Progranulin genetic polymorphisms influence progression of disability and relapse recovery in multiple sclerosis.

BACKGROUND: Progranulin (GRN) is a multifunctional protein involved in inflammation and repair, and also a neurotrophic factor critical for neuronal survival. Progranulin is strongly expressed in multiple sclerosis (MS) brains by macrophages and microglia. METHODS: In this study we evaluated GRN genetic variability in 400 MS patients, in correlation with clinical variables such as disease severity and relapse recovery. We also evaluated serum progranulin levels in the different groups of GRN variants carriers. RESULTS: We found that incomplete recovery after a relapse is correlated with an increased frequency of the rs9897526 A allele (odds ratio (OR) 4.367, p = 0.005). A more severe disease course (Multiple Sclerosis Severity Score > 5) is correlated with an increased frequency of the rs9897526 A allele (OR 1.886, p = 0.002) and of the rs5848 T allele (OR 1.580, p = 0.019). Carriers of the variants associated with a more severe disease course (rs9897526 A, rs5848 T) have significantly lower levels of circulating progranulin (80.5 ± 9.1 ng/mL vs. 165.7 ng/mL, p = 0.01). CONCLUSION: GRN genetic polymorphisms likely influence disease course and relapse recovery in MS.

Progranulin expression in brain tissue and cerebrospinal fluid levels in multiple sclerosis.

BACKGROUND: Progranulin (PGRN) is a fundamental neurotrophic factor, and is also involved in inflammation and wound repair. PGRN may have pro- or anti-inflammatory properties, depending upon proteolysis of the anti-inflammatory parent PGRN protein and the generation of pro-inflammatory granulin peptides. OBJECTIVES: Our objectives were as follows: (1) to evaluate the presence and distribution of PGRN in multiple sclerosis (MS) brain tissue, correlating it with demyelination and inflammation; (2) to evaluate cerebrospinal fluid (CSF) PGRN concentrations in patients with MS and controls, in relationship to the clinical features of the disease. METHODS: Our study involved the following: (1) neuropathological study of PGRN on post-mortem tissue of 19 MS and six control brains; (2) evaluation of PGRN CSF concentration in 40 MS patients, 15 non-inflammatory controls and five inflammatory controls (viral encephalitis). RESULTS: In active demyelinating lesions, PGRN was expressed on macrophages/microglia. In the normal-appearing white matter (NAWM), expression of PGRN was observed on activated microglia. PGRN was expressed by neurons and microglia in cortical lesions and in normal-appearing cortex. No expression of PGRN was observed in controls, except on neurons. PGRN CSF concentrations were significantly higher in patients with relapsing-remitting MS during relapses and in progressive MS patients, compared with relapsing-remitting MS patients during remissions and with non-inflammatory controls. CONCLUSIONS: PGRN is strongly expressed in MS brains, by macrophages/microglia in active lesions, and by activated microglia in the NAWM; PGRN CSF concentrations in MS are correspondingly increased in conditions of enhanced macrophage/microglia activation, such as during relapses and in progressive MS.

Spinocerebellar ataxia type 12 identified in two Italian families may mimic sporadic ataxia.

SCA12 is an autosomal dominant cerebellar ataxia characterized by onset in the fourth decade of life with action tremor of arms and head, mild ataxia, dysmetria, and hyperreflexia. The disease is caused by an expansion of >or=51 CAGs in the 5' region of the brain- specific phosphatase 2 regulatory subunit B-beta isoform (PPP2R2B) gene. SCA12 is very rare, except for a single ethnic group in India. We screened 159 Italian ataxic patients for SCA12 and identified two families that segregated an expanded allele of 57 to 58 CAGs, sharing a common haplotype. The age at onset, phenotype, and variability of symptoms were compatible with known cases. In one family, the disease was apparently sporadic due to possible incomplete penetrance and/or late age at onset. Our data indicate that SCA12 is also present in Italian patients, and its genetic testing should be applied to both sporadic and familial ataxias.

Family burden after severe brain injury: the Italian experience with families and volunteer associations.

BACKGROUND: As part of the development of the Italian National Consensus Conference investigating the period from the hospital rehabilitation of patients with severe brain injury to their return to the community, a working group was appointed to identify the needs of brain injury patients and their families in Italy. METHODS: Two postal self-administered survey questionnaires were carried out: one targeted families of patients with severe brain injury to evaluate their objective and subjective burdens and needs; the other focused on the viewpoints of volunteer associations helping people with severe brain injury. Issues explored were quality of discharge from hospital (information received, family participation, etc.), needs of the family (work, financial resources, spare time, relationships with friends and other relatives), and the viewpoint of volunteer associations. RESULTS: A total of 234 families (54% of sample) of patients (69% male, mean age 41 years) with severe brain injury returned the questionnaire. Most said they had been involved and informed in the hospital discharge process; about 17% had not been involved at all and only about one-third of families received satisfactory support during the discharge phase. Few families received any help from community social services (10%). Almost two-thirds of families had experienced financial difficulties and, in many cases, one family member had to change his/her work situation. Families' social relationships, travelling, hobbies, and spare time were significantly reduced. The 57 volunteer associations who returned the survey (84% response rate) confirmed that their members had experienced the same difficulties. CONCLUSIONS: Considering the difficulties and problems documented by these two surveys, more research is needed on effective interventions to support patients with severe brain injury and their families, particularly during the discharge phase from hospital to home and community life.