P. Tonali

Different mutations in the LMNA gene cause autosomal dominant and autosomal recessive Emery-Dreifuss muscular dystrophy.

Emery-Dreifuss muscular dystrophy (EMD) is a condition characterized by the clinical triad of early-onset contractures, progressive weakness in humeroperoneal muscles, and cardiomyopathy with conduction block. The disease was described for the first time as an X-linked muscular dystrophy, but autosomal dominant and autosomal recessive forms were reported. The genes for X-linked EMD and autosomal dominant EMD (AD-EMD) were identified. We report here that heterozygote mutations in LMNA, the gene for AD-EMD, may cause diverse phenotypes ranging from typical EMD to no phenotypic effect. Our results show that LMNA mutations are also responsible for the recessive form of the disease. Our results give further support to the notion that different genetic forms of EMD have a common pathophysiological background. The distribution of the mutations in AD-EMD patients (in the tail and in the 2A rod domain) suggests that unique interactions between lamin A/C and other nuclear components exist that have an important role in cardiac and skeletal muscle function.

Neurophysiological classification and sensitivity in 500 carpal tunnel syndrome hands

Objectives‐ To evaluate the following points about carpal tunnel syndrome (CTS): 1) characterization of a wide population; 2) sensitivity of electrodiagnostic tests, and particularly the contribution of disto‐proximal ratio test; 3) validity of a neurophysiological classification developed by us. Material and methods ‐ Prospective study in 500 hands with CTS symptoms. Neurophysiological “standard” tests were always performed: sensory nerve conduction velocity (SNCV) first‐ and third digit‐wrist and distal motor latency (DML). In “standard negative” hands disto‐proximal ratio technique (R) was performed. Neurophysiological classification: Extreme CTS (absence of median motor, sensory responses), Severe (absence of sensory response, abnormal DML), Moderate (abnormal SNCV, abnormal DML), Mild (abnormal SNCV, normal DML), Minimal (abnormal R or other segmental/comparative test, normal standard tests). Results‐ Sensibility of standard tests: 77%. R increased the diagnostic yield by 20%. CTS classification appeared reliable with significant differences between groups. Conclusion ‐ R is a useful test, the classification may be useful in clinical/therapeutical decisions.

Coenzyme Q10 reverses pathological phenotype and reduces apoptosis in familial CoQ10 deficiency

Two brothers with myopathic coenzyme Q10 (CoQ10) deficiency responded dramatically to CoQ10 supplementation. Muscle biopsies before therapy showed ragged-red fibers, lipid storage, and complex I + III and II + III deficiency. Approximately 30% of myofibers had multiple features of apoptosis. After 8 months of treatment, excessive lipid storage resolved, CoQ10 level normalized, mitochondrial enzymes increased, and proportion of fibers with TUNEL-positive nuclei decreased to 10%. The authors conclude that muscle CoQ10 deficiency can be corrected by supplementation of CoQ10, which appears to stimulate mitochondrial proliferation and to prevent apoptosis.

Multiperspective follow-up of untreated carpal tunnel syndrome A multicenter study

Objective: To assess the course of untreated carpal tunnel syndrome (CTS). Methods: The Italian CTS Study Group prospectively followed up (10 to 15 months) 196 untreated patients (274 hands) with idiopathic CTS with multiple measurements of CTS. Baseline factors were used to predict the evolution of untreated CTS in multiple regression analysis. Results: Comparison of baseline and follow-up data showed a significant spontaneous improvement of patient-oriented and neurophysiologic measurements. A significant correlation between evolution and initial severity of CTS was observed. CTS measurements improved in patients with more severe initial impairment whereas they worsened in patients with milder initial impairment. The main positive prognostic factor was short duration of symptoms. Similarly, spontaneous improvement was more frequently associated with young age. Conversely, baseline bilateral symptoms and positive Phalen predicted a poor prognosis. Conclusions: Some patients with CTS improve spontaneously without surgical treatment.

A systematic review of conservative treatment of carpal tunnel syndrome

Objective : To assess the effectiveness of conservative therapy in carpal tunnel syndrome. Data sources : A computer-aided search of MEDLINE and the Cochrane Collaboration was conducted for randomized controlled trials (RCTs) from January 1985 to May 2006. Review methods : RCTs were included if: (1) the patients, with clinically and electrophysiologically confirmed carpal tunnel syndrome, had not previously undergone surgical release, (2) the efficacy of one or more conservative treatment options was evaluated, (3) the study was designed as a randomized controlled trial. Two reviewers independently selected the studies and performed data extraction using a standardized form. In order to assess the methodological quality, the criteria list of the Cochrane Back Review Group for systematic reviews was applied. The different treatment methods were grouped (local injections, oral therapies, physical therapies, therapeutic exercises and splints). Results : Thirty-three RCTs were included in the review. The studies were analysed to determine the strength of the available evidence for the efficacy of the treatment. Our review shows that: (1) locally injected steroids produce a significant but temporary improvement, (2) vitamin B6 is ineffective, (3) steroids are better than non-steroidal anti-inflammatory drugs (NSAIDs) and diuretics, but they can produce side-effects, (4) ultrasound is effective while laser therapy shows variable results, (5) exercise therapy is not effective, (6) splints are effective, especially if used full-time. Conclusion : There is: (1) strong evidence (level 1) on efficacy of local and oral steroids; (2) moderate evidence (level 2) that vitamin B6 is ineffective and splints are effective and (3) limited or conflicting evidence (level 3) that NSAIDs, diuretics, yoga, laser and ultrasound are effective whereas exercise therapy and botulinum toxin B injection are ineffective.

Multiperspective assessment of carpal tunnel syndrome A multicenter study

Objective: To assess the clinical and neurophysiologic dissociation often observed in clinical practice, and to improve patient evaluation for diagnosis of carpal tunnel syndrome (CTS). Methods: The Italian CTS Study Group studied 1,123 idiopathic CTS hands with multiple measurements—clinical, neurophysiologic, and patient-oriented—of CTS. Results: Clinical and neurophysiologic relationships were very strong when the clinical picture was evaluated by the hand functional measurements, with an exponential increase in functional impairment as the classification of neurophysiologic severity progressed. Conversely, symptoms and pain did not increase as the classification of neurophysiologic severity progressed: 1) A large part of the CTS population complained of severe symptoms, although minimal functional impairment and minimal or no electrophysiologic abnormalities were observed; and 2) symptoms improved in the patients with more severe neurophysiologic and clinical examination scenarios. Conclusions: Multiperspective and multimeasurement assessment, even when using a validated patient-oriented tool, provided interesting information that confirmed and clarified the clinical neurophysiologic dissociation often observed in carpal tunnel syndrome (CTS) patients. Furthermore, CTS appeared to be an ideal model for evaluating the importance of patient-oriented measurement.

Long-term follow up of subthalamic nucleus stimulation in Parkinson’s disease

Twenty-two patients with PD received bilateral implants for high frequency stimulation of the subthalamic nucleus. The patients were treated for more than 1 year (up to 36 months). At the last visit, the Unified Parkinson Disease Rating Scale (UPDRS) motor score without medication improved by 50.2% (p < 0.001) and the UPDRS activities of daily living score improved by 68.4% (p < 0.001). The most common long-lasting adverse events were hypophonia and dysarthria; transient events were increased sexuality and mania. The surgical procedure induced transient intraoperative psychosis in seven patients.

Course and treatment of myasthenia gravis during pregnancy

Objective: To evaluate the influence of myasthenia gravis (MG) on pregnancy and potential treatment risks for infants and mothers. Background: MG frequently affects young women in the second and third decades of life, overlapping with the childbearing years. Knowledge of the potential effects of 1) pregnancy on the course of MG and 2) the use of immunosuppressive drugs during pregnancy is limited, rendering decision-making difficult for both patient and physician. Methods: We studied 47 women who became pregnant after the onset of MG. Immunosuppressive drugs were administered when MG symptoms were not controlled with anticholinesterases. Sixty-four pregnancies resulted in 55 children and 10 abortions. Results: During pregnancy, MG relapsed in 4 of 23 (17%) asymptomatic patients who were not on therapy before conception; in patients taking therapy, MG symptoms improved in 12 of 31 pregnancies (39%), remained unchanged in 13 (42%), and deteriorated in 6 (19%). MG symptoms worsened after delivery in 15 of 54 (28%) pregnancies. Anti-acetylcholine receptor antibody (anti-AChR ab) was positive in 40 of 47 mothers and was assayed in 30 of 55 newborns; 13 were positive and 5 of 55 (9%) showed signs of neonatal MG (NMG). All affected babies were seropositive. Conclusions: Pregnancy does not worsen the long-term outcome of MG. The course of the disease is highly variable and unpredictable during gestation and can change in subsequent pregnancies. The occurrence of NMG does not correlate with either maternal disease severity or anti-AChR antibody titer. Immunosuppressive therapy, plasmapheresis, and IV human immunoglobulins can be administered safely if needed.

Dominantly inherited mitochondrial myopathy with multiple deletions of mitochondrial DNA: clinical, morphologic, and biochemical studies.

We studied a large family with a dominantly inherited mitochondrial myopathy characterized by progressive external ophthalmoplegia, dysphagia, cataract, lactic acidosis, exercise intolerance, and early death. Morphologic studies of muscle biopsies suggested mitochondrial heteroplasmy and revealed ragged-red fibers and decreased histochemical reactions for cytochrome c oxidase and succinate dehydrogenase. Biochemistry showed a partial defect of cytochrome c oxidase and a mild generalized reduction of other mitochondrial enzymes requiring mitochondrial DNA-encoded subunits. Southern blot analysis and PCR amplification showed mitochondrial DNA deletions in muscle of all affected members, but not in lymphocytes or fibroblasts, suggesting a tissue-specific distribution. Deletions were multiple and seemed to increase with time and to correlate with the severity of the disease.

Genetic homogeneity between childhood-onset and adult-onset autosomal recessive spinal muscular atrophy

Molecular diagnosis of childhood proximal spinal muscular atrophy has been enhanced by the discovery of the survival motor neuron (SMN) gene, which is absent or truncated in 98.6% of patients. To determine whether deletion analysis of the SMN gene may also be diagnostic for adult-onset disease, we studied six patients and found deletions in all. This finding will facilitate the diagnosis of adult-onset spinal muscular atrophy, and provides evidence for genetic homogeneity between the clinically diverse adult and childhood forms of the disease.