With the exception of hereditary sensory radicular neuropathy (HSAN I), which presents in the second decade and is transmitted as a dominant disorder, the other HSAN are present at birth and are transmitted as autosomal recessive disorders (Table ). HSAN I has been associated with a mutation in the SPTLC1
gene which encodes for serine palmitoyltransferase – the rate limiting enzyme for the synthesis of the sphingolipids, ceramide and sphingomyelin. [5
]. Other HSAN with specific genetic mutations are HSAN III (FD) and HSAN IV (CIPA), which are transmitted as autosomal recessive disorders.
FD is almost exclusive to individuals of Eastern European Jewish extraction [7
]. In this population the carrier rate is estimated as approximately 1 in 30 with a disease incidence of 1 per 3600 live births [10
]. In 1993 the FD gene was localized to the long arm of chromosome 9 (9q31) [11
]. In 2001 the gene was cloned. A single point mutation was identified on the IKBKAP
gene and greater than 99% of affected individuals are homozygous for this common mutation that occurs within intron 20. The result is tissue-specific mis-splicing which results in decreased amounts of normal transcript, especially in neuronal tissue. Therefore, there is a predicted lack of expression of the normal protein product, IKAP [7
IKAP is a subunit of the highly conserved complex Elongator, which is involved in transcriptional elongation. Recently, RNA interference studies have shown that depletion of IKAP, and thus Elongator, results in reduced transcriptional elongation of several target genes via histone H3 hypoacetylation. A subset of these target genes are required for cell motility, and FD patient cells were shown to be defective in cell migration assays, suggesting that defective cellular motility may underlie the developmental neuropathology of FD. Furthermore, studies in yeast suggest that the Elongator complex is involved in exocytosis and tRNA modification and studies in mammalian cells implicate IKAP as a scaffold protein involved in cytoplasmic JNK activation in response to extracellular stress. IKAP's role in these processes, and how they relate to the FD phenotype, is not yet understood.
Two other missense mutations that cause FD have been reported. One mutation, in exon 19, was noted in four unrelated Jewish patients heterozygous for the major splice mutation [7
]; the second mutation, in exon 26, was reported in a single patient who was also heterozygous for the major splice mutation but inherited the new mutation from a non-Jewish parent [9
]. FD is the only HSAN for which genetic testing is commercially available.
HSAN IV is caused by mutations in the NTRK1
(TRKA) gene that is located on chromosome 1 (1q21-q22). This gene encodes for neurotrophic tyrosine kinase receptor type 1 that is autophosphorylated in response to NGF (nerve growth factor) [12
]. As a result of loss of function mutations, signal transduction at the NGF receptor is impeded and NGF dependent neurons, the small sensory and sympathetic neurons, fail to survive. There does not seem to be a particular ethnic distribution for this recessive disorder but onehalf of reported cases have occurred in consanguineous marriages [1
]. As many mutations have been described, commercial molecular genetic diagnostic testing is not yet feasible.
Specific genetic mutations have not been identified for the other HSAN disorders, although there is some evidence that a mutation in the NTRK1
gene also may be responsible for HSAN V [14
The other HSANs including HSAN II, are presumed to be autosomal recessive disorders or de novo dominant mutations. In each of the disorders, other siblings but not parents have been affected. None of the disorders has a sex preference or particular ethnic distribution.