Hereditary Spastic Paraplegia

Inherited neurological conditions are one of our main areas of research, in particular the hereditary spastic paraplegias (the ‘HSPs'),  which are a large genetically complex group of conditions associated with stiffness of the legs and walking difficulties. Eighteen different ‘types’ of the condition have now been genetically identified, although many more remain to be determined.

To learn as much as possible about the cause of this condition we study many of the different subtypes of HSP in parallel with each other.  We are studying five HSP subtypes that we have seen within the Amish community (below), as well as a number of other HSP subtypes present in other populations around the world.  We are fortunate that these investigations have been enormously successful and have made a significant contribution to our understanding of the genetic basis of HSP which, in turn, has revealed new subcellular processes that when malfunction appear to cause this condition. For example our studies of Troyer syndrome led to our suggestion that defective transport systems within brain cells may be a mechanism that is common to a range of subtypes of HSP. More recent studies by other groups as well as Windows of Hope are providing additional evidence for this mechanism.

‘Troyer’ syndrome (SPG20)

Troyer syndrome is an early onset and progressive form of hereditary spastic paraplegia (HSP) associated with developmental delay, subtle speech abnormalities and mild shortness of stature. As part of this project we have seen many families with Troyer syndrome, and using samples from these families we were able to map the position of the responsible gene to chromosome 13. Our sequencing studies of the genes in this region led us to discover a mutation in a new gene that causes the condition. The gene encodes a protein which we called ‘spartin’, the function of which was unknown.

Our initial studies of spartin led to the discovery of a region of the molecule (that we called ‘MIT’) that was also present in another protein (spastin) that is mutated to cause another form of HSP, suggesting that there may be some functional overlap between these two molecules. To learn more about the function of spartin, we have grown neuronal cells in the laboratory and studied the location of spartin within these cells. In this way we were able to show that spartin is located in the cell nucleus, which houses the chromosomes, as well as in a few other regions of the cell suggesting that it has a function in these structures.

Our current studies are examining the effect that the Troyer syndrome spartin mutation has on other genes and proteins in patient cells and we have made some important breakthroughs recently.

‘Mast’ syndrome (SPG21)

Mast syndrome is another form of HSP in which the leg stiffness is associated with dementia and other central nervous system abnormalities. As with Troyer syndrome the Windows of Hope laboratories studied samples from a large number of families which enabled us to show that the gene that causes this condition lies on chromosome 15. Our subsequent analysis of genes in this region identified the responsible mutation in the ACP33 gene. The function of the protein encoded by this gene, which we called ‘maspardin’, was not known.

Our studies of maspardin revealed that it belongs to the 'hydrolase' family of molecules. These molecules are all characterised by the presence of three essential structural features which are required for their normal function as enzymes. As maspardin possesses only two of these features it does not belong to this family of molecules and so is not likely to be an enzyme, but instead has another function inside our cells. As with spartin our most recent studies are investigating the effect of the maspardin mutation on other genes and proteins in patient cells.

Although Troyer syndrome and Mast syndrome are both inherited forms of HSP,  it is important to stress that they are unrelated to each other genetically and families with Troyer syndrome are not at an increased risk of developing the Mast syndrome, or vice versa.

Spastic ataxia

We have identified a single family with many children affected by a condition similar to HSP, but in which the children also have additional problems with coordinating their movement (‘spastic ataxia’). Affected cases also have a speech disorder (dysarthria) and a degenerative eye disease (optic atrophy). Our genetic studies showed that the gene responsible for the condition lies on chromosome 10, and analysis of the genes in this region showed that a mutation in a gene with a role in 'mitochondrial function' was responsible for the condition. This finding has provided a new insight into the molecular causes of spastic ataxia.

Other HSP subtypes

As well as the above HSP subtypes which are present amongst the Amish community, we have also found the genes responsible for other forms of the condition:

• SPG5 (CYP7B1)

We previously undertook linkage studies in a large British HSP family which revealed 'linkage' of the gene to chromosome 8. Sequence analysis of the genes in the region eventually identified mutations in the cytochrome P450-7B1 (CYP7B1) gene. When we examined this gene in other HSP families with a similar clinical presentation we found a number of other mutations, confirming that this was the responsible gene. The CYP7B1 gene encodes an enzyme that is  known to be involed in 'neurosteroid' metabolism and these findings provided the first direct evidence of alteration of these molecules in HSP. We are now investigating this potential mechanism in Troyer syndrome and Mast syndrome, as well as in other forms of the disease.

• SPG17 (BSCL2)

Our studies of another large British family with an autosomal dominant form of HSP led to the positioning  of another new gene for this condition (SPG17). Our sequencing studies subsequently identified mutations in the BSCL2 gene associated with this disease. More detailed clinical evaluation of a large number of patients revealed that mutation of this gene is in fact associated with a number of other neurological conditions as well as HSP.

• SPG35 (FA2H)

We recently studied a large family from Oman with children affected by HSP associated with intellectual disability and seizures. Our DNA analyses showed that the gene responsible for the condition in this familiy is on chromosome 16, and our analysis of the genes in this region revealed a mutations in fatty acid 2-hydroxylase (FA2H). Our analysis of a second British family with the same clinical presentation revealed another mutation in this gene. FA2H is important in for the formation of myelin, which an electrically-insulation material around nerves.

To see all of the publications from our laboratory on HSP and related motor neuron conditions, click here.