Guidelines for diagnosis and management of the cobalamin-related remethylation disorders cblC, cblD, cblE, cblF, cblG, cblJ and MTHFR deficiency

BACKGROUND: Remethylation defects are rare inherited disorders in which impaired remethylation of homocysteine to methionine leads to accumulation of homocysteine and perturbation of numerous methylation reactions. OBJECTIVE: To summarise clinical and biochemical characteristics of these severe disorders and to provide guidelines on diagnosis and management. DATA SOURCES: Review, evaluation and discussion of the medical literature (Medline, Cochrane databases) by a panel of experts on these rare diseases following the GRADE approach. KEY RECOMMENDATIONS: We strongly recommend measuring plasma total homocysteine in any patient presenting with the combination of neurological and/or visual and/or haematological symptoms, subacute spinal cord degeneration, atypical haemolytic uraemic syndrome or unexplained vascular thrombosis. We strongly recommend to initiate treatment with parenteral hydroxocobalamin without delay in any suspected remethylation disorder; it significantly improves survival and incidence of severe complications. We strongly recommend betaine treatment in individuals with MTHFR deficiency; it improves the outcome and prevents disease when given early

Microtia: A Combined Approach by Genetics and Audiology

En Abstract Introduction Microtia is a condition in which the external portion of the ear (the auricle) is malformed. In the strictest definition, there is also narrowing or absence of the external auditory canal (external auditory meatus). Microtia varies in severity from barely discernible to an external ear with major structural changes. Hearing loss is a common feature that can be associated with microtia. There are different types of hearing loss–conductive, sensorineural, or mixed–depending on which part of the ear is not working as it should. Objectives The present study was designed with the following aims: (i) identification of the genetic etiology and patterns of inheritance of microtia for proper genetic counseling; (ii) early detection and identification of associated hearing impairment for proper management including use of a hearing aid and surgical intervention. Patients and methods Twenty children with microtia ranging in age between 1 and 15 years (mean: 6.2 ± 3.68 years) irrespective of sex were included in this study: 14 males and six females. All children were subjected to a full assessment of medical history, a general examination, an ENT examination, tympanometry, pure tone audiometry, and an auditory steady-state response test for patients not responding to a conventional audiometric test. Karyotyping, fluorescence in-situ hybridization (FISH) for Treacher Collins cases, radiological investigations, and fundus examination were also performed. Results Syndromic microtia was more frequent than nonsyndromic microtia. Treacher Collins syndrome was the most clinically diagnosed syndrome, followed by Goldenhar’s syndrome. There was one case of Down’s syndrome and another single case of Johnson–McMillin syndrome. Meatal atresia and preauricular tags were frequently present in the microtia cases, whereas middle ear and inner ear anomalies were only found in some cases. The most common presenting symptom of microtia is hearing loss. Its degree and type differ according to the severity of the disease and frequencies affected. In total, 88.5% (23 ears) have conductive hearing loss and 11.5% (three ears) have mixed hearing loss. Karyotyping was performed for 10 cases; nine cases were normal, whereas one case was abnormal (47XY, +21) (Down’s syndrome), which represents 5% of all cases studied. FISH was performed for four cases of Treacher Collins syndrome using a probe for chromosome 5 with gene map locus 5q31q33, but no deletion was found in the chromosome 5 Treacher Collins–Franceschetti 1 (TCOF1) gene. Conclusion Genetic predisposition for both autosomal dominant and autosomal recessive inheritance seems to be a strong determinant factor in the etiology of microtia than the environmental one. As for Treacher Collins, which is the most frequently clinically diagnosed syndrome in the current study, the FISH study showed that the 5q31-q33 locus may not carry the causative mutation as no single case was positive for this locus. Hearing impairment, of the conductive type, is the most frequent symptom that leads parents to seek medical advice and genetic counseling

In situ hybridization of bat chromosomes with human (TTAGGG)n probe, after previous digestion with Alu I

The purpose of this work was to verify the ability of the enzyme Alu I to cleave and/or remove satellite DNA sequences from heterochromatic regions in chromosomes of bats, by identifying the occurrence of modifications in the pattern of fluorescence in situ hybridization with telomeric DNA. The localization and fluorescence intensity of the telomeric DNA sites of the Alu-digested and undigested chromosomes of species Eumops glaucinus, Carollia perspicillata, and Platyrrhinus lineatus were analyzed. Telomeric sequences were detected at the termini of chromosomes of all three species, although, in C. perspicillata, the signals were very faint or absent in most chromosomes. This finding was interpreted as being due to a reduced number of copies of the telomeric repeat, resulting from extensive telomeric association and/or rearrangements undergone by the chromosomes of Carollia. Fluorescent signals were also observed in centromeric and pericentromeric regions in several two-arm chromosomes of E. glaucinus and C. perspicillata. In E. glaucinus and P. lineatus, some interstitial and terminal telomeric sites were observed to be in association with regions of constitutive heterochromatin and ribosomal DNA (NORs). After digestion, these telomeric sites showed a significant decrease in signal intensity, indicating that enzyme Alu I cleaves and/or removes part of the satellite DNA present in these regions. These results suggest that the telomeric sequence is a component of the heterochromatin, and that the C-band- positive regions of bat chromosomes have a different DNA composition