title: A complex form of hereditary spastic paraplegia in three siblings due to somatic mosaicism for a novel SPAST mutation in the mother.
abstract: 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.
authors.affiliation: Department of Neurology, University Hospital Ulm, Oberer Eselsberg 45, 89081 Ulm, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Aulitzky
authors.affiliation: 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.
authors.forename: Katrin
authors.initials: K
authors.lastname: Friedrich
authors.affiliation: genetikum, Laboratory of Cytogenetics and Molecular Genetics, Wegener Str. 15, 89231 Neu-Ulm, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Gläser
authors.affiliation: Department of Neurology, University Hospital Ulm, Oberer Eselsberg 45, 89081 Ulm, Germany.
authors.forename: Regina
authors.initials: R
authors.lastname: Gastl
authors.affiliation: 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.
authors.forename: Christian
authors.initials: C
authors.lastname: Kubisch
authors.affiliation: Department of Neurology, University Hospital Ulm, Oberer Eselsberg 45, 89081 Ulm, Germany. Electronic address: Albert.Ludolph@rku.de.
authors.forename: Albert C
authors.initials: AC
authors.lastname: Ludolph
authors.affiliation: 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: a.volk@uke.de.
authors.forename: Alexander E
authors.initials: AE
authors.lastname: Volk
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D005260:Female; D005820:Genetic Testing; D006579:Heterozygote; D006801:Humans; D008297:Male; D009030:Mosaicism; D009035:Mothers; D035781:Siblings; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics*; D000074181:Spastin; D055815:Young Adult
chemical_list: D000251:Adenosine Triphosphatases; D000074181:Spastin; C400283:SPAST protein, human
keywords: De novo mutation; Genetic testing; Hereditary spastic paraplegia; SPAST; SPG4; Somatic mosaicism