Abstract
To describe the clinical and neurophysiologic phenotype of a family with hereditary sensory and autonomic neuropathy type 1 (HSANI) due to a novel mutation in SPTLC2 and to characterize the biochemical properties of this mutation. We screened 107 patients with HSAN who were negative for other genetic causes for mutations in SPTLC2. The biochemical properties of a new mutation were characterized in cell-free and cell-based activity assays. A novel mutation (A182P) was found in 2 subjects of a single family. The phenotype of the 2 subjects was an ulcero-mutilating sensory-predominant neuropathy as described previously for patients with HSANI, but with prominent motor involvement and earlier disease onset in the first decade of life. Affected patients had elevated levels of plasma 1-deoxysphingolipids (1-deoxySLs). Biochemically, the A182P mutation was associated with a reduced canonical activity but an increased alternative activity with alanine, which results in largely increased 1-deoxySL levels, supporting their pathogenicity. This study confirms that mutations in SPTLC2 are associated with increased deoxySL formation causing HSANI.
Highlights
This study confirms that mutations in SPTLC2 are associated with increased deoxySL formation causing hereditary sensory and autonomic neuropathy type 1 (HSANI)
One hundred seven patients with HSAN were selected from our inherited neuropathy database, including patients seen in the National Hospital for Neurology and Neurosurgery peripheral neuropathy clinics as well as patients whose DNA was referred from other hospitals for diagnostic and research testing
Sequencing of SPTLC2 in 107 index patients with HSANI revealed a novel mutation in one family. c.544G.C, A182P, was found in the index case; this mutation was not present in 358 control chromosomes
Summary
A novel mutation (A182P) was found in 2 subjects of a single family. The phenotype of the 2 subjects was an ulcero-mutilating sensory-predominant neuropathy as described previously for patients with HSANI, but with prominent motor involvement and earlier disease onset in the first decade of life. Affected patients had elevated levels of plasma 1-deoxysphingolipids (1-deoxySLs). The A182P mutation was associated with a reduced canonical activity but an increased alternative activity with alanine, which results in largely increased 1-deoxySL levels, supporting their pathogenicity
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