Nephrotic Syndrome, Type 5, With Or Without Ocular Abnormalities

A number sign (#) is used with this entry because this form of hereditary renal disease, referred to here as nephrotic syndrome type 5 (NPHS5), can be caused by homozygous or compound heterozygous mutation in the LAMB2 gene (150325) on chromosome 3p.

Description

Nephrotic syndrome type 5 is an autosomal recessive disorder characterized by very early onset of progressive renal failure manifest as proteinuria with consecutive edema starting in utero or within the first 3 months of life. A subset of patients may develop mild ocular anomalies, such as myopia, nystagmus, and strabismus (summary by Hasselbacher et al., 2006).

Mutation in the LAMB2 gene can also cause Pierson syndrome (609049), which is characterized by nephrotic syndrome, distinct ocular anomalies, namely microcoria, and neurodevelopmental delay.

For a general phenotypic description and a discussion of genetic heterogeneity of nephrotic syndrome, see NPHS1 (256300).

Clinical Features

Hasselbacher et al. (2006) reported 2 unrelated families with congenital nephrotic syndrome, one of which also had mild ocular abnormalities. In 1 family 2 sibs developed proteinuria before the age of 3 months and end-stage renal failure within the first year of life. Kidney biopsy in 1 child showed focal and segmental glomerulosclerosis with abnormalities of the glomerular basement membrane. Neither sib had any other primary abnormality. In the other family, 2 sibs had congenital nephrotic syndrome progressing to end-stage renal failure within the first year of life. One sib had congenital nystagmus with a hypopigmented fundus, strabismus, and myopia, and the other had a hypopigmented retina and mild narrowing of the pupils.

Maselli et al. (2009) reported a 20-year-old woman with congenital nephrotic syndrome and ocular abnormalities. In the neonatal period, she had persistently constricted pupils and massive proteinuria. She received a renal transplant at age 15 months, which allowed unusually long survival. Motor milestones were delayed, and she had severe proximal limb muscle weakness. Detailed neuromuscular examination at age 7 years showed congenital myasthenic syndrome with normal acetylcholinesterase (ACHE; 100740) activity. There was a decremental response of muscle action potential amplitude and a profound reduction of the quantal content of endplate potentials. Electron microscopy of the neuromuscular junction showed small axon terminal size and encasement of nerve endings by the Schwann cell, widening of the primary synaptic clefts with invasion of the synaptic space by processes of Schwann cells, moderate simplification of postsynaptic membranes, and decreased number of synaptic vesicles. Other clinical features included scoliosis, ptosis, impaired visual acuity, hypoplastic macular areas and poor foveal reflex, reactive pinpoint pupils, and limited extraocular movements. Cognition was normal. Molecular analysis detected compound heterozygosity for 2 truncating mutations in the LAMB2 gene (150325.0009 and 150325.0010). Maselli et al. (2009) noted that the muscular phenotype was similar to that observed in Lamb2-null mice (Noakes et al., 1995).

Mohney et al. (2011) reported a consanguineous Mennonite family with chronic kidney disease and bilateral chorioretinal pigmentary changes, with or without retinal detachment, but without microcoria or neurodevelopmental deficits, segregating in an autosomal recessive pattern. The authors considered it to be a variant form of Pierson syndrome.

Molecular Genetics

In 2 affected sibs in a consanguineous Turkish family segregating isolated congenital nephrotic syndrome, Hasselbacher et al. (2006) identified a homozygous missense mutation in the LAMB2 gene (150325.0006). In a German-Caucasian family in which 2 sibs had congenital nephrotic syndrome and mild ocular anomalies, Hasselbacher et al. (2006) identified compound heterozygosity for 3 missense mutations in the LAMB2 gene (see 150325.0007-150325.0008), 2 of which were inherited from the mother and the other from the father.

Mohney et al. (2011) described 11 (9 living) members of an extended consanguineous Old Order Mennonite family in which 11 (9 living) of 52 members had chronic kidney disease and bilateral chorioretinal pigmentary changes, with or without retinal detachment, but without microcoria or neurodevelopmental deficits, segregating in an autosomal recessive pattern. All affected members had a novel homozygous mutation in the LAMB2 gene (H147R; 150325.0011); all obligate carriers were heterozygous, and normal sibs were either heterozygous or wildtype. Screening of 91 non-Mennonite control subjects did not identify the mutation, whereas screening of 96 Old Order Mennonite control samples revealed 2 heterozygotes, yielding a carrier frequency of 2.1%.

Genotype/Phenotype Correlations

Hasselbacher et al. (2006) stated that homozygosity or compound heterozygosity for LAMB2 mutations conferring complete loss of function (e.g., truncating mutations) appear to be associated consistently with the typical features of Pierson syndrome, including neonatal renal failure, severe ocular abnormalities, and neurologic impairment in long-term survivors, whereas patients with nontruncating (missense) LAMB2 mutations may display variable phenotypes ranging from a milder variant of Pierson syndrome to isolated congenital nephrotic syndrome.