Posted - December 2014 in Research Highlights
Lack of family history not definitive
A family of 3 children all have complicated HSP and their parents are unaffected. Normally this would rule out autosomal dominant inheritance such as with SPG4 HSP. However in this case, that was exactly what was cause, with a new mutation identified in the mother who has somatic mosaicism*. The lesson for clinicians is to consider such a possibility when presenting circumstances do not apparently support such a diagnosis.
Hereditary spastic paraplegias (HSPs) represent a clinically and genetically heterogeneous group of diseases. Major symptoms comprise progressive bilateral leg stiffness, spasticity at rest and diffuse muscle weakness. Complex forms are characterized by additional symptoms like dementia, cerebellar dysfunction or seizures. Autosomal dominant, autosomal recessive, X-linked recessive and possibly mitochondrial inheritance have been described in familial HSP.
The most frequently mutated gene in familial cases of uncomplicated autosomal dominant HSP is SPAST, however de novo mutations in SPAST are rarely found.
Here, we report on the clinical and genetic findings in a family with three children afflicted by complex HSP and their unaffected parents. Although autosomal dominant inheritance seemed unlikely in this family, genetic testing revealed a novel SPAST mutation, c.1837G>C (p.Asp613His), in a heterozygous state in all affected individuals and somatic mosaicism of this mutation in the unaffected mother. Our study thus expands the knowledge on SPAST-associated HSP and emphasizes that de novo mutations and somatic mosaicism should be taken into consideration in HSP families presenting with a family history not suggestive for an autosomal dominant inheritance pattern.
*Somatic mosaicism occurs when the somatic cells of the body are of more than one genotype. Somatic cells make up all the organs, skin, bones, blood and connective tissue in the body (pretty much all cells except sex cells and stem cells).
SOURCE: J Neurol Sci. 2014 Oct 2. pii: S0022-510X(14)0) 0646-7. doi: 10.1016/j.jns.2014.09.046. [Epub ahead of print] Copyright © 2014 Elsevier B.V. All rights reserved.
A complex form of hereditary spastic paraplegia in three siblings due to somatic mosaicism for a novel SPAST mutation in the mother.
1 Department of Neurology, University Hospital Ulm, Oberer Eselsberg 45, 89081 Ulm, Germany.
2 Institute of Human Genetics, University of Ulm, Albert-Einstein Allee 11, 89081 Ulm, Germany; Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany.
3 genetikum, Laboratory of Cytogenetics and Molecular Genetics, Wegener Str. 15, 89231 Neu-Ulm, Germany.
4 Department of Neurology, University Hospital Ulm, Oberer Eselsberg 45, 89081 Ulm, Germany. Electronic address: [email protected]
5 Institute of Human Genetics, University of Ulm, Albert-Einstein Allee 11, 89081 Ulm, Germany; Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany. Electronic address: [email protected]