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.

Neurotransmitter abnormalities and response to supplementation in SPG11

“…The finding of retinal abnormalities is consistent with Kjellin syndrome, and was previously felt to distinguish the clinically similar SPG15 (caused by mutations in KIAA0321 encoding spastizin) from SPG11, but recently described in SPG11 patients, 17, 18 . Kejellin syndrome is additionally characterized by cerebellar signs, and amyotrophy, 2 also seen clinically in some of our patients.…”

Microstructural Integrity of Cerebral Fiber Tracts in Hereditary Spastic Paraparesis withSPG11Mutation

“…28,29 This functional-anatomic dissociation can be partially explained by cerebral hypometabolism at bilateral sensorimotor cortices, thalami, and probably medial frontal cortices in later stages of the disease. 25,30,31 Our results revealed that association fibers were affected diffusely with severity comparable to that in colossal fibers. Severely impaired microstructural integrity in association fibers might be another theory explaining diffuse cognitive deficits with respect to the current theory of restricted cerebral hypometabolism.…”

Alu elements mediate large SPG11 gene rearrangements: further spatacsin mutations

“…To date, more than 100 different mutations [1][2][3][4][5][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] have been reported worldwide, in a total of 128 families with complex autosomal recessive spastic paraplegia.…”