A Novel Homozygous Mutation in the COL4A4 Gene (Gly1436del) Causing Alport Syndrome Exposed by Pregnancy: A Case Report and Review of the Literature

Background. Alport syndrome results from a hereditary defect of collagen IV synthesis. This causes progressive glomerular disease, ocular abnormalities, and inner ear impairment. Case Presentation. Herein, we present a case of Alport syndrome in a 28-year-old woman caused by a novel mutation (Gly1436del) in the COL4A4 gene that was not unveiled until her first pregnancy. Within the 29th pregnancy week, our patient presented with massive proteinuria and nephrotic syndrome. Light microscopic examination of a kidney biopsy showed typical histological features of segmental sclerosis, and electron microscopy revealed extensive podocyte alterations as well as thickness of glomerular basement membranes with splitting of the lamina densa. One and a half years after childbirth, renal function deteriorated to a preterminal stage, whereas nephrotic syndrome subsided quickly after delivery. Conclusion. This case report highlights the awareness of atypical AS courses and emphasizes the importance of genetic testing in such cases.

Permeation of macromolecules into the renal glomerular basement membrane and capture by the tubules

How the kidney prevents urinary excretion of plasma proteins continues to be debated. Here, using unfixed whole-mount mouse kidneys, we show that fluorescent-tagged proteins and neutral dextrans permeate into the glomerular basement membrane (GBM), in general agreement with Ogston's 1958 equation describing how permeation into gels is related to molecular size. Electron-microscopic analyses of kidneys fixed seconds to hours after injecting gold-tagged albumin, negatively charged gold nanoparticles, and stable oligoclusters of gold nanoparticles show that permeation into the lamina densa of the GBM is size-sensitive. Nanoparticles comparable in size with IgG dimers do not permeate into it. IgG monomer-sized particles permeate to some extent. Albumin-sized particles permeate extensively into the lamina densa. Particles traversing the lamina densa tend to accumulate upstream of the podocyte glycocalyx that spans the slit, but none are observed upstream of the slit diaphragm. At low concentrations, ovalbumin-sized nanoparticles reach the primary filtrate, are captured by proximal tubule cells, and are endocytosed. At higher concentrations, tubular capture is saturated, and they reach the urine. In mouse models of Pierson’s or Alport’s proteinuric syndromes resulting from defects in GBM structural proteins (laminin β2 or collagen α3 IV), the GBM is irregularly swollen, the lamina densa is absent, and permeation is increased. Our observations indicate that size-dependent permeation into the lamina densa of the GBM and the podocyte glycocalyx, together with saturable tubular capture, determines which macromolecules reach the urine without the need to invoke direct size selection by the slit diaphragm.

Light and transmission electron microscopy of generalized dystrophic epidermolysis bullosa (Pasini's albopapuloid subtype)

Pasini's albopapuloid epidermolysis bullosa is a very rare subtype of generalized dystrophic dominant epidermolyis bullosa. A 30 year-old white female patient presented since her childhood disseminated small blisters and papules. Light microscopy of a blister showed dermal-epidermal cleavage; moreover, focal areas of dermal-epidermal splitting were also observed. Transmission electron microscopy also identified focal areas of cleavage, which were seen below the lamina densa. It is important to recognize this condition as a variant of epidermolysis bullosa, since the most important cutaneous findings are generalized papules and not blisters and erosions as in other forms of epidermolysis bullosa.

Junctional epidermolysis bullosa in a calf

A case of epidermolysis bullosa in a calf descendent from a Gir bull and a Gir crossbreed cow is reported. The calf presented with exungulation of all hooves, widespread erosions and crusts on the skin, and ulcers in the oral cavity. Histologically, the skin showed subepidermal separation with clefts occasionally filled with eosinophilic clear fluid, cellular debris, or neutrophils. Ultrastructurally, there was epidermal–dermal separation at the level of the lamina lucida, with the lamina densa attached to the papillary dermis. The hemidesmosomes were poorly defined and small. The clinical, histological, and ultrastructural findings are characteristic of junctional epidermolysis bullosa.

Epidermólise bolhosa distrófica recessiva mitis: relato de caso clínico

As epidermólises bolhosas são dermatoses bolhosas congênitas que levam à formação de bolhas espontaneamente ou após trauma. São reconhecidos três grupos de da doença, de acordo com o segundo consenso internacional: simples, juncional e distrófica. Nas formas distróficas, o defeito genético deve-se à mutação no gene COL7A1, responsável pela codificação do colágeno VII, principal constituinte das fibrilas de ancoragem, que participam na aderência da lâmina densa à derme. Os autores relatam o caso de paciente do sexo feminino, de 15 anos, apresentando ulcerações nas pernas, bolhas serosas e lesões atrófico-acastanhadas nos braços e tronco. Foram observadas distrofias ungueais e alterações dentárias, iniciadas a partir do nascimento. O exame histopatológico da bolha revelou quadro compatével com epidermólise bolhosa, que, associado aos dados clínicos, permitiram a classificação do caso na forma distrófica recessiva mitis.

Thin and Strong! The Bioengineering Dilemma in the Structural and Functional Design of the Blood-Gas Barrier

In gas exchangers, the tissue barrier, the partition that separates the respiratory media (water/air and hemolymph/blood), is exceptional for its remarkable thinness, striking strength, and vast surface area. These properties formed to meet conflicting roles: thinness was essential for efficient flux of oxygen by passive diffusion, and strength was crucial for maintaining structural integrity. What we have designated as “three-ply” or “laminated tripartite” architecture of the barrier appeared very early in the evolution of the vertebrate gas exchanger. The design is conspicuous in the water-blood barrier of the fish gills through the lungs of air-breathing vertebrates, where the plan first appeared in lungfishes (Dipnoi) some 400 million years ago. The similarity of the structural design of the barrier in respiratory organs of animals that remarkably differ phylogenetically, behaviorally, and ecologically shows that the construction has been highly conserved both vertically and horizontally, i.e., along and across the evolutionary continuum. It is conceivable that the blueprint may have been the only practical construction that could simultaneously grant satisfactory strength and promote gas exchange. In view of the very narrow allometric range of the thickness of the blood-gas barrier in the lungs of different-sized vertebrate groups, the measurement has seemingly been optimized. There is convincing, though indirect, evidence that the extracellular matrix and particularly the type IV collagen in the lamina densa of the basement membrane is the main stress-bearing component of the blood-gas barrier. Under extreme conditions of operation and in some disease states, the barrier fails with serious consequences. The lamina densa which in many parts of the blood-gas barrier is <50 nm thin is a lifeline in the true sense of the word.