Steroid Resistant Nephrotic Syndrome with Clumsy Gait Associated With INF2 Mutation
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Steroid Resistant Nephrotic Syndrome with Clumsy Gait Associated With INF2 Mutation
member of the formin family of actin-regulatory proteins with an N-terminal Diaphenous Inhibitory Domain (DID) formin homology 1 and 2 domains and a C-terminal WASP Homology 2 domain, which has the hallmarks of the diaphanous autoregulatory domain (DAD) similar to other formins [4]. The CNV although currently classified as VUS in our child is particularly important as unlike all other previously reported mutations which were in the DID region, our case had it in the DAD region. Although interaction between the DID and DAD has been reported to be crucial in regulating INF2 depolymerization [5], clinical cases with mutations in DAD region have not been described earlier. INF2 is strongly expressed in Schwann cell cytoplasm and interacts with myelin and lymphocyte protein (MAL2) and with GTP binding protein CDC42. These are essential for myelination and maintaining myelin structural integrity explaining the pathogenesis of CMTD. Proteinuria probably results from disruption in cytoskeletal dynamics due to defect in actin polymerization depolymerization balance secondary to INF2 mutation [2]. INF2 mutation has also been reported to result in isolated autosomal dominant FSGS without CMTD and it is postulated that the relative positions of the deletions results in different clinical manifestation [2,3].
There has been significant improvement in our understanding of steroid resistant nephrotic syndrome (SRNS) with identification of multiple newer genes that are involved in regulating podocyte protein and maintaining podocyte architecture. Mutations in these genes have been linked to various forms of SRNS [1]. We hereby describe a child with SRNS whose associated neurological problem gave us a clue to the underlying etiology and genetic analysis provided the most likely link between his SRNS and neurological manifestations. A 3-year-old boy born out of a non-consanguineous marriage presented with generalized swelling of body and decreased urine output. Blood and urine investigations confirmed the diagnosis of nephrotic syndrome. Remission was not achieved despite six weeks of full dose (2 mg/kg bodyweight) prednisolone and child was classified as SRNS. Renal biopsy revealed focal segmental glomerulosclerosis (FSGS) histopathology and tacrolimus therapy was added. Proteinuria failed to respond to tacrolimus as well as to subsequent addition of rituximab. During this period the child’s gait was noticed to be clumsy. Neurological examination was unremarkable apart from mild bilaterally diminished ankle jerks. Nerve conduction velocity study was consistent with bilateral motor axonal neuropathy in lower limbs suggestive of Charcot Marie Tooth disease (CMTD). Next Generation Sequencing (NGS) and analysis of the exome data for any copy number variation revealed a heterozygous deletion (chr14:105181575-105196577) involving the INF2 gene, which was extending to the proximal part of an adjoining gene ADSSL1. ADSSL1 gene is implicated for distal myo
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