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Congenital sodium diarrhea (CSD) refers to an intractable diarrhea of intrauterine onset with high fecal sodium loss. CSD is clinically and genetically heterogeneous. Syndromic CSD is caused by SPINT2 mutations. While we recently described four cases of the non-syndromic form of CSD that were caused by dominant activating mutations in intestinal receptor guanylate cyclase C (GC-C), the genetic cause for the majority of CSD is still unknown. Therefore, we aimed to determine the genetic cause for non-GC-C non-syndromic CSD in 18 patients from 16 unrelated families applying whole-exome sequencing and/or chromosomal microarray analyses and/or direct Sanger sequencing. SLC9A3 missense, splicing and truncation mutations, including an instance of uniparental disomy, and whole-gene deletion were identified in nine patients from eight families with CSD. Two of these nine patients developed inflammatory bowel disease (IBD) at 4 and 16 years of age. SLC9A3 encodes Na(+)/H(+) antiporter 3 (NHE3), which is the major intestinal brush-border Na(+)/H(+) exchanger. All mutations were in the NHE3 N-terminal transport domain, and all missense mutations were in the putative membrane-spanning domains. Identified SLC9A3 missense mutations were functionally characterized in plasma membrane NHE null fibroblasts. SLC9A3 missense mutations compromised NHE3 activity by reducing basal surface expression and/or loss of basal transport function of NHE3 molecules, whereas acute regulation was normal. This study identifies recessive mutations in NHE3, a downstream target of GC-C, as a cause of CSD and implies primary basal NHE3 malfunction as a predisposition for IBD in a subset of patients., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Purpose: "Jaffe-Campanacci syndrome" describes the complex of multiple nonossifying fibromas of the long bones, mandibular giant cell lesions, and café-au-lait macules in individuals without neurofibromas. We sought to determine whether Jaffe-Campanacci syndrome is a distinct genetic entity or a variant of neurofibromatosis type 1., Methods: We performed germline NF1, SPRED1, and GNAS1 (exon 8) mutation testing on patients with Jaffe-Campanacci syndrome or Jaffe-Campanacci syndrome-related features. We also performed somatic NF1 mutation testing on nonossifying fibromas and giant cell lesions., Results: Pathogenic germline NF1 mutations were identified in 13 of 14 patients with multiple café-au-lait macules and multiple nonossifying fibromas or giant cell lesions ("classical" Jaffe-Campanacci syndrome); all 13 also fulfilled the National Institutes of Health diagnostic criteria for neurofibromatosis type 1. Somatic NF1 mutations were detected in two giant cell lesions but not in two nonossifying fibromas. No SPRED1 or GNAS1 (exon 8) mutations were detected in the seven NF1-negative patients with Jaffe-Campanacci syndrome, nonossifying fibromas, or giant cell lesions., Conclusion: In this study, the majority of patients with café-au-lait macules and nonossifying fibromas or giant cell lesions harbored a pathogenic germline NF1 mutation, suggesting that many Jaffe-Campanacci syndrome cases may actually have neurofibromatosis type 1. We provide the first proof of specific somatic second-hit mutations affecting NF1 in two giant cell lesions from two unrelated patients, establishing these as neurofibromatosis type 1-associated tumors.

N-carbamylglutamate (NCG) has been reported to decrease ammonia levels in patients with propionic aciduria (PA) and methylmalonic aciduria (MMA), but reports on clinical outcomes remain scant. Here, we report a retrospective series of four patients with neonatal PA treated with NCG at presentation. Patients presented between 2 and 9 days of age and peak plasma ammonia ranged from 524 to 1,572 μM. Patients received bolus (30-200 mg/kg) and sustaining (115-300 mg/kg per day) doses of NCG in addition to a standard treatment regimen that included ammonia scavenger drugs. Ammonia levels decreased significantly in three of the four cases within 2 h after administration of NCG and fell below 100 μM in all within 12-29 h. Two patients received NCG (bolus 200 mg/kg) while ammonia was above 500 μM (740 and 1,572) and their levels fell below 500 μM by 4 and 8 h post-treatment, respectively. Outcomes of these NGC-treated patients were not improved over previously reported PA patients who did not receive NCG: two died during the initial episode and one after his third metabolic decompensation at 46 days. The survivor is now 3 years old and has a well-controlled seizure disorder and a mild developmental delay mostly in language. We conclude that despite a trial of NCG and a rapid fall in plasma ammonia, the short-term outcome of these patients was not improved.

Unlabelled: Abbreviated acquisition protocols were designed for stress and rest to decrease stress and rest SPECT image acquisition times but maintain the high count density of 99mTc-sestamibi separate-day cardiac images., Methods: Scan findings were compared visually and quantitatively with standard SPECT for 12 rest and 32 stress patient studies., Results: Of 29 stress defects detected by standard SPECT, 27 were present with the fast technique; of 8 resting SPECT defects, all were detected with fast SPECT. Two stress and no resting false-positive defects occurred with fast SPECT. Linear correlations (r) between standard and fast quantitative defect extent and severity were 0.76 and 0.86, respectively for stress SPECT, and 0.88 and 0.96 for rest SPECT. Stress fast defects were slightly less severe (p = 0.02) than those observed using standard acquisition., Conclusion: We conclude that these fast protocols for separate-day 99mTc-MIBI SPECT accurately detect and characterize perfusion defects and provide a means to improve patient tolerance and increase laboratory throughput.

Unlabelled: Generally performed in a single anterior or right anterior oblique (RAO) view, first-pass radionuclide angiocardiography (RNA) is limited due to its inability to evaluate septal and posterior wall motion., Methods: Thirty-five patients undergoing stress/rest sestamibi SPECT (22 mCi/22 mCi 2-day protocol) underwent biplane RNA at the time of resting injection. The stress SPECT images (acquired with the patient at rest) were ECG-gated to evaluate resting regional myocardial wall thickening. By this means wall motion assessed by RNA was compared to the presence of a resting SPECT perfusion defect accompanied by a localized decrease in wall thickening., Results: In 16 patients in whom both resting perfusion and wall thickening were normal one demonstrated apical hypokinesis by RNA in the RAO view. In the other 29 patients, a total of 58 resting segmental perfusion defects with abnormal wall thickening were present (12 anterior, 13 inferior, 14 apical, 11 septal and 8 posterolateral). Wall motion abnormalities were detected in all these patients and in 57/58 segments (98%) by biplane RNA. Septal and posterolateral wall motion abnormalities were detected in only the LAO RNA study. In three patients, wall motion abnormalities were detected by LAO imaging only. Of the remaining 87 normally perfused segments in these 29 patients, RNA wall motion was normal in 85. Two posterolateral segments demonstrated apparent hypokinesis, probably due to left atrial overlap in the LAO projection., Conclusion: Simultaneous biplane RNA accurately detects wall motion abnormalities frequently missed by single-plane RAO imaging.

The frequency of hprt mutants in peripheral blood T-lymphocytes of two putative Lesch-Nyhan individuals and their parents was determined by a cell cloning assay to quantify the frequency of thioguanine-resistant mutants. The results confirmed the Lesch-Nyhan diagnosis and demonstrated that the mother has an elevated mutant frequency consistent with being heterozygous for an hprt mutation. Mass cultures of T-lymphocytes from both the children and their mother, as well as cultures of hprt mutant clones from the mother, were employed as sources of mRNA for cDNA sequence analysis. These hprt mutants show a single base substitution (T----C transition) at position 170 (exon 3). The predicted amino acid change is the substitution of threonine for methionine56. We have designated this new Lesch-Nyhan mutation hprtMontreal. The use of T-lymphocyte cultures allows rapid sequence analyses of hprt mutations, as well as family studies to define the origin of a particular mutation.

Epithelial and fibroblast cells were obtained from cultures of amniotic fluid cells. Epithelial cells demonstrated high activities of histidase. In contrast, histidase activity was not detected in fibroblasts derived from the same original culture. This observation indicates that cultures of amniotic fluid cells consist of cells with different biochemical properties as well as morphological characteristics.