Familial hyperaldosteronism

Aldosterone, the major circulating mineralocorticoid, participates in blood volume and serum potassium homeostasis. Primary aldosteronism is a disorder characterised by hypertension and hypokalaemia due to autonomous aldosterone secretion from the adrenocortical zona glomerulosa. Improved screening techniques, particularly application of the plasma aldosterone:plasma renin activity ratio, have led to a suggestion that primary aldosteronism may be more common than previously appreciated among adults with hypertension. Glucocorticoid-remediable aldosteronism (GRA) was the first described familial form of hyperaldosteronism. The disorder is characterised by aldosterone secretory function regulated chronically by ACTH. Hence, aldosterone hypersecretion can be suppressed, on a sustained basis, by exogenous glucocorticoids such as dexamethasone in physiologic range doses. This autosomal dominant disorder has been shown to be caused by a hybrid gene mutation formed by a crossover of genetic material between the ACTH-responsive regulatory portion of the 11ß-hydroxylase (CYP11B1) gene and the coding region of the aldosterone synthase (CYP11B2) gene. Familial hyperaldosteronism type II (FH-II), so named to distinguish the disorder from GRA or familial hyperaldosteronism type I (FH-I), is characterised by autosomal dominant inheritance of autonomous aldosterone hypersecretion which is not suppressible by dexamethasone. Linkage analysis in a single large kindred, and direct mutation screening, has shown that this disorder is unrelated to mutations in the genes for aldosterone synthase or the angiotensin II receptor. The precise genetic cause of FH-II remains to be elucidated.

Frequency of Fanconi anemia in Brazil and efficacy of screening for the FANCA 3788-3790del mutation

Fanconi anemia (FA) is an autosomal recessive genetic disease characterized by progressive bone marrow failure, susceptibility to cancer and multiple congenital anomalies. There is important clinical variability among patients and the knowledge of factors which might predict outcome would greatly help the decision making regarding the choices of treatment and the appropriate time to start it. Future studies of the possible correlation between specific mutations with specific clinical presentations will provide the answer to one of these factors. At our Center we standardized a rapid and precise screening test using a mismatch PCR assay for a specific mutation (3788-3790del in exon 38 of gene FANCA) in Brazilian FA patients. We present the results obtained after screening 80 non-consanguineous FA patients referred from all regions of Brazil with a clinical diagnosis of FA supported by cellular hypersensitivity to diepoxybutane. We were able to detect the 3788-3790del allele in 24 of the 80 (30%) FA patients studied. Thirteen of the 80 (16.25%) were homozygotes and 11 of the 80 (13.75%) were compound heterozygotes, thus confirming the high frequency of the FANCA 3788-3790del mutation in Brazilian FA patients. The identification of patients with specific mutations in the FA genes may lead to a better clinical description of this condition, also providing data for genotype-phenotype correlations, to a better understanding of the interaction of this specific mutation with other mutations in compound heterozygote patients, and ultimately to the right choices of treatment for each patient with improvement of the prognosis on future studies.

p.F508del in a heterogeneous cystic fibrosis population from Minas Gerais, Brazil

Cystic fibrosis (CF) is the most common autosomal recessive disease of the Caucasian population. Among the various CF mutations, p.F508del is the most frequent, accounting for two-thirds of the global CF chromosomes, although showing great variability among populations. We have studied 115 unrelated CF patients from a mixed population of Minas Gerais (Brazil). To evaluate part of the DNA sequence of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, blood DNA was obtained and PCR was performed using two pairs of primers that anneal to exons 10 and 24 of the CFTR gene. The PCR product was then submitted to automatic sequencing using the ABI PRISM 310 Genetic Analyzer. The p.F508del mutation was found in 50 (21.7%) of 230 unrelated CF alleles. Fifteen (13.0%) patients were homozygous for this mutation, while 20 (17.4%) were heterozygous; the remaining 80 (69.6%) patients did not carry the p.F508del mutation. Exon 24 sequence had no change in 75 (65.2%) patients, 21 (18.3%) had the sequence variation 4521G/A, 11 (9.6%) had a not yet described sequence variation 4407T/A and 8 (7.0%) patients had both sequence variations (4521G/A and 4407T/A). The polymorphism 4407T/A results in an amino acid modification from aspartic acid to glutamic acid, which will probably have no function effect in CFTR. This low p.F508del prevalence can be due to the variable ethnic origin of this population from Minas Gerais, which may have a high diversity of CF rare mutations.

Roles of mitogen-activated protein kinases and angiotensin II in renal development

Experimental and clinical evidence suggests that angiotensin II (AII) participates in renal development. Renal AII content is several-fold higher in newborn rats and mice than in adult animals. AII receptors are also expressed in higher amounts in the kidneys of newborn rats. The kidneys of fetuses whose mother received a type 1 AII receptor (AT1) antagonist during gestation present several morphological alterations. Mutations in genes that encode components of the renin-angiotensin system are associated with autosomal recessive renal tubular dysgenesis. Morphological changes were detected in the kidneys of 3-week-old angiotensin-deficient mice. Mitogen-activated protein kinases (MAPKs) are important mediators that transduce extracellular stimuli to intracellular responses. The MAPK family comprises three major subgroups, namely extracellular signal-regulated protein kinase (ERK), c-jun N-terminal kinases (JNK), and p38 MAPK (p38). Important events in renal growth during nephrogenesis such as cellular proliferation and differentiation accompanied by apoptosis on a large scale can be mediated by MAPK pathways. A decrease in glomerulus number was observed in embryos cultured for 48 and 120 h with ERK or p38 inhibitors. Many effects of AII are mediated by MAPK pathways. Treatment with losartan during lactation provoked changes in renal function and structure associated with alterations in AT1 and type 2 AII (AT2) receptors and p-JNK and p-p38 expression in the kidney. Several studies have shown that AII and MAPKs play an important role in renal development. However, the relationship between the effects of AII and MAPK activation on renal development is still unclear.

Neonatal screening for cystic fibrosis in São Paulo State, Brazil: a pilot study

Cystic fibrosis is one of the most common autosomal recessive hereditary diseases in the Caucasian population, with an incidence of 1:2000 to 1:3500 liveborns. More than 1000 mutations have been described with the most common being F508del. It has a prevalence of 23-55% within the Brazilian population. The lack of population-based studies evaluating the incidence of cystic fibrosis in São Paulo State, Brazil, and an analysis concerning the costs of implantation of a screening program motivated the present study. A total of 60,000 dried blood samples from Guthrie cards obtained from April 2005 to January 2006 for neonatal screening at 4 reference centers in São Paulo State were analyzed. The immunoreactive trypsinogen (IRT)/IRT protocol was used with the cut-off value being 70 ng/mL. A total of 532 children (0.9%) showed IRT >70 ng/mL and a 2nd sample was collected from 418 (80.3%) of these patients. Four affected children were detected at two centers, corresponding to an incidence of 1:8403. The average age at diagnosis was 69 days, and 3 of the children already showed severe symptoms of the disease. The rate of false-positive results was 95.2% and the positive predictive value for the test was 8%. The cost of detecting an affected subject was approximately US$8,000.00 when this cystic fibrosis program was added to an existing neonatal screening program. The present study clearly shows the difficulties involved in cystic fibrosis screening using the IRT/IRT protocol, particularly in a population with no long-term tradition of neonatal screening.

A Brazilian family with hereditary inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia

Inclusion body myopathy associated with Paget disease and frontotemporal dementia (IBMPFD) is a progressive and usually misdiagnosed autosomal dominant disorder. It is clinically characterized by a triad of features: proximal and distal myopathy, early onset Paget disease of bone (PDB), and frontotemporal dementia (FTD). It is caused by missense mutations in the valosin-containing protein (VCP) gene. We describe here the clinical and molecular findings of the first Brazilian family identified with IBMPFD. Progressive myopathy affecting the limb girdles was detected by clinical examination followed by muscle biopsy and creatine kinase measurement. PDB was suggested after anatomopathological bone examination and FTD was diagnosed by clinical, neuropsychological and language evaluations. Brain magnetic resonance revealed severe atrophy of the anterior temporal lobes, including the hippocampi. A R93C mutation in VCP was detected by direct sequencing screening in subject W (age 62) and in his mother. Four more individuals diagnosed with "dementia" were reported in this family. We also present a comprehensive genotype-phenotype correlation analysis of mutations in VCP in 182 patients from 29 families described in the literature and show that while IBM is a conspicuously penetrant symptom, PDB has a lower penetrance when associated with mutations in the AAAD1 domain and FTD has a lower penetrance when associated with mutations in the Junction (L1-D1) domain. Furthermore, the R93C mutation is likely to be associated with the penetrance of all the clinical symptoms of the triad.

Adeno-associated virus for cystic fibrosis gene therapy

Gene therapy is an alternative treatment for genetic lung disease, especially monogenic disorders such as cystic fibrosis. Cystic fibrosis is a severe autosomal recessive disease affecting one in 2500 live births in the white population, caused by mutation of the cystic fibrosis transmembrane conductance regulator (CFTR). The disease is classically characterized by pancreatic enzyme insufficiency, an increased concentration of chloride in sweat, and varying severity of chronic obstructive lung disease. Currently, the greatest challenge for gene therapy is finding an ideal vector to deliver the transgene (CFTR) to the affected organ (lung). Adeno-associated virus is the most promising viral vector system for the treatment of respiratory disease because it has natural tropism for airway epithelial cells and does not cause any human disease. This review focuses on the basic properties of adeno-associated virus and its use as a vector for cystic fibrosis gene therapy.

Successful domino liver transplantation in maple syrup urine disease using a related living donor

Maple syrup urine disease (MSUD) is an autosomal recessive disease associated with high levels of branched-chain amino acids. Children with MSUD can present severe neurological damage, but liver transplantation (LT) allows the patient to resume a normal diet and avoid further neurological damage. The use of living related donors has been controversial because parents are obligatory heterozygotes. We report a case of a 2-year-old child with MSUD who underwent a living donor LT. The donor was the patient's mother, and his liver was then used as a domino graft. The postoperative course was uneventful in all three subjects. DNA analysis performed after the transplantation (sequencing of the coding regions of BCKDHA, BCKDHB, andDBT genes) showed that the MSUD patient was heterozygous for a pathogenic mutation in the BCKDHB gene. This mutation was not found in his mother, who is an obligatory carrier for MSUD according to the family history and, as expected, presented both normal clinical phenotype and levels of branched-chain amino acids. In conclusion, our data suggest that the use of a related donor in LT for MSUD was effective, and the liver of the MSUD patient was successfully used in domino transplantation. Routine donor genotyping may not be feasible, because the test is not widely available, and, most importantly, the disease is associated with both the presence of allelic and locus heterogeneity. Further studies with this population of patients are required to expand the use of related donors in MSUD.

Lipoprotein glomerulopathy: a case report of a rare disease in a brazilian child

Lipoprotein glomerulopathy (LPG) is a rare autosomal recessive glomerulopathy associated with the deposition of lipoprotein thrombi in the capillary lumina due to apoE gene mutations. Abnormal plasma lipoprotein profile and marked increase in serum apoliprotein E (apoE) are characteristic clinical data. The compromised patients can present nephrotic syndrome, hematuria, and progressive renal failure. Herein, the authors present the first described case of LPG in a Brazilian male patient, 11 years, who presented with a steroid-resistant nephrotic syndrome. Renal function was normal. Kidney biopsy showed markedly enlarged glomerulus, with dilated capillary loops and weak eosinophilic lipoprotein thrombi in the capillary lumina. Interstitium, tubules, arteries, and veins showed normal histologic aspect. Genotypic study for the apoE gene showed the presence of the alleles E3 and E4. The diagnosis of LPG was then performed. The patient received lipid-lowering treatment. After 2 years of follow-up, renal function is gradually decreasing, with persisting heavy proteinuria, despite a marked decrease in serum cholesterol and triglycerides levels.

Methylphenidate use in children with attention deficit hyperactivity disorder

A Brazilian Health Technology Assessment Bulletin (BRATS) article regarding scientific evidence of the efficacy and safety of methylphenidate for treating attention deficit hyperactivity disorder (ADHD) has caused much controversy about its methods. Considering the relevance of BRATS for public health in Brazil, we critically reviewed this article by remaking the BRATS search and discussing its methods and results. Two questions were answered: did BRATS include all references available in the literature? Do the conclusions reflect the reviewed articles? The results indicate that BRATS did not include all the references from the literature on this subject and also that the proposed conclusions are different from the results of the articles chosen by the BRATS authors themselves. The articles selected by the BRATS authors showed that using methylphenidate is safe and effective. However, the BRATS final conclusion does not reflect the aforementioned and should not be used to support decisions on the use of methylphenidate.

Whipple's disease: rare disorder and late diagnosis

Whipple's disease is a rare systemic infectious disorder caused by the bacterium Tropheryma whipplei. We report the case of a 61-year-old male patient who presented to emergency room complaining of asthenia, arthralgia, anorexia, articular complaints intermittent diarrhea, and a 10-kg weight loss in one year. Laboratory tests showed the following results: Hb = 7.5 g/dL, albumin = 2.5 mg/dL, weight = 50.3 kg (BMI 17.4 kg/m²). Upper gastrointestinal endoscopy revealed areas of focal enanthema in the duodenum. An endoscopic biopsy was suggestive of Whipple's disease. Diagnosis was confirmed based on a positive serum polymerase chain reaction. Treatment was initiated with intravenous ceftriaxone followed by oral trimethoprim-sulfamethoxazole. After one year of treatment, the patient was asymptomatic, with Hb = 13.5 g/dL, serum albumin = 5.3 mg/dL, and weight = 70 kg (BMI 24.2 kg/m²). Whipple's disease should be considered a differential diagnosis in patients with prolonged constitutional and/or gastrointestinal symptoms. Appropriate antibiotic treatment improves the quality of life of patients.

Noonan syndrome: a clinical and genetic study of 31 patients

Noonan syndrome is a multiple congenital anomaly syndrome, inherited in an autosomal dominant pattern. We studied 31 patients (18 males and 13 females) affected by this disorder regarding their clinical and genetic characteristics. The most frequent clinical findings were short stature (71%); craniofacial dysmorphisms, especially hypertelorism, ptosis, downslanting of the palpebral fissures; short or webbed neck (87%); cardiac anomalies (65%), and fetal pads in fingers and toes (70%). After studying the probands' first-degree relatives, we made the diagnosis of Noonan syndrome in more than one family member in three families. Therefore, the majority of our cases were sporadic.

Oral manifestations of Albright hereditary Osteodystrophy: a case report

Albright hereditary osteodystrophy is a hereditary metabolic disorder of dominant autosomal etiology that is commonly characterized by short stature, round face, small metacarpus and metatarsus, mental retardation, osteoporosis, subcutaneous calcification, variable hypocalcemia, and hyperphosphatemia. In this study, we report a clinical case of a 17-year-old woman with Albright hereditary osteodystrophy, and we discuss her clinical, radiographic, and laboratory test characteristics together with the oral manifestations, and we correlate them with the characteristics found in the literature. We also discuss the odontological management of treatment of related periodontal disease and planning for corrections of related malocclusions.

Impact of alcohol intoxication and withdrawal syndrome on social phobia and panic disorder in alcoholic inpatients

PURPOSE: To investigate the impact of alcohol intoxication and withdrawal on the course of social phobia and panic disorder. METHOD: A group of 41 alcoholic inpatients undergoing detoxification therapy were interviewed using the SCID-I (DSM-IV) and questions to detect fluctuations in the course of social phobia and panic disorder as a function of the different phases in alcohol dependence (intoxication, withdrawal, and lucid interval). RESULTS: Only 1 (2.4%) patient presented panic disorder throughout life, and 9 (21.9%) had panic attacks during alcohol intoxication or during the withdrawal syndrome. Sixteen (39%) alcoholic patients showed social phobia with onset prior to drug use. However, drinking eventually became unable to alleviate social phobia symptoms or worsened such symptoms in 31.2% of social-phobic patients. While patients with social phobia reported a significant improvement in psychiatric symptoms during alcohol intoxication, patients experiencing panic attacks worsened significantly during intoxication. In the withdrawal phase, patients with social phobia tended to have more and more intense phobic symptoms. CONCLUSION: Our findings indicate that the impact of alcohol intoxication is different for social phobia as compared to panic disorder, at first decreasing the social-phobic symptoms but later aggravating them. In panic disorder, the impact of intoxication by alcohol is more harmful, at least in the short term.

Adverse life events and coping skills in panic disorder

Research literature and clinical experience shows that panic patients are often able to identify stressors that preceded the onset of their first attacks. In this study we investigated the relation between life events, coping skills, and panic disorder. METHODS: Forty-tree panic patients were compared with 29 control subjects regarding the occurrence and the impact of stressful life events in a 1-year period preceding the onset of panic attacks using the Social Readjustment Rating Scale and London Life Event and Difficulty Schedule. Coping skills were measured using the Ways of Coping Questionnaire. RESULTS: No differences were observed between panic patients and controls regarding the number of reported stressful life events in the previous year. Panic patients compared to controls reported loss of social support as the most meaningful class of events significantly more often. In response to stressful situations, panic patients more often used coping skills judged as ineffective. CONCLUSIONS: The present study suggests that the type of life event and the coping skills used in response to them, more than the occurrence of stressful events itself, may be associated with the onset of panic disorder.