Autosomal dominant inheritance of non-syndromic renal hypoplasia and dysplasia: dramatic variation in clinical severity in a single kindred.
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Adolescent↗
Biomedical subjects
Jonathan Berg
Publications and source records attributed to Jonathan Berg.
The value of measuring serum cholesterol-adjusted vitamin E in routine practice.
BACKGROUND: If the lipid concentration is not taken into account, then in certain situations the vitamin E status of a patient may be wrongly assigned based on serum measurement alone. In this study, the utility of using the calculated vitamin E:cholesterol ratio to determine vitamin E status was compared to the measurement of vitamin E alone. METHODS: The vitamin E:cholesterol ratio was measured in 457 patient samples received for routine vitamin E analysis. Serum vitamin E concentration was determined by high-performance liquid chromatography (HPLC) with UV detection and cholesterol concentration, using a Roche analyser and reagents. RESULTS: The mean vitamin E concentration and vitamin E:cholesterol ratio for the total study population was 22.0 micromol/L and 5.9 micromol/mmol, respectively. Of the 457 patient samples analysed, 57 (12.5%) were found to have a low vitamin E concentration, but only 25 (47%) of these patients had a low vitamin E:cholesterol ratio as well. Two patients both with cholestasis had a normal vitamin E concentration but low vitamin E:cholesterol ratio. CONCLUSION: The determination of vitamin E:cholesterol ratios can be used to better define the vitamin E status of patients with disease states or disorders likely to raise LDL cholesterol, for example cholestasis. For the majority of samples, measurement of serum vitamin E concentration alone is sufficient to establish patient vitamin E status.
Adolescent↗
Whole-blood thiopurine S-methyltransferase activity with genotype concordance: a new, simplified phenotyping assay.
BACKGROUND: We have developed a new thiopurine S-methyltransferase (TPMT) phenotyping method that measures TPMT activity in whole blood. To evaluate this assay, we compared it with conventional TPMT phenotyping, which uses a red blood cell (RBC) lysate and genotyping for analysis of common TPMT mutations. METHODS: Whole-blood and RBC lysates were prepared from 402 patients' samples received for routine analysis. The TPMT activity of lysates was determined using 6-thioguanine as substrate with high-performance liquid chromatographic (HPLC) analysis and fluorimetric detection. DNA was extracted from buffy coats using phenol-chloroform extraction. A multiplex amplification refractory mutation system (ARMS) strategy was used to screen for the common TPMT mutations TPMT*2 and TPMT*3 (TPMT*3A, TPMT*3C and TPMT*3D). RESULTS: TPMT activities were higher in the whole-blood (mean TPMT activity 51 nmol 6-MTG/gHb/h) compared with the RBC lysate (37 nmol 6-MTG/gHb/h). Overall, concordance with TPMT genotypic analysis was 97% for both the new whole-blood and standard RBC lysate methods. Between low TPMT activity and heterozygotes, both phenotypic methods gave a concordance of 79%. CONCLUSION: Using multiplex ARMS testing for TPMT*2 and 3*C mutations to define the cut-off between low and normal TPMT activity, we have demonstrated that the new whole-blood TPMT phenotyping method performs as well as the conventional RBC lysate assay. This new method overcomes the need to prepare a RBC lysate, a process which is time consuming and increases analytical variation. The resulting assay is better suited to a regional or national TPMT phenotyping service.
Black or African American↗
Vitamin D concentrations in an UK inner-city multicultural outpatient population.
BACKGROUND: Vitamin D deficiency is still thought to be widespread in the UK and in recent years the number of cases of rickets reported in children has increased. In this study, the distribution of vitamin D and the prevalence of vitamin D deficiency have been determined for a multi-ethnic population from the inner-city area of Birmingham, UK, where a vitamin D testing service has been readily available for over 10 years. METHODS: Serum 25-hydroxyvitamin D concentration was determined using an automated platform (Nichol's Advantage Speciality System) for 830 outpatient samples collected randomly at the end of summer (September). RESULTS: In our total study population, prevalence of vitamin D deficiency, defined as a 25-hydroxyvitamin D concentration < 10 microg/L, was high (24%): one in eight Caucasians, one in four Black Afro-Caribbeans and one in three Asians were found to be deficient. Levels of deficiency were much higher in Asian women, with almost one in two individuals (43%) found to have a vitamin D level below 10 microg/L. CONCLUSION: Our study has shown that widespread vitamin D deficiency in a UK inner-city population remains an issue. In concordance with other studies, we found a high prevalence of vitamin D deficiency in Afro-Caribbean and Asians, and, in particular, women. It is clear that more routine screening of vitamin D is needed.
Adolescent↗
Whose TPMT activity is it anyway?
Determination of thiopurine S-methyltransferase (TPMT) activity prior to starting azathioprine therapy is used to identify individuals with low or deficient TPMT activities who are at risk of severe complications and even death This case describes a patient treated with azathioprine without prior knowledge of TPMT status. Pancytopaenia developed over several months and at this point TPMT activity was determined and found to be low at 16 nmol 6-methyl thioguanine (6-MTG)/g Hb/h, which is within the reference interval associated with heterozygosity for TPMT mutant alleles. On repeating the TPMT measurement 3 months later, the TPMT activity was 2 nmol 6-MTG/g Hb/h, consistent with deficient TPMT activity (homozygosity for TPMT mutant alleles), suggesting the patient is at high risk of myelosuppression if treated with thiopurine drugs. Retrospectively, it was found that the patient had received transfusions of red blood cell and platelets 6 days before TPMT activity was first measured. This case underlines the importance of determining TPMT activity status prior to azathioprine treatment, rather than taking a dose incrementation approach. It also highlights the caution that must be taken in interpreting TPMT activity in patients who have recently been transfused.
Chromatography, High Pressure Liquid↗
Multiplex ligation-dependent probe amplification using a completely synthetic probe set.
The recent development of multiplex ligation-dependent probe amplification (MLPA) has provided an efficient and reliable assay for dosage screening of multiple loci in a single reaction. However, a drawback to this method is the time-consuming process of generating a probe set by cloning in single-stranded bacteriophage vectors. We have developed a synthetic probe set to screen for deletions in a region spanning 18.5 Mb within chromosome 3q. In a pilot study, we tested 15 synthetic probes on 4 control samples and on 2 patients previously found to possess a heterozygous deletion in the region 3q26-q28. These synthetic probes detected deletions at all previously known deleted loci. Furthermore, using synthetic probes, the variability of results within samples was similar to that reported for commercially available M13-derived probes. Our results demonstrate that this novel approach to MLPA provides a generic solution to the difficulties of probe development by cloning; such synthetically generated probes may be used to screen a large number of loci in a single reaction. We conclude that the use of synthetic probes for MLPA is a rapid, robust, and efficient alternative for research (and potentially diagnostic) deletion and duplication screening of multiple genomic loci.
Chromosome Deletion↗
Deletion of the distal long arm of chromosome 10; is there a characteristic phenotype? A report of 15 de novo and familial cases.
It has been suggested previously that patients with terminal deletions of chromosome 10q have a recognizable phenotype including a characteristic facial appearance combined with other abnormalities including mental retardation, cardiac and anogenital anomalies. We report the largest published series of new cases of terminal 10q deletion, including eight familial and four de novo cases and three cases with interstitial deletions involving chromosome bands 10q25.2-26.3. The deleted regions were defined by FISH using YAC probes, as well as standard karyotyping. The most consistent clinical features in our cases are cranial anomalies including facial asymmetry, prominent nose and nasal bridge, prominent ears, thin upper lip, along with growth retardation, developmental delay, and digital abnormalities. Visceral abnormalities were only identified in a small number of the patients, with renal involvement in three cases and structural cardiac malformations in two others. Learning difficulties of varying severity were found in 11 cases and behavioral problems described in four. Candidate genes for behavioral and learning difficulties within the deleted region include Calcyon. Other genes in the region that might have a role in causing the phenotype include the genes coding for fibroblast growth factor receptor type 2 (FGFR2) and C-terminal binding protein 2 (CTBP2).
Abnormalities, Multiple↗
Choanal atresia: the result of maternal thyrotoxicosis or fetal carbimazole?
We present the fourth published case of a child affected with choanal atresia following maternal treatment with carbimazole. The mother was receiving her highest dose of carbimazole at the crucial period for development of the choanae, between days 35 and 38.
Adult↗
Delineation of an estimated 6.7 MB candidate interval for an anophthalmia gene at 3q26.33-q28 and description of the syndrome associated with visible chromosome deletions of this region.
Anophthalmia or microphthalmia occur in approximately one in 10 children who have severe visual impairment. These eye malformations are often of unknown aetiology, but can be inherited in autosomal dominant, recessive or X-linked forms, and can also occur in association with specific chromosome abnormalities. Four children are described in the medical literature with microphthalmia or anophthalmia in association with chromosome rearrangements involving distal 3q, suggesting the presence of a micro/anophthalmia gene in this region. We have identified two further patients with micro/anophthalmia and chromosome rearrangements involving 3q26-->3q27 and identified a 6.7 MB common deleted region. Patient 1 had multiple abnormalities including bilateral anophthalmia, abnormalities of the first and second cranial nerves and partial absence of the corpus callosum. His karyotype was 46,XY,del(3)(q26.33q28). Patient 2 had right anophthalmia and left extreme microphthalmia. Her karyotype was 46,XX,del(3)(q26.33q28)t(3;7)(q28;q21.1). Both patients had intrauterine growth retardation (IUGR) and strikingly similar dysmorphic facies consisting of bossed forehead, downward-slanting palpebral fissures, grooved bridge of the nose, prominent low-set ears, small down-turned mouth and small mandible. We identified BAC clones mapping to distal 3q from the ENSEMBL and NCBI Entrez databases. These BAC clones were used as fluorescence in situ hybridisation (FISH) probes to identify the minimum deleted region common to both patients. This interval, between clones RPC11-134F2 and RPC11-132N15, was estimated to be 6.7 MB. We conclude that there is an anophthalmia locus within this interval. Candidate genes mapping to this region include Chordin and DVL3, a homologue of the Drosophila Dishevelled gene.
Anophthalmos↗