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American Journal of Medical Genetics.... Feb 2007Pierson syndrome is an autosomal recessive disorder comprising congenital nephrotic syndrome with diffuse mesangial sclerosis and distinct eye abnormalities with...
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.
Topics: Abnormalities, Multiple; Base Sequence; Blindness; Child, Preschool; Eye Abnormalities; Female; Humans; Infant; Laminin; Molecular Sequence Data; Muscle Hypotonia; Muscle, Skeletal; Mutation; Nephrotic Syndrome; Psychomotor Disorders; Syndrome
PubMed: 17256789
DOI: 10.1002/ajmg.a.31564 -
Nephrology, Dialysis, Transplantation :... Nov 2006Pierson syndrome (OMIM 609049) is a severe congenital oculorenal disorder with early lethality. The condition is caused by mutations in the LAMB2 gene leading to...
BACKGROUND
Pierson syndrome (OMIM 609049) is a severe congenital oculorenal disorder with early lethality. The condition is caused by mutations in the LAMB2 gene leading to complete loss of function of the gene product laminin beta2, an essential component of the glomerular and other basement membranes.
METHODS
We present a non-consanguineous family with seven offspring affected by childhood-onset nephrotic syndrome progressing to end-stage renal failure and ocular abnormalities including cataracts, anterior chamber and iris abnormalities, and progressive blindness due to retinal detachment. The LAMB2 gene was analysed in this family by direct sequencing.
RESULTS
The disorder turned out to segregate with compound heterozygosity for two novel LAMB2 mutations, triangle upV79 and Q1728X. Whereas the mutation Q1728X is predicted to confer complete loss of function, triangle upV79 probably represents a hypomorphic allele, thus explaining the substantially milder phenotype in this family.
CONCLUSION
This observation demonstrates that the phenotypic spectrum of LAMB2-associated disorders is broader than previously anticipated, and suggests that milder, non-lethal phenotypes may be associated with mutations retaining some residual function.
Topics: Adolescent; Adult; Age of Onset; Amino Acid Sequence; Amino Acid Substitution; Child; Child, Preschool; Disease Progression; Eye Abnormalities; Female; Humans; Laminin; Male; Molecular Sequence Data; Nephrotic Syndrome; Pedigree; Phenotype; Vision Disorders
PubMed: 16921188
DOI: 10.1093/ndt/gfl463 -
Kidney International Sep 2006Congenital nephrotic syndrome is clinically and genetically heterogeneous. The majority of cases can be attributed to mutations in the genes NPHS1, NPHS2, and WT1. By...
Congenital nephrotic syndrome is clinically and genetically heterogeneous. The majority of cases can be attributed to mutations in the genes NPHS1, NPHS2, and WT1. By homozygosity mapping in a consanguineous family with isolated congenital nephrotic syndrome, we identified a potential candidate region on chromosome 3p. The LAMB2 gene, which was recently reported as mutated in Pierson syndrome (microcoria-congenital nephrosis syndrome; OMIM #609049), was located in the linkage interval. Sequencing of all coding exons of LAMB2 revealed a novel homozygous missense mutation (R246Q) in both affected children. A different mutation at this codon (R246W), which is highly conserved through evolution, has recently been reported as causing Pierson syndrome. Subsequent LAMB2 mutational screening in six additional families with congenital nephrotic syndrome revealed compound heterozygosity for two novel missense mutations in one family with additional nonspecific ocular anomalies. These findings demonstrate that the spectrum of LAMB2-associated disorders is broader than previously anticipated and includes congenital nephrotic syndrome without eye anomalies or with minor ocular changes different from those observed in Pierson syndrome. This phenotypic variability likely reflects specific genotypes. We conclude that mutational analysis in LAMB2 should be considered in congenital nephrotic syndrome, if no mutations are found in NPHS1, NPHS2, or WT1.
Topics: Child, Preschool; Chromosomes, Human, Pair 3; Consanguinity; Exons; Female; Genes, Recessive; Genetic Markers; Haplotypes; Humans; Introns; Laminin; Male; Microsatellite Repeats; Mutation, Missense; Nephrotic Syndrome; Physical Chromosome Mapping
PubMed: 16912710
DOI: 10.1038/sj.ki.5001679 -
Przeglad Lekarski 2006Mutations in the LAMB2 gene encoding laminin beta2, a component of the glomerular basement membrane and the neuro-muscular junction are responsible for the...
UNLABELLED
Mutations in the LAMB2 gene encoding laminin beta2, a component of the glomerular basement membrane and the neuro-muscular junction are responsible for the characteristic renal and eye abnormalities of Pierson syndrome. We report a girl with confirmed LAMB2 mutation who presented with early onset Congenital Nephrotic Syndrome (CNS) with renal failure and ocular findings of bilateral microcoria, persistent hyperplastic primary vitreous, right microphtalmia and left eye cataract. Automated peritoneal dialysis was started from the 3rd month of life. Severe muscle hypotonia with motor and mental delay were observed during the first year of life. She experienced numerous serious infections from birth and died at the age of 15 months due to a fulminant infection. Genetic studies revealed two novel mutations in LAMB2 gene (compound heterozygosity).
CONCLUSIONS
1. Mutations in LAMB2 gene should be included in the work-up of patients with CNS in the presence of eye anomalies. 2. Severe phenotypes of Pierson syndrome are associated with marked handicaps and a poor outcome.
Topics: Eye Abnormalities; Fatal Outcome; Female; Humans; Infant; Laminin; Molecular Sequence Data; Muscle Hypotonia; Mutation, Missense; Nephrotic Syndrome; Pregnancy; Treatment Outcome
PubMed: 16898484
DOI: No ID Found -
The Journal of Clinical Investigation Aug 2006Primary defects in either podocytes or the glomerular basement membrane (GBM) cause proteinuria, a fact that complicates defining the barrier to albumin. Laminin beta2...
Primary defects in either podocytes or the glomerular basement membrane (GBM) cause proteinuria, a fact that complicates defining the barrier to albumin. Laminin beta2 (LAMB2) is a GBM component required for proper functioning of the glomerular filtration barrier. To investigate the GBM's role in glomerular filtration, we characterized GBM and overlying podocyte architecture in relation to development and progression of proteinuria in Lamb2-/- mice, which model Pierson syndrome, a rare congenital nephrotic syndrome. We found ectopic deposition of several laminins and mislocalization of anionic sites in the GBM, which together suggest that the Lamb2-/- GBM is severely disorganized, although it is ultrastructurally intact. Importantly, albuminuria was detectable shortly after birth and preceded podocyte foot process effacement and loss of slit diaphragms by at least 7 days. Expression and localization of slit diaphragm and foot process-associated proteins appeared normal at early stages. GBM permeability to the electron-dense tracer ferritin was dramatically elevated in Lamb2-/- mice, even before widespread foot process effacement. Increased ferritin permeability was not observed in nephrotic CD2-associated protein-null (Cd2ap-/-) mice, which have a primary podocyte defect. Together these data show that the GBM serves as a barrier to protein in vivo and that the glomerular slit diaphragm alone is not sufficient to prevent the passage of albumin into the urinary space.
Topics: Albuminuria; Animals; Basement Membrane; Disease Models, Animal; Ferritins; Kidney Glomerulus; Laminin; Mice; Mice, Knockout; Microscopy, Electron, Scanning; Nephrotic Syndrome; Podocytes; Proteinuria
PubMed: 16886065
DOI: 10.1172/JCI28414 -
Pediatrics Aug 2006In this report, we describe a newborn infant who presented with congenital nephrotic syndrome and renal insufficiency, as well as bilateral microcoria. This...
In this report, we describe a newborn infant who presented with congenital nephrotic syndrome and renal insufficiency, as well as bilateral microcoria. This constellation of findings is a hallmark of Pierson syndrome, a newly recognized genetic disorder that is caused by a deficiency of beta2 laminin in the basement membrane. Our patient demonstrated classic histopathologic findings of Pierson syndrome on renal biopsy, including absence of beta2 laminin on immunofluorescent staining, and genetic testing confirmed the diagnosis. We conclude that Pierson syndrome should be included in the differential diagnosis for congenital nephrotic syndrome, especially in patients with ocular abnormalities.
Topics: Adult; Basement Membrane; Biopsy; Diagnosis, Differential; Edema; Female; Heterozygote; Humans; Hypertension, Renal; Infant, Newborn; Infant, Small for Gestational Age; Kidney; Kidney Glomerulus; Laminin; Male; Mesangial Cells; Miosis; Nephrotic Syndrome; Oligohydramnios; Pregnancy; Syndrome; Ultrasonography, Prenatal
PubMed: 16864643
DOI: 10.1542/peds.2005-3154 -
Development (Cambridge, England) Mar 2006Pierson syndrome is a recently defined disease usually lethal within the first postnatal months and caused by mutations in the gene encoding laminin beta2 (LAMB2). The...
Pierson syndrome is a recently defined disease usually lethal within the first postnatal months and caused by mutations in the gene encoding laminin beta2 (LAMB2). The hallmarks of Pierson syndrome are congenital nephrotic syndrome accompanied by ocular abnormalities, including microcoria (small pupils), with muscular and neurological developmental defects also present. Lamb2(-/-) mice are a model for Pierson syndrome; they exhibit defects in the kidney glomerular barrier, in the development and organization of the neuromuscular junction, and in the retina. Lamb2(-/-) mice fail to thrive and die very small at 3 weeks of age, but to what extent the kidney and neuromuscular defects each contribute to this severe phenotype has been obscure, though highly relevant to understanding Pierson syndrome. To investigate this, we generated transgenic mouse lines expressing rat laminin beta2 either in muscle or in glomerular epithelial cells (podocytes) and crossed them onto the Lamb2(-/-) background. Rat beta2 was confined in skeletal muscle to synapses and myotendinous junctions, and in kidney to the glomerular basement membrane. In transgenic Lamb2(-/-) mice, beta2 deposition in only glomeruli prevented proteinuria but did not ameliorate the severe phenotype. By contrast, beta2 expression in only muscle restored synaptic architecture and led to greatly improved health, but the mice died from kidney disease at 1 month. Rescue of both glomeruli and synapses was associated with normal weight gain, fertility and lifespan. We conclude that muscle defects in Lamb2(-/-) mice are responsible for the severe failure to thrive phenotype, and that renal replacement therapy alone will be an inadequate treatment for Pierson syndrome.
Topics: Animals; Glomerular Basement Membrane; Kidney Diseases; Laminin; Mice; Mice, Knockout; Mice, Transgenic; Muscle, Skeletal; Muscular Diseases; Mutation; Neuromuscular Junction; Podocytes; Rats; Synapses; Syndrome
PubMed: 16452099
DOI: 10.1242/dev.02270 -
Prenatal Diagnosis Mar 2006To describe the prenatal findings in Pierson syndrome, a newly defined autosomal recessive entity, comprising congenital nephrotic syndrome (CNS) with diffuse mesangial...
OBJECTIVE
To describe the prenatal findings in Pierson syndrome, a newly defined autosomal recessive entity, comprising congenital nephrotic syndrome (CNS) with diffuse mesangial sclerosis and distinct eye abnormalities due to LAMB2 mutations.
METHODS
Serial prenatal ultrasound examinations were performed in four consecutive pregnancies affected by Pierson syndrome in the same family. LAMB2 mutations were demonstrated in retrospect by direct sequencing of the gene in the newborn index patient and three abortuses.
RESULTS
Fetal ultrasound consistently revealed marked renal hyperechogenicity associated with variable degree of pyelectasis. These features were detectable by 15 weeks of gestation in all fetuses. Hydrops fetalis due to severe hypalbuminemia demonstrated by chordocentesis occurred in one fetus. Placentas were significantly enlarged. Development of oligohydramnios indicated prenatal decline of renal excretory function. Anencephaly was detected in another fetus with molecularly proven Pierson syndrome at 12 weeks of gestation.
CONCLUSION
We conclude that Pierson syndrome has to be considered in the differential diagnosis of nephrotic disorders with prenatal onset. Ultrasound criteria for differentiation from the most common type of CNS-congenital nephrosis of the Finnish type (CNF)-are discussed. Because of its prognostic relevance, we advocate molecular genetic testing of LAMB2 in any case of prenatally detected nephrotic syndrome with negative results of NPHS1 mutational screening, especially in the presence of the typical sonomorphologic findings of the kidneys and the development of oligohydramnios.
Topics: Abnormalities, Multiple; Anencephaly; Consanguinity; Eye Abnormalities; Fatal Outcome; Female; Fetal Death; Fetal Diseases; Glomerular Mesangium; Humans; Infant; Lamin Type B; Male; Mutation; Nephrotic Syndrome; Pedigree; Pregnancy; Syndrome; Ultrasonography, Prenatal
PubMed: 16450351
DOI: 10.1002/pd.1393 -
American Journal of Medical Genetics.... Sep 2005
Topics: Abnormalities, Multiple; Aged; Codon, Nonsense; DNA Mutational Analysis; Eye Abnormalities; Family Health; Female; Humans; Laminin; Male; Mutation; Nephrosis; Pedigree; Syndrome
PubMed: 16097004
DOI: 10.1002/ajmg.a.30894 -
American Journal of Medical Genetics.... Oct 2004We observed the occurrence of congenital nephrotic syndrome (CNS) and distinct ocular anomalies in two unrelated families. Eleven children from both families presented... (Review)
Review
We observed the occurrence of congenital nephrotic syndrome (CNS) and distinct ocular anomalies in two unrelated families. Eleven children from both families presented with a similar course of renal disease starting with nephrotic syndrome and renal failure prenatally or immediately after birth that resulted in death before the age of 2 months. Kidney histopathology showed diffuse mesangial sclerosis (DMS). Clinically obvious eye abnormalities were recognized in six of the eight patients in whom sufficient clinical data were available. Ocular anomalies included enlarged or large appearing corneae in some cases suggesting buphthalmos, and extremely narrow, nonreactive pupils (microcoria). Pathological examination of the eyes of two aborted fetuses revealed a more complex ocular maldevelopment including posterior lenticonus as well as anomalies of cornea and retina. On the basis of these observations and other cases in the literature, we delineate a previously unrecognized distinct entity characterized by congenital nephrotic syndrome, DMS, and eye abnormalities with microcoria as the leading clinical feature. Pedigrees of affected families with parental consanguinity support autosomal recessive inheritance. We propose that this syndrome should be designated microcoria-congenital nephrosis syndrome or Pierson syndrome. Possible overlap with Galloway-Mowat syndrome and relations to other oculo-renal syndromes are discussed.
Topics: Abnormalities, Multiple; Consanguinity; Eye Abnormalities; Family Health; Fatal Outcome; Female; Genes, Recessive; Glomerular Mesangium; Humans; Infant; Infant, Newborn; Male; Necrosis; Nephrosis; Pedigree; Pupil Disorders; Syndrome; Turkey
PubMed: 15372515
DOI: 10.1002/ajmg.a.30310