Body Mass Index is Inversely Correlated with the Expanded CAG Repeat Length in SCA3/MJD Patients

Spinocerebellar ataxia type 3, also known as Machado-Joseph disease (SCA3/MJD), is an autosomal dominant neurodegenerative disorder with no current treatment. We aimed to evaluate the body mass index (BMI) of patients with SCA3/MJD and to assess the correlations with clinical, molecular, biochemical, and neuroimaging findings. A case-control study with 46 SCA3/MJD patients and 42 healthy, non-related control individuals with similar age and sex was performed. Clinical evaluation was done with the ataxia scales SARA and NESSCA. Serum insulin, insulin-like growth factor 1 (IGF-1) and magnetic resonance imaging normalized volumetries of cerebellum and brain stem were also assessed. BMI was lower in SCA3/MJD patients when compared to controls (p?=?0.01). BMI was associated with NESSCA, expanded CAG repeat number (CAG)n, age of onset, age, disease duration, and serum insulin levels; however, in the linear regression model, (CAG)n was the only variable independently associated with BMI, in an inverse manner (R?=?-0.396, p?=?0.015). In this report, we present evidence that low BMI is not only present in SCA3/MJD, but is also directly related to the length of the expanded CAG repeats, which is the causative mutation of the disease. This association points that weight loss might be a primary disturbance of SCA3/MJD, although further detailed analyses are necessary for a better understanding of the nutritional deficit and its role in the pathophysiology of SCA3/MJD.     

Searching for modulating effects of SCA2, SCA6 and DRPLA CAG tracts on the Machado-Joseph disease (SCA3) phenotype

CONTEXT: Machado-Joseph disease (MJD/SCA3) is an autosomal dominant cerebellar ataxia of adult onset. The variability in age at onset and the complex and heterogeneous neurologic findings indicate that MJD, caused by a major gene, is modulated by modifier factors. OBJECTIVE: To study if the polymorphic CAG repeats at other loci (namely, SCA2, SCA6 and DRPLA) thus acted as modifier factors of this disease. DESIGN: Case-control. SETTING: Ambulatory care in a referral center. PATIENTS: A convenience sample of 39 unrelated, Brazilian patients with MJD. Main outcome measures: age of onset, anticipation, clinical subtypes and neurological findings. RESULTS: Fasciculations were associated with CAG repeat length of the long SCA2 allele (Mann-Whitney U-test, P < 0.03, after Bonferroni procedure). Other measures (age of onset, anticipation, clinical types and other neurological signs) were not associated with CAG repeat length of SCA2, SCA6 and DRPLA genes. CONCLUSIONS: The present results show that the CAG tract of SCA2 gene interferes with MJD phenotype. Further studies, with patients of other origins and with typing of other (CAG)n loci, are necessary.     

Spinocerebellar ataxia 3 and machado-joseph disease: Clinical,molecular, and neuropathological features

Patients with spinocerebellar ataxia 3 (SCA3) and Machado-Joseph disease (MJD) carry an expanded CAG repeat in the MJDl gene. One hundred twenty families of different geographic origin with autosomal dominant cerebellar ataxia (ADCA) type I were tested. Thirty-four families (126 patients) carried an expanded CAG repeat. The expanded and the normal allele did not overlap and the repeat was unstable during transmission, with variation in the size of the CAG length ranging from ?8 to +5 and a mean expansion of 0.86 repeats without differences according to the parental sex. There was a combined effect of the number of CAG repeats of the expanded and normal allele on the age at onset, which accounted for 70% of its variability. The length of the CAG repeat influenced the frequency of clinical signs associated with cerebellar ataxia, such as abnormal tendon reflexes or decreased vibration sense, whereas the interindividual variation of supranuclear ophthalmoplegia, sphincter and swallowing difficulties, and amyotrophy was mostly determined by different disease durations. We compared the clinical profile of 91 SCA3/MJD patients with 51 SCAl and 32 SCA2 patients. There were striking differences between the SCA3/MJD and SCA2 but not with SCAl groups of patients. Despite their clinical similarities, distinct neuropathological features were observed in 2 SCA3/MJD and SCAl patients.     

Prospective study of peripheral neuropathy in Machado–Joseph disease

Peripheral neuropathy (PN) has long been recognized in Machado–Joseph disease (MJD), but its natural history is an unsettled issue. Therefore, we prospectively assessed 40 with MJD for 13 months with nerve conduction (NC) studies and the revised total neuropathy score (TNSr) to study the progression of PN. There was no significant change in the TNSr score over the follow‐up period. In contrast, the average sural sensory nerve action potential (SNAP) amplitude decreased significantly over the same interval from a mean of 13.2 μV to 9.8 μV (P < 0.001). There was an inverse correlation between the change in the sural SNAP amplitude and the length of the CAG triplet repeat expansion (r = 0.574, P < 0.001). The reduction in the mean sural SNAP amplitude also correlated with progression of ataxia. This indicates that PN progresses faster in individuals with larger (CAG)_n expansions, and nerve conduction studies may be useful to study disease progression in MJD. Muscle Nerve, 2009     

Restless legs syndrome in spinocerebellar ataxia types 1, 2, and 3

To identify the prevalence and determinants of restless legs syndrome (RLS) in spinocerebellar ataxia (SCA) we studied 58 patients with a molecular diagnosis of SCA1, SCA2 and SCA3. Data on the symptoms of RLS were collected by a standardized questionnaire, and RLS was diagnosed when patients met the four minimal criteria of the syndrome as recently defined by an international study group. In addition, we studied the relationship between RLS and age, age at ataxia onset, CAG repeat length, and nerve conduction and evoked potentials data. RLS was significantly more frequent in SCA patients than in controls (28 % vs. 10 %). Age at RLS onset in SCA was 49.0 ± 10.9 years. There were no significant differences in nerve conduction or evoked potentials between RLS and non-RLS SCA patients. The probability of developing RLS increased with age but not with CAG repeat length or higher age of ataxia onset. The data provide evidence that patients with SCA1, SCA2 and SCA3 are per se more susceptible to RLS than non-affected individuals. The probability of developing RLS is related principally to the period over which the CAG repeat mutation exerts its effect and not to CAG repeat length or age of ataxia onset. Received: 18 July 2000, Received in revised form: 10 November 2000, Accepted: 15 November 2000     

High body mass and kidney dysfunction relate to worse nerve function,even in adults without neuropathy

Polyneuropathy is a prevalent and disabling disorder. Despite extensive evaluation, the cause often remains unknown. Factors that predispose for the development of polyneuropathy need to be identified. We investigated the effect of anthropometric and metabolic factors on peripheral nerve function in 908 participants of the population‐based Rotterdam Study without any symptoms or signs of polyneuropathy. Participants underwent nerve conduction studies of the sural and peroneal nerve. Data on age, height, weight, waist circumference, diabetes, lipid levels, hypertension, and kidney function were collected. Regression analyses were used to investigate determinants of nerve action potential amplitudes. The frequency of abnormal sural sensory nerve action potential (SNAP) amplitudes increased with age from 1% under 60 years to 23% over 80 years. Similarly, the frequency of abnormal peroneal nerve compound motor action potential (CMAP) amplitudes increased from 4% to 13%. High weight and body mass index were independently associated with reduced sural SNAP amplitudes and peroneal CMAP amplitudes. Participants with hypertension and kidney dysfunction were more likely to have abnormal sural SNAP amplitudes. Older age, high weight, hypertension, and moderate kidney dysfunction might thus lead to peripheral nerve dysfunction in persons yet without symptoms or signs of polyneuropathy.     

Sleep apnea in Machado-Joseph disease: a clinical and polysomnographic evaluation

Objective/BackgroundMachado-Joseph disease (MJD) or spinocerebellar ataxia type 3 (SCA3) is the most common type of autosomal dominant spinocerebellar ataxia (SCA). Sleep disorders have been described as frequent non-motor symptoms in MJD, and with marked impairment on quality of life. However, few studies have evaluated the frequency and characteristics of sleep apnea in MJD.Patients/MethodsThis study analyzed the prevalence of sleep apnea in 47 patients with MJD by using polysomnography. Clinical variables such as age, age at onset of symptoms, duration of symptoms (at time of evaluation), body index mass, ataxia scales severity and CAG repeat length were compared with polysomnographic findings.ResultsThirty four percent of MJD patients had OSAS, and 42.5% had excessive daytime somnolence. There were no differences considering ataxia severity, CAG repetition length or other clinical variable.ConclusionsPatients with MJD have high frequency of obstructive sleep apnea, and this sleep disorder is not correlated with ataxia severity, CAG repetition length or other clinical variable.     

Spinocerebellar ataxia type 3/Machado-Joseph disease starting before adolescence

Onset of Machado-Joseph disease (SCA3/MJD) before adolescence has been rarely reported. This study aims to describe a cohort of SCA3/MJD with onset before 12 years of age, comparing their disease progression with the progression observed in patients with usual disease onset. We identified all cases from our cohort whose onset was before adolescence. After consent, patients were examined with clinical scales Scale for the Assessment and Rating of Ataxia (SARA) and Neurological Examination Score for Spinocerebellar Ataxia (NESSCA). Gender, age, age at onset, disease duration, CAG expanded repeats, transmitting parent, and anticipation of cases with infantile and adult onset were studied. Progression of NESSCA and SARA scores was estimated through a mixed model, and was compared with a historical group with onset after adolescence. Between 2000 and 2014, 461 symptomatic individuals from our region were diagnosed as SCA3/MJD. Onset of eight cases (2.2 %), all heterozygotes, was before adolescence: seven were females (p?=?0.054). CAG expanded repeats—75?±?3 versus 84?±?4—and anticipations—7?±?9.7 versus 14.4?±?7.2 years—were different between early childhood and adult onset groups (p?<?0.03). The median survival of early childhood onset group was 23 years of age. The annual progression of SARA—2.3 and 0.6 points/year (p?=?0.001)—and NESSCA—2.04 and 0.88 points/year (p?=?0.043)—was faster in childhood than in adult onset group. Onset of SCA3/MJD before adolescence was related to larger expanded CAG repeats in heterozygosis; females seemed to be at higher risk. Disease progression was faster than in SCA3/MJD starting after 12 years.     

Double-blind crossover trial of trimethoprim-sulfamethoxazole in spinocerebellar ataxia type 3/Machado-Joseph disease

OBJECTIVE: To evaluate the efficiency of a combination of trimethoprim and sulfamethoxazole in patients with spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD). DESIGN: Placebo-controlled, double-blind crossover trial in 22 patients with genetically confirmed SCA3/MJD. Study phases of 6 months were separated by a washout period of 4 weeks. Dosages were a combination of trimethoprim, 160 mg, and sulfamethoxazole, 800 mg, twice daily for 2 weeks, followed by a combination of trimethoprim, 80 mg, and sulfamethoxazole, 400 mg, twice daily for 5.5 months. SETTING: Outpatient department of the Neurological Clinic, Ruhr-University, Bochum, Germany. MAIN OUTCOME MEASURES: Ataxia ranking scale, self-assessment score, static posturography, and results of motor performance testing. Effects on the visual system were studied using the achromatic Vision Contrast Test System and the Farnsworth-Munsell 100-hue test for color discrimination. Physical and mental health were documented using the Medical Outcomes Study 36-Item Short-Form Health Survey. Subgroup analyses assessed the influence of age, sex, age at onset, duration of the disease, phenotype, and CAG repeat length on test performance. RESULTS: Twenty of 22 patients completed the study. Dropouts were due to a rash (placebo phase) and an attempted suicide in a family conflict. Trimethoprim-sulfamethoxazole therapy had no significant effect in SCA3/MJD patients in the short-term analysis (2 weeks) or in the long-term interval (6 months). CONCLUSIONS: In contrast to previous reports that studied smaller groups of patients, treatment with trimethoprim-sulfamethoxazole did not improve the diverse and complex movement disorders caused by SCA3/MJD. Trimethoprim-sulfamethoxazole had no effect on the visual system and cannot be recommended as a continuous treatment for SCA3/MJD patients.     

Peripheral Neuropathy in Spinocerebellar Ataxia Type 1, 2, 3, and 6

Spinocerebellar ataxias (SCAs) are characterized by autosomal dominantly inherited progressive ataxia but are clinically heterogeneous due to variable involvement of non-cerebellar parts of the nervous system. Non-cerebellar symptoms contribute significantly to the burden of SCAs, may guide the clinician to the underlying genetic subtype, and might be useful markers to monitor disease. Peripheral neuropathy is frequently observed in SCA, but subtype-specific features and subclinical manifestations have rarely been evaluated. We performed a multicenter nerve conduction study with 162 patients with genetically confirmed SCA1, SCA2, SCA3, and SCA6. The study proved peripheral nerves to be involved in the neurodegenerative process in 82 % of SCA1, 63 % of SCA2, 55 % of SCA3, and 22 % of SCA6 patients. Most patients of all subtypes revealed affection of both sensory and motor fibers. Neuropathy was most frequently of mixed type with axonal and demyelinating characteristics in all SCA subtypes. However, nerve conduction velocities of SCA1 patients were slower compared to other genotypes. SCA6 patients revealed less axonal damage than patients with other subtypes. No influence of CAG repeat length or biometric determinants on peripheral neuropathy could be identified in SCA1, SCA3, and SCA6. In SCA2, earlier onset and more severe ataxia were associated with peripheral neuropathy. We proved peripheral neuropathy to be a frequent site of the neurodegenerative process in all common SCA subtypes. Since damage to peripheral nerves is readily assessable by electrophysiological means, nerve conduction studies should be performed in a longitudinal approach to assess these parameters as potential progression markers.     

Machado-Joseph disease/SCA3 and myotonic dystrophy type 1 in a single patient

We report here, for the first time, the case of a 41-year-old man with both Machado-Joseph disease (MJD)/spinocerebellar ataxia type 3 (SCA3) and myotonic dystrophy type 1. The patient noted dysarthria at 14 years of age and unsteady gait at 30 years of age. Similar sized expansions of the CAG trinucleotide repeats in one allele of the ataxin-3 (ATXN3) gene were found in both the patient and his father, although in the other allele the length of the CAG repeats was shorter in the father compared with the patient. In the dystrophia myotonica protein kinase (DMPK) gene the CTG repeats were much more expanded in the patient compared with his father. Thus it is possible that, in the farther, the short CAG repeat in the non-expanded ATXN3 allele delayed the onset of cerebellar symptoms, and/or that the expanded CTG repeat in the DMPK gene in the patient accelerated the pathogenesis of MJD/SCA3.     

Frequency of SCA1, SCA2, SCA3/MJD, SCA6, SCA7, and DRPLA CAG trinucleotide repeat expansion in patients with hereditary spinocerebellar ataxia from Chinese kindreds

OBJECTIVE: To assess the frequency of SCA1 (spinocerebellar ataxia type 1), SCA2, SCA3/MJD (spinocerebellar ataxia type 3/Machado-Joseph disease), SCA6, SCA7, and DRPLA (dentatorubropallidoluysian atrophy) CAG trinucleotide repeat expansions [(CAG)n] among persons diagnosed with hereditary SCA from Chinese families. PATIENTS AND METHODS: Spinocerebellar ataxia type 1, SCA2, SCA3/MJD, SCA6, SCA7, and DRPLA (CAG)n mutation were detected with the polymerase chain reaction, highly denaturing polyacrylamide gel electrophoresis, and silver staining technique in 167 patients with autosomal dominant SCA from 85 Chinese families and 37 patients with sporadic SCA. RESULTS: Spinocerebellar ataxia type 1 (CAG)n mutation in 7 patients from 4 kindreds (4.70%) was expanded to 53 to 62 repeats. Spinocerebellar ataxia type 2 (CAG)n mutation in 12 patients from 5 kindreds (5.88%) was expanded to 42 to 47 repeats. Spinocerebellar ataxia type 3/Machado-Joseph disease (CAG)n mutation in 83 patients from 41 kindreds (48.23%) was expanded to 68 to 83 repeats. Sixty-five patients from 35 kindreds (41.19%) and 37 patients with sporadic SCA did not test positive for SCA1, SCA2, SCA3/MJD, SCA6, SCA7, or DRPLA. There was a predictable inverse relationship between the number of CAG repeats and the age at onset for SCA3/MJD and SCA2. Clinically, dementia and hyporeflexia were more frequent in patients with SCA2, while spasticity, hyperreflexia, and Babinski signs were more frequent in patients with SCA3/ MJD, and those might be helpful in clinical work to primarily distinguish patients with SCA3/MJD and SCA2 from others with different types of SCA. CONCLUSIONS: The frequency of SCA3/MJD is substantially higher than that of SCA1 and SCA2 in patients with autosomal dominant SCA from Chinese kindreds, who are non-Portuguese. Clinical expressions of the various types of SCAs overlap one another; therefore, for clinical study it is important to make a gene diagnosis and genetic classification for patients with SCA.     

Autosomal dominant cerebellar ataxia type I in Morocco: presence of the SCA1 and SCA3/MJD mutations

We searched for CAG repeat expansions at the SCA1 and SCA3/MJD loci in nine families, including 15 examined patients, with autosomal dominant cerebellar ataxia type I from Morocco. Expansion of the CAG repeat was found in one family at the SCA1 and two at the SCA3/MJD locus, demonstrating the existence of genetic heterogeneity among ADCA type I families in Morocco. Instability during transmission was observed at both loci as in other unstable mutations. The phenotypes of the SCA1 and SCA3/MJD patients were similar.     

肌萎缩侧索硬化患者205例的神经传导特点分析

目的 分析肌萎缩侧索硬化(ALS)患者的神经传导和F波特点,并探讨其与肌力、病程和首发部位等之间的关系.方法 收集于1997年1月至2008年5月期间我院门诊或病房收治的ALS患者205例,均采用常规肌电图检查,测定其运动神经传导、F波以及感觉神经传导(SCV).结果 在205例ALS患者中,仅有3例SCV异常,正中神经、尺神经及胫后神经末端潜伏期(DML)延长者分别占24.9%(48/193)、15.3%(25/163)、21.2%(7/33),复合肌肉动作电位(CMAP)波幅下降者分别占57.0%(110/193)、49.7%(81/163)、39.4%(13/33);68.9%(122/177)患者F波出现率下降,其中31.1%(55/177)F波出现率为0,肌力下降者DML、CMAP波幅及F波出现率改变明显.肢体起病组正中神经CMAP波幅下降[81.5%(53/65)]和F波异常率[70.9%(44/62)出现率下降,45.1%(28/62)出现率为0]较延髓部起病者[32.4%(11/34);F波38.2%(13/34)出现率下降,14.7%(5/34)出现率为0]更明显,两组比较差异有统计学意义(x2=23.629、9.753、9.029,均P<0.01);DML异常两组间差异无统计学意义.Logistic回归分析显示CMAP波幅的降低与上肢远端肌力、首发部位、病程显著相关,F波出现率的降低与上肢远端肌力、首发部位相关.结论 ALS患者可出现DML延长和CMAP波幅降低(后者改变更显著),F波出现率明显下降而传导速度相对正常;DML、CMAP波幅及F波出现率的异常与肌力明显相关.首发部位为肢体和(或)上肢远端肌力下降者CMAP波幅及F波异常率更明显.

Abstract：

Objective To investigate the F-wave and nerve conduction in patients with amyotrophic lateral sclerosis (ALS) and explore the correlation between these parameters and muscle strength, disease duration and onset site.Methods The data of outpatients and inpatients diagnosed with ALS were collected in Peking Union Medical College Hospital from January 1997 to May 2008.Standard sensory and motor nerve conduction study of the median nerve, ulnar nerve and tibial nerve was performed in 205 patients with ALS.F-wave velocity and frequency was measured in median nerve.Parameters for analyses included sensory conduction velocity and amplitude, distal motor latency (DML), and compound muscle action potential (CMAP) amplitude.Correlation between muscle strength and DML, CMAP amplitude or F-wave frequency were also explored.Results Delayed DML of the median nerve, ulnar nerve and tibial nerve were found in 24.9% (48/193), 15.3% (25/163), 21.2% (7/33) of patients respectively.Decreased CMAP amplitudes were found in 57.0% (110/193), 49.7% (81/163), 39.4% (13/33) of patients respectively.Decreased F-wave frequency of the median nerve was found in 68.9% (122/177) of patients.The abnormality of DML,CMAP amplitude and F-wave frequency of median nerve were increased in weaker muscles.Decreased median nerve CMAP amplitude (81.5% (53/65)) and F-wave abnormality (decreased persistence 70.9%(44/62), absent responses 45.1% (28/62)) in spinal onset groups were significantly higher than those in bulbar onset groups (CMAP 32.4% (11/34); F-wave: decreased persistence 38.2% (13/34), absent responses 14.7% (5/34); x2 = 23.629, 9.753, 9.029,all P <0.01).Compared with the bulbar onset group,the abnormality of DML in spinal onset group was higher, but not reach statistical significance.Logistic regression revealed a strong direct association between decreased CMAP amplitudes and upperextremity muscles strength, disease duration and onset symptom.Abnormality of F-wave frequency was associated with upper-extremity muscles strength and onset symptom.Conclusions Delayed DML and decreased amplitude of CMAP are found in ALS patients.CMAP amplitude is a sensitive parameter related to the severity of ALS.F-wave velocity is relatively normal while F-wave frequency of the median nerve is correlated with muscle strength.Decreasing CMAP amplitude and F-wave frequency are correlated strongly with muscle weakening,disease duration and symptom onset over limbs.     

Compound sensory action potential in normal and pathological human nerves

The compound sensory nerve action potential (SNAP) is the result of phase summation and cancellation of single fiber potentials (SFAPs) with amplitudes that depend on fiber diameter, and the amplitude and shape of the SNAP is determined by the distribution of fiber diameters. Conduction velocities at different conduction distances are determined by summation of SFAPs of varying fiber diameters, and differ in this respect, also, from the compound muscle action potential (CMAP) for which conduction velocities are determined by the very fastest fibers in the nerve. The effect and extent of temporal dispersion over increasing conduction distance is greater for the SNAP than CMAP, and demonstration of conduction block is therefore difficult. In addition, the effect of temporal dispersion on amplitude and shape is strongly dependent on the number of conducting fibers and their distribution, and, with fiber loss or increased conduction velocity variability changes of the SNAP may be smaller than expected from normal nerve. The biophysical characteristics of sensory and motor fibers differ, and this may to some extent determine divergent pathophysiological changes in sensory and motor fibers in different polyneuropathies. In this review, different factors that characterize sensory fibers and set the SNAP apart from the CMAP are discussed to emphasize the supplementary and complementary information that can be obtained from sensory conduction studies. Sensory conduction studies require particular effort and attention to theory and practical detail that may be time consuming.     

Peripheral nerve abnormalities in pediatric patients with spinal muscular atrophy

We examined the specific nerve conduction deficits distinguishing spinal muscular atrophy (SMA) subtypes I and II. Five SMA I patients (age, 0.2–1.1 years) and 10 SMA II patients (age, 1.0–2.8 years) were examined. Patients were compared to age-matched controls for motor and sensory conduction velocity (MCV and SCV) changes, compound muscle and sensory nerve action potential amplitudes (CMAP and SNAP), and F-wave occurrence (FO). Slower MCVs were found in three of five SMA I patients; all five exhibited markedly decreased CMAP amplitudes. Tibial nerve CMAP amplitudes significantly reduced in SMA II patients (p < 0.01). Slower SCVs and decreased SNAP amplitudes were observed in three of five SMA I patients but not in SMA II patients. Although FOs were reduced in both extremities of SMA I patients, the reduction was prominent in the tibial nerve of SMA II patients (p = 0.031). Loss of motor units may be widespread in the early stage of SMA I, while specific to the legs in young SMA II patients. SMA I showed sensory nerve degeneration, especially of large myelinated fibers. SMA II showed no sensory nerve abnormalities.     

Relations between genotype and phenotype in German patients with the Machado-Joseph disease mutation.

OBJECTIVE: Machado-Joseph disease (MJD) is an autosomal dominant cerebellar ataxia with extensive phenotypic variability originally described in families of Portuguese ancestry. Recently, the mutation causing the disease has been identified as an expanded CAG trinucleotide repeat. In this study relations between genotype and phenotype were investigated. METHODS: A series of 180 German patients with degenerative forms of ataxia were clinically and genetically examined. Patients bearing the MJD mutation were assigned to three phenotypes: phenotype 1 characterised by early onset and dystonia or pronounced rigidity associated with ataxia and spasticity. Main symptoms in phenotype 2 were ataxia and spasticity. In phenotype 3 onset was relatively late and peripheral neuropathy accompanied ataxia. Clinical and molecular data were correlated. RESULTS: An expanded CAG array was found in 42 patients from 22 families. Repeat length of CAG varied between 67 and 80 CAG motifs and showed an inverse correlation with the age of onset. For the development of phenotype 1 early onset (< 20 years) seemed more decisive than extensive repeat length. Phenotype 2 was present in all patients with more than 73 CAG motifs and onset between 20 and 40. Phenotype 3 developed in most patients with less than 73 CAG motifs and onset was regularly beyond the age of 40. Intrafamilial variability of both repeat length and phenotype was large reflecting meiotic instability of the expanded CAG repeat. CONCLUSIONS: The MJD mutation is the most frequent cause of dominantly inherited ataxia in Germany. Variations in repeat lengths substantially influence age of onset as well as phenotype but cannot explain why MJD characteristics of Portuguese families such as "bulging eyes", dystonia, and rigidity are essentially missing in German families. Despite the genotypic and phenotypic relations found in this study a reliable individual prognosis of the course of the disease is not possible at a presymptomatic stage.     

Comparison of CMT1A and CMT2: similarities and differences

To evaluate the clinical and electrophysiological similarities and differences between two large groups of patients with Charcot-Marie-Tooth disease, i.e. CMT1A and CMT2, we performed a post hoc comparison of clinical and electrophysiological data.Most CMT1A and CMT2 patients had the classical CMT phenotype. Age of onset was significantly later in CMT2. Total areflexia was present in approximately half of the CMT1A patients whereas it was rare in CMT2. Foot deformities and weakness of knee extensor and foot dorsal flexor muscles were more frequent in CMT1A. Median nerve motor nerve conduction velocities (MNCV) were always less than 38 m/s in CMT1A patients, whereas this was also the case in 16% of the CMT2 patients. Sensory nerve conduction velocities showed less overlap. In both CMT1A and CMT2 CMAP and SNAP amplitudes were often reduced or not obtainable in the legs. In CMT1A, SNAP amplitude was more reduced and SNAP duration more prolonged than in CMT2.We conclude that there are no robust clinical signs or symptoms that differentiate between CMT1A and CMT2 patients. Electrodiagnostical studies show a length-dependent motor and sensory axonal dysfunction in both CMT-types. Additional SNAP and SNCV evaluation may be helpful in focusing molecular genetic analysis in the occasional case of CMT2 showing slow motor nerve conduction velocities overlapping with CMT1A values. The reduction of CMAP and SNAP amplitudes in CMT1A is probably a combined effect of demyelination and axonal dysfunction.     

Early symptoms in spinocerebellar ataxia type 1, 2, 3, and 6

Onset of genetically determined neurodegenerative diseases is difficult to specify because of their insidious and slowly progressive nature. This is especially true for spinocerebellar ataxia (SCA) because of varying affection of many parts of the nervous system and huge variability of symptoms. We investigated early symptoms in 287 patients with SCA1, SCA2, SCA3, or SCA6 and calculated the influence of CAG repeat length on age of onset depending on (1) the definition of disease onset, (2) people defining onset, and (3) duration of symptoms. Gait difficulty was the initial symptom in two‐thirds of patients. Double vision, dysarthria, impaired hand writing, and episodic vertigo preceded ataxia in 4% of patients, respectively. Frequency of other early symptoms did not differ from controls and was regarded unspecific. Data about disease onset varied between patients and relatives for 1 year or more in 44% of cases. Influence of repeat length on age of onset was maximum when onset was defined as beginning of permanent gait disturbance and cases with symptoms for more than 10 years were excluded. Under these conditions, CAG repeat length determined 64% of onset variability in SCA1, 67% in SCA2, 46% in SCA3, and 41% in SCA6 demonstrating substantial influence of nonrepeat factors on disease onset in all SCA subtypes. Identification of these factors is of interest as potential targets for disease modifying compounds. In this respect, recognition of early symptoms that develop before onset of ataxia is mandatory to determine the shift from presymptomatic to affected status in SCA. © 2008 Movement Disorder Society