Smoking is associated with age at disease onset in Parkinson's disease.

BACKGROUND: Previous studies linked disease-progression variables such as age at onset or survival to both genetic, and non-genetic factors in Parkinson's disease (PD) patients. OBJECTIVE: The aim of this study was to assess how genetic and non genetic factors act as modifiers of age at onset and survival and in a cohort of 753 PD patients, and to determine how these variables interact to define the overall risk. METHODS: We analyzed the effect of gender, tobacco, alcohol, type of PD (genetic, gPD or idiopathic, iPD) and three genetic variants rs5848- GRN, rs1042522- TP53 and APOE. We studied two cohorts (PPMI and IPDGC) to replicate positive results. RESULTS: Regarding age at onset, male smokers PD had a significantly lower mean age compared to non-smoker (p = 0.001). APOE-Ɛ4 carriers had a younger onset-age compared to non-carriers (p = 0.03) in the Spanish cohort, but these results were not replicated in the other cohorts. Concerning survival, PD patients with an early onset (below 50 years) had an increased survival rate (p < 0.001). CONCLUSIONS: Our study showed how several genetic and non-genetic risk factors influenced the age at onset and survival in PD.

Drug-refractory myasthenia gravis: Clinical characteristics, treatments, and outcome.

OBJECTIVE: To describe the clinical characteristics and outcomes in patients with refractory myasthenia gravis (MG) and to determine the effectiveness and side effects of the drugs used for their treatment. METHODS: This observational retrospective cross-sectional multicenter study was based on data from the Spanish MG Registry (NMD-ES). Patients were considered refractory when their MG Foundation of America post-interventional status (MGFA-PIS) was unchanged or worse after corticosteroids and two or more other immunosuppressive agents. Clinical and immunologic characteristics of drug-refractory patients, efficiency and toxicity of drugs used, and outcome (MGFA-PIS) at end of follow-up were studied. RESULTS: We included 990 patients from 15 hospitals. Eighty-four patients (68 of 842 anti-acetylcholine receptor [AChR], 5 of 26 anti-muscle-specific tyrosine kinase [MusK], 10 of 120 seronegative, and 1 of 2 double-seropositive patients) were drug refractory. Drug-refractory patients were more frequently women (p < 0.0001), younger at onset (p < 0.0001), and anti-MuSK positive (p = 0.037). Moreover, they more frequently presented a generalized form of the disease, bulbar symptoms, and life-threatening events (p < 0.0001; p = 0.018; and p = 0.002, respectively) than non-drug-refractory patients. Mean follow-up was 9.8 years (SD 4.5). Twenty-four (50%) refractory patients had side effects to one or more of the drugs. At the end of follow-up, 42.9% of drug-refractory patients (42.6% of anti-AChR, 100% of anti-MuSK, and 10% of seronegative patients) and 79.8% of non-drug-refractory patients (p < 0.0001) achieved remission or had minimal manifestations. Eighty percent of drug-refractory-seronegative patients did not respond to any drug tested. INTERPRETATION: In this study, 8.5% of MG patients were drug-refractory. New more specific drugs are needed to treat drug-refractory MG patients.

Cancer in Parkinson's Disease: An Approximation to the Main Risk Factors.

BACKGROUND: Many evidences suggest a pathological link between neurodegenerative diseases and cancer. In fact, several epidemiologic studies indicate a decreased incidence of most cancer types in Parkinson's disease (PD) patients and some PD genes are involved in cancer networks. OBJECTIVE: The aim of this study is to assess the influence of several factors in the risk of cancer in a cohort of 753 PD patients and to study how these variables interact with each other. METHODS: We analyzed the effect of gender, tobacco, alcohol, type of PD (genetic or idiopathic PD), and two genetic variants, previously associated with cancer, rs5848-GRN and rs1042522-TP53. RESULTS: A higher age at PD onset was observed in patients who develop cancer before PD (p < 0.001). Alcohol consumption was a risk factor to develop cancer in PD patients (p = 0.011), while smoking was not a cancer risk factor in our cohort (p = 0.098). Among the genetic factors, the genotype TT GRN-rs5848 was statistically more frequent in PD patients without cancer (p = 0.05). CONCLUSIONS: Our study identified several factors, genetic and nongenetic, which contribute to the risk for cancer in PD.

Recurrent rhabdomyolysis and exercise intolerance: A new phenotype of late-onset thymidine kinase 2 deficiency.

A 29-year-old man developed, since the age of 18, exercise intolerance and exercise-induced rhabdomyolysis, with myoglobinuria. Muscle biopsy showed ragged-red fibers. Multiple mitochondrial DNA deletions were detected. The previously reported pathogenic homozygous mutation c.323C>T (p.Thr108Met) in TK2 was identified. This case expands the phenotypic spectrum of TK2 deficiency and indicates that it should be considered in the differential diagnosis of episodic rhabdomyolysis and exercise intolerance, along with other metabolic and mitochondrial myopathies. Since a new treatment is under development, it is essential improving knowledge of the natural history of TK2 deficiency.

Clinical and therapeutic features of myasthenia gravis in adults based on age at onset.

OBJECTIVE: To describe the characteristics of patients with very-late-onset myasthenia gravis (MG). METHODS: This observational cross-sectional multicenter study was based on information in the neurologist-driven Spanish Registry of Neuromuscular Diseases (NMD-ES). All patients were >18 years of age at onset of MG and onset occurred between 2000 and 2016 in all cases. Patients were classified into 3 age subgroups: early-onset MG (age at onset <50 years), late-onset MG (onset ≥50 and <65 years), and very-late-onset MG (onset ≥65 years). Demographic, immunologic, clinical, and therapeutic data were reviewed. RESULTS: A total of 939 patients from 15 hospitals were included: 288 (30.7%) had early-onset MG, 227 (24.2%) late-onset MG, and 424 (45.2%) very-late-onset MG. The mean follow-up was 9.1 years (SD 4.3). Patients with late onset and very late onset were more frequently men (p < 0.0001). Compared to the early-onset and late-onset groups, in the very-late-onset group, the presence of anti-acetylcholine receptor (anti-AChR) antibodies (p < 0.0001) was higher and fewer patients had thymoma (p < 0.0001). Late-onset MG and very-late-onset MG groups more frequently had ocular MG, both at onset (<0.0001) and at maximal worsening (p = 0.001). Although the very-late-onset group presented more life-threatening events (Myasthenia Gravis Foundation of America IVB and V) at onset (p = 0.002), they required fewer drugs (p < 0.0001) and were less frequently drug-refractory (p < 0.0001). CONCLUSIONS: Patients with MG are primarily ≥65 years of age with anti-AChR antibodies and no thymoma. Although patients with very-late-onset MG may present life-threatening events at onset, they achieve a good outcome with fewer immunosuppressants when diagnosed and treated properly.

Fecal microbiota profile in a group of myasthenia gravis patients.

The intestinal microbiota plays a key role in the maintenance of human health. Alterations in this microbiota have been described in several autoimmune diseases, including nervous system diseases. Nevertheless, the information regarding neuromuscular conditions is still limited. In this study, we aimed at characterizing the intestinal microbiota composition in myasthenia gravis patients (MG). To this end fecal samples were taken from ten patients, with antibodies against the acetylcholine receptor, and ten age and sex matched controls from the same population (Asturias region, Spain). Fecal samples were submitted to microbiota analyses by 16S rRNA gene profiling, bifidobacterial ITS-region profiling and qPCR. The fecal levels of short chain fatty acids were determined by gas chromatography. MG patients were found to harbor lower relative proportions of Verrucomicrobiaceae and Bifidobacteriaceae, among others, and increased of the phylum Bacteroidetes and the family Desulfovibrionaceae. The increase of these latter microbial groups was also confirmed at quantitative level by qPCR. In contrast, no statistically significant differences were found between MG patients and the control group in the bifidobacterial population at the species level or in short chain fatty acids profiles. Our data indicates an altered fecal microbiota pattern in MG patients and point out at specific microbiota targets for intervention in this population.

Netrin-1 receptor antibodies in thymoma-associated neuromyotonia with myasthenia gravis.

OBJECTIVE: To identify cell-surface antibodies in patients with neuromyotonia and to describe the main clinical implications. METHODS: Sera of 3 patients with thymoma-associated neuromyotonia and myasthenia gravis were used to immunoprecipitate and characterize neuronal cell-surface antigens using reported techniques. The clinical significance of antibodies against precipitated proteins was assessed with sera of 98 patients (neuromyotonia 46, myasthenia gravis 52, thymoma 42; 33 of them with overlapping syndromes) and 219 controls (other neurologic diseases, cancer, and healthy volunteers). RESULTS: Immunoprecipitation studies identified 3 targets, including the Netrin-1 receptors DCC (deleted in colorectal carcinoma) and UNC5A (uncoordinated-5A) as well as Caspr2 (contactin-associated protein-like 2). Cell-based assays with these antigens showed that among the indicated patients, 9 had antibodies against Netrin-1 receptors (7 with additional Caspr2 antibodies) and 5 had isolated Caspr2 antibodies. Only one of the 219 controls had isolated Caspr2 antibodies with relapsing myelitis episodes. Among patients with neuromyotonia and/or myasthenia gravis, the presence of Netrin-1 receptor or Caspr2 antibodies predicted thymoma (p < 0.05). Coexisting Caspr2 and Netrin-1 receptor antibodies were associated with concurrent thymoma, myasthenia gravis, and neuromyotonia, often with Morvan syndrome (p = 0.009). Expression of DCC, UNC5A, and Caspr2 proteins was demonstrated in paraffin-embedded thymoma samples (3) and normal thymus. CONCLUSIONS: Antibodies against Netrin-1 receptors (DCC and UNC5a) and Caspr2 often coexist and associate with thymoma in patients with neuromyotonia and myasthenia gravis. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that antibodies against Netrin-1 receptors can identify patients with thymoma (sensitivity 21.4%, specificity 100%).

Inflammatory bowel disease: an increased risk factor for neurologic complications.

Only a very few systematic studies have investigated the frequency of neurologic disorders in patients with Crohn's disease (CD) and ulcerative colitis (UC), which are the two main types of inflammatory bowel disease (IBD). Results have been inconsistent and variable, owing to differences in case-finding methods and evaluated outcomes in different studies. The most frequent neurologic manifestations reported in CD and UC populations are cerebrovascular disease (with either arterial or venous events), demyelinating central nervous system disease, and peripheral neuropathy (whether axonal or demyelinating); however, the literature describes numerous nervous system disorders as being associated with IBD. The pathogenesis of nervous system tissue involvement in IBD has yet to be elucidated, although it seems to be related to immune mechanisms or prothrombotic states. The recently-introduced tumor necrosis factor (TNF) inhibitors have proven successful in controlling moderate to severe IBD activity. However, severe neurologic disorders associated with TNF inhibitors have been reported, which therefore raises concerns regarding the effect of anti-TNF-α antibodies on the nervous system. Although neurological involvement associated with IBD is rarely reported, gastroenterologists should be aware of the neurologic manifestations of IBD in order to provide early treatment, which is crucial for preventing major neurologic morbidity.

Mitochondrial DNA polymorphisms/haplogroups in hereditary spastic paraplegia.

Mitochondrial dysfunction could contribute to the development of spastic paraplegia. Among others, two of the genes implicated in hereditary spastic paraplegia encoded mitochondrial proteins and some of the clinical features frequently found in these patients resemble those observed in patients with mitochondrial DNA (mtDNA) mutations. We investigated the association between common mtDNA polymorphisms and spastic paraplegia. The ten mtDNA polymorphisms that defined the common European haplogroups were determined in 424 patients, 19% with a complicated phenotype. A rare haplogroup was associated with the disease in patients without a SPG3A, SPG4, or SPG7 mutation. Allele 10398G was more frequent among patients with a pure versus complicated phenotype. This mtDNA polymorphism was previously associated with the risk of developing other neurodegenerative diseases. In conclusion, some mtDNA polymorphisms could contribute to the development of spastic paraplegia or act as modifiers of the phenotype.

Mutational spectrum of the SPG4 (SPAST) and SPG3A (ATL1) genes in Spanish patients with hereditary spastic paraplegia.

BACKGROUND: Hereditary Spastic Paraplegias (HSP) are characterized by progressive spasticity and weakness of the lower limbs. At least 45 loci have been identified in families with autosomal dominant (AD), autosomal recessive (AR), or X-linked hereditary patterns. Mutations in the SPAST (SPG4) and ATL1 (SPG3A) genes would account for about 50% of the ADHSP cases. METHODS: We defined the SPAST and ATL1 mutational spectrum in a total of 370 unrelated HSP index cases from Spain (83% with a pure phenotype). RESULTS: We found 50 SPAST mutations (including two large deletions) in 54 patients and 7 ATL1 mutations in 11 patients. A total of 33 of the SPAST and 3 of the ATL1 were new mutations. A total of 141 (31%) were familial cases, and we found a higher frequency of mutation carriers among these compared to apparently sporadic cases (38% vs. 5%). Five of the SPAST mutations were predicted to affect the pre-mRNA splicing, and in 4 of them we demonstrated this effect at the cDNA level. In addition to large deletions, splicing, frameshifting, and missense mutations, we also found a nucleotide change in the stop codon that would result in a larger ORF. CONCLUSIONS: In a large cohort of Spanish patients with spastic paraplegia, SPAST and ATL1 mutations were found in 15% of the cases. These mutations were more frequent in familial cases (compared to sporadic), and were associated with heterogeneous clinical manifestations.

Cryoglobulinaemic neuropathy: a further cause of bilateral sciatic neuropathy.

Bilateral sciatic neuropathy is a rare condition and it has been described as a compression or entrapment neuropathy but it is an uncommon clinical manifestation due to necrotizing vasculitis. We report an unusual case of cryoglobulinaemic neuropathy in an elderly woman with no underlying infectious or neoplastic cause; acute bilateral sciatic mononeuropathy was the presenting clinical manifestation of the cryoglobulinaemia.