Clinical aspects and management of cytomegalovirus infection

The previous article discussed recent advances in understanding the biology of HCMV infection. Here we discuss current approaches to the clinical management of HCMV disease, and how understanding the biology of the virus may affect these.     

Inborn errors of pyrimidine degradation: Clinical, biochemical and molecular aspects

The pyrimidines, uracil and thymine, are degraded in four steps. The first three steps of pyrimidine catabolism, controlled by enzymes shared by both pathways, result in the production of the neurotransmitter amino acid -alanine from uracil and the nonfunctional (R)-(-)--aminoisobutyrate from thymine. The fourth step is controlled by several aminotransferases, which have different affinities for -alanine, -aminoisobutyrate and GABA. Defects concerning the first three steps all lead to a reduced production of -alanine; defects of the transaminases involving the metabolism of -alanine and GABA lead to accumulation of these neurotransmitter substances. In addition, other metabolites will accumulate or be reduced depending on the specific enzyme defect. Analysis of the abnormal concentrations of these metabolites in the body fluids is essential for the detection of patients with pyrimidine degradation defects. Clinically these disorders are often overlooked because symptomatology is highly aspecific. The growth in our knowledge concerning inborn errors of pyrimidine degradation has emphasized the importance of the clinical awareness of these defects as a possible cause of neurological disease and a contraindication for treatment of cancer patients with certain pyrimidine analogues. The various defects are discussed and attention is paid to clinical, genetic and diagnostic aspects.     

Clinical and molecular aspects of congenital isolated hypogonadotropic hypogonadism

Congenital isolated hypogonadotropic hypogonadism (IHH) is characterized by partial or complete lack of pubertal development due to defects in migration, synthesis, secretion or action of gonadotropin-releasing hormone (GnRH). Laboratory diagnosis is based on the presence of low levels of sex steroids, associated with low or inappropriately normal levels of pituitary gonadotropins (LH and FSH). Secretion of other pituitary hormones is normal, as well magnetic resonance imaging of the hypothalamohypophyseal tract, which shows absence of an anatomical defects. When IHH is associated with olfactory abnormalities (anosmia or hyposmia), it characterizes Kallmann syndrome. A growing list of genes is involved in the etiology of IHH, suggesting the heterogeneity and complexity of the genetic bases of this condition. Defects in olfactory and GnRH neuron migration are the etiopathogenic basis of Kallmann syndrome. Mutations in KAL1, FGFR1/FGF8, PROK2/PROKR2, NELF, CHD7, HS6ST1 and WDR11 are associated with defects in neuronal migration, leading to Kallmann syndrome. Notably, defects in FGFR1, FGF8, PROKR2, CHD7 and WDR11 are also associated with IHH, without olfactory abnormalities (normosmic IHH), although in a lower frequency. Mutations in KISS1R, TAC3/TACR3 and GNRH1/GNRHR are described exclusively in patients with normosmic IHH. In this paper, we reviewed the clinical, hormonal and genetic aspects of IHH.     

Andersen–Tawil syndrome: Clinical and molecular aspects

Andersen–Tawil syndrome (ATS) is a rare hereditary multisystem disorder. Ventricular arrhythmias, periodic paralysis and dysmorphic features constitute the classic triad of ATS symptoms. The expressivity of these symptoms is, however, extremely variable, even within single ATS affected families, and not all ATS patients present with the full triad of symptoms. ATS patients may show a prolongation of the QT interval, which explains the classification as long QT syndrome type 7 (LQT7), and specific neurological or neurocognitive defects. In ATS type 1 (ATS1), the syndrome is associated with a loss-of-function mutation in the KCNJ2 gene, which encodes the Kir2.1 inward rectifier potassium channel. In ATS type 2 (ATS2), which does not differ from ATS1 in its clinical symptoms, the genetic defect is unknown. Consequently, ATS2 comprises all cases of ATS in which genetic testing did not reveal a mutation in KCNJ2. The loss-of-function mutations in KCNJ2 in ATS1 affect the excitability of both skeletal and cardiac muscle, which underlies the cardiac arrhythmias and periodic paralysis associated with ATS. Thus far, the molecular mechanism of the dysmorphic features is only poorly understood. In this review, we summarize the clinical symptoms, the underlying genetic and molecular defects, and the management and treatment of ATS.     

Clinical and molecular aspects of a pediatric metachronous adrenocortical tumor

The occurrence of metachronous adrenocortical carcinoma has rarely been described. We report a case of a child with virilizing adrenocortical metachronous tumors that, despite several metastases, presented long-term survival (15 years). We analyzed in this tumor IGF2, IGF1R and FGFR4 gene expression, and evaluated the presence of p.R337H germline p53 mutation and somatic CTNNB1 mutation. IGF2 gene was over-expressed in both left (Weiss score 5) and right (Weiss 7) adrenocortical tumors. IGF1R expression levels were higher in the right adrenocortical tumor. FGFR4 over-expression was also detected in the right adrenocortical tumor. In addition, this patient harbors the germline p.R337H p53 mutation and loss of heterozygosity (LOH) was detected in the tumors. No somatic CTNNB1 mutations were found in both tumors. In conclusion, we demonstrated in this unusual case the over-expression of growth signaling pathways, which are molecular mechanisms previously related to adrenocortical tumorigenesis. Furthermore, the absence of somatic CTNNB1 mutations, which is a molecular marker of poor prognosis in adults, might be related to the long-term survival of this patient.     

Clinical aspects, outcome assessment, and management of ankylosing spondylitis and postenteric reactive arthritis

The cause of ankylosing spondylitis remains unclear. Proof that this disorder is an autoimmune disease attributable to crossreactivity between bacteria and HLA-B27 is still lacking. Differences in endogenous peptide presentation by HLA-B27 subtypes might be relevant in the etiopathogenesis. Fractures of the osteoporotic spine contribute to morbidity. Spinal cord injury may occur. MR imaging enables identifying sacroiliitis earlier than plain radiography. Sweet syndrome has now been described in patients with ankylosing spondylitis and Crohn disease. Progress has been made in the assessment of ankylosing spondylitis. There are now core sets for different settings and validated instruments for functioning and disease activity that will enable demonstrating efficacy of new therapeutic interventions.The debate continues on classification of postinfectious and reactive arthritis. Bacterial antigens may be found in the inflamed joints; occasionally 16S ribosomal RNA is also demonstrated. Antibiotics seem not to be effective in postenteric reactive arthritis.More than 25 years have now elapsed since the association between ankylosing spondylitis and HLA-B27 was first described in 1973. The cause of this disease is still unknown, but a lot of progress has been made regarding the molecular structure of HLA-B27, the spectrum of disease, the clinical and radiographic assessment of ankylosing spondylitis, and its treatment. Recent advances in research on ankylosing spondylitis are reviewed here.     

Clinical and molecular aspects of juvenile hemochromatosis in Saguenay-Lac-Saint-Jean (Quebec, canada)

We report the clinical, biochemical, and genetic characteristics of 13 hemochromatosis patients from Saguenay-Lac-Saint-Jean in whom the first symptoms appeared before age 30. Although the mean age at onset of the first symptoms was 21. 5 years, their mean age at diagnosis was 23.8 years; the diagnosis was particularly delayed among women. Seventy-seven percent of the patients had hypogonadotrophic hypogonadism and 69% heart failure and/or cardiac arrhythmias. Genetic analysis of the HFE gene revealed heterozygosity for the C282Y mutation in 2 patients and for the S65C mutation in 2 others and homozygosity for the H63D mutation in 1 patient. The remaining 8 patients had no identified mutation in the HFE gene, although sequencing of all seven codons and intron-exon junctions was performed (5 patients). All 13 patients fulfill the clinical criteria of juvenile hemochromatosis and represent the largest cluster thus far reported.     

Clinical aspects and molecular genetics of the Jervell- and Lange-Nielsen Syndrome

In contrast to the Romano-Ward (R-W) syndrome, the Jervell and Lange-Nielsen (J-LN) syndrome is an autosomal recessive inherited disease characterized by QT-prolongation in the electrocardiogram (ECG) and recurrent syncopal attacks which are also typical for the R-W syndrome, but also by congenital deafness. Recently, defect alleles in the genes for KCNQ1 and KCNE1 have been identified in patients with the J-LN syndrome. These genes may be causative for the R-W syndrome as well but in J-LN patients, they are only present in the homozygote or compound heterozygote form. In the present paper, we review the clinical and genetic similarities and differences of the J-LN and the R-W syndrome as well as the diagnostic and therapeutic management of these patients and their family members.     

Disorders of phosphate metabolism—pathomechanisms and management of hypophosphataemic disorders

Hypophosphataemia does not necessarily indicate phosphate (Pi) depletion. In acute emergencies such as septicaemia, alkalosis or re-feeding, hypophosphataemia may result from redistribution of Pi from the extracellular to the intracellular space. Hypophosphataemia from true Pi depletion gives rise to skeletal (osteomalacia) and extraskeletal (myopathy, cardiomyopathy) disorders. It is practically never the result of diminished nutritional intake. The most severe syndromes of Pi depletion result from diminished tubular Pi re-absorption and renal Pi wasting. In the differential diagnosis mainly four conditions have to be considered: (i) tumour-associated osteomalacia, (ii) X-linked hypophosphataemia (XLH), (iii) autosomal dominant hypophosphataemia, and (iv) hypercalcaemic renal phosphate wasting. Recent molecular insight has put fibroblast growth factor (FGF-23) into the centre of pathophysiological considerations because of (i) overproduction (tumour-associated osteomalacia) or (ii) hypothetically, accumulation resulting from mutations causing resistance to processing or degradation (autosomal dominant hypophosphataemia) or (iii) loss-of-function of a protease (PHEX) interfering with FGF-23 breakdown (XLH).In oncogenic osteomalacia the treatment of choice is resection of the tumour. Recently, pharmacological treatment has also become possible, i.e. administration of octreotide. XLH and autosomal dominant hypophosphataemia must be managed by oral administration of phosphate and calcitriol. In patients with gastrointestinal intolerance to phosphate or with severely symptomatic bone disease, prolonged intravenous administration of Pi is necessary.     

Clinical aspects of familial cholestasis (with molecular explanations)

Familial cholestatic diseases exhibit familial patterns of occurrence and result from known or presumed gene defects. Until recently, these diseases were all considered syndromes, with recognizable patterns of clinical characteristics. Moreover, little was know about the molecular pathophysiology of cholestasis in general, and nothing was known about any of these diseases. The recent discovery and characterization of the genes involved in five of these diseases has led to improved understanding of the diseases and of the physiologic function and importance of the gene products. Furthermore, as has happened many times in the past, these patients with genetic disease have served as human models of disease pathophysiology. Study of the course of the disease in these patients has rapidly increased our understanding of the molecular mechanisms of bile formation, cholestasis, and liver injury caused by cholestasis.     

Clinical diagnosis and management of pancreatic cancer: Markers,molecular mechanisms,and treatment options

Pancreatic cancer (PC) is the third-leading cause of cancer deaths. The overall 5-year survival rate of PC is 9%, and this rate for metastatic PC is below 3%. However, the PC-induced death cases will increase about 2-fold by 2060. Many factors such as genetic and environmental factors and metabolic diseases can drive PC development and progression. The most common type of PC in the clinic is pancreatic ductal adenocarcinoma, comprising approximately 90% of PC cases. Multiple pathogenic processes including but not limited to inflammation, fibrosis, angiogenesis, epithelial-mesenchymal transition, and proliferation of cancer stem cells are involved in the initiation and progression of PC. Early diagnosis is essential for curable therapy, for which a combined panel of serum markers is very helpful. Although some mono or combined therapies have been approved by the United States Food and Drug Administration for PC treatment, current therapies have not shown promising outcomes. Fortunately, the development of novel immunotherapies, such as oncolytic viruses-mediated treatments and chimeric antigen receptor-T cells, combined with therapies such as neoadjuvant therapy plus surgery, and advanced delivery systems of immunotherapy will improve therapeutic outcomes and combat drug resistance in PC patients. Herein, the pathogenesis, molecular signaling pathways, diagnostic markers, prognosis, and potential treatments in completed, ongoing, and recruiting clinical trials for PC were reviewed.     

Clinical and molecular aspects of 23 patients affected by paroxysmal nocturnal hemoglobinuria

We reviewed clinical and molecular data of 23 consecutive unrelated patients affected by paroxysmal nocturnal hemoglobinuria (PNH) (19 with hemolytic PNH, 3 with aplastic anemia/PNH, and 1 with myelodysplasia/PNH syndrome) with a mean follow-up of 11.8 years. Five patients had thrombotic episodes, and 10 needed regular blood transfusions; 2 died for cerebral hemorrhage and kidney failure, and 2 spontaneously recovered from PNH. Twenty different PIG-A gene mutations were detected in 21/23 patients: 15 frameshift, 1 splicing, 2 nonsense, and 2 missense mutations. Two mutations (DelG341 and IVS2 +1g-a) were detected twice. A PIG-A mutated clone was also revealed in the two patients in complete clinical remission. One patient with aplastic anemia/PNH syndrome was treated with two courses of antilymphocyte globulin and cyclosporin with partial sustained response. Six patients were given rHu-EPO 150 U/kg/day s.c. for at least 6 months: one became transfusion-independent for 8 months and then discontinued treatment for clinical complications; one displayed a mean rise of Hb of 1.5 g/dL and is currently maintaining Hb levels higher than 9 g/dL after 54 months of therapy. Mutation specific quantitative-competitive PCR showed that the rise of hemoglobin was related to an increase of PIG-A negative molecules, suggesting that the efficacy of rHu-EPO therapy may be due to the stimulation of the abnormal clone.