Search

Contains fulltext : 69641.pdf (publisher's version ) (Closed access)

Contains fulltext : 70185.pdf (publisher's version ) (Closed access), We identified a SNP in the DPP6 gene that is consistently strongly associated with susceptibility to amyotrophic lateral sclerosis (ALS) in different populations of European ancestry, with an overall P value of 5.04 x 10(-8) in 1,767 cases and 1,916 healthy controls and with an odds ratio of 1.30 (95% confidence interval (CI) of 1.18-1.43). Our finding is the first report of a genome-wide significant association with sporadic ALS and may be a target for future functional studies.

Contains fulltext : 69600.pdf (publisher's version ) (Closed access), OBJECTIVE: It is unclear to what extent muscle phosphorylase b kinase (PHK) deficiency is associated with exercise-related symptoms and impaired muscle metabolism, because 1) only four patients have been characterized at the molecular level, 2) reported symptoms have been nonspecific, and 3) lactate responses to ischemic handgrip exercise have been normal. METHODS: We studied a 50-year-old man with X-linked PHK deficiency using ischemic forearm and cycle ergometry exercise tests to define the derangement of muscle metabolism. We compared our findings with those in patients with McArdle disease and in healthy subjects. RESULTS: Sequencing of PHKA1 showed a novel pathogenic mutation (c.831G>A) in exon 7. There was a normal increase of plasma lactate during forearm ischemic exercise, but lactate did not change during dynamic, submaximal exercise in contrast to the fourfold increase in healthy subjects. Constant workload elicited a second wind in all patients with McArdle disease, but not in the patient with PHK deficiency. IV glucose administration appeared to improve exercise tolerance in the patient with PHK deficiency, but not to the same extent as in the patients with McArdle disease. Lipolysis was higher in the patient with PHK deficiency than in controls. CONCLUSION: These findings demonstrate that X-linked PHK deficiency causes a mild metabolic myopathy with blunted muscle glycogen breakdown and impaired lactate production during dynamic exercise, which impairs oxidative capacity only marginally. The different response of lactate to submaximal and maximal exercise is likely related to differential activation mechanisms for myophosphorylase.

Contains fulltext : 70438.pdf (publisher's version ) (Closed access), Small surface motor unit potentials (S-MUPs) may have a negative influence on the variability of the motor unit number estimate (MUNE). According to published consensus criteria S-MUPs with a negative peak amplitude smaller than 10 muV should be omitted. The effect of omitting small S-MUPs on the MUNE was evaluated using a simulation model. The model incorporated a healthy and amyotrophic lateral sclerosis (ALS) distribution formed with real S-MUPs. Using a random drawing process the MUNE was calculated with and without small S-MUPs. In the healthy population 27% of all S-MUPs were small. MUNE determined without these S-MUPs was marginally less variable. However, MUNE values dropped about 24% at a sample size of 20. In ALS, only 12% of the total population of 130 S-MUPs were small. MUNE dropped about 12% without the small S-MUPs. By omitting small S-MUPs the differences between the healthy and ALS distributions become smaller. Therefore, incorporating small S-MUPs in the estimate is suggested.

Contains fulltext : 70976.pdf (publisher's version ) (Open Access)

Contains fulltext : 70139.pdf (publisher's version ) (Closed access)

Contains fulltext : 71289.pdf (publisher's version ) (Closed access), In this study, we examined whether quantitative muscle ultrasonography can detect structural muscle changes in early-stage amyotrophic lateral sclerosis (ALS). Bilateral transverse scans were made of five muscles or muscle groups (sternocleidomastoid, biceps brachii/brachialis, forearm flexor group, quadriceps femoris and anterior tibialis muscles) in 48 patients with ALS. Twenty-five patients were also screened for fasciculations. Quantitative analysis revealed a significant increase in echo intensity in all muscles and a decrease in muscle thickness of the biceps brachii, forearm flexors and quadriceps femoris on both sides. Fasciculations were easy to detect in multiple muscles of all screened patients except one. We conclude that quantitative ultrasonography can be used to detect muscle changes caused by ALS in an early phase of the disease. (E-mail: m.zwarts@neuro.umcn.nl).

Contains fulltext : 69050.pdf (publisher's version ) (Open Access), Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS: MIM 270550) is a neurodegenerative disorder characterized by early-onset cerebellar ataxia with spasticity and peripheral neuropathy. This disorder, considered to be rare, was first described in the late seventies among French Canadians in the isolated Charlevoix-Saguenay region of Quebec. Nowadays, it is known that the disorder is not only limited to this region but occurs worldwide. Our objective was to identify cases of autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) in Dutch patients with recessive early-onset cerebellar ataxia by sequencing the complete SACS gene. In a Dutch cohort of 43 index patients with ataxia onset before age 25, we identified 16 index patients (total 23 patients) with mutations in the SACS gene. Nine of them had homozygous mutations, and seven of them had compound heterozygous mutations. Retrospectively, the phenotype of patients carrying mutations was remarkably uniform: cerebellar ataxia with onset before age 13 years, lower limb spasticity and sensorimotor axonal neuropathy, and cerebellar (vermis) atrophy on magnetic resonance imaging, consistent with the core ARSACS phenotype previously described. The high rate of mutations (37%) identified in this cohort of Dutch patients suggests that ARSACS is substantially more frequent than previously estimated. We predict that the availability of SACS mutation analysis as well as an increasing awareness of the characteristic ARSACS phenotype will lead to the diagnosis of many additional patients, possibly even at a younger age.

Contains fulltext : 70400.pdf (publisher's version ) (Closed access)

Contains fulltext : 69522.pdf (publisher's version ) (Closed access), Transcutaneous botulinum toxin injection in the salivary glands was introduced in 2000 as a new treatment for sialorrhoea in amyotrophic lateral sclerosis (ALS). We describe an ALS patient who developed serious complications of botulinum toxin treatment for sialorrhoea, and we review the relevant literature. A 64-yr-old woman with bulbar ALS for 6 mos was treated for disabling sialorrhoea. She had moderate dysphagia, but she was able to swallow. The submandibular and parotid glands were injected transcutaneously, under ultrasound guidance, with botulinum toxin (Dysport), 80 U on each side. Four days later, her bulbar function rapidly deteriorated, resulting in complete aphagia and anarthria on the fifth day. A PEG catheter was placed. Although according to the literature this treatment can be made safer by cautiously increasing the dosage and injecting the parotid glands first, BTX should not be the first-line treatment of sialorrhoea in ALS; comparative studies of BTX, amitryptiline, scopolamine, and radiation should be performed first.

Contains fulltext : 70233.pdf (publisher's version ) (Open Access), BACKGROUND: In amyotrophic lateral sclerosis (ALS), the origin of fasciculations is disputed. We hypothesized that the discharge pattern of fasciculation potentials (FPs) would be different for FPs arising in the motor axon or in the spinal motor neuron. METHOD: FPs were recorded by high-density surface EMG of the biceps brachii or vastus lateralis muscle for 15 minutes in 10 patients with ALS. Records were decomposed into different FP waveforms and their firing moments. Interspike interval (ISI) histograms were constructed for FPs that fired more than 100 times. RESULTS: Two types of ISI histograms were found. 1) In 23 of 30 different FPs with a total of 8,597 ISIs, the refractory period was 3 to 4 msec. ISIs longer than 15 msec had a Poisson distribution. Five of these 23 FPs discharged doublets with an ISI of approximately 5 msec, indicative of supernormality. This is consistent with the FPs arising in motor axons. 2) In the other 7 FPs, accounting for 11,266 ISIs, the refractory period was 17 to 46 msec. The preferred ISI duration was around 80 msec. Both timing factors are consistent with origin in the spinal motor neuron. CONCLUSIONS: Firing pattern analysis, based on high-density surface EMG, can detect fasciculation potentials (FPs) of axonal and neuronal origin in amyotrophic lateral sclerosis. The two FP types coexist within the same muscle. The recognition that clinically identical fasciculations conceal the existence of two types of FP that can be studied in a noninvasive manner will introduce a new aspect in the research of motor neuron disease.

Contains fulltext : 51859.pdf (publisher's version ) (Open Access), AIM AND METHODS: We prospectively investigated whether early diagnosis of amyotrophic lateral sclerosis (ALS) could be facilitated by demonstrating signs of denervation in a muscle of a clinical and electromyographical unaffected region. Muscle fibre conduction velocity (MFCV) was determined in 18 patients in whom the diagnosis ALS was considered but not established beyond a level of clinically possible ALS according to the revised El Escorial criteria. A muscle biopsy was obtained from the same muscle, to demonstrate neurogenic changes. The study followed the guidelines from the STARD initiative. RESULTS AND CONCLUSION: Results were analysed with respect to the final diagnosis. After a mean follow-up of 16 months, 9 patients developed probable or definite ALS. Sensitivity of abnormal MFCV for developing ALS was 89%. Muscle biopsy confirmed that denervation was the cause of abnormal MFCV. We concluded that MFCV can be used to detect denervation in muscles that show no clinical or electromyographical signs of lower motor neuron disease, and thus may contribute to early diagnosis of probable laboratory-supported ALS.

Contains fulltext : 53464.pdf (publisher's version ) (Closed access), We evaluated a modified measurement of the cortical silent period (CSP) as a simple procedure to add further confidence in the diagnostic work-up for ALS. Thirty-seven consecutive patients with a suspicion of having ALS were included together with 25 healthy volunteers, and followed until a final diagnosis (ALS versus 'ALS mimic') was reached. Using a CSP cut-off value of 200 ms for males and 150 ms for females, the following test characteristics were obtained for ALS versus ALS mimics together with controls: sensitivity for excluding ALS 0.83, specificity 0.56 (males) and sensitivity 0.81, specificity 0.82 (females). A CSP longer than the mentioned cut-off values should alarm the clinician for the presence of a disorder other than ALS.

Contains fulltext : 53565.pdf (publisher's version ) (Closed access), BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating disease characterised by progressive degeneration of motor neurons in the brain and spinal cord. ALS is thought to be multifactorial, with both environmental and genetic causes. Our aim was to identify genetic variants that predispose for sporadic ALS. METHODS: We did a three-stage genome-wide association study in 461 patients with ALS and 450 controls from The Netherlands, using Illumina 300K single-nucleotide polymorphism (SNP) chips. The SNPs that were most strongly associated with ALS were analysed in a further 876 patients and 906 controls in independent sample series from The Netherlands, Belgium, and Sweden. We also investigated the possible pathological functions of associated genes using expression data from whole blood of patients with sporadic ALS and of control individuals who were included in the genome-wide association study. FINDINGS: A genetic variant in the inositol 1,4,5-triphosphate receptor 2 gene (ITPR2) was associated with ALS (p=0.012 after Bonferroni correction). Combined analysis of all samples (1337 patients and 1356 controls) confirmed this association (p=3.28x10(-6), odds ratio 1.58, 95% CI 1.30-1.91). ITPR2 expression was greater in the peripheral blood of 126 ALS patients than in that of 126 healthy controls (p=0.00016). INTERPRETATION: Genetic variation in ITPR2 is a susceptibility factor for ALS. ITPR2 is a strong candidate susceptibility gene for ALS because it is involved in glutamate-mediated neurotransmission, is one of the main regulators of intracellular calcium concentrations, and has an important role in apoptosis.

Contains fulltext : 52470.pdf (publisher's version ) (Open Access)

Contains fulltext : 53011.pdf (publisher's version ) (Closed access), The primary goal of this study was to identify secondary functional changes in the peripheral motor units of the paretic upper extremity (UE) in patients with severe ischemic stroke and to determine how these changes develop during the first weeks after stroke. An inception cohort of 27 consecutive patients with an acute ischemic supratentorial stroke and an initial UE paralysis was compared with 10 healthy control subjects. The ulnar nerve was electrically stimulated proximal to the wrist and electromyographic recordings were obtained from the abductor digiti minimi muscle. Hemiparetic side mean values of the compound muscle action potential (CMAP) 1 and 3 weeks after stroke were compared with the nonparetic side and with CMAP values obtained from healthy control subjects. The mean CMAP amplitude in patients was significantly lower on the paretic side compared with the nonparetic side and with control subjects. Decrease in CMAP amplitude was observed in more than half of the stroke patients, sometimes as early as 4 days after stroke, and persisted in most cases. Whenever present, it was accompanied by absence of motor recovery at that specific time after stroke. Decreased CMAP amplitude in the abductor digiti minimi muscle can be seen already in the very acute phases after stroke unrelated to peripheral neuropathy, radiculopathy, or plexopathy, and it is accompanied by absence of UMN recovery. This knowledge is important for interpreting electrophysiological data in stroke patients.

RU Radboud Universiteit Nijmegen, 14 december 2007, Promotores : Zwarts, M.J., Stegeman, D.F. Co-promotor : Schelhaas, H.J., Contains fulltext : 52347.pdf (publisher's version ) (Open Access), A muscle fibre can be excited by electrical stimulation using a needle electrode. Action potentials elicited this way will be conducted through the muscle fibre and can be recorded at some distance with a second needle electrode. This way, muscle fibre conduction velocity can be estimated. In the present study we have investigated the determinants of conduction velocity in healthy subjects and in patients with various neuromuscular disorders. Our main result was a linear relationship between conduction velocity and fibre diameter that we demonstrated in both groups, using data obtained from muscle biopsies. Furthermore, we evaluated the diagnostic value of the technique to measure muscle fibre conduction velocity with needle electrodes. Our findings showed that the diagnostic value was similar to those of the reference techniques, which were electromyography and muscle biopsy. In some myopathies, such as mitochondrial myopathies, channelopathies, and early motor neuron disease, our technique rendered superior results. In conclusion, this thesis contributes to the knowledge of muscle fibre physiology, and clarifies the use of an invasive technique to measure conduction velocity in electrodiagnosis.

Contains fulltext : 52264timmermans.pdf (publisher's version ) (Closed access), Mutations in the myosin heavy chain gene (MYH7) can cause several distinct phenotypes depending on the location of the mutation: hypertrophic cardiomyopathy (several exons), myosin storage myopathy (exon 37/39) or Laing distal myopathy (exons 32-36). Here, we describe a unique combination of hypertrophic cardiomyopathy and hypertrophic distal myopathy in a family with a MYH7 Val606Met mutation (exon 16).

Contains fulltext : 52273.pdf (publisher's version ) (Open Access), Frontotemporal dementia is accompanied by motor neuron disease (FTD + MND) in approximately 10% of cases. There is accumulating evidence for a clinicopathological overlap between FTD and MND based on observations of familial aggregation and neuropathological findings of ubiquitin-positive neuronal cytoplasmatic inclusions (NCI) in lower motor neurons, hippocampus and neocortex in both conditions. Several familial forms exist with different genetic loci and defects. We investigated the familial aggregation and clinical presentation of FTD + MND cases in a large cohort of 368 FTD patients in The Netherlands. Immunohistochemistry of available brain tissue of deceased patients was investigated using a panel of antibodies including ubiquitin, p62 and TAR DNA-binding protein of 43 kDa antibodies. A total of eight patients coming from six families had a family history positive for FTD + MND (mean age at onset 53.2 +/- 8.4 years). Five patients presented with behavioural changes and cognitive changes followed by motor neuron disease, whereas symptoms of motor neuron disease were the presenting features in the remaining three patients. Other affected relatives in these families showed dementia/FTD, MND or FTD + MND reflecting the clinical interfamilial variation. No mutations were identified in any of the candidate genes, including Superoxide Dismutase 1, dynactin, angiogenin, Microtubule-Associated Protein Tau, valosin-containing protein and progranulin. Available brain tissue of five patients with familial FTD + MND showed NCI in hippocampus, neocortex and spinal cord in all, and neuronal intranuclear inclusions (NII) in two brains. TDP-43 antibody showed robust staining of neuronal inclusions similar in distribution and morphology to NCI and NII. Additionally, TDP-43 antibody also stained ubiquitin-negative glial inclusions in the basal striatum of one case. In conclusion, there exists considerable clinical variation within families with FTD + MND, which may be determined

Frontotemporal dementia is accompanied by motor neuron disease (FTD + MND) in ∼10% of cases. There is accumulating evidence for a clinicopathological overlap between FTD and MND based on observations of familial aggregation and neuropathological findings of ubiquitin-positive neuronal cytoplasmatic inclusions (NCI) in lower motor neurons, hippocampus and neocortex in both conditions. Several familial forms exist with different genetic loci and defects. We investigated the familial aggregation and clinical presentation of FTD + MND cases in a large cohort of 368 FTD patients in the Netherlands. Immunohistochemistry of available brain tissue of deceased patients was investigated using a panel of antibodies including ubiquitin, p62 and TAR DNA-binding protein of 43kDa antibodies. A total of eight patients coming from six families had a family history positive for FTD + MND (mean age at onset 53.2 ± 8.4 years). Five patients presented with behavioural changes and cognitive changes followed by motor neuron disease, whereas symptoms of motor neuron disease were the presenting features in the remaining three patients. Other affected relatives in these families showed dementia/FTD, MND or FTD + MND reflecting the clini

Contains fulltext : 50508.pdf (publisher's version ) (Open Access), To determine the relation between muscle fiber conduction velocity (MFCV) and muscle fiber diameter (MFD) in pathological conditions, we correlated invasively measured MFCV values with MFD data obtained from muscle needle biopsies in 96 patients with various neuromuscular disorders. MFCV was significantly correlated with MFD and independent of the underlying disorder. Pathological diameter changes were fiber-type dependent, with corresponding MFCVs. A linear equation expresses the relation well: MFCV (m/s)=0.043.MFD (microm)+0.83. We conclude that fiber diameter determines MFCV largely independent of the underlying neuromuscular disorders studied.

Item does not contain fulltext, OBJECTIVE: We analyzed the expression of the inflammatory mediators IL-1beta, IL-1ra, IL-6 and the transcription factors IRF-1 and C/EBPdelta (previously identified in a transgenic model of spinocerebellar ataxia type 3 (SCA3) by gene expression profiling) in the central nervous system of SCA3 patients in relation to neuronal cell loss and ataxin-3-positive neuronal intranuclear inclusions (NI), to identify a putative upregulation of cytokines or microglia in SCA3 brains and to investigate whether enhanced cytokine expression was a generalized event mediating neuronal dysfunction in SCA3. MATERIALS AND METHODS: Light- and electronmicroscopic immunohistochemistry was performed on SCA3 tissues derived from five patients from unrelated families with genetically confirmed diagnosis, and six individuals without a history of neurological or inflammatory disease. RESULTS: NI were found almost exclusively in brain regions that also showed neuronal cell loss, i.e. in pons and dentate nucleus neurons, rarely in putamen and thalamus, but not in cerebral or cerebellar cortex. NI displayed an irregular surface and were mostly attached to the nucleoli. Quantitative analysis of NI in the pons revealed an inverse relation of NI and cell loss, i.e. patients with more severe neuronal cell loss had a smaller proportion of neurons with NI. Thus, formation of NI is not necessarily an indicator of cell death but could exert a protective effect. We found increased expression of IL-1beta, IL-1ra, IL-6 and C/EBPdelta only in pons and dentate nucleus neurons and both in neurons with and without NI, suggesting that NI are not a prerequisite for transcriptional changes. CONCLUSIONS: Our data suggest that the selectively affected neuronal populations in SCA3 undergo a complex alteration of gene expression independent from the formation of NI.

Contains fulltext : 50863.pdf (publisher's version ) (Closed access), Mutations in the BSCL2 gene have recently been identified in families with (SPG17-linked) Silver syndrome-type hereditary spastic paraparesis as well as in families with distal hereditary motor neuropathy (HMN). We describe the first two Dutch families with BSCL2 mutations and corroborate the phenotypic variability of this gene mutation, as features compatible with Silver syndrome, variant Silver syndrome (with predominant foot rather than hand muscle involvement), distal HMN type II, or distal HMN type V were all encountered.

Contains fulltext : 49328.pdf (publisher's version ) (Open Access), Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are both relentlessly progressive and ultimately fatal neurological disorders. ALS is familial in approximately 10% of cases and FTD in approximately 30%. Inheritance is usually autosomal dominant with variable penetrance. Phenotypic overlap between ALS and FTD can occur within the same kindred. Mutations in copper/zinc superoxide dismutase 1 (SOD1) are found in approximately 20% of familial and approximately 3% of sporadic ALS cases but are not associated with dementia. Mutations in microtubule associated protein tau (MAPT) are detected in approximately 30% of familial FTD kindreds. Dominant ALS with FTD has previously been linked to 9q21 and pure ALS to loci on 16q21, 18q21, 20p13. Here we report the results of a genome-wide linkage study in a large ALS and FTD kindred using Affymetrix 10K GeneChip microarrays. Linkage analysis of single nucleotide polymorphism (SNP) data identified consistently positive log of the odds (LOD) scores across chromosome 9p (maximal LOD score of 2.4). Fine mapping the region with microsatellite markers generated a maximal multipoint LOD score of 3.02 (theta = 0) at D9S1878. Recombination narrowed the conserved haplotype to 12 cM (11 Mb) at 9p13.2-21.3 (flanking markers D9S2154 and D9S1874). Bioinformatic analysis of the region has identified 103 known genes.

Contains fulltext : 49778.pdf (publisher's version ) (Closed access), Recognizing an ALS-mimic can be challenging. Here, we describe a patient with a slowly progressive dysarthria and dysphagia, with fasciculations of the tongue and general hyperreflexia, fulfilling the diagnostic criteria of 'clinical probable ALS'. Because of a non-conclusive EMG, a muscle biopsy was performed that surprisingly showed widespread nemaline rods. The clinical features and the histological findings were compatible with a sporadic late onset nemaline myopathy. Three years after initial presentation the patient died and post-mortem examination not only showed nemaline bodies in every muscle examined, but also revealed an unsuspected final diagnosis: sarcoid brainstem encephalitis. Nemaline rods can be found in various disorders, and neurosarcoidosis should be added to this list.

Contains fulltext : 51239.pdf (publisher's version ) (Closed access), We report a patient with Leber hereditary optic neuropathy (G11778A mtDNA) and a severe demyelinating neuropathy, for which no other cause except his mitochondrial disorder could be found. The involvement of the peripheral nervous system of patients with LHON, in particular with a 11778 mtDNA, is discussed.

Contains fulltext : 49430.pdf (publisher's version ) (Closed access), The discovery of the gene for Friedreich's ataxia (FRDA) has not only broadened the FRDA phenotype, but has also identified patients with early-onset cerebellar ataxia who resemble FRDA clinically but who do not carry a mutation in the frataxin gene. In order to identify subgroups that may represent a uniform underlying disorder, we performed neurophysiologic studies, including nerve conduction studies, electromyography, and transcranial magnetic stimulation, in 15 patients with a slowly progressive, unexplained, early-onset cerebellar ataxia (EOCA). In addition, sural nerve biopsy data were available in four patients. The neurophysiologic data identified three distinctive groups of EOCA patients: three patients with normal motor and sensory conduction velocities and borderline sensory amplitudes (group 1); three patients with a mild, predominantly motor, axonal neuropathy (group 2); and nine patients with a highly uniform syndrome characterized by pyramidal features and a severe sensory and motor axonal neuropathy (group 3). We conclude that, on the basis of neurophysiologic studies, distinctive groups of patients with EOCA can be delineated, and that differentiation between patients with EOCA can be useful for differential diagnostic consideration. Whether this splitting also reflects a fundamental phenotypic difference and, therefore, may direct future DNA studies, remains to be established.

Contains fulltext : 50833.pdf (publisher's version ) (Closed access), The term 'split hand' refers to a pattern of dissociated atrophy of hand muscles and was first described in ALS. We hypothesize that this phenomenon also occurs in 'normal' aging. We investigated healthy subjects of different ages and found a progressive dissociation in atrophy of the hand muscles, as measured with compound muscle action potential amplitudes, with increasing age. Different possible causes of this progressive dissociation are discussed. It might be related to preferential use of thenar muscles in humans, which render these muscles and their motor neurons more susceptible to oxidative stress. In addition, a difference in intrinsic susceptibility to oxidative stress might be involved. The relation between normal age-related muscle loss (sarcopenia) and the pathologic loss in motor neuron disease is discussed.

RU Radboud Universiteit Nijmegen, 16 juni 2005, Promotores : Kremer, H.P.H., Zwarts, M.J. Co-promotor : Hageman, G., Item does not contain fulltext

Contains fulltext : 48803.pdf (publisher's version ) (Closed access), The SCA19 locus on chromosome 1p21-q21 was identified in a Dutch family in 2002. Affected individuals displayed a lateonset slowly progressive mild cerebellar ataxia, hyporeflexia, and signs of frontal lobe dysfunction. A postural head tremor and myoclonic movements were observed occasionally. Before the SCA19 locus was identified, the SCA22 symbol had been assigned to a locus on 1p21-q23 following a linkage study of a Chinese family with spinocerebellar ataxia. Although both SCA19 and SCA22 are linked to 1p21-q21, the clinical features are slightly different. While it cannot be excluded that the genes lie in close approximation at this locus, it is more likely that the same gene is mutated in both the Dutch and Chinese families, and that SCA19 and SCA22 represent the same condition.

Contains fulltext : 59324.pdf (publisher's version ) (Open Access)

Contains fulltext : 59319.pdf (publisher's version ) (Open Access)

Contains fulltext : 58514.pdf (publisher's version ) (Open Access)

Contains fulltext : 58763.pdf (publisher's version ) (Closed access)

Contains fulltext : 59252.pdf (publisher's version ) (Closed access), BACKGROUND: In autosomal dominant cerebellar ataxias (ADCAs), it is unclear whether the associated peripheral nerve involvement is always a typical length-dependent axonopathy rather than primary neuronopathy due to neuronal degeneration in the spinal anterior horns and/or dorsal root ganglia. OBJECTIVE: To study the nature and extent of peripheral nerve involvement in patients with ADCA. PATIENTS AND METHODS: Standardized clinical and electrophysiologic studies of 27 genotyped patients with ADCA were conducted prospectively, with special emphasis on the distinction between primary neuronopathy and dying-back axonopathy. RESULTS: Electrophysiologic evidence of involvement of the peripheral nervous system was present in 70% of patients. Findings were compatible with dying-back axonopathy in 30%, while in 40% of patients, neuronopathy was diagnosed. Patients with spinocerebellar ataxia (SCA) 1 and SCA2 mostly displayed features of neuronopathy, while patients with SCA3 and SCA7 displayed both neuronopathy and axonopathy. In SCA6, no significant peripheral nerve involvement was demonstrated. We did not observe an influence of age, disease duration, or ataxia severity on the presence or type of peripheral nerve involvement. CONCLUSIONS: Peripheral nerve involvement in ADCA manifests not only as distal axonal neuropathy, but also as primary neuronopathy. Electrodiagnostic studies in this group of patients should be conducted in such a way that primary neuronopathy is detected.

Contains fulltext : 57964.pdf (publisher's version ) (Closed access)

Item does not contain fulltext, The clinical phenomenon of a split hand, dominant muscle atrophy in the thenar as compared to the hypothenar complex, has been used to support the theory of primary cortical degeneration in amyotrophic lateral sclerosis. However, the same phenomenon, both clinically and electrophysiologically, was observed in three diseases with a second but not first motor neuron affection: autosomal dominant spinal muscular atrophy, spinocerebellar ataxia type 3, and juvenile muscular atrophy. Neurogenic loss in a split hand distribution points to a spinal instead of cortical origin.

Item does not contain fulltext, We present a linkage study in a four-generation autosomal dominant cerebellar ataxia (ADCA) family of Dutch ancestry. The family shows a clinically and genetically distinct form of ADCA. This neurodegenerative disorder manifests in the family as a relatively mild ataxia syndrome with some additional characteristic symptoms. We have identified a SCA19 locus, approved by the Human Genome Nomenclature Committee that can be assigned to the chromosome region 1p21-q21. Our mutation analysis failed to identify any mutations in the known spinocerebellar ataxia ( SCA) genes and linkage analysis excluded the remaining SCA loci. We therefore performed a genome-wide scan with 350 microsatellite markers to identify the location of the disease-causing gene in this family. Multi-point analysis was performed and exclusion maps were generated. Linkage and haplotype analysis revealed linkage to an interval located on chromosome 1. The estimated minimal prevalence of ADCA in the Netherlands is about 3:100,000. To date, sixteen different SCA loci have been identified in ADCA ( SCA1-8 and SCA10-17). However, mutation analysis has been commercially available only for the SCA1, 2, 3, 6 and 7 genes. So far, a molecular analysis in these SCA genes cannot be made in about one-third of the ADCA families. Thus, the identification of this new, additional SCA19 locus will contribute to expanding the DNA diagnostic possibilities.

Item does not contain fulltext