Our identification of a novel, disease-associated SPG20
mutation in an Omani kindred indicates for the first time that Troyer syndrome is not restricted to the Amish, as previously proposed.2
Complicated autosomal recessive HSPs are heterogeneous disorders often lacking clear clinical and molecular diagnostic guidelines. Of the 17 distinct loci for complicated HSP identified to date, more than half have been described in single families or isolated populations.1, 2
In the past 4 decades, several HSP syndromes with Troyer-like features have been reported, but none matched the clinical presentation in the Amish cases.5
Some of these disorders were later mapped to different loci such as SPG26
Even within the isolated region where these Omani families reside, we had described a similar extended pedigree with dysarthria, mental retardation, cerebral palsy, and microcephaly.24
Linkage analysis ruled out the SPG20
locus in the second kindred, confirming that the 2 disorders are separate clinical and genetic entities (A.R., R.S.H., C.A.W., unpublished data). Four individuals in this extended family (N = 45 individuals) also were heterozygous carriers for the SPG20
mutation, highlighting its presence in this isolated population. Thus, this novel mutation in SPG20
is geographically and genetically distinct from that in the Amish population; nevertheless, both mutations result in the phenotypic spectrum associated with Troyer syndrome.
Although a clear Troyer syndrome diagnosis is difficult to reach in young subjects due to the variability and mildness of their symptoms, direct comparison of clinical features showed that the Omani cohort closely resembled the age-matched Amish Troyer syndrome group (Amish I), suggesting that SPG20
null mutations cause a well-defined phenotype. As in the Amish, we observed short stature, skeletal abnormalities in the extremities, developmental delay, and dysarthria of possible cerebellar origin from an early age. Therefore, a diagnosis of Troyer syndrome must be considered when this constellation of phenotypes is present in young children. Facial dysmorphism and skeletal features are subtle, and in single cases in nonconsanguineous populations this disorder could be initially diagnosed simply as cerebral palsy. Spasticity and distal amyotrophy appeared in the teenage years and worsened slowly over time. In the Amish, brain MRI revealed white matter abnormalities, which were less severe in the youngest patient examined (age 15 years), suggesting a progressive worsening of the condition.5
MRI analysis indicates that the Omani Troyer syndrome individuals of comparable ages also have mild white matter abnormalities, supporting the hypothesis that white matter degeneration accompanies disease progression, although direct neuronal degeneration cannot be ruled out. In addition, we identified mild cerebellar atrophy, which is consistent with the cerebellar signs. Serial MRI scans of the Omani individuals might resolve whether progressive neurological symptoms are correlated with increased white or gray matter degeneration. Despite many similarities to the Amish cohort, a few specific differences were observed in the affected Omani individuals, including the presence of hypertelorism and a pronounced overbite, and the absence of inappropriate emotional responses. As new cases are identified it will be interesting to assess whether these traits have variable penetrance or are population specific.
Functional studies on spartin, the protein encoded by SPG20,
have identified multiple roles in protein ubiquitination25–27
and lipid droplet formation,19, 25, 26
and a possible link to endothelial growth factor receptor signaling.27
Previous expression analyses by Northern blot or qPCR identified widespread SPG20
/spartin localization in the brain and in other tissues10, 19
; however, it was unclear whether regional and cellular dynamism in SPG20
expression could explain the phenotypes observed in the affected individuals. Our study shows that whereas SPG20
expression is modest and virtually ubiquitous in the adult and developing brain, early stages of embryonic development show maximal levels of Spg20
in the limbs, face, and forebrain primordia. This localized expression suggests a parallel role for SPG20
in morphogenesis and differentiation at these phenotypic sites; accordingly, a loss of function mutation may contribute to the phenotypic spectrum of Troyer syndrome.