Background and purpose: Increasing evidence suggests a direct role of the TAR DNA‐binding protein 43 (TDP‐43) in neurodegeneration. Mutations in the TARDBP gene, which codes for TDP‐43, have been ...recently reported in familial and sporadic amyotrophic lateral sclerosis (ALS) cases.
Methods: To further define the spectrum and frequency of TARDBP mutations, we present genetic analysis data on TARDBP in 314 ALS mainly Italian patients, including 16 subjects with non‐SOD1 familial ALS.
Results: We identified four heterozygous missense mutations in five unrelated ALS patients (1.6%). Two of these mutations (p.G348C and p.A382T) were detected in carriers coming from families with an autosomal dominant transmission of different geographic origin (Belgian and Italian, respectively). The Belgian pedigree showed several affected members within five generations and with variable clinical features. Two novel mutations (p.G294V and p.G295S) were identified in two sporadic cases.
Conclusion: The identification of five ALS patients carrying TARDBP alterations extends the spectrum of TARDBP mutations and supports the pathological role of TDP‐43 in motor neurone disease. Our findings provide evidence that TARDBP mutations are not frequent in Italian sporadic ALS patients (1%); however, combined with the literature, our data further support TARDBP mutations as a relevant cause of familial ALS.
The recognition of a series of metabolic/enzymatic dysfunctions in glycogenoses has allowed new therapeutic advances for their treatment due to the development of recombinant enzyme. A recent advance ...appears enzymatic replacement therapy (ERT) in glycogenosis type II in both infantile, juvenile and adult form. Targeted manipulation of diet has been tried both in glycogenosis type II (Pompe disease) and type V (Mc Ardle disease).
Over the years various steroid trials have been conducted in Duchenne muscular dystrophy (DMD). In children who are still able to walk as well as in those who are wheelchair‐bound, corticosteroids ...have been found to stabilize muscle strength for a period of time. Controlled clinical observations have shown that some boys remain ambulatory for years longer than reported in natural history data. The two main steroids used are prednisone/prednisolone and deflazacort. They are probably equally effective in stabilizing muscle strength but may have different side‐effect profiles; for instance, deflazacort causes less weight gain. The exact mechanism by which steroids slow the dystrophic process is under investigation. DMD children treated long term also seem to develop other complications of the condition less frequently. For instance, they develop respiratory insufficiency later and have fewer cardiac symptoms. The therapeutic value of corticosteroids is limited, but these drugs represent the best treatment option currently available. Muscle Nerve, 2007
Periodic paralyses and paramyotonia congenita are rare disorders causing disabling weakness and myotonia. Mutations in sodium, calcium, and potassium channels have been recognized as causing disease.
...To analyze the clinical phenotype of patients with and without discernible genotype and to identify other mutations in ion channel genes associated with disease.
The authors have reviewed clinical data in patients with a diagnosis of hypokalemic periodic paralysis (56 kindreds, 71 patients), hyperkalemic periodic paralysis (47 kindreds, 99 patients), and paramyotonia congenita (24 kindreds, 56 patients). For those patients without one of the classically known mutations, the authors analyzed the entire coding region of the SCN4A, KCNE3, and KCNJ2 genes and portions of the coding region of the CACNA1S gene in order to identify new mutations.
Mutations were identified in approximately two thirds of kindreds with periodic paralysis or paramyotonia congenita. The authors found differences between the disorders and between those with and without identified mutations in terms of age at onset, frequency of attacks, duration of attacks, fixed proximal weakness, precipitants of attacks, myotonia, electrophysiologic studies, serum potassium levels, muscle biopsy, response to potassium administration, and response to treatment with acetazolamide.
Hypokalemic periodic paralysis, hyperkalemic periodic paralysis, and paramyotonia congenita may be distinguished based on clinical data. This series of 226 patients (127 kindreds) confirms some clinical features of this disorder with notable exceptions: In this series, patients without mutations had a less typical clinical presentation including an older age at onset, no changes in diet as a precipitant, and absence of vacuolar myopathy on muscle biopsy.
Abstract Myotonic dystrophy type 1 (DM1) is a complex multisystemic disorder caused by an expansion of a CTG repeat located at the 3′ untranslated region (UTR) of DMPK on chromosome 19q13.3. Aberrant ...messenger RNA (mRNA) splicing of several genes has been reported to explain some of the symptoms of DM1 including insulin resistance, muscle wasting and myotonia. In this paper we analyzed the expression of the MYH14 mRNA and protein in the muscle of DM1 patients (n = 12) with different expansion lengths and normal subjects (n = 7). The MYH14 gene is located on chromosome 19q13.3 and encodes for one of the heavy chains of the so called class II “nonmuscle” myosins (NMHCII). MYH14 has two alternative spliced isoforms: the inserted isoform (NMHCII-C1) which includes 8 amino acids located in the globular head of the protein, not encoded by the non inserted isoform (NMHCII-C0). Results showed a splicing unbalance of the MYH14 gene in DM1 muscle, with a prevalent expression of the NMHCII-C0 isoform more marked in DM1 patients harboring large CTG expansions. Minigene assay indicated that levels of the MBNL1 protein positively regulates the inclusion of the MYH14 exon 6. Quantitative analysis of the MYH14 expression revealed a significant reduction in the DM1 muscle samples, both at mRNA and protein level. No differences were found between DM1 and controls in the skeletal muscle localization of MYH14, obtained through immunofluorescence analysis. In line with the thesis of an “RNA gain of function” hypothesis described for the CTG mutation, we conclude that the alterations of the MYH14 gene may contribute to the DM1 molecular pathogenesis.
Fanin M, Anichini A, Cassandrini D, Fiorillo C, Scapolan S, Minetti C, Cassanello M, Donati MA, Siciliano G, D’Amico A, Lilliu F, Bruno C, Angelini C. Allelic and phenotypic heterogeneity in 49 ...Italian patients with the muscle form of CPT‐II deficiency.
As genotype–phenotype correlations require the study of large patient populations, we investigated 49 Italian patients (33 unreported) with the muscle form of carnitine‐palmitoyl‐transferase‐II (CPT‐II) deficiency and CPT2 gene mutations. CPT enzyme activity below 25% of controls would lead to the development of muscle symptoms, and CPT activity below 15% would cause a relatively severe phenotype of the muscle form. Of the 15 different mutations found, 6 are novel (40%). A functional significance of mutations could be derived only for the two homozygous missense mutations found: both the p.S113L and the p.R631C (recurring in four unrelated patients from a genetic isolate) alleles caused a severe CPT enzyme defect (15% and 7%, respectively) and a relatively severe clinical phenotype of the muscle form. We identified three genotypes (homozygous p.R631C, homozygous p.S113L, and heterozygous null mutations) usually associated with a relatively severe and often life‐threatening condition, which should be considered both in the clinical management of newly diagnosed patients (to prevent symptoms) and in their possible inclusion in therapeutic trials. We confirmed the existence of symptomatic heterozygous patient(s), through a family study, providing an important issue when offering genetic counseling and suggesting the crucial role of polymorphisms or environmental factors in determining the phenotype.
Emotional processing may be abnormal in amyotrophic lateral sclerosis (ALS). Our aim was to explore functional anatomical correlates in the processing of aversive information in ALS patients. We ...examined the performance of nine non-demented ALS patients and 10 healthy controls on two functional MRI (fMRI) tasks, consisting of an emotional attribution task and a memory recognition task of unpleasant versus neutral stimuli. During the emotional decision task, subjects were asked to select one of three unpleasant or neutral words. During the memory task, subjects were asked to recognize words presented during the previous task. Controls showed, as expected, greater activation in the right middle frontal gyrus during selection of unpleasant than neutral words, and a greater activation mainly in right-sided cerebral areas during the emotional recognition task. Conversely, patients showed a general increase in activation of the left hemisphere, and reduced activation in right hemisphere in both emotional tasks. Such findings may suggest extra-motor neurodegeneration involving key circuits of emotions, mostly negative, commonly involved in FTD.
Objective: Autosomal recessive limb girdle muscular dystrophies (LGMD type 2) are a clinically and genetically heterogeneous group of disorders, characterized by progressive involvement and wasting ...of limb girdle muscles. In order to describe the peculiar clinical features of LGMD2A (calpainopathy) and LGMD2B (dysferlinopathy), the most frequent forms of LGMD in European countries, we analysed and compared the phenotype and the clinical course in two relatively large groups of these patients.
Methods: We selected 22 patients with a molecular diagnosis of LGMD2A and 21 patients with LGMD2B and reported their clinical data collected from both clinical history and during periodical neuromuscular examinations: age and distribution of muscle involvement at onset, clinical functional score by the use of ten-point modified scale of Gardner-Medwin and Walton at onset and at last clinical examination, and the rate of disease progression.
Results: LGMD2A group included patients with different ages at onset (early-onset or late-onset), different phenotypes (upper girdle in Erb LGMD or lower girdle in Leyden-Moebius LGMD) and different disease progressions (rapid or slow course). LGMD2B patients differed for pattern of muscle involvement at onset (distal in Miyoshi dystrophy or proximal in Leyden-Moebius LGMD) but they had a rather homogeneous age at onset (in the second/third decade) and rate of disease progression.
Discussion: Our data show that besides the clinical differences within each group of patients, the two forms of LGMD present distinctive clinical features. The various phenotypes and courses can be attributed to specific pathogenetic mechanisms and might suggest differential therapeutic strategies.
Aims: We compared myopathological features in myasthenia gravis (MG) patients with antibodies against AChR (seropositive) and muscle‐specific tyrosin‐kinase (MuSK). While the immunopathogenesis of ...seropositive MG is well known, there is a lack of pathological studies in anti‐MuSK antibody‐positive (MuSK+) MG. Methods: We analysed skeletal muscle biopsy features of 13 MG patients: 6 MuSK+ (all women) and 7 anti‐AchR antibody‐positive (AChR+) (2 women and 5 men). In our histopathological examination, we quantified the atrophy factor of both fibre types, and the extent of minicores, myofibrillar disarray, cytochrome c oxidase (COX)‐negative fibres, mitochondrial aggregates and fibre type grouping. Results: Mean muscle fibre atrophy factor was higher in AChR+ MG than MuSK+ MG, both in type I fibres (494 vs. 210) and particularly in type II fibres (1023 vs. 300). Fibre type grouping was observed in AChR+ MG whereas COX‐negative fibres were common in MuSK+ MG. Bulbar muscles were more severely affected in MuSK+ MG and the disease was more severe: the onset was usually earlier (39 years) with Myasthenia Gravis Foundation of America score III in MuSK+ MG, and score II was found in AChR+ MG (62 years). Conclusions: Muscle biopsies of MuSK+ MG show myopathic signs with prominent mitochondrial abnormalities, whereas neurogenic features and atrophy are more frequently found in AChR+ MG. The mitochondrial impairment could explain the oculo‐bulbar involvement in MuSK+ MG.
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