Temporal macular thinning associated with X-linked Alport syndrome.

IMPORTANCE: Optical coherence tomography (OCT) findings of temporal macular thinning are important in the diagnosis and prognosis of X-linked Alport syndrome (XLAS). OBJECTIVES: To report OCT findings and severity of temporal macular thinning in a cohort with XLAS and to correlate these and other ocular findings with mutation genotype. DESIGN: Patients with XLAS underwent genotyping for COL4A5 mutations and complete eye examinations with retinal imaging using spectral domain OCT and fundus photography. Temporal macular thinning was calculated from OCT measurements by comparing the ratio of the retinal thickness of the temporal to the nasal subfields with a published normative database. SETTING: University departments of ophthalmology and nephrology. PARTICIPANTS: Thirty-two patients from 24 families. MAIN OUTCOME AND MEASURES: Temporal thinning index calculated from spectral domain OCT scans. RESULTS: All study patients had a mutation associated with the X-linked COL4A5 gene. Eleven different mutations were identified. Eleven of 32 patients (34%) expressed the L1649R mutation. Of a total of 63 eyes with available OCT scans, 44 (70%) had severe pathological temporal macular thinning. The L1649R mutation was associated with the least amount of severe temporal macular thinning and later onset of renal failure. CONCLUSIONS AND RELEVANCE: Temporal macular thinning is a prominent sign associated with XLAS, suggesting that OCT measurements are essential in the diagnosis and prognosis of the disease. The L1649R mutation in the COL4A5 gene causes a relatively mild form of XLAS characterized by late-onset renal failure and less frequent, severe temporal macular thinning relative to other COL4A5 mutations. The pathological basis for the retinal abnormalities of XLAS remains to be established.

Genotype-phenotype correlation in X-linked Alport syndrome.

Mutations in the COL4A5 gene cause X-linked Alport syndrome (XLAS). Understanding the correlation between clinical manifestations and the underlying mutations adds prognostic value to genetic testing, which is increasingly available. Our aim was to determine the association between genotype and phenotype in 681 affected male participants with XLAS from 175 US families. Hearing loss and ocular changes were present in 67 and 30% of participants, respectively. Average age of participants at onset of ESRD was 37 years for those with missense mutations, 28 years for those with splice-site mutations, and 25 years for those with truncating mutations (P < 0.0001). We demonstrated a strong relationship between mutation position and age at onset of ESRD, with younger age at onset of ESRD associated with mutations at the 5' end of the gene (hazard ratio 0.766 [95% confidence interval 0.694 to 0.846] per 1000 bp toward the 3' end; P < 0.0001). Affected participants with splice mutations or truncating mutations each had two-fold greater odds of developing eye problems than those with missense mutations; development of hearing impairment showed a similar trend. Hearing loss and ocular changes associated with mutations located closer to the 5; end of the gene. These strong genotype-phenotype correlations could potentially help in the evaluation and counseling of US families with XLAS.

Cost-effective dialysis for the developing world.

INTRODUCTION: Dialysis is an effective treatment for end-stage renal disease, but it is available to only approximately half of those who need it in the world. METHODS: Two prototype passive-flow dialysate delivery systems were constructed. RESULTS: Each dialysate delivery system provided a flow of dialysate in the range of 200-300 mL/minute. In one example, flow regulation was good, but ultrafiltration could not be monitored. The second prototype could monitor and regulate ultrafiltration but required repeated manual adjustment to maintain nearly constant dialysate flow. Approaches to the remaining obstacles to a fully passive dialysis system are outlined, but these will require further work to prove feasibility. CONCLUSION: In principle, costs of providing hemodialysis could be reduced and equipment created to function without electricity by exploiting passive-flow techniques.

Reification of abstract concepts to improve comprehension using interactive virtual environments and a knowledge-based design: a renal physiology model.

Several abstract concepts in medical education are difficult to teach and comprehend. In order to address this challenge, we have been applying the approach of reification of abstract concepts using interactive virtual environments and a knowledge-based design. Reification is the process of making abstract concepts and events, beyond the realm of direct human experience, concrete and accessible to teachers and learners. Entering virtual worlds and simulations not otherwise easily accessible provides an opportunity to create, study, and evaluate the emergence of knowledge and comprehension from the direct interaction of learners with otherwise complex abstract ideas and principles by bringing them to life. Using a knowledge-based design process and appropriate subject matter experts, knowledge structure methods are applied in order to prioritize, characterize important relationships, and create a concept map that can be integrated into the reified models that are subsequently developed. Applying these principles, our interdisciplinary team has been developing a reified model of the nephron into which important physiologic functions can be integrated and rendered into a three dimensional virtual environment called Flatland, a virtual environments development software tool, within which a learners can interact using off-the-shelf hardware. The nephron model can be driven dynamically by a rules-based artificial intelligence engine, applying the rules and concepts developed in conjunction with the subject matter experts. In the future, the nephron model can be used to interactively demonstrate a number of physiologic principles or a variety of pathological processes that may be difficult to teach and understand. In addition, this approach to reification can be applied to a host of other physiologic and pathological concepts in other systems. These methods will require further evaluation to determine their impact and role in learning.

Distribution of type IV collagen in the cochlea in Alport syndrome.

OBJECTIVE: To determine the distribution of alpha1, alpha3, and alpha5 chains of type IV collagen in the cochlea in Alport syndrome. DESIGN: Case-control study. PATIENTS: Two patients with sensorineural hearing loss due to Alport syndrome. Both patients had known mutations in the COL4A5 gene. MAIN OUTCOME MEASURES: Immunostaining was used to study the distribution of type IV collagen (alpha1, alpha3, and alpha5 chains) within the cochlea. Immunostaining was also performed in the cochlear tissues of an unaffected individual used as a control. RESULTS: In the control ear, alpha1 staining was observed in the basement membrane overlying the basilar membrane, in the basement membrane of cochlear blood vessels and Schwann cells, and within the spiral limbus. In the control ear, we also observed strong staining for alpha3 and alpha5 chains in the basement membrane overlying the basilar membrane and within the spiral ligament. In both cases with Alport syndrome, no immunostaining was observed for alpha3 or alpha5 chains within the cochlea, whereas alpha1 staining was present in locations similar to that seen in the control ear. CONCLUSIONS: The results indicate that isotype switching does not occur within the cochlea in Alport syndrome. The results are also consistent with the hypothesis that the sensorineural hearing loss in Alport syndrome may be due to alterations in cochlear micromechanics and/or dysfunction of the spiral ligament.

The clinical features of thin basement membrane nephropathy.

Thin basement membrane nephropathy (TBMN) is a common, lifelong condition affecting the kidneys that is characterized by microscopic glomerular hematuria, minimal or no proteinuria, and normal renal function. It often is discovered incidentally, and usually has an excellent prognosis. Many cases are familial and show autosomal-dominant inheritance. The defining characteristic is a glomerular basement membrane (GBM) that is thinned to about half its normal thickness on ultrastructural examination of the renal biopsy specimen. However, occasionally patients with TBMN develop marked proteinuria or renal impairment. It is unclear whether individuals with TBMN and impaired renal function represent part of the spectrum of TBMN associated with heterozygous COL4A3 or COL4A4 mutations, or if their disease is caused by mutations of other genes, or whether it is caused by a second coexistent renal lesion or is misdiagnosed Alport syndrome.

Temporal bone histopathology in alport syndrome.

OBJECTIVE: To determine the histopathologic abnormalities within the cochlea in Alport syndrome. BACKGROUND: Alport syndrome, which manifests as hereditary nephritis and sensorineural hearing loss (SNHL), is caused by mutations in genes that code for the proportional, variant3, proportional, variant4, and proportional, variant5 chains of type IV collagen. The proportional, variant3, proportional, variant4, and proportional, variant5 chains of type IV collagen are present in the basement membrane of the organ of Corti. Previous temporal bone studies have failed to identify histopathologic correlates for the SNHL. METHODS: We examined temporal bones from nine individuals with a clinical diagnosis of Alport syndrome. One of our cases also had genetic testing that showed a mutation in the type IV collagen proportional, variant5 chain gene. RESULTS: By light microscopy, eight of nine cases demonstrated two unique pathologic changes: 1) a "zone of separation" between the basilar membrane and overlying cells of the organ of Corti and 2) presence of cells filling the tunnel of Corti and extracellular spaces of Nuel. The cytologic losses of hair cells, stria vascularis, and cochlear neuronal cells were insufficient to account for the observed SNHL in our cases. Electron microscopy was performed in four cases; all four demonstrated the following: 1) the zone of separation that was observed at light microscopy occurred between the basement membrane and the basilar membrane, 2) the cells within the tunnel of Corti and spaces of Nuel were morphologically similar to supporting cells, and 3) the basement membrane of strial capillaries and the spiral vessel (under the basilar membrane) were normal. CONCLUSIONS: The histopathologic correlates of cochlear involvement in Alport syndrome are abnormalities of the basement membrane of cells of the organ of Corti and dysmorphogenesis (cellular infilling of the tunnel and extracellular spaces) of the organ of Corti. We hypothesize that these abnormalities result in SNHL by altering cochlear micromechanics.