Analysis of the C9orf72 gene in patients with amyotrophic lateral sclerosis in Spain and different populations worldwide.

A hexanucleotide repeat expansion in chromosome 9 open reading frame 72 (C9orf72) can cause amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD). We assessed its frequency in 781 sporadic ALS (sALS) and 155 familial ALS (fALS) cases, and in 248 Spanish controls. We tested the presence of the reported founder haplotype among mutation carriers and in 171 Ceph Europeans from Utah (CEU), 170 Yoruba Africans, 81 Han Chinese, and 85 Japanese subjects. The C9orf72 expansion was present in 27.1% of fALS and 3.2% of sALS. Mutation carriers showed lower age at onset (P = 0.04), shorter survival (P = 0.02), greater co-occurrence of FTD (P = 8.2 × 10(-5)), and more family history of ALS (P = 1.4 × 10(-20)), than noncarriers. No association between alleles within the normal range and the risk of ALS was found (P = 0.12). All 61 of the mutation carriers were tested and a patient carrying 28 hexanucleotide repeats presented with the founder haplotype. This haplotype was found in 5.6% Yoruba Africans, 8.9% CEU, 3.9% Japanese, and 1.6% Han Chinese chromosomes.

Long-term outcome in chronic inflammatory demyelinating polyneuropathy patients treated with intravenous immunoglobulin: a retrospective study.

INTRODUCTION: The objective of this retrospective study was to describe the short- and long-term patterns of IVIg use, safety, and response to treatment in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). METHODS: Response to therapy was defined as an improvement of ≥ 1 point on the modified Rankin score at short- and mid-term visits. Patient status at long term was classified as remission, stability, or non-responder. RESULTS: Eighty-six patients were included; 60.5% responded at short term and 54.6% at mid-term. At long term, 25.6% of patients were in remission, 65.1% were stable, and 9.3% were non-responders. The only variable associated with remission was a better response during the first 6 months of follow-up. CONCLUSIONS: A significant percentage of patients did not require any additional drugs in the long term. This suggests that treatment effect or disease outcome may be stable over time, and treatment regimens should therefore be individualized to avoid overtreatment.

Mitochondrial Aconitase Enzymatic Activity: A Potential Long-Term Survival Biomarker in the Blood of ALS Patients.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a multisystemic, progressive, neurodegenerative disorder. Despite it being generally fatal within a period of 2-4 years, it is highly heterogeneous; as a result, survival periods may vary greatly among individual patients. Biomarkers can serve as tools for diagnosis, prognosis, indicators of therapeutic response, and future therapeutics. Free-radical-dependent mitochondrial damage is believed to play a crucial role in neurodegeneration in ALS. Mitochondrial aconitase, which is also known as aconitase 2 (Aco2), is a key Krebs cycle enzyme and is involved in the regulation of cellular metabolism and iron homeostasis. Aco2 is very sensitive to oxidative inactivation and can aggregate and accumulate in the mitochondrial matrix, causing mitochondrial dysfunction. Loss of Aco2 activity may therefore reflect increased levels of mitochondrial dysfunction due to oxidative damage and could be relevant to ALS pathogenesis. The aim of our study was to confirm changes in mitochondrial aconitase activity in peripheral blood and to determine whether such changes are dependent on, or independent of, the patient's condition and to propose the feasibility of using them as possible valid biomarkers to quantify the progression of the disease and as a predictor of individual prognosis in ALS. METHODS: We measured the Aco2 enzymatic activity in the platelets of blood samples taken from 22 controls and 26 ALS patients at different stages of disease development. We then correlated antioxidant activity with clinical and prognostic variables. RESULTS: Aco2 activity was significantly lower in the 26 ALS patients than in the 22 controls (p < 0.05). Patients with higher levels of Aco2 activity survived longer than those with lower levels (p < 0.05). Aco2 activity was also higher in patients with earlier onset (p < 0.05) and in those with predominantly upper motor neuron signs. CONCLUSIONS: Aco2 activity seems to be an independent factor that could be used in the long-term survival prognosis of ALS. Our findings suggest that blood Aco2 could be a leading candidate for use as a biomarker to improve prognosis. More studies are needed to confirm these results.

Neurological manifestations in patients with Gaucher disease and their relatives, it is just a coincidence?

Gaucher disease (GD) is an autosomal recessive disorder characterized by defective function of glucocerebrosidase. GD presents a wide spectrum of manifestations, and patients and their relatives may develop neurological abnormalities more frequently than the general population. This study aims to determine the presence of neurological symptoms (NS) and Parkinson's disease (PD) in Spanish GD patients and their relatives. We surveyed 87 GD Spanish families and validated the information obtained on the neurological involvement through their physicians, as well as the historical data included in the Spanish Gaucher Disease Registry. Neurological abnormalities were correlated with the genetic characteristics. Statistical analyses included descriptive parameters, ANOVA, t-test, correlation study and Pearson coefficient. Information was obtained from 118 patients and 324 relatives. Out of 110 patients with type 1 GD, 32 (29.1%) reported NS and 7 (6.4%) had PD. In relatives, a total of 39 (13.1%) subjects had NS, including 16 with PD (5.3%). The prevalence of NS in genetic carriers (15.9%) was greater than that in non-carriers (5.9%; p < 0.01). Patients with PD carried the following GBA mutations: S364R, D409H, L444P, R257Q, IVS4-2A > G, c.500insT, and L336P. Relatives with PD exhibited a wide spectrum of mutations: L444P, N370S, V398I, R257Q, G202R, c.1439-1445del7, [E326K; N188S], and c.953delT. We observed a high incidence of PD in type 1 GD and relative's carriers. PD was more frequent in carriers of L444P and other rare GBA mutations. Therefore, it is important to perform a systematic neurological exam in patients with type 1 GD and carriers with high risk mutations.

[Neurological manifestations in patients with Gaucher disease and in their relatives]. / Manifestaciones neurológicas en pacientes con enfermedad de Gaucher y en sus familiares.

BACKGROUND AND OBJECTIVE: Gaucher disease (GD) is characterized by a wide spectrum of manifestations. Previous reports indicate that GD relatives could develop neurological abnormalities more frequently than the general population. We aimed to know the presence of neurological symptoms (NS) in GD patients and their relatives. PATIENTS AND METHOD: From January to December 2006 we performed a postal survey contacting 42 physicians and 92 families to evaluate NS and correlate them with genetic characteristics. Statistical analysis using descriptive parameters, ANOVA, t-test and a correlation study including Pearson coefficient were performed. RESULTS: Information from 72 families (78.3% responses) including 99 patients and 266 relatives was obtained. Thirty type 1 GD (32.6%) reported NS: tremor 8 (8.7%), uncoordinated movements 9 (9.8%), concentration defects 11 (11.9%), strabism 7 (7.6%), deafness 8 (8.7%), Parkinson disease (PD) 7 (7.6%) and peripheral neuropathy 10 (10.9%). Thirty-six (13.5%) first or second degrees relatives presented the following NS: PD 14 (4.9%), epilepsy 8 (3.0%), tremor 7 (2.6%), deafness 2 (0.7%) and others 5 (1.9%). 17.3% of carriers had NS versus 5.7% in non-carriers (p = 0.0096). Patients with PD had mutations in S364R, D409H, L444P, [IVS4-2a ==> g; c.(-203)A ==> G], c.500insT and L336P. In relatives with PD a wide spectrum of mutations was observed: L444P, N370S, V398I, G202R, c.1439-1445del7, [E326K; N188S] and c.953delT. In other NS, predominant mutations were D409H, G195W, R120W, R147X, L336P and G377S. CONCLUSIONS: A higher incidence than expected of PD and other NS in GD type 1 patients and relatives was observed. These manifestations appear frequently in L444P or rare mutations carriers. It is important to perform a systematic neurological exam in type 1 GD patients and carriers with risk mutations.

Endosseous dental implant fractures: an analysis of 21 cases.

Implant fracture is an infrequent cause of implant failure. The present study evaluates 21 fractured implants, with an analysis of patient age and sex, the type, length and diameter of the implant, positioning in the dental arch, the type of prosthetic rehabilitation involved, the number of abutments and pontics, the presence or absence of distal extensions or cantilevers, and loading time to fracture. Implant fracture was more common in males than in females (15:4), and the mean patient age was 56.9 years. Most cases (n = 19) corresponded to implant-supported fixed prostheses - 16 with cantilevers of different lengths - while only two fractured implants were supporting overdentures instead of fixed prostheses. The great majority of fractured implants (80.9%) were located in the molar and premolar regions, and most fractured within 3-4 years after loading. It is important to know and apply the measures required to prevent implant fracture, and to seek the best individualized solution for each case - though complete implant removal is usually the treatment of choice.

Altered expression of master regulatory genes of adipogenesis in lipomas from patients bearing tRNA(Lys) point mutations in mitochondrial DNA.

The mechanisms underlying the appearance of lipomas in patients bearing mutations in the tRNA(Lys) gene of mitochondrial DNA are unknown. We investigated changes in gene expression patterns in lipomas from three patients bearing A8344G or G8363A tRNA(Lys) gene mutations. Uncoupling protein-1 mRNA was detected in the lipomas, in contrast with undetectable expression in normal adipose tissue. However, expression of other markers of brown fat, such as PGC-1alpha, was unaltered. PPARgamma and retinoblastoma gene expression was down regulated in the lipomas, but C/EBPalpha mRNA was not affected. The expression of Pref-1 was dramatically down regulated. Thus, lipomatosis due to tRNA(Lys) mutations is associated with a pattern of altered expression of master regulators of adipogenesis consistent with enhanced proliferation but maintenance of adipocyte features, and with a distorted pattern of brown versus white adipocyte differentiation.

Endosseous dental implant fractures an analysis of 21 cases

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Implant fracture is an infrequent cause of implant failure. The present study evaluates 21 fractured implants, with an analysis of patient age and sex, the type, length and diameter of the implant, positioning in the dental arch, the type of prosthetic rehabilitation involved, the number of abutments and pontics, the presence or absence of distal extensions or cantilevers, and loading time to fracture.Implant fracture was more common in males than in females (15:4), and the mean patient age was 56.9 years. Most cases (n = 19) corresponded to implant-supported fixed prostheses - 16 with cantilevers of different lengths – while only two fractured implants were supporting overdentures instead of fixed prostheses. The great majority of fractured implants (80.9%) were located in the molar and premolar regions, and most fractured within 3-4 years after loading.It is important to know and apply the measures required to prevent implant fracture, and to seek the best individualized solution for each case - though complete implant removal is usually the treatment of choice