Distal hereditary motor neuropathy (dHMN) or distal spinal muscular atrophy 
(OMIM #182960) is a heterogeneous group of disorders characterized by an almost 
exclusive degeneration of motor nerve fibers, predominantly in the distal part 
of the limbs. Silver syndrome (OMIM #270685) is a rare form of hereditary 
spastic paraparesis mapped to chromosome 11q12-q14 (SPG17) in which spasticity 
of the legs is accompanied by amyotrophy of the hands and occasionally also the 
lower limbs. Silver syndrome and most forms of dHMN are autosomal dominantly 
inherited with incomplete penetrance and a broad variability in clinical 
expression. A genome-wide scan in an Austrian family with dHMN-V (ref. 4) showed 
linkage to the locus SPG17, which was confirmed in 16 additional families with a 
phenotype characteristic of dHMN or Silver syndrome. After refining the critical 
region to 1 Mb, we sequenced the gene Berardinelli-Seip congenital lipodystrophy 
(BSCL2) and identified two heterozygous missense mutations resulting in the 
amino acid substitutions N88S and S90L. Null mutations in BSCL2, which encodes 
the protein seipin, were previously shown to be associated with autosomal 
recessive Berardinelli-Seip congenital lipodystrophy (OMIM #269700). We show 
that seipin is an integral membrane protein of the endoplasmic reticulum (ER). 
The amino acid substitutions N88S and S90L affect glycosylation of seipin and 
result in aggregate formation leading to neurodegeneration.