EP.111Identification of novel biallelic mutations in SPTBN4 in a child with NEDHND featuring a spinal muscular atrophy phenotype

Abstract

Neurodevelopmental disorder with hypotonia, neuropathy, and deafness (NEDHND, OMIM: #617519) is an autosomal recessive disorder caused by homozygous or compound heterozygous mutations in the SPTBN4. Mutations in SPTBN4 disrupt cytoskeletal machinery that control proper localization of ion channels and function of axonal domains, generating severe neurological dysfunction. Recently, recessive mutations in human SPTBN4 have been described in 7 patients manifesting with severe hypotonia, developmental delay and mixed neuropathic and myopathic features, with central deafness and severe epilepsy in some cases. Here we report a six-year-old Chilean patient with a phenotype characterized by severe early-onset hypotonia, areflexia, proximal and distal weakness with an axonal motor neuropathy and evidence of acute denervation by EMG. At first evaluation at ten months of age, she presented as a spinal muscular atrophy phenotype and negative result for SMN1 deletion. Subsequently, a muscle biopsy showed neurogenic type grouping. The clinical evolution was characterized by global developmental delay, absent speech, deafness, progressive swallowing and respiratory difficulties. A tracheostomy and gastrostomy were indicated. Later in her evolution, appearance of severe generalized EEG epileptic abnormalities and absence of manifest clinical seizures were noted. A specific motor neuron diseases panel failed to find any mutation, and trio whole exome sequencing identified an apparent homozygous single base pair duplication in the SPTBN4 in the proband; this variant was also detected as heterozygous in the patient's father but was not detected in the patient's mother. However, a deletion involving multiple exons of the SPTBN4, which overlaps this variant, was identified in the proband and in the patient's mother, indicating that the two variants are in trans in the proband. This is the first multi-exon deletion that has been reported in the SPTBN4 to date. Additionally, this case highlights the early predominant motor axonal involvement in this patient manifesting as severe hypotonia and areflexia similar to others non-5q SMA patients, and the consecutive appearance of another feature in the clinical evolution as the auditory neuropathy and epileptic activity in EEG as key elements to suspect SPTBN4 mutation.