Randomized trial of intravenous immunoglobulin maintenance treatment regimens in chronic inflammatory demyelinating polyradiculoneuropathy.

BACKGROUND AND PURPOSE: High peak serum immunoglobulin G (IgG) levels may not be needed for maintenance intravenous immunoglobulin (IVIg) treatment in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and such high levels may cause side effects. More frequent lower dosing may lead to more stable IgG levels and higher trough levels, which might improve efficacy. The aim of this trial is to investigate whether high frequent low dosage IVIg treatment is more effective than low frequent high dosage IVIg treatment. METHODS: In this randomized placebo-controlled crossover trial, we included patients with CIDP proven to be IVIg-dependent and receiving an individually established stable dose and interval of IVIg maintenance treatment. In the control arm, patients received their individual IVIg dose and interval followed by a placebo infusion at half the interval. In the intervention arm, patients received half their individual dose at half the interval. After a wash-out phase patients crossed over. The primary outcome measure was handgrip strength (assessed using a Martin Vigorimeter). Secondary outcome indicators were health-related quality of life (36-item Short-Form Health Survey), disability (Inflammatory Rasch-built Overall Disability Scale), fatigue (Rasch-built Fatigue Severity Scale) and side effects. RESULTS: Twenty-five patients were included and were treated at baseline with individually adjusted dosages of IVIg ranging from 20 to 80 g and intervals ranging from 14 to 35 days. Three participants did not complete the trial; the main analysis was therefore based on the 22 patients completing both treatment periods. There was no significant difference in handgrip strength change from baseline between the two treatment regimens (coefficient -2.71, 95% CI -5.4, 0.01). Furthermore, there were no significant differences in any of the secondary outcomes or side effects. CONCLUSIONS: More frequent lower dosing does not further improve the efficacy of IVIg in stable IVIg-dependent CIDP and does not result in fewer side effects.

Small-fibre neuropathy can be detected in patients with chronic idiopathic axonal polyneuropathy.

BACKGROUND: The main sensory presenting symptoms of chronic idiopathic axonal polyneuropathy (CIAP) are paraesthesias, numbness and burning pain in the feet. Although these symptoms indicate the involvement of small nerve fibres, clinical analysis or electrophysiological investigations have not yet been studied in detail. METHOD: Cardiovascular autonomic tests and cold and heat pain perception threshold tests were performed in 10 patients with CIAP, 10 patients with diabetes mellitus (DM) and 10 healthy volunteers. The results of the DM group were used to see whether the tests were able to detect small-fibre neuropathy in patients with diabetes and pain. RESULTS: Quantitative sensory threshold and autonomic tests showed more frequent abnormal test results in the patients compared to the healthy control group. The proportion of abnormal test results reached significance for the deep breathing tests in both patient groups and for the cold threshold and heat pain test in patients with CIAP. The spectral analysis of RR intervals showed a significant decrease in the high frequency in both patients with DM and CIAP. CONCLUSION: The results of this study demonstrated that small-fibre neuropathy can be detected in patients with CIAP.

The additional yield of combined nerve/muscle biopsy in vasculitic neuropathy.

BACKGROUND: vasculitic neuropathy can be confirmed by demonstrating vasculitis in a nerve biopsy, but it is uncertain to what extent combined (i.e. nerve/muscle) biopsy improves the yield. METHODS: a random-effects meta-analysis was performed to assess the additional yield of combined biopsy in vasculitic neuropathy. Medline, Embase, LILACS and ISI were searched from January 1980 until January 2009 for relevant articles on the yield of nerve, muscle or combined biopsy to diagnose vasculitic neuropathy. Fourteen (15%) studies were included. Methodological quality was scored using a modified Quality Assessment for Diagnostic Accuracy Studies tool. RESULTS: in patients clinically suspected of vasculitic neuropathy, the additional yield of definite vasculitis in combined biopsy was 5.1% (95% CI 1.1-9.2%; P = 0.013). In patients diagnosed with vasculitic neuropathy, the additional yield of definite vasculitis in combined biopsy was 15% (95% CI 2.1-28%; P = 0.023). CONCLUSIONS: there is a modest additional yield of definite vasculitis in combined biopsy compared to nerve biopsy alone. Because of methodological flaws in analysed studies, the findings should be validated in a prospective study.

Randomised controlled trial comparing two different intravenous immunoglobulins in chronic inflammatory demyelinating polyradiculoneuropathy.

BACKGROUND: Different preparations of intravenous immunoglobulin (IVIg) are considered to have comparable clinical efficacy but this has never been formally investigated. Some patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) report that some IVIg brands are more effective than others. A liquid IVIg preparation is more user friendly and potentially can be infused at a faster rate. OBJECTIVES: The primary objective was to compare the efficacy of two different IVIg brands in CIDP. The secondary objective was to compare their safety. METHODS: This was an investigator-initiated multi-centre randomised controlled double-blind trial. Twenty-seven patients with active but stable CIDP treated with their individual stable IVIg (Gammagard S/D) maintenance dose and interval were randomised to receive four infusions of freeze-dried 5% IVIg (Gammagard S/D) or the new liquid 10% IVIg (Kiovig). The overall disability sum score (ODSS) was used as the primary outcome scale. The equivalence margin was defined as a difference of ≤1 point in mean ΔODSS between treatment groups. Main secondary outcome scales were the MRC sum score and the Vigorimeter. RESULTS: Repeated measurements analysis of variance, adjusted for baseline ODSS, showed a clinically insignificant treatment difference of 0.004 (95% CI -0.4 to 0.4). We also found no significant differences in any of the other outcome measures. Besides a lower occurrence of cold shivers in patients randomised to Kiovig (p=0.03), no significant differences were found in the occurrence of adverse events. CONCLUSIONS: This trial demonstrated equal clinical efficacy between a freeze-dried and a liquid IVIg preparation for maintenance treatment of CIDP.

Peripheral Nerve Society Guideline on the classification, diagnosis, investigation, and immunosuppressive therapy of non-systemic vasculitic neuropathy: executive summary.

Non-systemic vasculitic neuropathy (NSVN) is routinely considered in the differential diagnosis of progressive axonal neuropathies, especially those with asymmetric or multifocal features. Diagnostic criteria for vasculitic neuropathy, classification criteria for NSVN, and therapeutic approaches to NSVN are not standardized. The aim of this guideline was to derive recommendations on the classification, diagnosis, investigation, and treatment of NSVN based on the available evidence and, where evidence was not available, expert consensus. Experts on vasculitis, vasculitic neuropathy, and methodology systematically reviewed the literature for articles addressing diagnostic issues concerning vasculitic neuropathy and NSVN as well as treatment of NSVN and the small-to-medium vessel primary systemic vasculitides using MEDLINE, EMBASE, and the Cochrane Library. The selected articles were analyzed and classified. The group initially reached consensus on a classification of vasculitides associated with neuropathy. Non-diabetic radiculoplexus neuropathy was incorporated within NSVN. The consensus definition of pathologically definite vasculitic neuropathy required that vessel wall inflammation be accompanied by vascular damage. Diagnostic criteria for pathologically probable vasculitic neuropathy included five predictors of definite vasculitic neuropathy: vascular deposits of IgM, C3, or fibrinogen by direct immunofluorescence; hemosiderin deposits; asymmetric nerve fiber loss; prominent active axonal degeneration; and myofiber necrosis, regeneration, or infarcts in peroneus brevis muscle biopsy (Good Practice Points from class II/III evidence). A case definition of clinically probable vasculitic neuropathy in patients lacking biopsy proof incorporated clinical features typical of vasculitic neuropathy: sensory or sensory-motor involvement, asymmetric/multifocal pattern, lower-limb predominance, distal-predominance, pain, acute relapsing course, and non-demyelinating electrodiagnostic features (Good Practice Points from class II/III evidence). Proposed exclusionary criteria for NSVN--favoring the alternate diagnosis of systemic vasculitic neuropathy--were clinicopathologic evidence of other-organ involvement; anti-neutrophil cytoplasmic antibody (ANCAs); cryoglobulins; sedimentation rate ≥100 mm/h; and medical condition/drug predisposing to systemic vasculitis (Good Practice Points supported by class III evidence). Three class III studies on treatment of NSVN were identified, which were insufficient to permit a level C recommendation. Therefore, the group reviewed the literature on treatment of primary small-to-medium vessel systemic vasculitides prior to deriving Good Practice Points on treatment of NSVN. Principal treatment recommendations were: (1) corticosteroid (CS) monotherapy for at least 6 months is considered first-line; (2) combination therapy should be used for rapidly progressive NSVN and patients who progress on CS monotherapy; (3) immunosuppressive options include cyclophosphamide, azathioprine, and methotrexate; (4) cyclophosphamide is indicated for severe neuropathies, generally administered in IV pulses to reduce cumulative dose and side effects; (5) in patients achieving clinical remission with combination therapy, maintenance therapy should be continued for 18-24 months with azathioprine or methotrexate; and (6) clinical trials to address all aspects of treatment are needed.

Rituximab for polyneuropathy with IgM monoclonal gammopathy.

BACKGROUND: Polyneuropathy with IgM monoclonal gammopathy can be a disabling disorder necessitating treatment. METHODS: In a prospective open label trial, 17 patients with disabling IgM MGUS polyneuropathy were treated with rituximab, a chimeric anti-CD-20 monoclonal antibody. RESULTS: Rituximab induced an improvement of >or=1 point on the Overall Disability Sum Score in 2/17 patients, an improvement of >or=5% of the distal MRC sum score in 4/17 and the sensory sum score in 9/17 patients. Bone marrow investigations showed CD 20 B cell depletion in all patients. There were no serious adverse events. Compared with treatment with intermittent cyclophosphamide with prednisone or treatment with fludarabine, it shows a comparable response percentages but fewer side effects. The presence of anti-MAG and a disease duration shorter than 10 years may predict treatment response. CONCLUSION: Rituximab is a candidate for treatment of IgM MGUS polyneuropathy and should be further investigated in a double-blind randomised trial.

The realistic yield of lower leg SNAP amplitudes and SRAR in the routine evaluation of chronic axonal polyneuropathies.

OBJECTIVE: To assess the realistic yield of lower leg sensory nerve action potential amplitudes (SNAP) and the sural/radial nerve amplitude ratio (SRAR) in the routine evaluation of suspected distal axonal polyneuropathy. METHODS: Investigated were 721 people. In 393 referents without and 328 patients with chronic distal symmetrical polyneuropathy the SRAR, sural, superficial peroneal and dorsal sural SNAP were determined. RESULTS: The dorsal sural SNAP could not be elicited in 26 % of referents. Axonal polyneuropathy was confirmed by an abnormally low value of the sural or superficial peroneal SNAP or SRAR in 70 % of patients, and most often (68 %) by an absent sural or superficial peroneal SNAP. In 9 % of patients there was a normal sural but abnormal superficial peroneal SNAP, and 11 % had an abnormal sural but normal superficial peroneal SNAP. ROC curve analysis demonstrated equal accuracy of the sural and superficial peroneal SNAP. CONCLUSIONS: To confirm distal axonal polyneuropathy in routine clinical practice the sural and superficial peroneal SNAP had equal and complementary yield, whereas the SRAR and dorsal sural SNAP had limited additional yield.

[Progressive, ascending neurological impairment: a spinal epidural abscess that presents as Guillain-Barré syndrome]. / Progressieve, opstijgende neurologische uitval: een spinaal epiduraal abces dat zich presenteert als het syndroom van Guillain-Barré.

Over the course of 4 days, a 65-year-old man developed fever and thoracic back pain, followed by weakness and sensory changes in both legs. Physical examination revealed dyspnoea, subfebrile temperature, neck pain withoutnuchal rigidity, sensory impairment, areflexia and weakness in both legs (and arms to a lesser extent). Guillain-Barré syndrome was considered, and treatment with intravenous immunoglobulins was started. The patient nevertheless developed respiratory insufficiency, progressive leg paresis and nuchal rigidity. Spinal MRI revealed an extensive cervicothoracic epidural abscess. Surgical decompression and drainage were performed, followed by antibiotic treatment; the patient recovered and was able to walk with assistance. A spinal epidural abscess can be difficult to recognise and is potentially lethal. The diagnosis should be considered in patients with fever and back pain, especially when these coincide with symptoms of neurological impairment. The efficacy of therapy depends on timely recognition; to this end, neuroimaging with MRI is essential.

The Dutch neuromuscular database CRAMP (Computer Registry of All Myopathies and Polyneuropathies): development and preliminary data.

Each of the various neuromuscular diseases is rare. Consequently, solid epidemiological data are not available and it is often difficult to find sufficient patients for studies. For this reason, the Dutch neuromuscular database, CRAMP (Computer Registry of All Myopathies and Polyneuropathies), was developed in 2004 by the Dutch Neuromuscular Research Support Centre, to store information on patient characteristics and diagnoses (based on Rowland and McLeod's classification) in a uniform and easily retrievable manner. Care was taken to preserve data confidentiality. It is envisaged that CRAMP will prove particularly useful for studies in which multicentre collaboration is needed to recruit a sufficiently large number of patients. More than 10,000 patients with neuromuscular diseases (4,837 female, 5,476 male) have been registered since 2004, half of whom (n=5059) have peripheral nerve disorders.

Immunosuppressive treatment for non-systemic vasculitic neuropathy.

BACKGROUND: Non-systemic vasculitic neuropathy is a rare disabling disease that usually has a subacute onset of progressive or relapsing-remitting sensory or sensorimotor deficits. Asymmetry, pain and weakness are key features. The diagnosis can only be made by exclusion of other causes, the absence of systemic vasculitis or other rheumatic diseases, and the demonstration of vasculitis in a nerve or a combined nerve and muscle biopsy. There is a need for efficacious therapy to prevent disease progression and to improve prognosis. OBJECTIVES: To assess if immunosuppressive treatment in non-systemic vasculitic neuropathy reduces disability, and ameliorates neurological symptoms, and if such therapy can be given safely. SEARCH STRATEGY: The Cochrane Neuromuscular Disease Group Trials Register (March 2006), The Cochrane Library (Issue 1, 2006), MEDLINE, EMBASE, LILACS, and ISI were searched from January 1980 until April 2006. In addition, the reference lists of relevant articles, reviews and textbooks were handsearched. SELECTION CRITERIA: All randomised or quasi-randomised trials that examined the efficacy of immunosuppressive treatment for non-systemic vasculitic neuropathy at least one year after the onset of therapy were sought. Participants had to fulfill the following criteria: absence of systemic or neurological disease, exclusion of any recognised cause of the neuropathy by appropriate clinical or laboratory investigations, electrophysiological studies in agreement with axonal neuropathy, confirmation of vasculitis in a nerve or a combined nerve and muscle biopsy. The primary outcome measure was to be improvement in disability. Secondary outcome measures were to be change in the mean disability score, change in muscle strength measured with the Medical Research Council sum score, change in pain or other positive sensory symptoms, number of relapses, and adverse events. DATA COLLECTION AND ANALYSIS: Two authors independently reviewed and extracted details of all potentially relevant trials. For included studies pooled relative risks and pooled weighted standardised mean differences were to be calculated to assess treatment efficacy. MAIN RESULTS: Fifty-nine studies were identified and assessed for possible inclusion in the review, but all were excluded because of insufficient quality or lack of relevance. AUTHORS' CONCLUSIONS: No adequate randomised or quasi-randomised controlled clinical trials have been performed on which to base treatment for non-systemic vasculitic neuropathy. Randomised trials of corticosteroids and other immunosuppressive agents are needed.

[Unexpected symptoms of monoclonal gammopathy]. / Onverwachte gevolgen van monoklonale gammopathie.

Monoclonal gammopathy of undetermined significance (MGUS) is a common haematological disorder characterized by the presence of a monoclonal protein (M-protein). MGUS is considered an asymptomatic 'innocent' pre-malignant precursor condition of - mostly - multiple myeloma, without indication for treatment. We present three cases illustrating that MGUS can lead to serious problems. The first patient, a 51-year-old female, presented with polyneuropathy due to anti-MAG antibodies related to IgM MGUS. The second patient, a 37-year-old female, presented with proteinuria due to immunotactoid glomerulopathy caused by renal monoclonal IgG deposition associated with MGUS. The third patient, a 55-year-old female, presented with severe bleeding caused by an aspecific inhibitor of the coagulation cascade as part of IgG MGUS. In conclusion, in addition to the risk of progression to an overt haematological malignancy, MGUS can lead to severe symptoms and significant organ damage by auto-antibody activity or pathological accumulation in tissues of its toxic M-protein.

[Sensory disturbances caused by multivitamin preparations]. / Gevoelsstoornissen veroorzaakt door multivitaminepreparaten.

2 patients, men aged 60 and 65 years, presented with symptoms of chronic sensory polyneuropathy. Symptoms in the first patient were bilateral numbness in the hands and leg pain and, in the second patient, painful tingling in the legs. Pyridoxine (vitamin B6) toxicity due to daily use of multivitamin supplements was diagnosed. The patients were taking 24 and 40 mg per day, respectively. Neurotoxic syndromes due to pyridoxine overdose have been described before in patients taking high-dose vitamin B. These patients mostly developed progressive sersory neuronopathy with sensory ataxia. Chronic sensory polyneuropathy has not been associated with the use of vitamin supplements, which have previously been considered harmless. Both patients recovered after discontinuation of supplement intake.

Three families with polyneuropathy associated with monoclonal gammopathy.

OBJECTIVE: To report familial occurrence of polyneuropathy associated with monoclonal gammopathy. DESIGN: Case reports. PATIENTS: We describe 6 patients (3 pairs) with a polyneuropathy associated with IgM monoclonal gammopathy. Four of the 6 patients had a demyelinating polyneuropathy on neurophysiological examination. Three patients had elevated antibodies against myelin-associated glycoprotein. No duplication on chromosome 17 or a mutation on chromosome 1 was found in any family. CONCLUSION: Familial occurrence of polyneuropathy without the presence of hereditary motor and sensory neuropathy type I is a reason to search for the presence of monoclonal gammopathy.

Diagnostic value of myotactic reflexes in axonal and demyelinating polyneuropathy.

In 11 patients with chronic inflammatory demyelinating polyneuropathy (CIDP) and 11 patients with chronic idiopathic axonal polyneuropathy (CIAP), absent myotatic reflexes were significantly associated more often with CIDP than with CIAP, an absent biceps-reflex having the highest sensitivity and specificity for the diagnosis of CIDP. In CIDP, the latencies of electromyographically recorded myotatic reflexes often indicated demyelination, notwithstanding normal clinically assessed myotatic reflexes. Myotatic reflexes may therefore be useful for the distinction between axonal and demyelinating polyneuropathy.

Antiganglioside antibodies in polyneuropathy associated with monoclonal gammopathy.

Antibody reactivity to GA1, GM1, GM2, GD1a, GD1b, and GQ1b gangliosides was measured in 87 patients with polyneuropathy associated with monoclonal gammopathy (60 IgM, 25 IgG, 2 IgA) and 42 control patients with monoclonal gammopathy without polyneuropathy (21 IgM, 21 IgG). Of these 87 patients, 30% had anti-myelin-associated glycoprotein antibodies and 15% had antiganglioside antibodies. Antiganglioside antibodies were significantly associated with demyelinating neuropathy and with IgM monoclonal gammopathy. Anti-GD1b and anti-GQ1b antibodies were significantly associated with predominantly sensory ataxic neuropathy.

Neuropathy and IgM M-proteins: prognostic value of antibodies to MAG, SGPG, and sulfatide.

BACKGROUND: In polyneuropathy associated with immunoglobulin M (IgM) monoclonal gammopathy, antibodies to myelin-associated glycoprotein (MAG), sulfoglucuronyl paragloboside (SGPG), and sulfatide have been associated with specific clinical and electrophysiologic features. However, it is not known whether the results of antibody tests provide additional information for the individual patient (and the neurologist) in terms of future neurologic deficit or outcome. OBJECTIVE: To study the independent contribution of potential prognostic factors to the prediction of outcome of neuropathy associated with IgM monoclonal gammopathy. METHODS: In accordance with the chronology in which prognostic factors are available in clinical practice, the association between prognostic factors and outcome was evaluated by univariate and multivariate logistic regression analysis in 65 patients with polyneuropathy and IgM monoclonal gammopathy. RESULTS: In univariate analysis, the initial symptoms, the IgM light chain type, electrophysiologic and pathologic studies, the presence of sural nerve IgM deposition, and anti-MAG or anti-SGPG antibodies were significantly associated with outcome. However, multivariate analysis showed that only initial symptoms and electrophysiologic studies are independent prognostic factors: initial sensory symptoms of the feet are prognostic for a slowly progressive disease course and less disability at 4 years, and evidence for demyelination on electrophysiologic examination is prognostic for development of weakness and symptoms of the upper extremities at 4 years. Addition of anti-MAG or anti-SGPG antibody tests did not yield any additional prediction of outcome. CONCLUSION: These results indicate that in clinical practice, antibody tests in polyneuropathy associated with IgM monoclonal gammopathy do not have a prognostic value in terms of future neurologic deficit or outcome.

Intermittent cyclophosphamide and prednisone treatment of polyneuropathy associated with monoclonal gammopathy of undetermined significance.

In an open prospective study, we analyzed the effect of cyclophosphamide (300 mg/m2 body surface daily for 4 days) combined with prednisone (40 mg/m2 body surface daily for 5 days) at 4-week intervals during 6 months in 16 patients with polyneuropathy associated with monoclonal gammopathy of undetermined significance (MGUS). Eleven patients had an IgM-MGUS and five an IgG-MGUS. During a follow-up period of 3 years, eight patients had improvement and six patients stabilized, based on quantitative neurologic examination, the Rankin disability scale, and electrophysiologic studies. These 14 patients had neuropathy with demyelinating and axonal features. One patient with a purely axonal neuropathy had deterioration despite therapy. One other patients developed severe leukopenia as side effect of cyclophosphamide, necessitating withdrawal of treatment. A difference in response was not present in patient with IgM- or IgG-MGUS, nor in patients with or without autoantibodies against myelin-associated glycoprotein. Nine patients had a bone marrow biopsy before and 1 year after treatment. In eight patients, the monoclonal lymphoid IgM or plasma cell IgG infiltration decreased, while in four the monoclonality disappeared after treatment. In the patient who had neurologic deterioration, repeated bone marrow biopsy showed deposits of amyloid. In conclusion, short-term treatment with intermittent cyclophosphamide and prednisone may have a long-term favorable effect in patients with demyelinating polyneuropathy associated with MGUS.

Magnetic resonance imaging of the brachial plexus in patients with multifocal motor neuropathy.

We studied whether magnetic resonance (MR) imaging of the brachial plexus is useful to distinguish multifocal motor neuropathy (MMN) from lower motor neuron disease (LMND) and whether abnormalities resemble those of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). We compared MR images of the brachial plexus of nine patients with MMN with scans from five patients with CIDP, eight patients with LMND, and 174 controls. In two patients with MMN, and in three patients with CIDP, the MR images showed an increased signal intensity on the T2-weighted images of the brachial plexus. Two other patients with MMN demonstrated a more focal, increased signal intensity on the T2-weighted images, occurring in one patient only in the axilla, and in the other patient in the axilla and in the ventral rami of the roots. MR images of the brachial plexus of eight patients with LMND were normal. The distribution of the MR imaging abnormalities corresponded with the distribution of symptoms of the patients: asymmetrical in MMN and symmetrical in CIDP. These findings demonstrate that MR imaging abnormalities of the brachial plexus in patients with MMN resemble those seen in CIDP and may be useful to distinguish MMN from LMND.

Spinocerebellar ataxias in the Netherlands: prevalence and age at onset variance analysis.

BACKGROUND: International prevalence estimates of autosomal dominant cerebellar ataxias (ADCA) vary from 0.3 to 2.0 per 100,000. The prevalence of ADCA in the Netherlands is unknown. Fifteen genetic loci have been identified (SCA-1-8, SCA-10-14, SCA-16, and SCA-17) and nine of the corresponding genes have been cloned. In SCA-1, SCA2, SCA3, SCA6, SCA7, SCA-12 and SCA-17 the mutation has been shown to be an expanded CAG repeat. Previously, the length of the CAG repeat was found to account for 50 to 80% of variance in age at onset. Because of heterogeneity in encoded proteins, different pathophysiologic mechanisms leading to neurodegeneration could be involved. The relationship between CAG repeat length and age at onset would then differ accordingly. METHOD: Based on the results of SCA mutation analysis in the three DNA diagnostic laboratories that serve the entire Dutch population, the authors surveyed the number of families and affected individuals per SCA gene, as well as individual repeat length and age at onset. Regression analysis was applied to study the relationship between CAG repeat length and age at onset per SCA gene. The slopes of the different regression curves were compared. RESULTS: On November 1, 2000, mutations were found in 145 ADCA families and 391 affected individuals were identified. The authors extrapolated a minimal prevalence of 3.0 per 100,000 (range 2.8 to 3.8/100,000). SCA3 was the most frequent mutation. CAG repeat length contributed to 52 to 76% of age at onset variance. Regression curve slopes for SCA-1, SCA2, SCA3, and SCA7 did not differ significantly. CONCLUSIONS: The estimated minimal prevalence of ADCA in the Netherlands is 3.0 per 100,000 inhabitants. Except for SCA6, the relationship between age at onset and CAG repeat expansion does not differ significantly between SCA-1, SCA2, SCA3, and SCA7 patient groups in our population, indicating that these SCA subtypes share similar mechanisms of polyglutamine-induced neurotoxicity, despite heterogeneity in gene products.

Genetic heterogeneity in Miyoshi-type distal muscular dystrophy.

Miyoshi-type distal muscular dystrophy (MMD) is an autosomal recessively inherited progressive disorder. The putative locus of MMD is linked to the limb-girdle muscular dystrophy 2B locus on chromosome 2p12-14. In this study three of four MMD pedigrees show non-linkage to the region spanned by D2S134-D2S358-D2S145 on chromosome 2p, indicating genetic heterogeneity. A genome wide screen was performed to identify loci linked to MMD. In two non-chromosome 2-linked families, a 23 cM region on chromosome 10 segregated with MMD.