Laura Orsi

FMR1 gene premutation is a frequent genetic cause of late-onset sporadic cerebellar ataxia

In an Italian population of 275 unrelated men affected by adult-onset sporadic progressive cerebellar ataxia, the authors found six patients carrying an FMR1 gene premutation. Age at onset (range, 53 to 69 years) and clinical-neuropathologic findings were consistent with the fragile-X tremor ataxia syndrome (FXTAS), although tremor was not as common as previously described. FXTAS accounted for 4.2% of the cases diagnosed at >50 years, suggesting that it is a frequent genetic cause of late-onset sporadic ataxia.

Modulation of the age at onset in spinocerebellar ataxia by CAG tracts in various genes

Polyglutamine-coding (CAG)n repeat expansions in seven different genes cause spinocerebellar ataxias. Although the size of the expansion is negatively correlated with age at onset, it accounts for only 50-70% of its variability. To find other factors involved in this variability, we performed a regression analysis in 1255 affected individuals with identified expansions (spinocerebellar ataxia types 1, 2, 3, 6 and 7), recruited through the European Consortium on Spinocerebellar Ataxias, to determine whether age at onset is influenced by the size of the normal allele in eight causal (CAG)n-containing genes (ATXN1-3, 6-7, 17, ATN1 and HTT). We confirmed the negative effect of the expanded allele and detected threshold effects reflected by a quadratic association between age at onset and CAG size in spinocerebellar ataxia types 1, 3 and 6. We also evidenced an interaction between the expanded and normal alleles in trans in individuals with spinocerebellar ataxia types 1, 6 and 7. Except for individuals with spinocerebellar ataxia type 1, age at onset was also influenced by other (CAG)n-containing genes: ATXN7 in spinocerebellar ataxia type 2; ATXN2, ATN1 and HTT in spinocerebellar ataxia type 3; ATXN1 and ATXN3 in spinocerebellar ataxia type 6; and ATXN3 and TBP in spinocerebellar ataxia type 7. This suggests that there are biological relationships among these genes. The results were partially replicated in four independent populations representing 460 Caucasians and 216 Asian samples; the differences are possibly explained by ethnic or geographical differences. As the variability in age at onset is not completely explained by the effects of the causative and modifier sister genes, other genetic or environmental factors must also play a role in these diseases.

The effect of gender on planning: An fMRI study using the Tower of London task.

Since the introduction of brain mapping, evidences of functional gender differences have been corroborating previous behavioral and neuropsychological results showing a sex-specific brain organization. We investigated gender differences in brain activation during the performance of the Tower of London (TOL) task which is a standardized test to assess executive functions. Eighteen healthy subjects (9 females and 9 males) underwent fMRI scanning while solving a series of TOL problems with different levels of difficulty. Data were analyzed by modeling both genders and difficulty task load. Task-elicited brain activations comprised a bilateral fronto-parietal network, common to both genders; within this network, females activated more than males in dorsolateral prefrontal cortex (DLPFC) and right parietal cortex, whereas males showed higher activity in precuneus. A prominent parietal activity was found at low level of difficulty while, with heavier task demand, several frontal regions and subcortical structures were recruited. Our results suggest peculiar gender strategies, with males relying more on visuospatial abilities and females on executive processing.

Cerebellar syndrome in adult celiac disease with vitamin E deficiency

ABSTRACT We studied a woman with adult onset celiac disease complicated by a cerebellar syndrome that progressed despite the resolution of the malabsorption symptoms with a gluten free diet. The patient presented vitamin E deficiency and the cerebellar symptoms improved with vitamin E therapy. This case supports the possible role of this deficiency in the development of the neurological complications of celiac disease.

The Recognition of Facial Emotions in Spinocerebellar Ataxia Patients

Patients with cerebellar lesions present some affective and cognitive disorders, defining a peculiar pattern of cognitive impairment, so-called cerebellar cognitive affective syndrome. This pattern has been confirmed in many genotypes of spinocerebellar ataxias (SCA), a group of genetically defined pathologies characterized by the degeneration of the cerebellum and its connections. Recently, in SCA patients, some authors focused the interest on social cognition evidencing an impairment of theory of mind and basic emotion recognition by verbal material. The recognition of emotions in faces is an essential component of social cognition; therefore, we assessed this ability in SCA patients, expanding the study from the basic verbal emotions to the basic and social visual emotion recognition. We assessed facial emotion recognition using two basic and social emotion tasks in a group of SCA patients together with a complete clinical and neuropsychological evaluation. We compared results with the performance of a control group. We demonstrated a significant difference between patients and controls both in basic and social emotion recognition, although we found a specific impairment only for social emotions. The deficit was not correlated to clinical and demographic features. The cognitive and psychological profile did not explain the impairment in emotion recognition. This result supports the hypothesis that the impairment in social emotion recognition could be specifically related to a defect in the corticocerebellar network.

ELOVL5 Mutations Cause Spinocerebellar Ataxia 38

Spinocerebellar ataxias (SCAs) are a heterogeneous group of autosomal-dominant neurodegenerative disorders involving the cerebellum and 23 different genes. We mapped SCA38 to a 56 Mb region on chromosome 6p in a SCA-affected Italian family by whole-genome linkage analysis. Targeted resequencing identified a single missense mutation (c.689G>T [p.Gly230Val]) in ELOVL5. Mutation screening of 456 independent SCA-affected individuals identified the same mutation in two further unrelated Italian families. Haplotyping showed that at least two of the three families shared a common ancestor. One further missense variant (c.214C>G [p.Leu72Val]) was found in a French family. Both missense changes affect conserved amino acids, are predicted to be damaging by multiple bioinformatics tools, and were not identified in ethnically matched controls or within variant databases. ELOVL5 encodes an elongase involved in the synthesis of polyunsaturated fatty acids of the ω3 and ω6 series. Arachidonic acid and docosahexaenoic acid, two final products of the enzyme, were reduced in the serum of affected individuals. Immunohistochemistry on control mice and human brain demonstrated high levels in Purkinje cells. In transfection experiments, subcellular localization of altered ELOVL5 showed a perinuclear distribution with a signal increase in the Golgi compartment, whereas the wild-type showed a widespread signal in the endoplasmic reticulum. SCA38 and SCA34 are examples of SCAs due to mutations in elongase-encoding genes, emphasizing the importance of fatty-acid metabolism in neurological diseases.

Two Italian Families with ITPR1 Gene Deletion Presenting a Broader Phenotype of SCA15

Spinocerebellar ataxia type15 (SCA15) is a pure ataxia characterized by very slow progression. Only seven families have been identified worldwide, in which partial deletions and a missense mutation of the inositol triphosphate receptor type I gene (ITPR1) have been reported. We examined a four-generation Italian family segregating an autosomal dominant cerebellar ataxia, in which linkage analysis was positive for the SCA15 locus. We performed a genomic real-time polymerase chain reaction to search for ITPR1 gene deletions in this family and in 60 SCA index cases negative for mutations in the SCA1–3, 6–8, 10, 12, and dentatorubral-pallidoluysian atrophy genes. The deleted segments were characterized using a custom array comparative genomic hybridization analysis. We have identified two families with an ITPR1 gene deletion: in one, the deletion involved ITPR1 only, while in the other both sulfatase-modifying factor 1 and ITPR1. Clinical data of ten patients and brain MRI (available for six) showed that the phenotype substantially overlapped known SCA15 cases, but we also noted buccolingual dyskinesias, facial myokymias, and pyramidal signs never reported in SCA15. ITPR1 expression analysis of two deleted cases showed a half dose. Our results further support ITPR1 gene as causative of SCA15. The families reported show that SCA15 is present in Italy and has a greater variability in the age at onset and clinical features than previously reported. We propose that the search for ITPR1 deletions is mandatory in the clinical hypothesis of SCA15 and that ITPR1-reduced expression in blood may be a useful marker to identify SCA15 patients harboring genomic deletions and possibly point mutations causing reduction of mRNA level.

Linking coordinative and executive dysfunctions to atrophy in spinocerebellar ataxia 2 patients

Spinocerebellar ataxias type 2 (SCA2) is a rare genetic disorder characterised by the degeneration of the Cerebellum, its connections and many Brainstem areas. A voxel-based morphometry (VBM) analysis was performed on 12 genetically determined SCA2 patients and 31 controls, normalising the brains with two different atlases: one was created in-house with DARTEL (a diffeomorphic registration method) and the other was SUIT (an exclusive Cerebellum atlas). We administered two versions of a popular executive/planning functions test: the Tower of London, in the traditional and in a computerised version that does not require the use of hands, to correlate the regional atrophy with the tests’ performances and to discover the different associations of Cerebellum’s areas to cognitive dysfunctions. SCA2 showed a diffuse infratentorial atrophy with the whole Cerebellum and Brainstem affected, the overall patterns were highly overlapping between atlases with some minor differences. The DARTEL VBM also allowed detecting two sovratentorial clusters of atrophy, one in the left Inferior Parietal Lobule and the other in the Corticospinal Tracts. Additional analyses revealed a partial involvement of many White Matter tracts and of the Thalamus in the pathology. The classical Tower of London version correlated maximally with the right Lobule IV–V, when the computerised version correlated with the right Crus 1. The correlations of different versions of the test suggested a dissociation between the dysfunctions in SCA2: the Posterior Cerebellum was linked to the executive dysfunction while the Anterior Cerebellum was linked to the coordinative dysfunction.

Glycosaminoglycan changes in human gliomas. A biochemical study.

SummaryGlycosaminoglycans (GAGs) were isolated, separated by electrophoresis and quantified in 36 neurosurgical specimens of human gliomas and in 8 samples of normal white and gray matter. Gliomas of various degrees of malignancy exhibited different GAG patterns. Total GAG concentration was three times higher in low grade gliomas than in normal white matter. The mean percentage of single GAG classes was usually similar in both tissues, although in certain tumor samples a higher percentage of hyaluronate was found. GAG patterns in anaplastic astrocytomas, however, more closely resembled normal white and gray matter, both quantitatively and qualitatively. Glioblastomas, on the other hand, showed high GAG concentrations, in particular of heparan sulfate and dermatan sulfate. This finding could be secondary to the abundant vessels and mesodermal material associated with this oncotype. The hyaluronate/sulfated GAGs ratio was lower in oligodendrogliomas than in low grade astrocytomas. This biochemical feature may be correlated with the alcianophilia found in the honey-comb degeneration of oligodendrogliomas. The significance of these findings as they relate to tumor histology and biology have been discussed.

Neuropsychological picture of 33 spinocerebellar ataxia cases

We administered a large battery of neuropsychological tests to an heterogeneous cohort of genetically defined spinocerebellar ataxia (SCA) patients in order to assess their cognitive profile and to compare cognitive impairment among different SCA genotypes, particularly between SCA with the classical pattern of olivo-ponto-cerebellar atrophy (SCA1 and SCA2) and those with a relatively “pure” olivo-cerebellar atrophy (SCA6 and SCA8). Our data revealed a neuropsychological picture characterized by fronto-parietal involvement with mnestic, linguistic, visuospatial, attentional, executive, and mood changes, in agreement with the cerebellar cognitive affective syndrome definition. We found a homogeneous neuropsychological profile among SCA subgroups with a prominent role of frontal dysfunction—particularly, attention, memory, and executive functions. We analyzed the possible interactions between neuropsychological pattern and clinical, demographical, and genetic variables. We found the presence of a cognitive impairment at the early stages of the disease, without visuospatial alterations, which appeared later. Age and education represented the most important demographic factors to predict the neuropsychological performance in SCA and in controls, but their effect in patients had definitely more impact. In our sample education could represent a protective factor and a marker of an enriched environment or a better developmental cognitive differentiation. We demonstrated that in our patients there was a distinct subgroup of high functional subjects and that triplet repeats modulated the effect of aging on cognition and progression of motor disability.