Alternative splicing expands the clinical spectrum of NDUFS6-related mitochondrial disorders.

PURPOSE: We describe 3 families with Charcot-Marie-Tooth neuropathy (CMT), harboring a homozygous NDUFS6 NM_004553.6:c.309+5G>A variant previously linked to fatal Leigh syndrome. We aimed to characterize clinically and molecularly the newly identified patients and understand the mechanism underlying their milder phenotype. METHODS: The patients underwent extensive clinical examinations. Exome sequencing was done in 4 affected individuals. The functional effect of the c.309+5G>A variant was investigated in patient-derived EBV-transformed lymphoblasts at the complementary DNA, protein, and mitochondrial level. Alternative splicing was evaluated using complementary DNA long-read sequencing. RESULTS: All patients presented with early-onset, slowly progressive axonal CMT, and nystagmus; some exhibited additional central nervous system symptoms. The c.309+5G>A substitution caused the expression of aberrantly spliced transcripts and negligible levels of the canonical transcript. Immunoblotting showed reduced levels of mutant isoforms. No detectable defects in mitochondrial complex stability or bioenergetics were found. CONCLUSION: We expand the clinical spectrum of NDUFS6-related mitochondrial disorders to include axonal CMT, emphasizing the clinical and pathophysiologic overlap between these 2 clinical entities. This work demonstrates the critical role that alternative splicing may play in modulating the severity of a genetic disorder, emphasizing the need for careful consideration when interpreting splice variants and their implications on disease prognosis.

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.

Study of the effect of anti-rhGAA antibodies at low and intermediate titers in late onset Pompe patients treated with ERT.

Late onset Pompe disease (LOPD) is a genetic disorder characterized by slowly progressive skeletal and respiratory muscle weakness. Symptomatic patients are treated with enzyme replacement therapy (ERT) with alglucosidase alpha (rhGAA). Although most of ERT treated patients develop antibodies against rhGAA, their influence on clinical progression is not completely known. We studied the impact of anti-rhGAA antibodies on clinical progression of 25 ERT treated patients. We evaluated patients at visit 0 and, after 1 year, at visit 1. We performed several muscle function tests, conventional spirometry and quantitative muscle MRI (qMRI) using 3-point Dixon analysis of thigh muscles at both visits. We also obtained serum samples at both visits and anti-rhGAA antibodies were quantified using ELISA. Antibody titers higher than 1:200 were identified in 18 patients (72%) of our cohort. Seven patients (28%) did not develop antibodies (0 to <1:200), 17 patients (68%) developed low to intermediate titers (1:200 to <1:31,200) and 1 patient (4%) developed high titers (>1:31,200). We analyzed the effect of low and intermediate antibody titers in clinical and radiological progression. There were no differences between the results of muscle function tests, spirometry or fat fraction analyzed using qMRI between patients with and without antibodies groups at baseline. Moreover, antibody titers did not influence muscle function test, spirometry results or qMRI results at year 1 visit. Most of the LOPD patients developed antibodies against ERT that persisted over time at low or intermediate levels. However, antibodies at these low and intermediate titers might not influence clinical response to the drug.

Muscle MRI in a large cohort of patients with oculopharyngeal muscular dystrophy.

BACKGROUND AND OBJECTIVE: Oculopharyngeal muscular dystrophy (OPMD) is a genetic disorder caused by an abnormal expansion of GCN triplets within the PABPN1 gene. Previous descriptions have focused on lower limb muscles in small cohorts of patients with OPMD, but larger imaging studies have not been performed. Previous imaging studies have been too small to be able to correlate imaging findings to genetic and clinical data. METHODS: We present cross-sectional, T1-weighted muscle MRI and CT-scan data from 168 patients with genetically confirmed OPMD. We have analysed the pattern of muscle involvement in the disease using hierarchical analysis and presented it as heatmaps. Results of the scans were correlated with genetic and clinical data. RESULTS: Fatty replacement was identified in 96.7% of all symptomatic patients. The tongue, the adductor magnus and the soleus were the most commonly affected muscles. Muscle pathology on MRI correlated positively with disease duration and functional impairment. CONCLUSIONS: We have described a pattern that can be considered characteristic of OPMD. An early combination of fat replacement in the tongue, adductor magnus and soleus can be helpful for differential diagnosis. The findings suggest the natural history of the disease from a radiological point of view. The information generated by this study is of high diagnostic value and important for clinical trial development.

Parkinsonism and spastic paraplegia type 7: Expanding the spectrum of mitochondrial Parkinsonism.

BACKGROUND: Pathogenic variants in the spastic paraplegia type 7 gene cause a complicated hereditary spastic paraplegia phenotype associated with classical features of mitochondrial diseases, including ataxia, progressive external ophthalmoplegia, and deletions of mitochondrial DNA. OBJECTIVES: To better characterize spastic paraplegia type 7 disease with a clinical, genetic, and functional analysis of a Spanish cohort of spastic paraplegia type 7 patients. METHODS: Genetic analysis was performed in patients suspecting hereditary spastic paraplegia and in 1 patient with parkinsonism and Pisa syndrome, through next-generation sequencing, whole-exome sequencing, targeted Sanger sequencing, and multiplex ligation-dependent probe analysis, and blood mitochondrial DNA levels determined by quantitative polymerase chain reaction. RESULTS: Thirty-five patients were found to carry homozygous or compound heterozygous pathogenic variants in the spastic paraplegia type 7 gene. Mean age at onset was 40 years (range, 12-63); 63% of spastic paraplegia type 7 patients were male, and three-quarters of all patients had at least one allele with the c.1529C>T (p.Ala510Val) mutation. Eighty percent of the cohort showed a complicated phenotype, combining ataxia and progressive external ophthalmoplegia (65% and 26%, respectively). Parkinsonism was observed in 21% of cases. Analysis of blood mitochondrial DNA indicated that both patients and carriers of spastic paraplegia type 7 pathogenic variants had markedly lower levels of mitochondrial DNA than control subjects (228 per haploid nuclear DNA vs. 176 vs. 573, respectively; P < 0.001). CONCLUSIONS: Parkinsonism is a frequent finding in spastic paraplegia type 7 patients. Spastic paraplegia type 7 pathogenic variants impair mitochondrial DNA homeostasis irrespective of the number of mutant alleles, type of variant, and patient or carrier status. Thus, spastic paraplegia type 7 supports mitochondrial DNA maintenance, and variants in the gene may cause parkinsonism owing to mitochondrial DNA abnormalities. Moreover, mitochondrial DNA blood analysis could be a useful biomarker to detect at risk families. © 2019 International Parkinson and Movement Disorder Society.

Chronic pain has a strong impact on quality of life in facioscapulohumeral muscular dystrophy.

INTRODUCTION: Earlier small case series and clinical observations reported on chronic pain playing an important role in facioscapulohumeral dystrophy (FSHD). The aim of this study was to determine the characteristics and impact of pain on quality of life (QoL) in patients with FSHD. METHODS: We analyzed patient reported outcome measures collected through the U.K. FSHD Patient Registry. RESULTS: Of 398 patients, 88.6% reported pain at the time of study. The most frequent locations were shoulders and lower back. A total of 203 participants reported chronic pain, 30.4% of them as severe. The overall disease impact on QoL was significantly higher in patients with early onset and long disease duration. Chronic pain had a negative impact on all Individualised Neuromuscular Quality of Life Questionnaire domains and overall disease score. DISCUSSION: Our study shows that pain in FSHD type 1 (FSHD1) is frequent and strongly impacts on QoL, similar to other chronic, painful disorders. Management of pain should be considered when treating FSHD1 patients. Muscle Nerve 57: 380-387, 2018.

Sudden paraplegia after lumbar puncture as a clue in the diagnosis of a patient with spinal dural arteriovenous fistula.

PURPOSE: Spinal dural arteriovenous fistula (SDAVF) is manifested as congestive myelopathy with progressive motor, sensory and urinary symptoms. Sometimes, clinical picture and magnetic resonance imaging of the spinal cord are not specific and the diagnosis becomes troublesome. METHODS: We present a 68-year-old male with a progressive paraparesis of unknown etiology over the course of 12 months. Immediately after LP, the patient remarked a sudden worsening in muscular balance of his inferior limbs and a worsening of urinary retention. This fact was the clue to the SDAVF diagnosis. RESULTS: SDAVF was totally resolved after surgical treatment. During next months, paraplegia slightly improved and he is currently receiving rehabilitation treatment. CONCLUSIONS: Acute paraplegia or sudden worsening of previous symptoms secondary to decreasing in cerebrospinal fluid pressure after lumbar puncture has been described, so physicians should be aware of this dramatic and avoidable complication.

The screening of the 3'UTR sequence of LRRK2 identified an association between the rs66737902 polymorphism and Parkinson's disease.

Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) are the most common genetic determinants of familial and sporadic Parkinson's disease (PD). Most of the mutational screenings analyzed the exon-coding sequence. Our aim was to determine whether LRRK2 3' untranslated region (UTR) variants were associated with the risk of developing PD in a large cohort of patients (n=743) and controls (n=523) from Spain. We identified a total of 12 3'UTR variants (two new). Single-nucleotide polymorphism (SNP) rs66737902 C allele was overrepresented in patients (P=0.005; odds ratio=1.47). This SNP was in linkage disequilibrium with the p.R1441G mutation, but the association remained significant among mutation-negative cases. We found a significant lower level of the LRRK2 transcript in the Substantia nigra (SN) of PD postmortem donors (n=9) who were rs66737902 C carriers (P=0.01). This SNP was predicted to affect a binding site for miR-138-2-3p. We showed that this microRNA was expressed in all the SN samples. In conclusion, we found a significant association between SNP rs66737902 and the risk of developing PD. This effect on PD risk could be explained by differences in LRRK2 transcript levels between the two alleles.

Description of clinical and genetic features of 122 patients included in the Spanish Pompe registry.

Pompe disease is a rare genetic disorder with an estimated prevalence of 1:60.000. The two main phenotypes are Infantile Onset Pompe Disease (IOPD) and Late Onset Pompe Disease (LOPD). There is no published data from Spain regarding the existing number of cases, regional distribution, clinical features or, access and response to the treatment. We created a registry to collect all these data from patients with Pompe in Spain. Here, we report the data of the 122 patients registered including nine IOPD and 113 LOPD patients. There was a high variability in how the diagnosis was obtained and how the follow-up was performed among different centres. Seven IOPD patients were still alive being all treated with enzymatic replacement therapy (ERT) at last visit. Ninety four of the 113 LOPD patients had muscle weakness of which 81 were receiving ERT. We observed a progressive decline in the results of muscle function tests during follow-up. Overall, the Spanish Pompe Registry is a valuable resource for understanding the demographics, patient's journey and clinical characteristics of patients in Spain. Our data supports the development of agreed guidelines to ensure that the care provided to the patients is standardized across the country.

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.

Metrics of progression and prognosis in untreated adults with thymidine kinase 2 deficiency: An observational study.

This historical cohort study evaluated clinical characteristics of progression and prognosis in adults with thymidine kinase 2 deficiency (TK2d). Records were available for 17 untreated adults with TK2d (mean age of onset, 32 years), including longitudinal data from 6 patients (mean follow-up duration, 26.5 months). Pearson's correlation assessed associations between standard motor and respiratory assessments, clinical characteristics, and laboratory values. Longitudinal data were assessed by linear regression mixed models. Respiratory involvement progressed at an annual rate of 8.16% decrement in forced vital capacity (FVC). Most patients under noninvasive ventilation (NIV) remained ambulant (12/14, 86%), reduced FVC was not associated with concomitant decline in 6-minute walk test (6MWT), and 6MWT results were not correlated with FVC. Disease severity, assessed by age at NIV onset, correlated most strongly at diagnosis with: creatinine levels (r = 0.8036; P = 0.0009), followed by FVC (r = 0.7265; P = 0.0033), mtDNA levels in muscle (r = 0.7933; P = 0.0188), and age at disease onset (r = 0.7128; P = 0.0042). This population of adults with TK2d demonstrates rapid deterioration of respiratory muscles, which progresses independently of motor impairment. The results support FVC at diagnosis, mtDNA levels in muscle, and age at disease onset as prognostic indicators. Creatinine levels may also be potentially prognostic, as previously reported in other neuromuscular disorders.

Muscle MRI characteristic pattern for late-onset TK2 deficiency diagnosis.

BACKGROUND AND OBJECTIVE: TK2 deficiency (TK2d) is a rare mitochondrial disorder that manifests predominantly as a progressive myopathy with a broad spectrum of severity and age of onset. The rate of progression is variable, and the prognosis is poor due to early and severe respiratory involvement. Early and accurate diagnosis is particularly important since a specific treatment is under development. This study aims to evaluate the diagnostic value of lower limb muscle MRI in adult patients with TK2d. METHODS: We studied a cohort of 45 genetically confirmed patients with mitochondrial myopathy (16 with mutations in TK2, 9 with mutations in other nuclear genes involved in mitochondrial DNA [mtDNA] synthesis or maintenance, 10 with single mtDNA deletions, and 10 with point mtDNA mutations) to analyze the imaging pattern of fat replacement in lower limb muscles. We compared the identified pattern in patients with TK2d with the MRI pattern of other non-mitochondrial genetic myopathies that share similar clinical characteristics. RESULTS: We found a consistent lower limb muscle MRI pattern in patients with TK2d characterized by involvement of the gluteus maximus, gastrocnemius medialis, and sartorius muscles. The identified pattern in TK2 patients differs from the known radiological involvement of other resembling muscle dystrophies that share clinical features. CONCLUSIONS: By analyzing the largest cohort of muscle MRI from patients with mitochondrial myopathies studied to date, we identified a characteristic and specific radiological pattern of muscle involvement in patients with TK2d that could be useful to speed up its diagnosis.

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.

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.

Natural History, Phenotypic Spectrum, and Discriminative Features of Multisystemic RFC1 Disease.

OBJECTIVE: To delineate the full phenotypic spectrum, discriminative features, piloting longitudinal progression data, and sample size calculations of replication factor complex subunit 1 (RFC1) repeat expansions, recently identified as causing cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS). METHODS: Multimodal RFC1 repeat screening (PCR, Southern blot, whole-exome/genome sequencing-based approaches) combined with cross-sectional and longitudinal deep phenotyping in (1) cross-European cohort A (70 families) with ≥2 features of CANVAS or ataxia with chronic cough (ACC) and (2) Turkish cohort B (105 families) with unselected late-onset ataxia. RESULTS: Prevalence of RFC1 disease was 67% in cohort A, 14% in unselected cohort B, 68% in clinical CANVAS, and 100% in ACC. RFC1 disease was also identified in Western and Eastern Asian individuals and even by whole-exome sequencing. Visual compensation, sensory symptoms, and cough were strong positive discriminative predictors (>90%) against RFC1-negative patients. The phenotype across 70 RFC1-positive patients was mostly multisystemic (69%), including dysautonomia (62%) and bradykinesia (28%) (overlap with cerebellar-type multiple system atrophy [MSA-C]), postural instability (49%), slow vertical saccades (17%), and chorea or dystonia (11%). Ataxia progression was ≈1.3 Scale for the Assessment and Rating of Ataxia points per year (32 cross-sectional, 17 longitudinal assessments, follow-up ≤9 years [mean 3.1 years]) but also included early falls, variable nonlinear phases of MSA-C-like progression (SARA points 2.5-5.5 per year), and premature death. Treatment trials require 330 (1-year trial) and 132 (2-year trial) patients in total to detect 50% reduced progression. CONCLUSIONS: RFC1 disease is frequent and occurs across continents, with CANVAS and ACC as highly diagnostic phenotypes yet as variable, overlapping clusters along a continuous multisystemic disease spectrum, including MSA-C-overlap. Our natural history data help to inform future RFC1 treatment trials. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that RFC1 repeat expansions are associated with CANVAS and ACC.

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.

Analysis of the Micro-RNA-133 and PITX3 genes in Parkinson's disease.

MicroRNAs are small RNA sequences that negatively regulate gene expression by binding to the 3' untranslated regions of mRNAs. MiR-133b has been implicated in Parkinson's disease (PD) by a mechanism that involves the regulation of the transcription factor PITX3. The variation in these genes could contribute to the risk of developing PD. We searched for DNA variants in miR-133 and PITX3 genes in PD patients and healthy controls from Spain. We found common DNA variants in the three miR-133 genes. Genotyping of a first set of patients (n = 777) and controls (n = 650) showed a higher frequency of homozygous for a miR-133b variant (-90 del A) in PD-patients (6/575; 1%) than in healthy controls (0/650) (P = 0.03). However, this association was not confirmed in a second set of patients (1/250; 0.4%) and controls (2/210; 1%). No common PITX3 variants were associated with PD, although a rare missense change (G32S) was found in only one patient and none of the controls. In conclusion, we report the variation in genes of a pathway that has been involved in dopaminergic neuron differentiation and survival. Our work suggests that miR-133 and PITX3 gene variants did not contribute to the risk for PD.

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.

HTT gene intermediate alleles in neurodegeneration: evidence for association with Alzheimer's disease.

Huntington's disease (HD) is an autosomal progressive neurodegenerative disorder caused by the expansion of CAG repeats in the HTT gene. Intermediate alleles (IAs) are in the range of 27-35 repeats and have been associated to a normal phenotype. The aim of this work was to analyze the association between intermediate huntingtin CAG-repeat alleles (IAs) and neurodegenerative diseases, other than HD. We screened the HTT CAG repeats in patients with Alzheimer's disease (AD) (n = 1126), Parkinson's disease (PD) (n = 610), and frontotemporal lobar degeneration (FTLD) (n = 225). We also studied 509 healthy controls (HCs). The relative frequency of IAs for each group was 6.03% in AD, 5.3% in FTLD, 3.5% in PD, and 2.9% in HCs. The frequency of IA was significantly higher among patients with AD when compared to HCs (p = 0.011, OR = 2.11, 95% CI = 1.19-3.74); no significant difference was observed in FTLD (p = 0.17; OR = 1.88, 95% CI = 0.85-4.03) and PD (p = 0.69; OR = 1.21; 95% CI (0.61-2.37) versus HCs. No atypical symptoms or clinical features distinctive of HD were found among carriers of IAs. We found 3 cases with CAG expansions within the pathological range, one diagnosed with AD, one with PD, and one with FTD. Results suggest that IAs might have a role in the pathogenesis of AD. In addition, HD patients might be misdiagnosed with other neurodegenerative diseases, particularly when CAG repeats are in the lower pathological range.