Neurodevelopmental deficits in Pierson (microcoria‐congenital nephrosis) syndrome

Abstract

Pierson syndrome is an autosomal recessive disorder comprising congenital nephrotic syndrome with diffuse mesangial sclerosis and distinct eye abnormalities with microcoria reported as the most prominent clinical feature. LAMB2 mutations leading to lack of laminin beta2 were identified as the molecular cause underlying Pierson syndrome. Although LAMB2 is known to be expressed in the neuromuscular system, and defects of the neuromuscular junctions had been found in laminin beta2-deficient mice, no consistent neurological phenotype has been described clinically in murine or human laminin beta2-deficiency before. This is likely due to the early lethality from renal failure. Here we provide a detailed description of neurological manifestations and development in four patients affected by Pierson syndrome, who survived until the age of 1.3-4.8 years owing to renal replacement therapy. Severe muscular hypotonia, psychomotor retardation, and blindness were present in three patients harboring truncating mutations on both LAMB2 alleles. These symptoms were not attributable to complications of chronic renal failure, thus representing a primary feature of the genetic disorder. Alterations in skeletal muscle tissue from one case were compatible with a chronic denervating process. One affected girl, however, exhibited a milder course of renal disease, normal development, and preserved vision, presumably owing to some residual LAMB2 function. Our findings indicate that severe neurodevelopmental deficits have to be considered as part of Pierson syndrome, at least in the presence of biallelic functional null mutations (complete lack of laminin beta2). This is an important issue in the counseling of parents of an affected newborn or infant.

Basement Membranes: Cell Scaffoldings and Signaling Platforms

“…This was seemingly supported by the observation of the proteinuria that occurred following inactivation of either the gene (Lamb2) coding for the laminin b2 unit (a subunit found in kidney almost exclusively in the GBM) or podocyte-specific inactivation of the Lama5 gene (Noakes et al 1995b;Goldberg et al 2010). In humans, mutations of the Lamb2 gene cause Pierson syndrome, a disorder of congenital nephrosis and mesangial sclerosis associated with eye and (sometimes) neuromuscular junction abnormalities (Zenker et al 2004;Wuhl et al 2007). The GBM filtration model, however, was challenged by the discovery that absence of nephrin, a structural component of the slit diaphragm, also causes the nephrotic syndrome (Kestila et al 1998;Wartiovaara et al 2004).…”

Forced expression of laminin β1 in podocytes prevents nephrotic syndrome in mice lacking laminin β2, a model for Pierson syndrome

“…We used a renal biopsy from a 3-mo-old Pierson patient lacking Lamβ2 (20,21) to determine whether the loss of Lamβ2 in humans leads to the increased Lamβ1 observed in the GBM of Lamb2 −/− mice (11). Indeed, Lamβ1, which is in the mesangial matrix of normal glomeruli, was detected in the GBM of the patient (Fig.…”

Neurite Outgrowth andIn VivoSensory Innervation Mediated by a CaV2.2–Laminin β2 Stop Signal

“…Behaviorally, this may lead to hypersensitivity to light touch and/or mislocalization of sensory signals. Pierson syndrome, a rare human disorder caused by mutations to the LAMB2 gene that encodes laminin ␤2, has been characterized by kidney failure, blindness, muscle dystonia, microcephaly, and neurological disorders (Zenker et al, 2004;Wuhl et al, 2007). It is likely that these infants would also have abnormalities in somatosensation.…”