A founder mutation in COL4A3 causes autosomal recessive Alport syndrome in the Ashkenazi Jewish population.

Alport syndrome is an inherited progressive nephropathy arising from mutations in the type IV collagen genes, COL4A3, COL4A4, and COL4A5. Symptoms also include sensorineural hearing loss and ocular lesions. We determined the molecular basis of Alport syndrome in a non-consanguineous Ashkenazi Jewish family with multiple affected females using linkage analysis and next generation sequencing. We identified a homozygous COL4A3 mutation, c.40_63del, in affected individuals with mutant alleles inherited from each parent on partially conserved haplotypes. Large-scale population screening of 2017 unrelated Ashkenazi Jewish samples revealed a carrier frequency of 1 in 183 indicating that COL4A3 c.40_63del is a founder mutation which may be a common cause of Alport syndrome in this population. Additionally, we determined that heterozygous mutation carriers in this family do not meet criteria for a diagnosis of Thin Basement Membrane Nephropathy and concluded that carriers of c.40_63del are not likely to develop benign familial hematuria.

[Functional repercussions of meniscal injuries on the postoperative physical athletic performance of athletes]. / Repercusión funcional en el rendimiento físico-atlético postoperatorio de pacientes deportistas con lesiones meniscales.

UNLABELLED: The practice of sports has experienced a huge boom in societies worldwide. It often involves knee injuries, specifically meniscal tears that warrant surgical treatment which may include: fragment remodeling and resection, meniscal repair or, in extreme cases, the use of a meniscal graft. In this prospective study we performed fragment resection and meniscal remodeling in athletes and we measured their postoperative physical-athletic performance. METHODS: Inclusion criteria: Patients of both sexes who practice a sport either as amateurs or at a recreational competitive level, who sustained a meniscal injury. Exclusion criteria: Patients with associated total anterior cruciate ligament tear, patients lost to follow-up, and patients eligible for meniscal repair. 23-patient cohort including 10 females and 13 males who presented at our hospital. A diagnostic protocol to certify the injury was applied. Patients underwent surgery to perform meniscal fragment resection and remodeling. They later underwent rehabilitation at the physiatrics service and finally received approval to return to sports. The Tegner Lysholm Knee Scoring Scale was used to assess postoperative results. CONCLUSION: All patients were able to return to practice their pre-injury sport, but their performance was 20 to 30% lower than before. Recovery took longer in females.

Elevated phenylacetic acid levels do not correlate with adverse events in patients with urea cycle disorders or hepatic encephalopathy and can be predicted based on the plasma PAA to PAGN ratio.

BACKGROUND: Phenylacetic acid (PAA) is the active moiety in sodium phenylbutyrate (NaPBA) and glycerol phenylbutyrate (GPB, HPN-100). Both are approved for treatment of urea cycle disorders (UCDs) - rare genetic disorders characterized by hyperammonemia. PAA is conjugated with glutamine in the liver to form phenylacetyleglutamine (PAGN), which is excreted in urine. PAA plasma levels ≥ 500 µg/dL have been reported to be associated with reversible neurological adverse events (AEs) in cancer patients receiving PAA intravenously. Therefore, we have investigated the relationship between PAA levels and neurological AEs in patients treated with these PAA pro-drugs as well as approaches to identifying patients most likely to experience high PAA levels. METHODS: The relationship between nervous system AEs, PAA levels and the ratio of plasma PAA to PAGN were examined in 4683 blood samples taken serially from: [1] healthy adults [2], UCD patients of ≥ 2 months of age, and [3] patients with cirrhosis and hepatic encephalopathy (HE). The plasma ratio of PAA to PAGN was analyzed with respect to its utility in identifying patients at risk of high PAA values. RESULTS: Only 0.2% (11) of 4683 samples exceeded 500 µg/ml. There was no relationship between neurological AEs and PAA levels in UCD or HE patients, but transient AEs including headache and nausea that correlated with PAA levels were observed in healthy adults. Irrespective of population, a curvilinear relationship was observed between PAA levels and the plasma PAA:PAGN ratio, and a ratio>2.5 (both in µg/mL) in a random blood draw identified patients at risk for PAA levels>500 µg/ml. CONCLUSIONS: The presence of a relationship between PAA levels and reversible AEs in healthy adults but not in UCD or HE patients may reflect intrinsic differences among the populations and/or metabolic adaptation with continued dosing. The plasma PAA:PAGN ratio is a functional measure of the rate of PAA metabolism and represents a useful dosing biomarker.

Tomografía por emisión de positrones y fusión de imágenes con tomografía computada helicoidal (PET-TCH) en la estadificación del cáncer de pulmón / Dual Modality CT/PET imaging in lung cancer staging

Objetivo: Comparar la capacidad diagnóstica de la fusión de imágenes PET-TCH y de la tomografía computada helicoidal (TCH), en la detección de metástasis ganglionares y a distancia en pacientes con cáncer de pulmón. Material y Método: Se efectuó un análisis retrospectivo de los exámenes TCH y PET-TCH de 66 pacientes, 45 hombres y 21 mujeres (edad media: 63 años; rango:38 a96 años) atendidos en nuestro servicio entre febrero de 2003 y marzo del 2004. Se incluyó aquellos pacientes con diagnóstico de cáncer de pulmón, que se realizaron en un mismo momento la TCH y el PET, y en los cuales resultó posible establecer el diagnóstico definitivo en base a los resultados de anatomía patológica y/o seguimiento clínico-imagenológica alejado. Resultados: En la estadificación ganglionar global (hiliar y mediastinal) la TCH mostró una sensibilidad, especificidad, VPP y VPN de 72 por ciento, 47 por ciento, 62 por ciento y 58 por ciento respectivamente, versus 94 por ciento, 77 por ciento, 83 por ciento y 92 por ciento correspondientes al exámen PET-TCH. En la asignación de un estadio ganglionar avanzado el PET-TCH tuvo valores de 92 por ciento, 100 por ciento y 98 por ciento. En la detección de metástasis, la TCH sola, arrojó valores correspondientes de 67 por ciento, 93 por ciento, 84 por ciento y 83 por ciento respectivamente contra 100 por ciento, 98 por ciento, 96 por ciento y 100 por ciento para el PET-TCH. En 20 (30 por ciento) pacientes que habían sido sub o sobreestadísticos con la TCH sola, el PET-TCH asignó en forma correcta el estadio tumoral. Conclusión: El estudio PET-TCH mediante la fusión de imágenes, mejoró la prescisión diagnóstica y resultó más efectivo que la TCH sola para la detección de metástasis ganglionares y a distancia

Effects of dopamine D2 receptor (DRD2) and transporter (SLC6A3) polymorphisms on smoking cue-induced cigarette craving among African-American smokers.

Cue-induced craving for addictive substances has long been known to contribute to the problem of persistent addiction in humans. Research in animals over the past decade has solidly established the central role of dopamine in cue-induced craving for addictive substances, including nicotine. Analogous studies in humans, however, are lacking, especially among African-American smokers, who have lower quit rates than Caucasian smokers. Based on the animal literature, the study's objective was to test the hypothesis that smokers carrying specific variants in dopamine-related genes previously associated with risk for addictive behaviors would exhibit heightened levels of cigarette craving following laboratory exposure to cues. To this end, cigarette craving was induced in healthy African-American smokers (n=88) through laboratory exposure to smoking cues. Smokers carrying either the DRD2 (D2 dopamine receptor gene) TaqI A1 RFLP or the SLC6A3 (dopamine transporter gene) 9-repeat VNTR polymorphisms had stronger cue-induced cravings than noncarriers (Ps <0.05 and 0.01, respectively). Consistent with the separate biological pathways involved (receptor, transporter), carriers of both polymorphisms had markedly higher craving responses compared to those with neither (P<0.0006), reflecting additive effects. Findings provide support for the role of dopamine in cue-induced craving in humans, and suggest a possible genetic risk factor for persistent smoking behavior in African-American smokers.

Stress-induced cigarette craving: effects of the DRD2 TaqI RFLP and SLC6A3 VNTR polymorphisms.

Animal models have long implicated dopamine in stress-induced craving for a variety of addictive substances. However, translational studies of dopamine, stress and craving in humans are lacking. Based on the animal literature, this study's objective was to test the hypothesis that cigarette smokers carrying specific variants in dopamine-related genes would have heightened levels of cigarette craving following exposure to a laboratory stressor. Cigarette craving induced by controlled exposure to a laboratory stressor was assessed in healthy adult smokers (n=108) recruited by advertisement. Significantly stronger stress-induced cigarette craving was found for individuals carrying either the DRD2 (D2 dopamine receptor gene) A1, or the SLC6A3 (dopamine transporter gene) nine-repeat allelic variants. Stress-induced craving was markedly higher for those carrying both alleles, compared to those with neither, consistent with the separate biological pathways involved (receptor, transporter). Findings provide strong support for the possibility that dopamine involvement in stress-induced craving well established in animal models also applies to humans, and suggest a potential genetic risk factor for persistent smoking behavior.

Impact of the reduced folate carrier on the accumulation of active thiamin metabolites in murine leukemia cells.

The thiamin transporter encoded by SLC19A2 and the reduced folate carrier (RFC1) share 40% homology at the protein level, but the thiamin transporter does not mediate transport of folates. By using murine leukemia cell lines that express no, normal, or high levels of RFC1, we demonstrate that RFC1 does not mediate thiamin influx. However, high level RFC1 expression substantially reduced accumulation of the active thiamin coenzyme, thiamin pyrophosphate (TPP). This decreased level of TPP, synthesized intracellularly from imported thiamin, resulted from RFC1-mediated efflux of TPP. This conclusion was supported by the following observations. (i) Efflux of intracellular TPP was increased in cells with high expression of RFC1. (ii) Methotrexate inhibits TPP influx. (iii) TPP competitively inhibits methotrexate influx. (iv) Loading cells, which overexpress RFC1 to high levels of methotrexate to inhibit competitively RFC1-mediated TPP efflux, augment TPP accumulation. (v) There was an inverse correlation between thiamin accumulation and RFC1 activity in cells grown at a physiological concentration of thiamin. The modulation of thiamin accumulation by RFC1 in murine leukemia cells suggests that this carrier may play a role in thiamin homeostasis and could serve as a modifying factor in thiamin nutritional deficiency as well as when the high affinity thiamin transporter is mutated.

WHIM syndrome, an autosomal dominant disorder: clinical, hematological, and molecular studies.

The acronym WHIM refers to Warts, Hypogammaglobulinemia, Infections, and Myelokathexis. The latter refers to the retention of white cells in the marrow, which becomes hypercellular. We have found approximately 20 examples of WHIM syndrome in the literature under various designations; the first examples are Zuelzer [1964] and Krill et al. [1964]. Chronic noncyclic neutropenia and hypercellular bone marrow represent defective release of marrow cells into the peripheral stream (myelokathexis). The hypermature neutrophils are bizarre in form. Condensed nuclei connected by long, stringy filaments and vacuolated cytoplasm suggest apoptosis. Fever or other stress increases the release of neutrophils. Hypogammaglobulinemia is marked and associated with recurrent upper respiratory infections (sinusitis, tonsillitis, otitis media, pneumonia). Patients have numerous warts, some venereal, with resultant cervical and vulval premalignant dysplasia. We report on a kindred of 6 affected individuals in 3 generations with autosomal dominant WHIM syndrome. The sex ratio among reported patients and in our kindred is 17 female to 8 male. Because there had been no male-to-male transmssion, search of the entire X-chromosome including the pseudoautosomal area was carried out and no linkage was found. Recently, the propositus has had an unaffected daughter, confirming our finding that the gene is not X-linked. A genome-wide search is being carried out.

Sanjad-Sakati and autosomal recessive Kenny-Caffey syndromes are allelic: evidence for an ancestral founder mutation and locus refinement.

The Sanjad-Sakati syndrome (SSS; MIM241410), an autosomal recessive trait characterized by congenital hypoparathyroidism, growth and mental retardation, seizures, and a characteristic physiognomy, was recently linked to chromosome area 1q42-q43. SSS resembles the autosomal recessive form of Kenny-Caffey syndrome (KCS; MIM244460), with similar manifestations but lacking osteosclerosis. Since KCS was recently linked to the region 1q42-q43, the possibility that this disorder is allelic with SSS was considered. Eight Sanjad-Sakati families from Saudi Arabia were genotyped with polymorphic short tandem repeat markers from the SSS/KCS critical region. A maximum multipoint LOD score of 14.32 was obtained at marker D1S2649, confirming linkage of SSS to the same region as autosomal recessive KCS. Haplotype analysis refined the critical region to 2.6 cM and identified a rare haplotype present in all the SSS disease alleles, indicative of a common founder. In addition to the assignment of the Saudi SSS and Kuwaiti KCS syndromes to overlapping genetic intervals, comparison of the haplotypes unexpectedly demonstrated that the diseases shared an identical haplotype. This finding, combined with the clinical similarity between the two syndromes, suggests that the two conditions are not only allelic but are also caused by the same ancestral mutation.

The autosomal recessive Kenny-Caffey syndrome locus maps to chromosome 1q42-q43.

Kenny-Caffey syndrome (KCS) is an osteosclerotic bone dysplasia with associated hypocalcemia and ocular abnormalities. Both autosomal dominant (MIM127000) and autosomal recessive (MIM244460) inheritance patterns have been described. Using eight consanguineous Kuwaiti kindreds, a genome-wide search for linkage to the gene causing the autosomal recessive form of KCS was performed with polymorphic short tandem repeat markers. Significant linkage to a locus situated at chromosome 1q42 --> q43 with a maximal two-point lod score of 13.30 with marker D1S2649 was obtained. Haplotype analysis of flanking markers identified recombination events defining the KCS locus to a region between markers D1S2800 on the centromeric boundary and D1S2850 on the telomeric boundary, an approximately 4-cM interval. All affected individuals in these unrelated kindreds were homozygous for identical alleles at markers D1S2649 and D1S235, suggesting a single ancestral mutation underlying the disease in these families. Haploinsufficiency at 22q11, reported in another consanguineous KCS kindred, was not documented in these families.