Basic science meets clinical medicine: identification of a CD2AP-deficient patient.

Recent years have witnessed an explosion of research into the molecular basis of glomerular disease resulting in nephrotic- range urinary protein leak using both human genetics and animal models. Löwik et al. describe the first case report of an early-onset nephrotic syndrome presenting in conjunction with a homozygous CD2AP mutation. These data demonstrate the convergence between basic and clinical approaches and their potential to transform our understanding of the pathogenetic mechanisms underlying human glomerular disease.

Congenital nephrotic syndrome.

A female infant born at 34 weeks' gestation after several days of ruptured membranes had a Potter-like face and compression-induced limb posture consistent with oligohydramnios. Oedema developed on day 2; initial investigations showed massive proteinuria, hypoalbuminaemia, hyponatraemia, acidosis and marked renal insufficiency. The infant was intubated and despite albumin infusion and intravenous antibiotics she became oligoanuric by day 8 and required haemofiltration. Renal biopsy at this stage showed cystic dilatation of tubules in the cortex and glomerular lesions consisting of shrunken tufts with sclerotic centres and a corona of epithelial cells at the periphery. Due to a very poor prognosis treatment was withdrawn. Postmortem examination of the kidneys confirmed the histological diagnosis of diffuse mesangial sclerosis. Genetic studies found no mutations in WT1 and NPHS1 genes although the entire genes could not be screened for mutations due to lack of DNA.

Frasier syndrome, part of the Denys Drash continuum or simply a WT1 gene associated disorder of intersex and nephropathy?

Dysfunction of the Wilms' Tumour gene (WT1), a transcription factor critical for normal development and function of the urogenital tract, can result in both tumourigenesis [corrected] and urogenital abnormalities. The association of WT1 gene mutations with most cases of Denys-Drash syndrome is well described. More recently WT1 mutations have also been described in a related condition, Frasier syndrome. We report a case where genetic analysis showed a WT1 mutation typically associated with Frasier syndrome: a 1228 + 5 guanine to adenine substitution at the 3' alternative splice donor site in intron 9. The case provides a focus for the discussion of recent evidence that Denys Drash and Frasier syndrome form two ends of a spectrum of disorders. In addition, it illustrates the increasing significance of genetic investigation within clinical practice for diagnostic, prognostic and therapeutic purposes and the importance of karyotype analysis in phenotypically normal girls with renal disease.

Vincristine and focal segmental sclerosis: do we need a multicentre trial?

Over the last 10 years, eight children have received vincristine for the treatment of steroid- and cyclophosphamide-resistant nephrotic syndrome at Great Ormond Street Hospital for Children, London. We present our experience of these eight cases and put forward a case for reassessing the effectiveness of vincristine in this disorder. In our series, two children treated with vincristine achieved complete remission with preserved renal function, including relapses in one. Both had primary steroid- and cyclophosphamide-resistant focal segmental glomerulo sclerosis (FSGS). Of the other cases, four also had primary FSGS, one familial FSGS and one mesangioproliferative glomerulonephritis. We discuss in general the pros and cons of vincristine therapy in nephrotic syndrome versus the cytotoxic agents that are currently used and the differences in clinical features among the responders and non-responders in this small group. In addition, we explore why this may have occurred and summarise the literature over the last 25 years, where vincristine appeared to have been beneficial, especially in secondary forms of nephrotic syndrome associated with malignancy. We conclude that vincristine therapy warrants re-examination as it could be a valuable alternative therapeutic agent in some cases of FSGS with relatively minor side effects.

Frasier syndrome is caused by defective alternative splicing of WT1 leading to an altered ratio of WT1 +/-KTS splice isoforms.

The Wilms' tumor gene WT1 plays a key role in genitourinary development and subsequent normal function. Homozygous mutations of WT1 can be found in approximately 15% of Wilms' tumors. Furthermore, somatic heterozygous loss of WT1 is known to lead to cryptorchidism and hypospadias in males. A much more severe phenotype is seen in patients with Denys-Drash syndrome which results from heterozygous dominant-negative mutations of the gene. Characteristic features are mesangial sclerosis with early kidney failure, varying degrees of gonadal dysgenesis and high risk of Wilms' tumors. Here we show that a related disease, Frasier syndrome, characterized by focal glomerular sclerosis, delayed kidney failure and complete gonadal dysgenesis, is probably caused by specific intronic point mutations of WT1 that preferentially affect a CpG dinucleotide. Disruption of alternative splicing at the exon 9 splice donor site prevents synthesis of the usually more abundant WT1 +KTS isoform from the mutant allele. In contrast to Denys-Drash syndrome, no mutant protein is produced. The splice mutation leads to an imbalance of WT1 isoforms in vivo , as detected by RT-PCR on streak gonadal tissue. Thus, WT1 isoforms must have quite different functions, and the pathology of Frasier syndrome suggests that especially gonadal development may be particularly sensitive to imbalance or relative underrepresentation of the WT1 +KTS isoform.

Witchdoctors in Africa.

PIP: This article summarizes the experiences of medical students who spent elective time in the heart of Zululand at Charles Johnson Memorial Hospital in Nqutu, Kwazulu. It is a former mission hospital now under the jurisdiction of the Kwazulu government. The problems that the students encountered are characteristic of those in other black rural homeland hospitals and contrast greatly with those in white hospitals. There is a deep rooted conviction among many tribespeople that a withchdoctor must be visited before a visit to the hospital is considered. It is not unusual to have to treat a sick Zulu 1st for the effects of a witchdoctor's potions and only subsequently for the original complaint. Many Zulu believe also that some illnesses occur only among African peoples and so are amenable only to traditional treatment. At any such hospital the personalities of other staff are of paramount importance in influencing one's experiences and memories. Language and culture may readily obscure and frustrate in such a different environment, and attitudes, flexibility, and past experienes determine one's reactions.^ieng

Does the sympathetic nervous system influence sinus arrhythmia in man? Evidence from combined autonomic blockade.

The influences of vagal and sympathetic efferent activity on sinus arrhythmia in man have been studied in healthy subjects by administration of hyoscine butylbromide and atenolol alone and combined using a microcomputer-linked electrocardiogram (e.c.g.) system. Sinus arrhythmia was quantitated as the S.D. of the R-R interval. Sinus arrhythmia was reduced by hyoscine butylbromide, in some subjects to near abolition, but this end-point was unchanged by pre-treatment with atenolol. Atenolol alone prolonged the mean R-R interval and increased sinus arrhythmia. It is suggested that sinus arrhythmia in man is mediated through vagal efferents alone but that atenolol increases the arrhythmia through a central vagotonic effect.