Genetic studies of hereditary
nephrotic syndrome (NS) have identified more than 50 genes that, if mutated, are responsible for monogenic forms of
steroid-resistant NS (SRNS), either isolated or syndromic. Most of these genes encode
proteins expressed in the podocyte with various functions such as
transcription factors,
mitochondrial proteins, or
enzymes, but mainly structural
proteins of the slit diaphragm (SD) as well as cytoskeletal binding and regulator
proteins. Syndromic NS is sometimes associated with neurological features. Over recent decades, various studies have established links between the physiology of podocytes and neurons, both morphologically (slit diaphragm and synapse) and functionally (signaling platforms). Variants in genes expressed in different compartments of the podocyte and neurons are responsible for phenotypes associating kidney lesions with
proteinuria (mainly Focal and
Segmental Glomerulosclerosis (FSGS) or
Diffuse Mesangial Sclerosis (DMS)) and central and/or peripheral
neurological disorders. The
Galloway-Mowat syndrome (GAMOS, OMIM#251300) associates neurological defects,
microcephaly, and
proteinuria and is caused by variants in genes encoding
proteins of various functions (microtubule cytoskeleton regulation (WDR73), regulation of
protein synthesis via transfer RNAs (KEOPS and WDR4 complexes)).
Pierson syndrome (OMIM#609049) associating congenital
nephrotic syndrome and central neurological and ophthalmological anomalies is secondary to variants in LAMB2, involved in glomerular and ocular basement membranes. Finally, Charcot-Marie-Tooth-FSGS (OMIM#614455) combines peripheral sensory-motor neuropathy and
proteinuria and arises from INF2 variants, resulting in cytoskeletal polymerization defects. This review focuses on genetic syndromes associating nephrotic range
proteinuria and neurological involvement and provides the latest advances in the description of these neuro-renal disorders.