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The natural history of Charcot-Marie-Tooth type 1A in adults; a five-year follow-up study
Autor: C. Verhamme et al.
Brain. 2009 Oct 20.
Charcot-Marie-Tooth type 1A is the most prevalent hereditary demyelinating polyneuropathy. The aim of this study was to investigate the natural history of the disease in adults during a 5-year follow-up and to compare the changes over time with those found in normal ageing. In a cohort of 46 adult Charcot-Marie-Tooth type 1A patients, impairments and physical disability were scored at baseline and at 1, 3 and 5 years. Standardized nerve conduction studies and electromyography were performed at baseline and at 5 years. Twenty-six healthy age- and sex-matched controls were evaluated at baseline and at 5 years. Forty-four of 46 Charcot-Marie-Tooth type 1A patients (range 17-69 years) and 26 controls (range 25-65 years) completed the 5-year follow-up. The decrease in muscle strength and in compound muscle action potential amplitudes was similar for patients and controls alike. However, in contrast to the control group, physical disability increased over time in the patient group. In patients, muscle strength and physical disability after 5 years were closely related to these parameters at baseline. None of the other assessed baseline characteristics, i.e. age, gender, compound muscle action potential amplitude and motor nerve conduction velocity, predicted the extent of deterioration of muscle strength or physical disability. In adult Charcot-Marie-Tooth type 1A patients, the decline in axonal function and in muscle strength may reflect, to a considerable extent, a process of normal ageing. The slow increase in physical disability in adulthood may well be explained by decreased reserves and compensatory mechanisms together with progression of skeletal deformations due to muscle weakness.
20 October 2009

Randomized Sequential Trial of Valproic Acid in Amyotrophic Lateral Sclerosis
Autor: S. Piepers et al.
Ann Neurol. 2009 Aug;66(2):227-34
OBJECTIVE: To determine whether valproic acid (VPA), a histone deacetylase inhibitor that showed antioxidative and antiapoptotic properties and reduced glutamate toxicity in preclinical studies, is safe and effective in amyotrophic lateral sclerosis (ALS) using a sequential trial design. METHODS: Between April 2005 and January 2007, 163 ALS patients received VPA 1,500mg or placebo daily. Primary end point was survival. Secondary outcome measure was decline of functional status measured by the revised ALS Functional Rating Scale. Analysis was by intention to treat and according to a sequential trial design. This trial was registered with ClinicalTrials.gov (number NCT00136110). RESULTS: VPA did not affect survival (cumulative survival probability of 0.72 in the VPA group [standard error (SE), 0.06] vs 0.88 in the placebo group [SE, 0.04] at 12 months, and 0.59 in the VPA group [SE, 0.07] vs 0.68 in the placebo group [SE, 0.08] at 16 months) or the rate of decline of functional status. VPA intake did not cause serious adverse reactions. INTERPRETATION: Our finding that VPA, at a dose used in epilepsy, does not show a beneficial effect on survival or disease progression in patients with ALS has implications for future trials with histone deacetylase inhibitors in ALS and other neurodegenerative diseases. The use of a sequential trial design allowed inclusion of only half the number of patients required for a classic trial design and prevented patients from unnecessarily continuing potentially harmful study medication.
01 September 2009

Triplet-repeat oligonucleotide-mediated reversal of RNA toxicity in myotonic dystrophy
Autor: S. Mulders et al.

Proc Natl Acad Sci U S A. 2009 Aug 18;106(33):13915-20
Myotonic dystrophy type 1 (DM1) is caused by toxicity of an expanded, noncoding (CUG)n tract in DM protein kinase (DMPK) transcripts. According to current evidence the long (CUG)n segment is involved in entrapment of muscleblind (Mbnl) proteins in ribonuclear aggregates and stabilized expression of CUG binding protein 1 (CUGBP1), causing aberrant premRNA splicing and associated pathogenesis in DM1 patients. Here, we report on the use of antisense oligonucleotides (AONs) in a therapeutic strategy for reversal of RNA-gain-of-function toxicity. Using a previously undescribed mouse DM1 myoblast-myotube cell model and DM1 patient cells as screening tools, we have identified a fully 2'-O-methyl-phosphorothioate-modified (CAG)7 AON that silences mutant DMPK RNA expression and reduces the number of ribonuclear aggregates in a selective and (CUG)n-length-dependent manner. Direct administration of this AON in muscle of DM1 mouse models in vivo caused a significant reduction in the level of toxic (CUG)n RNA and a normalizing effect on aberrant premRNA splicing. Our data demonstrate proof of principle for therapeutic use of simple sequence AONs in DM1 and potentially other unstable microsatellite diseases.

25 August 2009

Weighted gene co-expression network analysis of the peripheral blood from Amyotrophic Lateral Sclerosis patients
Autor: C.G. Saris et al.
BMC Genomics. 2009 Aug 27;10:405
BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a lethal disorder characterized by progressive degeneration of motor neurons in the brain and spinal cord. Diagnosis is mainly based on clinical symptoms, and there is currently no therapy to stop the disease or slow its progression. Since access to spinal cord tissue is not possible at disease onset, we investigated changes in gene expression profiles in whole blood of ALS patients. RESULTS: Our transcriptional study showed dramatic changes in blood of ALS patients; 2,300 probes (9.4%) showed significant differential expression in a discovery dataset consisting of 30 ALS patients and 30 healthy controls. Weighted gene co-expression network analysis (WGCNA) was used to find disease-related networks (modules) and disease related hub genes. Two large co-expression modules were found to be associated with ALS. Our findings were replicated in a second (30 patients and 30 controls) and third dataset (63 patients and 63 controls), thereby demonstrating a highly significant and consistent association of two large co-expression modules with ALS disease status. Ingenuity Pathway Analysis of the ALS related module genes implicates enrichment of functional categories related to genetic disorders, neurodegeneration of the nervous system and inflammatory disease. The ALS related modules contain a number of candidate genes possibly involved in pathogenesis of ALS. CONCLUSION: This first large-scale blood gene expression study in ALS observed distinct patterns between cases and controls which may provide opportunities for biomarker development as well as new insights into the molecular mechanisms of the disease.
03 August 2009

Neuromuscular involvement in various types of Ehlers-Danlos syndrome
Autor: N.C. Voermans et al.
Ann Neurol. 2009 Jun;65(6):687-97
OBJECTIVE: Ehlers-Danlos syndrome (EDS) is a clinically and genetically heterogeneous group of heritable connective tissue disorders characterized by joint hypermobility, skin hyperextensibility, and tissue fragility. Muscle involvement is plausible based on recently discovered interactions between muscle cells and extracellular matrix molecules; however, muscle symptoms are only sporadically reported. We designed a cross-sectional study to find out whether neuromuscular features are part of EDS. METHODS: Standardized questionnaires, physical examination, nerve conduction studies, electromyography, muscle ultrasound, and muscle biopsy were performed in 40 EDS patients with the vascular, classic, tenascin-X (TNX)-deficient type EDS, and hypermobility type of EDS caused by TNXB haploinsufficiency. RESULTS: Muscle weakness, myalgia, and easy fatigability were reported by the majority of patients. Mild-to-moderate muscle weakness (85%) and reduction of vibration sense (60%) were common. Nerve conduction studies demonstrated axonal polyneuropathy in five patients (13%). Needle electromyography myopathic features in nine patients (26%) and a mixed neurogenic-myopathic pattern in most (60%). Muscle ultrasound showed increased echo-intensity (48%) and atrophy (50%). Mild myopathic features were seen on muscle biopsy of five patients (28%). Overall, patients with the hypermobility type EDS caused by TNXB haploinsufficiency were least affected. INTERPRETATION: Mild-to-moderate neuromuscular involvement is common in various types of EDS, with a remarkable relation between residual TNX level and degree of neuromuscular involvement, compatible with a dose-effect relation. The findings of this study should increase awareness of neuromuscular symptoms in EDS patients and improve clinical care. They also point to a role of the extracellular matrix in muscle and peripheral nerve function.
26 June 2009

Muscle ultrasound measurements and functional muscle parameters in non-dystrophic myotonias suggest structural muscle changes
Autor: J. Trip et al.
Neuromuscul Disord. 2009 Jul;19(7):462-7. Epub 2009 Jun 21.
Patients with non-dystrophic myotonias, including chloride (myotonia congenita) and sodium channelopathies (paramyotonia congenita/potassium aggravated myotonias), may show muscular hypertrophy in combination with some histopathological abnormalities. However, the extent of muscle changes has never been assessed objectively in a large group genetically confirmed patients. This study quantitatively determines echo intensities, thicknesses, ranges-of-motion and force of four skeletal muscles in 63 genetically confirmed patients. The main findings revealed elevated echo intensities in all muscles except the rectus femoris (+1.3-2.2SD, p<0.0001), and hypertrophy in the arms (+0.5-0.9SD, p<0.01). Muscle echo intensities were inversely correlated to the corresponding ranges-of-motion (biceps brachii: r= -0.43; p<0.001, forearm flexors: r= -0.47; p<0.001, rectus femoris: r= -0.40; p=0.001, and tibial anterior: r= -0.27; p=0.04) and correlated positively to age (r=0.22; p=0.05). The echo intensity of the forearm flexors was inversely correlated to their muscles' force (r= -0.30; p=0.02). Together, these data suggest that non-dystrophic myotonias may lead to structural muscle changes.
21 June 2009

Mutations in NDUFAF3 (C#ORF60), encoding an NDUFAF4 (C6ORF66)-interacting complex I assembly protein, cause fatal neonatal mitochondrial disease
Autor: R.O. Vogel et al.
Am J Hum Genet. 2009 Jun;84(6):718-27.
Mitochondrial complex I deficiency is the most prevalent and least understood disorder of the oxidative phosphorylation system. The genetic cause of many cases of isolated complex I deficiency is unknown because of insufficient understanding of the complex I assembly process and the factors involved. We performed homozygosity mapping and gene sequencing to identify the genetic defect in five complex I-deficient patients from three different families. All patients harbored mutations in the NDUFAF3 (C3ORF60) gene, of which the pathogenic nature was assessed by NDUFAF3-GFP baculovirus complementation in fibroblasts. We found that NDUFAF3 is a genuine mitochondrial complex I assembly protein that interacts with complex I subunits. Furthermore, we show that NDUFAF3 tightly interacts with NDUFAF4 (C6ORF66), a protein previously implicated in complex I deficiency. Additional gene conservation analysis links NDUFAF3 to bacterial-membrane-insertion gene cluster SecF/SecD/YajC and to C8ORF38, also implicated in complex I deficiency. These data not only show that NDUFAF3 mutations cause complex I deficiency but also relate different complex I disease genes by the close cooperation of their encoded proteins during the assembly process.
20 June 2009

Differentiation of Hereditary Spastic Paraparesis From Primary Lateral Sclerosis in Sporadic Adult-Onset Upper Motor Neuron Syndromes
Autor: F. Brugman et al.
Arch Neurol. 2009 Apr;66(4):509-14
OBJECTIVE: To study whether clinical characteristics can differentiate sporadic presentations of hereditary spastic paraparesis (HSP) from primary lateral sclerosis (PLS). Differentiation between these diseases is important for genetic counseling and prognostication. DESIGN: Case series. SETTING: Tertiary referral center. PATIENTS: One hundred four Dutch patients with an adult-onset, sporadic upper motor neuron syndrome of at least 3 years' duration. Hereditary spastic paraparesis was genetically confirmed in 14 patients (7 with SPG4 and 7 with SPG7 mutations). RESULTS: All 14 patients with the SPG4 or SPG7 mutation had symptom onset in the legs, and 1 of the patients with the SPG7 mutation also developed symptoms in the arms. Of the other 90 patients, 78 (87%) had symptom onset in the legs. Thirty-six patients developed a PLS phenotype (bulbar region involvement), 15 had a phenotype that was difficult to classify as similar to HSP or PLS (involvement of legs and arms only), and 39 continued to have a phenotype similar to typical HSP (involvement of the legs only). Median age at onset was lower in patients with the SPG4 or SPG7 mutation (39 [range, 29-69] years), but there was considerable overlap with patients with the PLS phenotype (52 [range, 32-76] years). No differences were found in the features used by previous studies to distinguish HSP from PLS, including evidence of mild dorsal column impairment (decreased vibratory sense or abnormal leg somatosensory evoked potentials), symptoms of urinary urgency, or mild electromyographic abnormalities. CONCLUSIONS: In most patients with a sporadic adult-onset upper motor neuron syndrome, differentiation of sporadic presentations of HSP from PLS based on clinical characteristics is unreliable and therefore depends on results of genetic testing.
20 April 2009

Muscles alive: Ultrasound detects fibrillations.
Autor: S. Pillen et. al
Clin Neurophysiol. 2009 Apr 6.
OBJECTIVE: Muscle ultrasound is capable of visualizing muscle movements. Recent improvements in ultrasound technology have raised the question whether it is also possible to detect small-scale spontaneous muscle activity such as denervation. In this study we investigated the ability of dynamic muscle ultrasound to detect fibrillations.
METHODS: Eight patients with fibrillations were measured simultaneously by ultrasound and EMG to verify which movements on ultrasound examination corresponded to fibrillation potentials on EMG. The temperature dependency of ultrasound detected fibrillations and the observer agreement was assessed in five healthy subjects with focal denervation induced by botulinum toxin.
RESULTS: Fibrillations appeared on ultrasound examination as small, irregularly oscillating movements within the muscle while the overall shape of the muscle remains undisturbed. Visibility of fibrillations with ultrasound decreased with lower temperatures, with a 32% decrease at 30 degrees C compared to 39 degrees C. The interobserver agreement was substantial with a kappa of 0.65 for experienced observers.
CONCLUSION: Fibrillations could be visualized with ultrasound. Consistent results could be obtained from trained observers. Care has to be taken to ensure an optimal muscle temperature to avoid false negative results, especially in distal muscles. SIGNIFICANCE: Visualization of fibrillations by muscle ultrasound opens the way for a new diagnostic application of this technique.
06 April 2009

Dysphagia is present but mild in myotonic dystrophy type 2
Autor: A.A. Tieleman et al.
Neuromuscul Disord. 2009 Mar;19(3):196-8. Epub 2009 Jan 22
The phenotype of myotonic dystrophy type 2 (DM2) shows similarities as well as differences to that of myotonic dystrophy type 1 (DM1). Dysphagia, a predominant feature in DM1, has not yet been examined in DM2. In a recent nationwide questionnaire survey of gastrointestinal symptoms in DM2, 12 out of 29 DM2 patients reported to have difficulty in swallowing for solid food. The aim of the study was to investigate the presence of dysphagia in patients with genetically proven DM2 who reported difficulty in swallowing for solid food at the questionnaire survey. Swallowing function and fiberoptic endoscopic evaluation of swallowing (FEES) were examined by a speech therapist and otorhinolaryngologist, respectively. In DM2 patients who reported difficulty in swallowing the presence of dysphagia could be confirmed (clinically in 100%, by FEES in 88%). A correlation exists between Dysphagia Outcome and Severity Score (DOSS) and age (p=0.05). None of the patients was underweight, and none of the patients had suffered aspiration pneumonia in the past. Dysphagia is present among DM2 patients and is more severe in older patients. However, dysphagia is generallymild, and do not lead to weight loss, or aspiration pneumonia.
31 March 2009

Evaluation of prednisone treatment in the acute phase of neuralgic amyotrophy
Autor: J.J. van Eijk et al.
J Neurol Neurosurg Psychiatry. 2009 Mar 24.
INTRODUCTION: Effective treatment for neuralgic amyotrophy (NA), a disabling brachial plexus syndrome of supposed immuno-mediated origin, is currently lacking. Given the circumstantial evidence of a beneficial effect of prednisolone on pain and paresis, this report evaluates the effects of prednisolone treatment administered in the acute phase in a retrospective case series of 50 NA patients. METHODS: Baseline variables (e.g. age, sex, type of NA, and number of attacks), treatment variables (e.g. time until treatment, regimen, and use of analgesics), and outcome measures (e.g. duration and severity of pain, time course and severity of paresis, and functional outcome) were statistically analyzed and compared to an historical control group of 203 untreated NA patients.
RESULTS: The baseline characteristics of the two patient groups were comparable. Median time until initial pain relief was lower in the study group (12.5 days vs. 20.5 days) and a significantly higher percentage already recovered strength in the first month of treatment (18% vs. 6.3 %; p= 0.011). Twelve percent had fully recovered within one year while this was 1% for the controls (p<0.001), with the proportion reporting a 'good' 12-month outcome also being higher (44% vs. 10.7%; p<0.001). Side effects were reported by 20%, but none led to a discontinuation of treatment.
CONCLUSION: Oral prednisolone seems effective in the acute phase of neuralgic amyotrophy with the current results supporting previous case reports. A regimen of oral prednisolone is therefore recommended in the acute phase of the syndrome pending a prospective, randomized trial verifying the results obtained.
27 March 2009

Health status in non-dystrophic myotonias: close relation with pain and fatigue
Autor: J. Trip et al.
J. Neurol. 2009
To determine self-reported health status in non-dystrophic myotonias (NDM) and its relationship to painful myotonia and fatigue. In a cross-sectional study, 32 NDM patients with chloride and 30 with sodium channelopathies, all off treatment, completed a standardised interview, the fatigue assessment scale (FAS), and the 36-item Short-Form Health Survey (SF-36). Beside formal assessment of pain, assessment of painful or painless myotonia was determined. The domain scores of the SF-36 were compared with Dutch community scores. Apart from the relationship among SF-36 scores and (1) painful myotonia and (2) fatigue, regression analyses in both NDM groups were conducted to determine the strongest determinants of the SF-36 domains general health perception, physical component (PCS) and mental component summary (MCS). All physically oriented SF-36 domains in both NDM groups (P </= 0.01) and social functioning in the patients with sodium channelopathies (P = 0.048) were substantially lower relative to the Dutch community scores. The patients with painful myotonia (41.9%) scored substantially (P < 0.05) lower on most SF-36 domains than the patients without painful myotonia (58.1%). Fatigued patients (53.2%) scored substantially lower (P </= 0.01) on all SF-36 domains than their non-fatigued counterparts (46.8%). The regression analysis showed that fatigue was the strongest predictor for the general-health perception and painful myotonia for the physical-component summary. None of the patients showed below-norm scores on the domain mental-component summary. The impact of NDM on the physical domains of patients' health status is substantial, and particularly painful myotonia and fatigue tend to impede their physical functioning.
15 March 2009

Redefining the clinical phenotypes of non-dystrophic myotonic syndromes
Autor: J. Trip et al.

J. Neurol. Neurosurg. Psychiatry Feb. 2009
OBJECTIVE: To redefine phenotypical characteristics for both chloride (ClCh) and sodium channelopathies (NaCh) in non-dystrophic myotonic syndromes (NDM). METHODS: In a cross-sectional, nationwide study, standardised interviews and clinical bedside tests were performed in 62 genetically confirmed NDM patients, 32 ClCh and 30 NaCh. RESULTS: Standardised interviews revealed that ClCh reported a higher frequency of muscle weakness (75 versus 36.7%; p<0.01), the warm-up phenomenon (100 versus 46.7%; p<0.001), and difficulties in standing up quickly (90.6 versus 50.0%; p<0.001), running (90.6% versus 66.7; p<0.05), and climbing stairs (90.6 versus 63.3%; p=0.01). Patients with NaCh reported an earlier onset (4.4 versus 9.6 years; p<0.001), and higher frequencies of paradoxical (50.0 versus 0%; p<0.001), and painful myotonia (56.7 versus 28.1%; p<0.05). Standardised clinical bedside tests showed a higher incidence and longer relaxation times of myotonia in the leg muscles for ClCh (100 vs. 60%; mean duration of chair tests 12.5 vs. 6.3 seconds; p<0.001), and in eyelid muscles for NaCh (96.7 vs. 46.9%; mean relaxation time of 19.2 vs. 4.3 seconds; p<0.001). Transient paresis was only observed in ClCh (62.5%) and paradoxical myotonia only in NaCh (30.0%). Multivariate logistic regression analyses allowed us to propose clinical guidelines for genetic testing. CONCLUSION: This study redefined the phenotypical characteristics of NDM in both ClCh and NaCh. The clinical guidelines that we proposed may help clinicians working in outpatient clinics to perform focussed genetic analysis of either CLCN1 or SCN4A.

10 February 2009

Clinical and molecular overlap between myopathies and inherited connective tissue diseases
Autor: N.Voermans, et al.
Neuromuscul Disord. 2008 Nov;18(11):843-56. Epub 2008 Sep 24. Review.
This review presents an overview of myopathies and inherited connective tissue disorders that are caused by defects in or deficiencies of molecules within the extracellular matrix (ECM).  It is argued that clinicians and researchers dealing with myopathies and inherited connective tissue disorders should be aware of overlap between these disorders. Only a multi-disciplinary approach will allow full recognition of the wide variety of symptoms present in the spectrum of ECM defects, which has important implications for scientific research, diagnosis, and for the treatment of these disorders.
01 November 2008

Screening for small-cell lung cancer: a follow-up study of patients with Lambert-Eaton myasthenic syndrome
Autor: M.J. Titulaer et al.
J Clin Oncol. 2008 Sep 10;26(26):4276-81.
In almost all patients (96%), the small-cell lung carcinoma (SCLC) was found within 1 year of diagnosis. computed tomography of the thorax (CT-thorax) scans detected most of the tumors (93%) and was far more sensitive than chest x-ray (51%). fluorodeoxyglucose positron emission tomography (FDG-PET) may have additive value in selected cases. We propose a screening protocol based on CT-thorax and FDG-PET.
01 September 2008

Copy-number variation in sporadic amyotrophic lateral sclerosis: a genome-wide screen
Autor: H.M. Blauw, et al.

Lancet Neurol. 2008 Apr;7(4):319-26. Epub 2008 Mar 3.

Common copy-number variants (CNVs) in the regions of the genome represented on the single nucleotide polymorphisms (SNP) array are unlikely to be associated with sporadic Amyotrophic lateral sclerosis (ALS). However, the high number of genes deleted specifically in patients with ALS strongly suggests that multiple rare deletions might have an important role in ALS pathogenesis.
01 April 2008