Pierson Syndrome in an Infant With Congenital Nephrotic Syndrome and Unique Brain Pathology

Pierson syndrome is caused by mutations in the laminin β2 gene causing absent β2 laminin, which is a normal component of the basement membranes of the mature glomerulus, structures in the anterior eye and neuromuscular junctions. The mutations manifest as congenital nephrotic syndrome and microcoria which are characteristic ocular features of this disease. These mutations may also result in neurological abnormalities such as hypotonia and psychomotor retardation. We report a two-month old boy who presented to the Pediatrics Department of Dr. Ruth K. M. Pfau Civil Hospital, Karachi, Pakistan, in 2015, with the typical features of microcoria and congenital nephrotic syndrome. The hypocalcaemia, hypoproteinaemia and probable immunocompromised state consequent to nephrotic syndrome resulted in seizures, hypothyroidism and urosepsis. Despite being treated aggressively with high dose antibiotics, ionotropic support, angiotensin-converting enzyme inhibitors, thyroxine replacement and nutritional support, the infant died due to significant multiorgan disease including renal failure and septic shock. Keywords: Pierson Syndrome; Microcoria and Congenital Nephrotic Syndrome; Congenital Microcoria; Hypothyroidism; Septic Shock; Case Report; Pakistan.

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Laminin-521 Protein Therapy for Glomerular Basement Membrane and Podocyte Abnormalities in a Model of Pierson Syndrome

Journal of the American Society of Nephrology ◽

10.1681/asn.2017060690 ◽

2018 ◽

Vol 29 (5) ◽

pp. 1426-1436 ◽

Cited By ~ 10

Author(s):

Meei-Hua Lin ◽

Joseph B. Miller ◽

Yamato Kikkawa ◽

Hani Y. Suleiman ◽

Karl Tryggvason ◽

...

Keyword(s):

Nephrotic Syndrome ◽

Congenital Nephrotic Syndrome ◽

Super Resolution ◽

Diffuse Mesangial Sclerosis ◽

Protein Therapy ◽

Correct Orientation ◽

Pierson Syndrome ◽

Foot Process ◽

And Function

Background Laminin α5β2γ1 (LM-521) is a major component of the GBM. Mutations in LAMB2 that prevent LM-521 synthesis and/or secretion cause Pierson syndrome, a rare congenital nephrotic syndrome with diffuse mesangial sclerosis and ocular and neurologic defects. Because the GBM is uniquely accessible to plasma, which permeates endothelial cell fenestrae, we hypothesized that intravenous delivery of LM-521 could replace the missing LM-521 in the GBM of Lamb2 mutant mice and restore glomerular permselectivity.Methods We injected human LM-521 (hLM-521), a macromolecule of approximately 800 kD, into the retro-orbital sinus of Lamb2−/− pups daily. Deposition of hLM-521 into the GBM was investigated by fluorescence microscopy. We assayed the effects of hLM-521 on glomerular permselectivity by urinalysis and the effects on podocytes by desmin immunostaining and ultrastructural analysis of podocyte architecture.Results Injected hLM-521 rapidly and stably accumulated in the GBM of all glomeruli. Super-resolution imaging showed that hLM-521 accumulated in the correct orientation in the GBM, primarily on the endothelial aspect. Treatment with hLM-521 greatly reduced the expression of the podocyte injury marker desmin and attenuated the foot process effacement observed in untreated pups. Moreover, treatment with hLM-521 delayed the onset of proteinuria but did not prevent nephrotic syndrome, perhaps due to its absence from the podocyte aspect of the GBM.Conclusions These studies show that GBM composition and function can be altered in vivovia vascular delivery of even very large proteins, which may advance therapeutic options for patients with abnormal GBM composition, whether genetic or acquired.

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Pierson Syndrome: A Novel Cause of Congenital Nephrotic Syndrome

PEDIATRICS ◽

10.1542/peds.2005-3154 ◽

2006 ◽

Vol 118 (2) ◽

pp. e501-e505 ◽

Cited By ~ 30

Author(s):

R. VanDeVoorde ◽

D. Witte ◽

J. Kogan ◽

J. Goebel

Keyword(s):

Nephrotic Syndrome ◽

Congenital Nephrotic Syndrome ◽

Pierson Syndrome

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Pathogenicity of a Human Laminin β2 Mutation Revealed in Models of Alport Syndrome

Journal of the American Society of Nephrology ◽

10.1681/asn.2017090997 ◽

2017 ◽

Vol 29 (3) ◽

pp. 949-960 ◽

Cited By ~ 12

Author(s):

Steven D. Funk ◽

Raymond H. Bayer ◽

Andrew F. Malone ◽

Karen K. McKee ◽

Peter D. Yurchenco ◽

...

Keyword(s):

Nephrotic Syndrome ◽

Basement Membrane ◽

Alport Syndrome ◽

Late Onset ◽

Congenital Nephrotic Syndrome ◽

Model Organisms ◽

Missense Mutations ◽

Amino Terminal ◽

Wide Range ◽

Pierson Syndrome

Pierson syndrome is a congenital nephrotic syndrome with eye and neurologic defects caused by mutations in laminin β2 (LAMB2), a major component of the glomerular basement membrane (GBM). Pathogenic missense mutations in human LAMB2 cluster in or near the laminin amino-terminal (LN) domain, a domain required for extracellular polymerization of laminin trimers and basement membrane scaffolding. Here, we investigated an LN domain missense mutation, LAMB2-S80R, which was discovered in a patient with Pierson syndrome and unusually late onset of proteinuria. Biochemical data indicated that this mutation impairs laminin polymerization, which we hypothesized to be the cause of the patient’s nephrotic syndrome. Testing this hypothesis in genetically altered mice showed that the corresponding amino acid change (LAMB2-S83R) alone is not pathogenic. However, expression of LAMB2-S83R significantly increased the rate of progression to kidney failure in a Col4a3−/− mouse model of autosomal recessive Alport syndrome and increased proteinuria in Col4a5+/− females that exhibit a mild form of X-linked Alport syndrome due to mosaic deposition of collagen α3α4α5(IV) in the GBM. Collectively, these data show the pathogenicity of LAMB2-S80R and provide the first evidence of genetic modification of Alport phenotypes by variation in another GBM component. This finding could help explain the wide range of Alport syndrome onset and severity observed in patients with Alport syndrome, even for family members who share the same COL4 mutation. Our results also show the complexities of using model organisms to investigate genetic variants suspected of being pathogenic in humans.

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