Proton magnetic resonance spectroscopy and cognition in patients with spastin mutations.

The hereditary spastic paraplegias (HSP) are heterogeneous neurodegenerative disorders characterized by progressive spasticity and weakness in the lower limbs. Axonal loss in the long corticospinal tracts has been shown. Supraspinal symptoms and findings in the most common dominant HSP type, SPG4, support the theory that the disease also causes cerebral neuronal damage in specific parts of the brain. To investigate whether SPG4-HSP is associated with neuronal biochemical changes detectable on MR spectroscopy (MRS), single-voxel proton MRS of the brain was performed in eight subjects from four families with genetically confirmed SPG4-type HSP and eight healthy age-matched controls. Volumes of interest (VOI) were located in the frontal white matter and motor cortex. N-acetyl-aspartate-to-creatine ratio (NAA/Cr), N-acetyl-aspartate-to-choline (NAA/Cho), cholin to creatin (Cho/Cr) and myo-inositol-to-creatine (Ins/Cr) ratios were calculated for both locations. Neuropsychological tests were performed to support the neuroradiological findings. The Cho/Cr ratio in motor cortex (MC) of SPG4-HSP subjects was significantly lower than in controls. This reduction of the Cho/Cr ratio in SPG4 subjects was significantly associated with age-related verbal learning- and memory (CVLT) reduction. Our findings support involvement of motor cortex in SPG4-HSP. Proton MRS could be a useful tool for detecting metabolite abnormalities in areas of brain that appear normal on MRI. Cho/Cr ratio may be a marker of neurodegenerative process in SPG4-HSP.

SPG11--the most common type of recessive spastic paraplegia in Norway?

BACKGROUND: Hereditary spastic paraplegias (HSP) are neurodegenerative diseases mainly characterized by lower limb spasticity with additional neurological symptoms and signs in complicated forms. Among the many autosomal recessive forms, SPG11 appears to be one of the most frequent. OBJECTIVE: Our objective was to select potential SPG11 patients based on phenotypes in our material, identify eventual disease-causing variants with the collaboration of laboratories abroad, estimate the frequency and spectrum of SPG11-mutations and describe their associated phenotypes. MATERIAL AND METHODS: Two isolated cases and two affected members of one family with cognitive impairment and confirmed thin corpus callosum on magnetic resonance imaging were selected from our database for inclusion into a multicenter study. Results - Mutations were found in the two isolated cases but not in the proband of the family. CONCLUSION: We present the first SPG11-HSP in the Norwegian population. SPG11 should be suspected in patients with isolated or recessive HSP, thin corpus callosum and mental retardation.

Seven novel mutations and four exon deletions in a collection of Norwegian patients with SPG4 hereditary spastic paraplegia.

To establish the phenotypic variation and frequency of SPAST mutations or deletions in Norwegian patients with hereditary spastic paraplegia (HSP), we examined 59 unrelated patients with HSP and screened for DNA point mutations and microdeletions in SPG4. Forty-one had a familial history, 35 had a clear dominant inheritance, six had other affected sibs and 18 were sporadic. We found 12 mutations in SPG4, seven of them novel, and four different heterozygous exon deletions, two of them novel. Mutations were found in 16 families showing autosomal dominant (AD) inheritance, and in one sporadic case. In two non-SPG4 families the S44L polymorphism/modifier was found in both affected and unaffected individuals. This is the first study of Norwegian patients with HSP since the 1970s, and the first report on SPG4 in Norway. Our results show that SPG4 mutations and deletions are a significant cause of HSP in our population and warrant SPG4 screening in AD families and selected sporadic cases.