G.A. Nicholson
In the 1990's, we showed that the common form of dominantly inherited hereditary sensory neuropathy was linked to chromosome 9 in a large Australian family originating from southern England (9). We later found mutations in the ubiquitously expressed housekeeping enzyme, serum palmitoyl transferase (10) which is the rate limiting enzyme in the sphingolipid pathway. Mutations were found in only subunit 1 (LCB1) of the dimeric membrane protein, which is located in the endoplasmic reticulum. We found a common haplotype (unique set of DNA markers situated around the gene) in the Australian family and in 3 families in southern England, indicating that the families had a common founder who probably lived prior to 1700 (11). As the family reported by Hicks had relatives in Exeter, we suspect this is the mutation in the family studied by both Hicks and Denny-Brown. There is one report of loss of enzyme activity occurred ranging from zero to 70 percent (12). Complete loss of enzyme activity occurs when the same mutation is expressed in a homozygous fashion in yeast showing that this enzyme is necessary for cell viability. However our results in peripheral blood lymphocytes showed a loss of enzyme activity ranging from 0-30% (13). There are no instances of dominantly inherited disease caused by mild or moderate loss of any enzyme's activity, as in this case. Since recessive diseases can be caused by loss of enzyme activity but only when particular enzyme activity is near zero. Mild loss of function is therefore unlikely to be the cause of the pathology in hereditary sensory neuropathy. Recently an novel mutation was found in an exon not likely to be related to the enzyme active site (14). Dominantly inherited disorders are usually produced by a gain of "toxic function" ie the mutant product has a toxic effect. This is a common feature of many hereditary neuropathies. Dominantly inherited hereditary sensory neuropathy is a true distal (or dying back) axonal degeneration. The disorder begins with loss of sensation first in the feet and later in the hands with secondary loss of power in the lower limbs and later the hands, first producing weakness of dorsiflexion and later footdrop. Later, there is weakness in the intrinsic hand muscles. Unlike most other dominantly inherited peripheral neuropathies, HSN does progress to involve the proximal limb girdles
106