuk a karnitin észter profilt tünetmenetes celiákiásokban, ulceratív colitisben és felnőtt Crohn betegekben. Beteganyagunkban az IGR2096a_1T és IGR2198a_1 C ellélok hajlamosítónak adódtak Crohn betegségre. A karnitin profil vizsgálata a IGR2230a_1 genotípusban nem mutatott eltérést. Elsőként vizsgáltuk az irodalomban a karnitin észterek profiljának alakulását a terhesség folyamán egészen a szülésig. A vizsgálatok dinamikus rendszert fedtek fel: átalakult a terhes nő karnitin profilja a graviditás során nem-terhes nőkhöz viszonyítva. Vizsgáltuk az SLC22A4 C6607T és a RUNX1 G24658C variánsokat rheumatoid arthritisben. Nem találtunk hajlamosító polimorfizmust vagy specifikus eltérést a karnitin észter profilban sem. Interleukin 23 receptor variánsokat tanulmányoztuk rheumatoid arthritises betegekben és megfigyeltük az allélok megosztott hajlamosító természetét. Megfigyeltük, hogy a gén 3?UTR C2370A allélikus variánsa hajlamosító gén relabáló-remittáló típusú multiplex sclerosisban. Vizsgáltuk az apolipoprotein A 5 gén T-1131C, T1259C, IVS3-476A, és C56G variánsai és a triglicerid szintek alakulását, megfigyeltük, hogy több allél hajlamosító variáns strokeban és metabolikus szindrómában | We observed dramatic decrease of the carnitine esters in primary carnitine deficiency which underwent a moderate increase on the effect of carnitine supplementation. In heterozygous relatives a proportional decrease of carnitine esters could be observed. We did not found the SLC22 TC haplotypes to confer risk. The carnitine ester profile was investigated n asymptomatic celiac disease patients, ulcerative colitis, and adult Crohn subjects. In our patients IGR2096a_1T and IGR2198a_1 C alleles were susceptibility genes for Crohn disease; the carnitine profile was normal in IGR2230a_1 genotype. We examined the carnitine ester profile during pregnancy first in the literature. We found a very dynamic system: in pregnant woman the carnitine ester profile was changed comparing with non-pregnants, and was further modified during the progress of pregnancy. We studied the SLC22A4 C6607T and RUNX1 G24658C variants in rheumatoid arthritis and could not establish their susceptibility nature, nor we could detect change in the carnitine ester profiles. In rheumatoid arthritis and in remitting-relapsing form of multiple sclerosis we found the functional variants of the interleukin 23 receptor as shared susceptibility factors. We studied the association of T-1131C, T1259C, IVS3-476A, and C56G variants with the plasma triglycerides, and could verify a susceptibility nature for some of the in stroke and metabolic syndrome

De novo SCN1A géndeletio terápiarezisztens Dravet-szindrómában

A Dravet-szindróma vagy régebbi nevén súlyos csecsemőkori myoclonusos epilepszia igen ritka formája az epilepsziának. Az autoszomális domináns öröklésmenetet mutató kórkép leggyakoribb oka a feszültségfüggő nátriumcsatorna alfa-1 alegységet kódoló SCN1A gén mutációja. Az esetek többségének hátterében de novo pontmutáció áll, azonban néhány betegben a gén kópiaszám-változása figyelhető meg. Az SCN1A gén által kódolt fehérje a neuronalis ingerület kiváltásában és vezetésében játszik szerepet. A génmutációk többsége következtében kialakuló funkcióvesztés a neuronalis hálózat fokozott ingerelhetőségéhez vezet, ami az epilepsziás görcsök kialakulását eredményezi. A szerzők intézetében 2013 óta elérhető az SCN1A gén kópiaszám-változásának (deletio/duplikáció) vizsgálata is a gén teljes szekvenálása mellett. Jelen közleményben egy 7 éves beteg esetét mutatják be, aki 2 éves betegút után került intézetükbe. A molekuláris genetikai vizsgálat, amely de novo SCN1A géndeletiót detektált heterozigóta formában, fényt derített a rendkívül terápiarezisztens görcsök hátterében az SCN1A gén asszociálta monogénes epilepszia szindrómára

Schizophrenia and oral health: a literature review [Skizofrénia és szájhigiénia: irodalmi áttekintés]

Az általános betegségek közvetlenül vagy közvetve befolyásolhatják a fogak egészségét és a páciens szájhigiénéjét.A fogorvosi rendelőben megjelenő betegek körében a pszichiátriai kórképek a leggyakoribb rendellenességek közé tartoznak.A fogászati kezelések során az érintetteknek speciális igényeik vannak. A skizofrénia egy olyan krónikus mentálisbetegség, amely a személyes érzelmek és érzések zavaraival jár, illetve mentális és bizonyos tudati funkciók romlásáhozvezet. A tünetek közé tartoznak a téveszmék, a hallucinációk, a rendezetlen gondolkodás és a következetlenség.Amennyiben hasadásos elmezavarban szenvedő páciens jelentkezik kezelésre a fogorvosi rendelőben, pszichiátriaikonzultációt kell biztosítani. Az elektív fogászati beavatkozásokat el kell halasztani mindaddig, amíg a páciens tüneteikontroll alá kerülnek. A gyógyszerek mellékhatásai súlyosak lehetnek, ezért elengedhetetlen a beteg gondos és folyamatosellenőrzése

Phenotypic variability in a Hungarian patient with the 4q21 microdeletion syndrome

BACKGROUND: Interstitial deletions of 4q21 (MIM 613509) have already been reported in more than a dozen patients with deletions ranging from 2 to 15.1 Mb delineating a common phenotype including marked growth restriction, hypotonia, severe developmental delay with absent or delayed speech and distinctive facial features. A minimal critical region of 1.37 Mb accounting for the common features with 5 known genes (PRKG2, RASGEF1B, HNRNPD, HNRPDL, and ENOPH1) has been described so far. RESULTS: Here we report on a 5 year-old Hungarian girl presenting with severe developmental delay, good receptive language but absent spoken speech, short stature, dystrophy, hypotonia, distinctive facies including broad forehead, frontal bossing, downward slanting palpebral fissures, hypertelorism, hypoplastic ear-lobes, anteverted nostrils, short philtrum, small mouth, higharched palate, short, small hands and feet, distally narrowing fingers and clinodactyly. Cerebral MRI showed ventricular dilation and an increase in periventricular signal intensity. After extensive metabolic tests and exclusion of subtelomeric deletions array CGH analysis was performed using the Agilent Human Genome G3 SurePrint 8x60K Microarray (Agilent Technologies, USA), which detected a 4,85 Mb de novo interstitial deletion of 4q21.21-4q21.23. The clinical symptoms only partly overlap with reported 4q21 microdeletion cases. Among multiple annotated genes our patient is also haploinsufficient for the following genes: RASGEF1B being a strong candidate for the neurodevelopmental features and PRKG2 for severe growth delay. CONCLUSION: The first Hungarian case of 4q21 deletion adds to the phenotypic spectrum of this novel microdeletion syndrome and underlines the importance of array CGH to uncover the heterogeneous causes of intellectual disability. KEYWORDS: 4q21; Array CGH; Intellectual disability; Short stature; Submicroscopic deletio

Prevalence of SLC22A4, SLC22A% and CARD15 gene mutations in Hungarian pediatric patients with Crohn's disease

AIM: To investigate the frequency of the common NOD2/CARD15 susceptibility variants and two functional polymorphisms of OCTN cation transporter genes in Hungarian pediatric patients with Crohn’s disease (CD). METHODS: A cohort of 19 unrelated pediatric and 55 unrelated adult patients with Crohn’s disease and 49 healthy controls were studied. Genotyping of the three common CD-associated CARD15 variants (Arg702Trp, Gly908Arg and 1007finsC changes) with the SLC22A4 1672C→T, and SLC22A5 -207G→C mutations was performed by direct sequencing of the specific regions of these genes. RESULTS: At least one CARD15 mutation was present in 52.6% of the children and in 34.5% of the adults compared to 14.3% in controls. Surprisingly, strongly different mutation profile was detected in the pediatric versus adult patients. While the G908R and 1007finsC variants were 18.4% and 21.1% in the pediatric group, they were 1.82% and 11.8% in the adults, and were 1.02% and 3.06% in the controls, respectively. The R702W allele was increased approximately two-fold in the adult subjects, while in the pediatric group it was only approximately 64% of the controls (9.09% in the adults, 2.63% in pediatric patients, and 4.08% in the controls). No accumulation of the OCTN variants was observed in any patient group versus the controls. CONCLUSION: The frequency of the NOD2/CARD15 susceptibility variants in the Hungarian pediatric CD population is high and the profile differs from the adult CD patients, whereas the results for SLC22A4 and SLC22A5 mutation screening do not confirm the assumption that the carriage of these genotypes means an obligatory susceptibility to CD

Changes of plasma fasting carnitine ester profile in patients with ulcerative colitis

AIM: To determine the plasma carnitine ester profile in adult patients with ulcerative culitis (UC) and compared with healthy control subjects. METHOD: Using ESI triple quadrupole tandem mass spectrometry, the carnitine ester profile was measured in 44 patients with UC and 44 age- and sex-matched healthy controls. RESULTS: There was no significant difference in the fasting free carnitine level between the patients with UC and the healthy controls. The fasting propionyl- (0.331 ± 0.019 vs 0.392 ± 0.017 μmol/L), butyryl- (0.219 ± 0.014 vs 0.265 ± 0.012), and isovalerylcarnitine (0.111 ± 0.008 vs 0.134 ± 0.008) levels were decreased in the UC patients. By contrast, the level of octanoyl- (0.147 ± 0.009 vs 0.114 ± 0.008), decanoyl- (0.180 ± 0.012 vs 0.137 ± 0.008), myristoyl- (0.048 ± 0.003 vs 0.039 ± 0.003), palmitoyl- (0.128 ± 0.006 vs 0.109 ± 0.004), palmitoleyl- (0.042 ± 0.003 vs 0.031 ± 0.002) and oleylcarnitine (0.183 ± 0.007 vs 0.163 ± 0.007; P < 0.05 in all comparisons) were increased in the patients with UC. CONCLUSION: Our data suggest selective involvement of the carnitine esters in UC patients, probably due to their altered metabolism