Identification of a novel COL4A5 mutation in the proband initially diagnosed as IgAN from a Chinese family with X-linked Alport syndrome

Alport syndrome(AS) is a hereditary progressive nephropathy characterized by hematuria, ultrastructural lesions of the glomerular basement membrane, ocular lesions and sensorineural hearing loss. Germline mutations of COL4 A5 are associated with X-linked AS with an extreme phenotypic heterogeneity. Here, we investigated a Chinese family with Alport syndrome. The proband was a 9-year-old boy with hematuria and proteinuria. Based on the test results of renal biopsy and immunofluorescence,the proband was initially diagnosed as Ig A nephropathy and the treatment was recommended accordingly. Meanwhile, we found that the treatment outcome was poor. Therefore, for proper clinical diagnosis and appropriate treatment, targeted exome-based next-generation sequencing has been undertaken. We identified a novel hemizygous single nucleotide deletion c.1902 del A in COL4 A5 gene. Segregation analysis identified that this novel mutation is co-segregated among the affected family members but absent in unaffected family members. The clinical diagnosis of the proband was revised as AS accompanied by Ig A nephropathy,which has been rarely reported. Our findings demonstrated the significance of the application of Genetic screening, expanded the mutation spectrum of COL4 A5 associated AS patients with atypical renal phenotypes and provided a good lesson to be learned from our detour during the diagnosis.     

Hyperglobulinaemic Renal Tubular Acidosis: A Report of Nine Cases

Of nine women with hyperglobulinaemic renal tubular acidosis four presented with acidosis and five had the “incomplete” form of the disorder. Seven patients had nephrogenic diabetes insipidus, but none had the Fanconi syndrome. Investigation showed abnormal immunoglobulins and autoantibodies in all nine patients. Diseases coexisting with renal tubular acidosis were Sjögren''s syndrome, hyperglobulinaemic purpura, autoimmune liver and thyroid disease, diffuse pulmonary fibrosis, and a peripheral neuropathy. It is suggested that this type of renal tubular acidosis might be due to an autoimmune process.     

Aid to a Declining Matriarch in the Giant Otter (Pteronura brasiliensis)

Scientists are increasingly revealing the commonalities between the intellectual, emotional and moral capacities of animals and humans. Providing assistance to elderly and ailing family members is a human trait rarely documented for wild animals, other than anecdotal accounts. Here I report observations of multiple forms of assistance to the declining matriarch of a habituated group of giant otters (Pteronura brasiliensis) in Manu National Park, Peru. The otter group had been observed annually for several years and all members were known individually. In 2007, the breeding female of the group failed to reproduce and appeared to be in physical decline. She begged from other family members 43 times over 41 contact hours and received food 11 times. Comparisons with 2004–2006 demonstrate that the family''s behavior in 2007 constitutes a role-reversal, in which the majority of assistance and prey transfers accrued from young-to-old rather than from old-to-young. As in human societies, both non-adaptive and adaptive hypotheses could explain the family members'' aid to their declining matriarch. I suggest that giant otter families may benefit from the knowledge and experience of an elderly matriarch and “grandparent helper,” consistent with the “Grandmother Hypothesis” of adaptive menopause in women.     

The genetics of congenital amusia (tone deafness): a family-aggregation study

Congenital amusia (commonly known as “tone deafness”) is a lifelong impairment of music perception that affects 4% of the population. To estimate whether congenital amusia can be genetically transmitted, its prevalence was quantified by direct auditory testing of 71 members of 9 large families of amusic probands, as well as of 75 members of 10 control families. The results confirm that congenital amusia is expressed by a deficit in processing musical pitch but not musical time and also show that the pitch disorder has a hereditary component. In amusic families, 39% of first-degree relatives have the same cognitive disorder, whereas only 3% have it in the control families. The identification of multiplex families with a high relative risk of experiencing a musical pitch deficit (λ_s=10.8; 95% confidence interval 8–13.5) enables the mapping of genetic loci for hereditary amusia.     

Fibrosing Alveolitis Associated with Renal Tubular Acidosis

The discovery of a case of renal tubular acidosis and fibrosing alveolitis led to the investigation of 19 further patients. Abnormal pulmonary function tests were found in a further four patients with overt renal tubular acidosis and in four out of eight patients with “incomplete” renal tubular acidosis. The response to an ammonium chloride test in seven patients with cryptogenic fibrosing alveolitis was normal. Those patients with a defect of both renal acidification and pulmonary gas transfer had concurrent autoimmune diseases such as Sjögren''s syndrome and primary biliary cirrhosis. It is suggested that the renal and pulmonary abnormalities may be part of a systemic disorder capable of affecting many organs. Moreover, hyperglobulinaemia and autoantibodies in these patients further suggests that immunological mechanisms are concerned in the pathogenesis of these abnormalities.     

Membranoproliferative Glomerulonephritis and Persistent Hypocomplementaemia

The clinical, laboratory, and histological findings of 50 patients with membranoproliferative glomerulonephritis are described. Three-quarters of the patients, who were mostly older children and young adults, presented clinically with a mixture of “nephritic” and “nephrotic” symptoms; the remaining quarter had no symptoms and were diagnosed after the discovery of proteinuria and microscopic haematuria.Though this clinical picture may occur in other forms of glomerulonephritis, the patients described here were unified as a group by their glomerular morphological appearance—namely, a combination of mesangial proliferation and capillary wall thickening, mainly due to subendothelial accumulations of mesangial matrix.In 68% serum C3 (β10-globulin) levels were reduced initially, while a further 16% subsequently showed a fall to abnormally low levels. All patients had substantial proteinuria, usually of moderately impaired selectivity, and all but one had haematuria in addition. Children frequently presented with an illness resembling acute nephritis, whereas adults usually had a nephrotic syndrome from the start.In 31 patients, followed for periods of one to eight and a half years, serial measurements of glomerular filtration rate were made. Sixteen have experienced no deterioration of renal function, though their proteinuria continues unchanged. Fifteen have shown progressive deterioration; six of them are still well, six are on regular dialysis treatment, and three have died. Treatment with corticosteroids, azathioprine, or cyclophosphamide, alone or in combination, did not seem to influence the course of the disease, and another two patients died from complications of steroid therapy. The disease usually runs a chronic course and appears to be progressive.     

NONOBSTRUCTIVE OLIGURIA—Differential Diagnosis

A review is presented of ten years'' experience with the differential diagnosis of oliguria, utilizing the standard tests of renal function with the addition of the phenolsulfonphthalein excretion and urinary chloride measurements. The histories of 60 patients seen in consultation because of 24-hour urinary volume of less than 400 ml were studied in order to clarify the value of these tests. Particular attention was given to the postoperative “dilution state,” the oliguria of which tends to mimic that of “acute tubular necrosis.”In only 25 per cent of the 60 cases was “acute tubular necrosis” responsible for the oliguria. In the remaining 75 per cent of patients, oliguria was due either to the effects of simple dehydration without tubular damage, or to tubular dysfunction on a physiologic rather than an organic basis. Thus, three out of four patients with oliguria required aggressive and specific fluid-electrolyte therapy, often with the intensive use of potassium. One out of four required the opposite in therapy—controlled dehydration without added potassium and, on occasion, peritoneal or extracorporeal dialysis, in order to allow six to ten days for tubular repair.     

Culture and Disability Behavior

A substantial amount of literature suggests that illness behavior in the United States is a product of a patient''s core culture; equally credible findings do not support this contention. Most students and graduates in the health care professions believe that illness and disability behavior are affected by a patient''s culture, but they are hard put to find convincing examples of that relationship. In experience with medical students studying the social and cultural bases of illness behavior, with patients who are disabled and with persons who claim disability in the absence of physical disease or disabling psychopathology, I observed no deviant disability behavior that was typical for the members of any cultural group, and no behavior was displayed by the members of one cultural group that was not seen in members of other cultural groups. No cultural stereotypes were upheld. I did find evidence that disability behavior is influenced by personality factors, social situations and the gains derived from the disability status. Evolving concepts of “entitlement,” which are closely related to socioeconomic status, also have a significant influence. The impact of feedback from others in a person''s many social and medical subcultures is a more crucial determinant of illness and disability behavior, except in those for whom illness and disability behavior is determined by the limitations imposed by the disease or by a personality structure resistant to cultural expectations and social feedback.     

Nephrotic Syndrome in Adult Africans in Nairobi

The adult nephrotic syndrome as met with in Nairobi is predominantly encountered in young sophisticated African women, most of whom began to use skin-lightening creams containing mercury before the symptomatic onset of their illness. The particular form of mercury involved is well known to cause the nephrotic syndrome in other circumstances—for example, when applied to the skin in the treatment of psoriasis. In these circumstances the pathogenetic mechanism is thought to be of an idiosyncratic type. The use of mercury-containing skin-lightening creams in the patients studied seemed to be particularly associated with a “minimal-change” (“light-negative”) renal glomerular lesion, this lesion being present in half of the patients. The prognosis in this group of patients seems remarkably good, with 50% entering remission, 77% of these doing so spontaneously on discontinuing the use of the creams.     

Histological Reassessment of Three Kidneys Originally Described by Richard Bright in 1827-36

Portions of kidney from three patients with renal disease that were originally described by Richard Bright between 1827 and 1836 have been preserved in the Gordon Museum at Guy''s Hospital. Histological study has shown that two cases fall into the current diagnostic category of mesangiocapillary (membranoproliferative) glomerulonephritis. One of these patients had a five-year clinical history and died with chronic renal failure and uraemia. The other patient died after three to four months with a severe nephrotic syndrome. The third patient was a young woman with chronic “phthisis pulmonalis” and renal amyloidosis.     

Multifocal White Matter Lesions Associated with the D313Y Mutation of the α-Galactosidase A Gene

White matter lesions (WML) are clinically relevant since they are associated with strokes, cognitive decline, depression, or epilepsy, but the underlying etiology in young adults without classical risk factors still remains elusive. Our aim was to elucidate the possible clinical diagnosis and mechanisms leading to WML in patients carrying the D313Y mutation in the α-galactosidase A (GLA) gene, a mutation that was formerly described as nonpathogenic. Pathogenic GLA mutations cause Fabry disease, a vascular endothelial glycosphingolipid storage disease typically presenting with a symptom complex of renal, cardiac, and cerebrovascular manifestations. We performed in-depths clinical, biochemical and genetic examinations as well as advanced magnetic resonance imaging analyses in a pedigree with the genetically determined GLA mutation D313Y. We detected exclusive neurologic manifestations of the central nervous system of the “pseudo”-deficient D313Y mutation leading to manifest WML in 7 affected adult family members. Furthermore, two family members that do not carry the mutation showed no WML. The D313Y mutation resulted in a normal GLA enzyme activity in leukocytes and severely decreased activities in plasma. In conclusion, our results provide evidence that GLA D313Y is potentially involved in neural damage with significant WML, demonstrating the necessity of evaluating patients carrying D313Y more thoroughly. D313Y might broaden the spectrum of hereditary small artery diseases of the brain, which preferably occur in young adults without classical risk factors. In view of the existing causal therapy regime, D313Y should be more specifically taken into account in these patients.     

Mediators and mechanisms of radiation nephropathy

Normal tissue radiation injury occurs after sufficient irradiation, thus limiting the curative potential of x-ray therapy. In the kidney, radiation injury results in fibrosis and, ultimately, renal failure. The mediators of fibrosis in radiation nephropathy have received scant attention. Therefore, we evaluated the sequential presence of alpha smooth muscle actin (alphasma), fibrin, collagen, and TGFbeta1 in a porcine model of radiation nephropathy using 9.8 Gy single-dose local kidney irradiation. During the 24-week study, there was progressive and significant collagen accumulation in glomeruli and in interstitium. In glomeruli, this was associated with significant mesangial alphasma expression by 2 weeks after irradiation, a further rise at 4 weeks, and then a gradual fall to baseline. Glomerular fibrin deposition was significant by 4 weeks after irradiation, and remained elevated thereafter. There was little or no glomerular TGFbeta1 expression at any time point. Tubular fibrin deposition was significant at 4 weeks after irradiation but declined thereafter. There was little or no tubulo-interstitial alphasma expression at any time after irradiation. At 6 weeks after irradiation, there was a significant peak of tubular epithelial TGFbeta1 expression that declined thereafter. The early glomerular injury is evident as mesangial alphasma expression but is not proceeded by TGFbeta1 expression. There is sustained glomerular fibrin deposition with deposition of fibrin in tubular lumens, suggesting that tubular fibrin derives and flows out from injured glomerular tufts. We conclude that i) alphasma expression is an early marker of glomerular radiation injury, presaging scarring; ii) fibrin deposition is involved in glomerular and tubular radiation injury; and iii) TGFbeta1 is not an early event in radiation nephropathy, and not apparent in glomeruli in this model, but may correlate with later tubulo-interstitial fibrosis. Thus, the mediators of scarring in this model differ according to time after injury and also according to the affected tissue compartment.     

Analysis of Excretion Fraction of Uric Acid

Excretion fraction of uric acid (EF_UA), is one of the most important hallmarks for diagnosis of familial juvenile hyperuricemic nephropathy (FJHN) and hereditary renal hypouricemia. EF_UA was measured in 20 patients with FJHN. However, low excretion fraction (<6%) was found also in healthy FJHN family members and healthy controls (ref. ranges EF_UA: men 6–12%, women 6–20%). Similar finding of low EF_UA was reported recently. Distribution of EF_UA was further studied in 2,416 healthy controls, which were selected from 6,000 samples and divided according to age. In conclusion, finding of low EF_UA in family members is a risk factor for renal damage and indication for purine metabolic investigations with subsequent molecular biology analysis. As EF_UA could be found also in healthy controls—it should be interpreted with care and other features of FJHN (such as hyperuricemia, progressive renal disease in family) should be taken to account.     

Molecular Pathophysiology of Renal Tubular Acidosis

Renal tubular acidosis (RTA) is characterized by metabolic acidosis due to renal impaired acid excretion. Hyperchloremic acidosis with normal anion gap and normal or minimally affected glomerular filtration rate defines this disorder. RTA can also present with hypokalemia, medullary nephrocalcinosis and nephrolitiasis, as well as growth retardation and rickets in children, or short stature and osteomalacia in adults. In the past decade, remarkable progress has been made in our understanding of the molecular pathogenesis of RTA and the fundamental molecular physiology of renal tubular transport processes. This review summarizes hereditary diseases caused by mutations in genes encoding transporter or channel proteins operating along the renal tubule. Review of the molecular basis of hereditary tubulopathies reveals various loss-of-function or gain-of-function mutations in genes encoding cotransporter, exchanger, or channel proteins, which are located in the luminal, basolateral, or endosomal membranes of the tubular cell or in paracellular tight junctions. These gene mutations result in a variety of functional defects in transporter/channel proteins, including decreased activity, impaired gating, defective trafficking, impaired endocytosis and degradation, or defective assembly of channel subunits. Further molecular studies of inherited tubular transport disorders may shed more light on the molecular pathophysiology of these diseases and may significantly improve our understanding of the mechanisms underlying renal salt homeostasis, urinary mineral excretion, and blood pressure regulation in health and disease. The identification of the molecular defects in inherited tubulopathies may provide a basis for future design of targeted therapeutic interventions and, possibly, strategies for gene therapy of these complex disorders.Key Words: Renal tubular acidosis, acid-base homeostasis, molecular physiology, tubular transport, gene mutations.     

Long-Term Responses to Loss of Renal Mass: Control Mechanisms: Glomerulotubular Dimensional Readjustments During Compensatory Renal Hypertrophy in the Hypothyroid Rat

Although growth of tubules is arrested and that of glomeruli retarded by hypothyroidism in rats, unilateral nephrectomy has been found to elicit a vigorous compensatory hypertrophy of the hypothyroid kidney. Microdissection and measurement of the dimensions of glomeruli and proximal convoluted tubules taken from the kidney removed first and from the hypertrophic contralateral organ removed two to three weeks later, disclosed a “normalization” of the typical glomerulotubular dimensional imbalance as a result of greater tubular than glomerular growth. A somewhat more striking but qualitatively identical response was observed in 9 euthyroid animals. Glomerular filtration rate and maximal glucose reabsorptive capacity (Tm_G) increased in both euthyroid and hypothyroid animals in accord with the structural shifts.     

Some epistatic two-locus models of disease. I. Relative risks and identity-by-descent distributions in affected sib pairs

A two-locus disease model is presented in which a marker locus interacts epistatically with another unlinked trait to cause the disease. Such a model can lead to disease-marker associations and distortions in the sharing of marker types among affected family members. These effects are quantified. In the case of HLA-disease associations, this model is presented as an alternative to the “hitchhiking” theory of tight linkage leading to linkage disequilibrium.     

Enterovirus Infections: Etiologic,Epidemiologic and Clinical Aspects

The term enteroviruses was introduced in 1957 to bring together in one large family the polioviruses, Coxsackie A and B and echoviruses, all agents for which the human alimentary tract is the natural habitat. At present more than 60 distinct members are recognized: three polioviruses, 24 Coxsackie A, six Coxsackie B and 30 echoviruses. The list of new members, particularly in the echo-group, grows regularly. The viruses are frequently widely disseminated in the summer and fall of the year, circulating chiefly among young children, causing both apparent and inapparent infection. The enteroviruses are responsible for a wide spectrum of clinical manifestations, including non-specific febrile illness, sometimes with rash, aseptic meningitis, paralytic disease, respiratory infections, pericarditis and myocarditis. There is considerable overlap in biologic behavior, and the same syndrome can be induced by many different agents.In a few instances the clinical pattern is distinct enough to suggest the group of agents involved. Thus, herpangina is associated with the Coxsackie A viruses and epidemic myalgia (devil''s grip) with the Coxsackie B group. Paralytic disease is caused primarily by the polioviruses, but recently it has been found that other members, particularly the Coxsackie B viruses and Coxsackie A7 can also cause “paralytic poliomyelitis.”The ultimate potential of enteroviruses in terms of central nervous system disease and other manifestations is unpredictable. Great variety in terms of clinical and epidemiologic behavior of known and “new” viruses has been the pattern in the past, and is likely to continue.     

Issues in Health Care of Middle Eastern Patients

Relationships between Middle Eastern patients and Western health care professionals are often troubled by mutual misunderstanding of culturally influenced values and communication styles. Although Middle Easterners vary ethnically, they do share a core of common values and behavior that include the importance of affiliation and family, time and space orientations, interactional style and attitudes toward health and illness. Problems in providing health care involve obtaining adequate information, “demanding behavior” by a patient''s family, conflicting beliefs about planning ahead and differing patterns of communicating grave diagnoses or “bad news.” There are guidelines that will provide an understanding of the cultural characteristics of Middle Easterners and, therefore, will improve rather than impede their health care. A personal approach and continuity of care by the same health care professional help to bridge the gap between Middle Eastern cultures and Western medical culture. In addition, periodic use of cultural interpreters helps ameliorate the intensity of some cultural issues.