Molecular genetics of inherited eye disorders

In the past 10 y, there have been considerable advances in the mapping, isolation, and characterization of many genes for important ocular conditions: retinitis pigmentosa, Norrie disease, Waardenburg syndrome, choroideremia, aniridia, retinoblastoma, and others. The candidate gene approach has now supplemented classical linkage studies and positional cloning in the investigation of ocular disorders. Developmentally expressed genes and animal models have provided insights as to the etiology of other disorders. With this knowledge at hand, genetic counselling for heritable eye diseases has been greatly improved.     

Biology and genetics of malignant brain tumours

Conventional therapies such as surgery, radiotherapy and, to a lesser extent, chemotherapy have produced significant increases in survival in patients with some types of brain tumours such as medulloblastoma. However, in many other types of brain tumour in both adults and children, the effect of these modalities has been more modest. A thorough understanding of the biology of malignant brain tumours is likely to provide the background for the development of new leads that might be amenable to therapeutic exploitation. This review examines some aspects of glioma biology that have been reported in the past 12 months, and which might be translated into clinical application.     

On a dominantly inherited myopathy with tubular aggregates

A 19-year-old patient presented with exercise-related myalgia, fatigue and elevated creatine kinase levels. Histology of a muscle biopsy was characterized by the presence of very large amounts of tubular aggregates. Both his father and paternal grandfather had elevated creatine kinase and large amounts of tubular aggregates in their muscle biopsies. The aggregates consisted of closely packed vesicles and tubules filled with electron-dense material or with one to several smaller tubules. Disorders with tubular aggregates in the muscle fibres such as hyperornithinaemia with gyrate atrophy of the retina, hypokalaemic periodic paralysis, hyperkalaemic periodic paralysis, myotonia congenita, alcoholism, osteomalacic myopathy etc. have been excluded. Tubular aggregates can be found in muscle disorders characterized by exercise-induced cramps, pain and stiffness. They also represent the predominant histological feature of some familial myopathies due to a yet unidentified genetic defect. In our family, there was male-to-male transmission, confirming dominant inheritance.     

DNA helicases in inherited human disorders

Six known or predicted helicases that are mutated in human syndromes are now recognized. These syndromes include xeroderma pigmentosum, Cockayne's syndrome, trichothiodystrophy, Bloom's syndrome, Werner's syndrome, and alpha-thalassemia mental retardation on the X chromosome. The clinical abnormalities in these syndromes cover a broad spectrum, pointing to different cellular processes of DNA manipulation that are defective in these syndromes.     

Genetic databases: online catalogues of inherited disorders

Current information on inherited disorders in domestic animals is available on the internet: Online Mendelian inheritance in animals (OMIA) and Mendelian inheritance in sheep (MIS) are the two major sources of information. OMIA was created (and is maintained) by workers at the University of Sydney. MIS has been compiled by the Committee on Genetic Nomenclature of Sheep and Goats (COGNOSAG), an international group of geneticists. In the future, similar catalogues for other species (starting with goats and cattle) will be made available by COGNOSAG. Electronic access to this information is freely accessible on the world-wide web at http:/(/)www.angis.su.oz.au/Databases/BIRX/om ia (for OMIA), http:/(/)probe.nalusda.gov:8300/animal/omia.h tml (for OMIA in the United States of America) and at http:/(/)www.angis.org.au/Databases/BIRX/mis (for MIS).     

Regulating factors of renal tubular hypertrophy

Understanding the mechanisms of tubular hypertrophy is important because these cells simply represent the bulk of the nephron, and there is a convincing link between early tubular enlargement and the progression of renal disease. It seems reasonable to assume that cytokines and polypeptide growth factors including inhibitory factors such as TGF-beta induce in concert, rather than as single factors, tubular hypertrophy. The important observations that the activation of the intrarenal renin-angiotensin axis is altered in situations associated with renal growth, and that ACE inhibitors abolish compensatory hypertrophy in many models provided for us a basis for investigating the growth effects of ANG-II on cultured proximal tubular cells. ANG-II induces, as a single factor, tubular hypertrophy in vitro, and this growth effect has been studied in detail on a molecular levels. Endogenous induction of TGF-beta by ANG-II is important in the peptide-mediated hypertrophy. While some genes induced by ANG-II, such as immediate early genes, are engaged as part of a generalized activation of the nucleus, the hypertrophic effects may be mediated by a set of novel genes which may be part of an identifiable genetic program causing tubular enlargement. The identification of hypertrophy genes may offer new insight into the modulation of cytoplasmic enlargement and its interface with elements that control the cell cycle and may provide a tool for further therapeutic interventions.     

ENT surgery in children with inherited bleeding disorders

Inherited bleeding disorders are frequently considered an absolute contraindication to tonsillectomy and other ENT procedures. Over a 15-year period we have performed ten elective tonsillectomies and five bilateral myringotomies on children with inherited bleeding disorders. All procedures were carried out with the close co-operation of the Haematology Department in the hospital. All patients underwent uneventful surgery. One patient returned after tonsillectomy with a secondary haemorrhage which did not require surgical intervention. We present our team approach to the management of these children and demonstrate that necessary surgical intervention can be undertaken safely in this select group of patients.     

The molecular genetics of post-transplantation lymphoproliferative disorders

The post-transplantation lymphoproliferative disorders represent a significant clinical and diagnostic problem. However, these disorders also represent an important biological model for studying the development and progression of lymphoid neoplasia in immune deficiency. Accurate diagnosis and classification of these disorders requires correlative multiparametric analysis of the clinical behavior of the patient with the histopathological features, immunophenotype, clonal composition, and genetic alterations of the lymphoproliferative disorder. Such analyses should also assist in furthering our understanding of the pathogenesis of these disorders.     

Transgenic models in renal tubular physiology

Animal transgenesis has proven to be useful for physiological as well as physiopathological studies. Besides the classical approach based on the random integration of a DNA construct in the mouse genome, gene targeting can be achieved using totipotent embryonic stem (ES) cells for targeted transgenesis. Transgenic mice are then derived from the transgenic ES cells. This allows the introduction of null mutations in the genome (so-called knock-out) or the control of the transgene expression by the endogenous regulatory sequences of the gene of interest (so-called knock-in). Development of these transgenic animals leads to a better understanding of the cellular function of many genes or to the generation of animal models for human diseases. The purpose of this short review is to describe animal models in renal tubular physiopathology. Recent progresses will allow the generation of animal models with conditional expression of the transgene of interest or with a conditional gene mutation. This permits spatial and temporal control of the expression of the transgene or of the mutation. This should allow the generation of models suitable for physiological analysis or closer to disease state.     

Effect of retabolil on renal tubular secretion

Chronic experiments on dogs and rats showed retabolil, an anabolic steroid (given in a dose of 2-5 mg/kg for 7 days) to produce an increase in renal tubular secretion of cardiotrast. Rats displayed a simultaneous elevation in the content of protein and RNA in the kidney cortex. The data obtained were interpreted from the aspect of protein nature of carriers taking part in the renal secretory transport.     

Distal renal tubular acidosis presenting with rhabdomyolysis

Severe hypokalemia is an uncommon cause of rhabdomyolysis. We describe a patient, 28-year-old woman, with distal renal tubular acidosis (DRTA) who developed severe hypokalemia and rhabdomyolysis. Muscle biopsy shows focal muscular necrosis mainly in type II muscle fibers and mild macrophagic reaction. After correcting the acidosis with oral administration of alkalinizing salts, clinical and laboratory improvement was seen. This clearly establish a causal relationship between the positive acid balance, hypokalemia and the muscular manifestation in DRTA.     

Dimercaptosuccinic acid distribution in renal tubular acidosis

A 99Tcm dimercaptosuccinic acid (DMSA) scan performed after a urinary tract infection demonstrated an unusual pattern of isotope uptake, promoting further investigations leading to a diagnosis of renal tubular acidosis secondary to nephropathic cystinosis. This is known to affect isotope imaging but a unique feature in this undiagnosed case was the uncorrected metabolic acidosis, which had further altered the distribution of the DMSA. It is noteworthy because other patients referred for imaging with renal disease may also have abnormalities of acid base balance.     

Thyrotoxicosis and renal tubular acidosis presenting as hypokalaemic paralysis

We report a case of oesophageal disease as the first manifestation in a patient with CREST syndrome. A 46-year-old man with achalasia-like syndrome developed CREST syndrome 4 years later. A pneumatic dilatation of the cardia was performed. After pneumatic dilatation the dysphagia and regurgitation disappeared but the patient developed reflux oesophagitis. Four years after diagnosis of oesophageal disease he presented with a clinical picture of CREST syndrome. An acute ileus and constipation developed later. After receiving medical therapy with omeprazole and cisapride the patient is free of oesophageal symptoms and bowel movements are normal. Oesophageal disease is common in patients with limited and diffuse scleroderma, but to our knowledge achalasia-like syndrome has not been previously described as the first manifestation of the systemic disease.     

The major inherited disorders of cornification. New advances in pathogenesis

This article provides a synopsis of the major (most common) inherited disorders of cornification. It also reviews the recent advances that have been made for each disorder and their practical applications.     

Siblings with congenital renal tubular acidosis and nerve deafness

The suppression of hyperinsulinism with diazoxide (300 mg/d during 30 days) in a young woman with PCOS and hirsutism, hyperinsulinism and insulinoresistance was followed by a modification of plasma androgens. Testosterone (T) and free testosterone (fT) were reduced after ten days and then increased but always remained below the baseline level. DHEAS had increased 200% by day 10, and 3 alpha-adiol G to three times its basal value by day 20. These modifications were constant during the treatment. fT decrease was secondary to reduction of hyperinsulinism which was followed by an increase of TeBG and a modest and transient reduction of androgen theca cells production. DHEAS increase was due to hyperinsulinism suppression which stimulated adrenal 17-20 lyase activity. 3 alpha-adiol G increase was concomittant, and can be considered as an index of adrenal androgen secretion.     

Prevalence of endemic distal renal tubular acidosis and renal stone in the northeast of Thailand

We have previously reported a large group of patients with endemic distal renal tubular acidosis (EdRTA) admitted to the hospitals in the northeast of Thailand. Since large number of patients were identified in a relatively short period of time, and in an area whose population is homogeneous, we were led to investigate the prevalence of the condition in the area. A survey was conducted in five villages (total population of 3,606) within the northeast of Thailand. 3,013 villagers were examined for urinary citrate concentration and short acid loading test was performed in those with low urinary citrate. 2.8% of the population (2.2-3.4%, 95% confidence interval) failed to lower their urine pH after acid loading; within this group, 0.8% of the population had serum potassium less than or equal to 3.5 mEq/l. In addition a large number of villagers were found to have low urinary citrate concentration and there was concurrent high prevalence of renal stone. The prevalence of EdRTA and renal stone was higher in villagers with poorer socioeconomic status, suggesting that environmental factors play a major role in their pathogenesis. Villagers with acidification defect have 2.4 times the chance of having renal stone and/or nephrocalcinosis. EdRTA is therefore one of the important factors responsible for the high prevalence of renal stone in the area. In conclusion we have confirmed the high prevalence of EdRTA in the northeast of Thailand and provided data showing high prevalence of renal stone and hypocitraturia in the same population.     

Clinical approach to inherited peroxisomal disorders: a series of 27 patients

To illustrate the clinical and biochemical heterogeneity of peroxisomal disorders, we report our experience with 27 patients seen personally between 1982 and 1997. Twenty patients presented with a phenotype corresponding either to Zellweger syndrome, neonatal adrenoleukodystrophy, or infantile Refsum disease, 3 of whom had a peroxisomal disorder due to a single enzyme defect. One patient had a mild form of rhizomelic chondrodysplasia punctata, 1 had classic Refsum disease. Finally, 5 patients presented with clinical manifestations that were either unusually mild or completely atypical, and initially did not arouse suspicion of a peroxisomal disorder. They showed multiple defects of peroxisomal functions with one or several functions remaining intact, suggesting a peroxisome biogenesis disorder. The defect in peroxisome biogenesis was further characterized by variable expression in different tissues and/or individual cells in 5 patients. Studies restricted to fibroblasts failed to identify abnormalities in this group. We demonstrate that clinical manifestations of peroxisomal disorders may be very mild or completely atypical, and therefore, peroxisomal disorders should be considered in a variety of clinical settings. Furthermore, we suggest performing extensive peroxisomal investigations in every patient suspected of suffering from a peroxisomal disorder, even when the clinical presentation is typical.