The syndrome caused by mutations in the LAMB2gene is a multisystem disorder with Autosomal recessive (AR) inheritance; and is called Nephrotic syndrome type 5, with or without ocular abnormalities (MIM614199) or Pierson syndrome (MIM609049). Biallelic LAMB2variants or LAMB2-nephropathy account for 1 – 9% of all patients in cohorts with proteinuria or steroid-resistant nephrotic syndrome.
Clinical features include proteinuria or Nephrotic syndrome often with an onset in infancy and resulting in kidney failure requiring a kidney transplant; and sometimes ocular and neuromuscular abnormalities. The kidney biopsy demonstrates diffuse mesangial sclerosis. Ocular features include microcoria, nystagmus, strabismus, myopia, cataracts, retinitis pigmentosa, and optic nerve hypoplasia. Neuromuscular abnormalities include muscular hypotonia, psychomotor disability and blindness. In severe disease the nephrotic syndrome is obvious within months of birth and kidney failure occurs soon after. The baby is typically born with the ocular abnormalities, and with muscular hypotonia. Electron microscopy of the neuromuscular junction may demonstrate small axon terminal , widening of the synaptic clefts and decreased number of synaptic vesicles.
In one series,the median age at onset of the nephropathy was 1 month, 81% of affected babies presented with nephrotic syndrome, and 22% with steroid resistant nephrotic syndrome or proteinuria. Most babies with congenital nephrotic syndrome progress to kidney failure by one year of age. Eighty-eight % of affected babies have ocular manifestations and 52% have neuromuscular features. Kidney survival is worse in babies with neuromuscular features and possibly in babies with ocular anomalies.
However there is also an increasing number of people diagnosed with biallelic LAMB2mutations who have milder later onset disease often confined to kidney features.
This disease is rare. It is usually caused by two mutations in LAMB2which may be homozygous or compound heterozygous. Truncating variants in LAMB2result in a more severe disease with early onset kidney failure and ocular manifestations. Missense changes are associated with a later age at kidney failure. Treatment for the kidney disease aims to minimise the proteinuria with ACE inhibitors and later transplantation.
Because of the autosomal recessive mode of inheritance, this disease is more common where the parents are consanguineous (and there are homozygous copies of the variant) but also occurs where the parents are not related (compound heterozygous copies of two different gene variants). One in four of the babies’ siblings may also be affected but in general the parents and the child’s offspring only have one copy of the mutation and do not develop the disease.
LAMB2