SPTLC1

At least nine mutations in the SPTLC1 gene have been found to cause hereditary sensory neuropathy type IA. This condition is characterized by nerve abnormalities in the legs and feet (peripheral neuropathy); a reduced ability to feel pain, which can lead to the development of open sores; and muscle weakness that can impair mobility. The SPTLC1 gene mutations change single protein building blocks (amino acids) in the SPTLC1 subunit. One mutation that has been found in multiple affected families worldwide replaces the amino acid cysteine with the amino acid tryptophan at position 133 in the SPTLC1 subunit (written as Cys133Trp or C133W).

SPTLC1 gene mutations reduce the amount of functional SPTLC1 subunit that is produced, which results in an SPT enzyme with altered activity. This altered enzyme makes molecules called deoxysphingoid bases, which it does not normally produce. Because of this new function, the SPT enzyme's production of sphingolipid is reduced. Overall, there does not seem to be a decrease in sphingolipid production because the body is able to compensate for the SPT enzyme's reduced production. When accumulated, deoxysphingoid bases are toxic to neurons. The gradual destruction of nerve cells caused by the buildup of toxic molecules results in loss of sensation and muscle weakness in people with hereditary sensory neuropathy type IA.

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