title: SPG11 mutations cause Kjellin syndrome, a hereditary spastic paraplegia with thin corpus callosum and central retinal degeneration.
abstract: Autosomal recessive hereditary spastic paraplegia (ARHSP) with thin corpus callosum (TCC) is genetically heterogenous and approximately 35% of patients carry mutations in either of the SPG11 or SPG15 genes. Disease onset is during the first three decades of life with spastic paraplegia and mental impairment. Peripheral neuropathy and amyotrophy may occur. Kjellin syndrome is characterized by central retinal degeneration in addition to ARHSP-TCC and the disease is associated with mutations in the SPG15 gene. We identified five patients in four unrelated kindreds with spastic paraplegia and mental impairment. Magnetic resonance imaging revealed TCC, atrophy elsewhere in the brain and increased T2 signal intensity in the periventricular white matter. Probands from the four kindreds were screened for mutations in the SPG11 gene. All patients were found homozygous or compound heterozygous for truncating SPG11 mutations of which four are reported for the first time. Ophthalmological investigations revealed that the four index cases have central retinal degeneration consistent with Kjellin syndrome. PET examinations with N-[11C-methyl]-L-deuterodeprenyl (DED) and fluor-18 2-fluorodeoxyglucose (FDG) were performed in two patients with Kjellin syndrome. We observed a reduced glucose uptake in the thalami, anterior cingulum, and sensorimotor cortex indicating neuronal loss, and an increased DED binding in the thalami and pons which suggests astrogliosis. From our results we extend the SPG11 associated phenotype to comprise also Kjellin syndrome, previously found to be associated with mutations in the SPG15 gene. We anticipate that degeneration of the central retina is a common and previously unrecognized feature in SPG11 related disease.
authors.affiliation: Department of Genetics and Pathology, The Rudbeck Laboratory, Uppsala University and University Hospital, Uppsala, Sweden.
authors.forename: Hanna
authors.initials: H
authors.lastname: Orlén
authors.forename: Atle
authors.initials: A
authors.lastname: Melberg
authors.forename: Raili
authors.initials: R
authors.lastname: Raininko
authors.forename: Eva
authors.initials: E
authors.lastname: Kumlien
authors.forename: Miriam
authors.initials: M
authors.lastname: Entesarian
authors.forename: Per
authors.initials: P
authors.lastname: Söderberg
authors.forename: Magnus
authors.initials: M
authors.lastname: Påhlman
authors.forename: Niklas
authors.initials: N
authors.lastname: Darin
authors.forename: Mårten
authors.initials: M
authors.lastname: Kyllerman
authors.forename: Eva
authors.initials: E
authors.lastname: Holmberg
authors.forename: Henry
authors.initials: H
authors.lastname: Engler
authors.forename: Urban
authors.initials: U
authors.lastname: Eriksson
authors.forename: Niklas
authors.initials: N
authors.lastname: Dahl
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D003337:Corpus Callosum / Q000473:pathology*; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009885:Ophthalmology; D010375:Pedigree; D049268:Positron-Emission Tomography; D011506:Proteins / Q000235:genetics*; D012162:Retinal Degeneration / Q000150:complications* / Q000235:genetics; D015419:Spastic Paraplegia, Hereditary / Q000150:complications* / Q000235:genetics*; D013577:Syndrome
chemical_list: D011506:Proteins; C520412:SPG11 protein, human