Relationship Between Orthodontic and Articulatory Impairments in Adolosecents

Različita su istraživanja pokazala da je broj izgovornih poremećaja veći u populaciji s ortodontskim anomalijama nego u osoba bez njih. Odnos između anatomskih struktura u orofacijalnoj regiji i izgovornih kompenzacijskih mehanizama u osoba s ortodontskim anomalijama zanimljiv je i s teoretskoga i s praktičnoga stajališta. U ovom je istraživanju na uzorku od 282 srednjoškolca (203 - 72% djevojaka i 79 - 28% dječaka) u dobi od 15 do 18 godina istražen odnos između ortodontskih i izgovornih poremećaja. Procjenom ortodontskog i izgovornoga statusa , koju je učinilo dvoje specijalista, svaki za svoje područje, dobiveni su sljedeći postotci ortodontskih anomalija: primarna kompresija - 43,6%, otvoreni zagriz - 11,0%, pokrovni zagriz - 8,5% , progenijski kompleks - 5,7%, križni zagriz - 3,5%, diastema medijana - 0,0%. Također je nađeno 41,4% ispitanika s kratkim frenulumom linguae i 25,2% s gotskim nepcem. Izgovorni su poremećaji registrirani u sljedećim postotcima: sigmatizam - 64,9%, rotacizam- 36,5% i lambdacizam - 39,0%. Ukupno 78% ispitanika imalo je ortodontske anomalije, a 72% izgovorne poremećaje, a njih je 52% imalo kombinirane ortodontske i izgovorne poremećaje. Samo je 9% ispitanika bilo s urednim ortodontskim i izgovornim statusom. Također je pokazano da su sve tri kategorije izgovornih poremećaja najviše povezane s primarnom kompresijom (oko 30%), praćeno s kratkim frenulumom linguae (oko 30%) i gotskim nepcem (od 15 do 20%). Također je očito da postoji 19% ispitanika koji imaju ortodontsku anomaliju ali i normalni izgovorni status, što potvrđuje da su oni razvili djelotvorne kompenzacijske izgovorne mehanizme. S druge strane, postoji 13% ortodontski normalnih ispitanika koji imaju izgovorne poremećaje, uzrokovane nekim drugim razlozima a ne ortodontskim statusom. Iako postoji jaka povezanost između ortodontskih i izgovornih poremećaja, moguće je zaključiti da njihov odnos nije neposredan ta da se drugi psiholingvistički, razvojni, neurogeni i ostali parametri moraju uzeti u razmatranje u daljnjem objašnjenju toga odnosa.Various investigations have shows that the number of articulatory impairments is greater in a population with orthodontic anomalies than in eugnathic subjects. The relationship between anatomic structures in the orofacial region and articulatory compensatory mechanisms in persons with orthodontic anomalies is interesing from the theoretical and practical point of view. In the present investigation on a sample of 282 high school adolescents (203 - 72% male and 79 - 28% female) aged from 15 to 18 years the relationship between orthodontic and articulatory impairments was investigated. Assessment of the orthodontic and articulatory status, judged two specialists in the fields, showed the following percentages of orthodontic anomalies : primary compression -43,6%, open bite - 11,0%, closed bite -8,5%, progenia complex -5,7%, cross bite 3,5%, diastema media - 0,0%, short frenulum linguae - 41,5%, gothic palate -25,2% and tthe following percentages of ariculatory impairments: sigmatism - 64,9%, rhotacism - 36,5% and lambdacism - 39,9%. 78% of the subjects had orthodontic anomalies and 72% had articulatory impairments while 52% had combined orthodontic and articulatory impairments and only 9% were eugnathic subjects with normal articulatory status. It was also show that all three categories of articulatory impairments are mostly combined with primary compression (approximately 30%) accompanied by short frenulum linguae (approximately 30%) and gothic palate (approximately 15 to 20%). It is also obvious that there are 19% of subjetcts with orthodontic anomalies who have normal articulatory status, meaning that they developed efficient compensatory mechanisms in articulation and also that there are 13% of eugnathic subjects who have articulatory imapirments, consequently, caused by some other reasons and not by the orthodontic status. Although there is a strong connection between orthodontica and articulatory characteristics it can be concluded that the relationship between them is not straight forward and that other psycholinguistic, developmental, neurogenic and other parameters should be taken into consideration in further explication of that relationship

Mutations in noncoding regions of GJB1 are a major cause of X-linked CMT

OBJECTIVE: To determine the prevalence and clinical and genetic characteristics of patients with X-linked Charcot-Marie-Tooth disease (CMT) due to mutations in noncoding regions of the gap junction β-1 gene (GJB1). METHODS: Mutations were identified by bidirectional Sanger sequence analysis of the 595 bases of the upstream promoter region, and 25 bases of the 3′ untranslated region (UTR) sequence in patients in whom mutations in the coding region had been excluded. Clinical and neurophysiologic data were retrospectively collected. RESULTS: Five mutations were detected in 25 individuals from 10 kindreds representing 11.4% of all cases of CMTX1 diagnosed in our neurogenetics laboratory between 1996 and 2016. Four pathogenic mutations, c.-17G>A, c.-17+1G>T, c.-103C>T, and c.-146-90_146-89insT were detected in the 5′UTR. A novel mutation, c.*15C>T, was detected in the 3′ UTR of GJB1 in 2 unrelated families with CMTX1 and is the first pathogenic mutation in the 3′UTR of any myelin-associated CMT gene. Mutations segregated with the phenotype, were at sites predicted to be pathogenic, and were not present in the normal population. CONCLUSIONS: Mutations in noncoding DNA are a major cause of CMTX1 and highlight the importance of mutations in noncoding DNA in human disease. Next-generation sequencing platforms for use in inherited neuropathy should therefore include coverage of these regions

Nekotorye otnoščenija meždu strukturami, polučennymi pri pomošči transformacii značimyh glavnyh komponentov matricy interkorrjaelcii i značnimyh glavnyh ocej imaž matricy kovariacii

Varimax and oblimin trasformations of significant principal components of complete intercorelation matrixes and significant principal axes of image matrixes of covariances were compared. Varimax poorl approximates simple structure, tending to produce general and poorly defined group factors and sometimes integrating those factors which in oblimin position are highly intercorrelated. Oblimin ususally gives very simple structure with well defined factors, especially if significant principal axes of image matrixes of covariances are transformed. The same analyses using the same tests on 9 subsamples (of which some overlapping from the same population were very similar. Not only that varimax invariance was not higher than direction oblimin invariance, but it was, as a rule, significantly lower. Therefore, ti seems that oblimin transformation of significant iage axes is very suitable method for explorative factor analyses of psychological measurement instruments

Prevalence study of genetically defined skeletal muscle channelopathies in England.

To obtain minimum point prevalence rates for the skeletal muscle channelopathies and to evaluate the frequency distribution of mutations associated with these disorders

Clinicopathologic and molecular spectrum of RNASEH1-related mitochondrial disease.

OBJECTIVE: Pathologic ribonuclease H1 (RNase H1) causes aberrant mitochondrial DNA (mtDNA) segregation and is associated with multiple mtDNA deletions. We aimed to determine the prevalence of RNase H1 gene (RNASEH1) mutations among patients with mitochondrial disease and establish clinically meaningful genotype-phenotype correlations. METHODS: RNASEH1 was analyzed in patients with (1) multiple deletions/depletion of muscle mtDNA and (2) mendelian progressive external ophthalmoplegia (PEO) with neuropathologic evidence of mitochondrial dysfunction, but no detectable multiple deletions/depletion of muscle mtDNA. Clinicopathologic and molecular evaluation of the newly identified and previously reported patients harboring RNASEH1 mutations was subsequently undertaken. RESULTS: Pathogenic c.424G>A p.Val142Ile RNASEH1 mutations were detected in 3 pedigrees among the 74 probands screened. Given that all 3 families had Indian ancestry, RNASEH1 genetic analysis was undertaken in 50 additional Indian probands with variable clinical presentations associated with multiple mtDNA deletions, but no further RNASEH1 mutations were confirmed. RNASEH1-related mitochondrial disease was characterized by PEO (100%), cerebellar ataxia (57%), and dysphagia (50%). The ataxia neuropathy spectrum phenotype was observed in 1 patient. Although the c.424G>A p.Val142Ile mutation underpins all reported RNASEH1-related mitochondrial disease, haplotype analysis suggested an independent origin, rather than a founder event, for the variant in our families. CONCLUSIONS: In our cohort, RNASEH1 mutations represent the fourth most common cause of adult mendelian PEO associated with multiple mtDNA deletions, following mutations in POLG, RRM2B, and TWNK. RNASEH1 genetic analysis should also be considered in all patients with POLG-negative ataxia neuropathy spectrum. The pathophysiologic mechanisms by which the c.424G>A p.Val142Ile mutation impairs human RNase H1 warrant further investigation

Clinical, pathological and functional characterization of riboflavin-responsive neuropathy.

Brown-Vialetto-Van Laere syndrome represents a phenotypic spectrum of motor, sensory, and cranial nerve neuropathy, often with ataxia, optic atrophy and respiratory problems leading to ventilator-dependence. Loss-of-function mutations in two riboflavin transporter genes, SLC52A2 and SLC52A3, have recently been linked to Brown-Vialetto-Van Laere syndrome. However, the genetic frequency, neuropathology and downstream consequences of riboflavin transporter mutations are unclear. By screening a large cohort of 132 patients with early-onset severe sensory, motor and cranial nerve neuropathy we confirmed the strong genetic link between riboflavin transporter mutations and Brown-Vialetto-Van Laere syndrome, identifying 22 pathogenic mutations in SLC52A2 and SLC52A3, 14 of which were novel. Brain and spinal cord neuropathological examination of two cases with SLC52A3 mutations showed classical symmetrical brainstem lesions resembling pathology seen in mitochondrial disease, including severe neuronal loss in the lower cranial nerve nuclei, anterior horns and corresponding nerves, atrophy of the spinothalamic and spinocerebellar tracts and posterior column-medial lemniscus pathways. Mitochondrial dysfunction has previously been implicated in an array of neurodegenerative disorders. Since riboflavin metabolites are critical components of the mitochondrial electron transport chain, we hypothesized that reduced riboflavin transport would result in impaired mitochondrial activity, and confirmed this using in vitro and in vivo models. Electron transport chain complex I and complex II activity were decreased in SLC52A2 patient fibroblasts, while global knockdown of the single Drosophila melanogaster riboflavin transporter homologue revealed reduced levels of riboflavin, downstream metabolites, and electron transport chain complex I activity. This in turn led to abnormal mitochondrial membrane potential, respiratory chain activity and morphology. Riboflavin transporter knockdown in Drosophila also resulted in severely impaired locomotor activity and reduced lifespan, mirroring patient pathology, and these phenotypes could be partially rescued using a novel esterified derivative of riboflavin. Our findings expand the genetic, clinical and neuropathological features of Brown-Vialetto-Van Laere syndrome, implicate mitochondrial dysfunction as a downstream consequence of riboflavin transporter gene defects, and validate riboflavin esters as a potential therapeutic strategy

Truncating and missense mutations in IGHMBP2 cause Charcot-Marie Tooth disease type 2.

Using a combination of exome sequencing and linkage analysis, we investigated an English family with two affected siblings in their 40s with recessive Charcot-Marie Tooth disease type 2 (CMT2). Compound heterozygous mutations in the immunoglobulin-helicase-μ-binding protein 2 (IGHMBP2) gene were identified. Further sequencing revealed a total of 11 CMT2 families with recessively inherited IGHMBP2 gene mutations. IGHMBP2 mutations usually lead to spinal muscular atrophy with respiratory distress type 1 (SMARD1), where most infants die before 1 year of age. The individuals with CMT2 described here, have slowly progressive weakness, wasting and sensory loss, with an axonal neuropathy typical of CMT2, but no significant respiratory compromise. Segregating IGHMBP2 mutations in CMT2 were mainly loss-of-function nonsense in the 5' region of the gene in combination with a truncating frameshift, missense, or homozygous frameshift mutations in the last exon. Mutations in CMT2 were predicted to be less aggressive as compared to those in SMARD1, and fibroblast and lymphoblast studies indicate that the IGHMBP2 protein levels are significantly higher in CMT2 than SMARD1, but lower than controls, suggesting that the clinical phenotype differences are related to the IGHMBP2 protein levels

Cerebellar ataxia, neuropathy, vestibular areflexia syndrome due to RFC1 repeat expansion

Ataxia, causing imbalance, dizziness and falls, is a leading cause of neurological disability. We have recently identified a biallelic intronic AAGGG repeat expansion in replication factor complex subunit 1 (RFC1) as the cause of cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) and a major cause of late onset ataxia. Here we describe the full spectrum of the disease phenotype in our first 100 genetically confirmed carriers of biallelic repeat expansions in RFC1 and identify the sensory neuropathy as a common feature in all cases to date. All patients were Caucasian and half were sporadic. Patients typically reported progressive unsteadiness starting in the sixth decade. A dry spasmodic cough was also frequently associated and often preceded by decades the onset of walking difficulty. Sensory symptoms, oscillopsia, dysautonomia and dysarthria were also variably associated. The disease seems to follow a pattern of spatial progression from the early involvement of sensory neurons, to the later appearance of vestibular and cerebellar dysfunction. Half of the patients needed walking aids after 10 years of disease duration and a quarter were wheelchair dependent after 15 years. Overall, two-thirds of cases had full CANVAS. Sensory neuropathy was the only manifestation in 15 patients. Sixteen patients additionally showed cerebellar involvement, and six showed vestibular involvement. The disease is very likely to be underdiagnosed. Repeat expansion in RFC1 should be considered in all cases of sensory ataxic neuropathy, particularly, but not only, if cerebellar dysfunction, vestibular involvement and cough coexist

Perinatal health monitoring through a European lens: eight lessons from the Euro-Peristat report on 2015 births

International audienceNo abstract availabl

De Novo and Bi-allelic Pathogenic Variants in NARS1 Cause Neurodevelopmental Delay Due to Toxic Gain-of-Function and Partial Loss-of-Function Effects

Aminoacyl-tRNA synthetases (ARSs) are ubiquitous, ancient enzymes that charge amino acids to cognate tRNA molecules, the essential first step of protein translation. Here, we describe 32 individuals from 21 families, presenting with microcephaly, neurodevelopmental delay, seizures, peripheral neuropathy, and ataxia, with de novo heterozygous and bi-allelic mutations in asparaginyl-tRNA synthetase (NARS1). We demonstrate a reduction in NARS1 mRNA expression as well as in NARS1 enzyme levels and activity in both individual fibroblasts and induced neural progenitor cells (iNPCs). Molecular modeling of the recessive c.1633C>T (p.Arg545Cys) variant shows weaker spatial positioning and tRNA selectivity. We conclude that de novo and bi-allelic mutations in NARS1 are a significant cause of neurodevelopmental disease, where the mechanism for de novo variants could be toxic gain-of-function and for recessive variants, partial loss-of-function