Severe Dizziness and Hypereosinophilia: Coincidence or Complication? A Case Report.

Hypereosinophilia is a common issue in medicine. One rare cause is myeloproliferative neoplasm with PDGFRA rearrangement. In these patients, the gold standard for therapy is low-dose imatinib. We present the case of a patient with a new diagnosis of myeloproliferative neoplasm following an unconventional diagnostic pattern, which developed clinically relevant unexplained dizziness a week after starting treatment. Our case presented with lower back pain and multiple bone lesions at MRI investigation. Bone marrow and cytogenetic analysis led to the diagnosis of myeloproliferative neoplasm with PDGFRA rearrangement. We started a treatment with a tyrosine kinase inhibitor (imatinib), and the patient noticed an onset of severe, persistent and intense dizziness, which was more intense with closed eyes. Diagnostic tests were not conclusive, and dizziness persisted at 48 months of follow-up. In conclusion, clinically relevant dizziness was never described in patients with myeloproliferative neoplasm. Even if the exact physiopathological mechanism is not clear, clinicians should know that hypereosinophilia could lead to central nervous system damage.

Expanding the importance of HMERF titinopathy: new mutations and clinical aspects.

OBJECTIVE: Hereditary myopathy with early respiratory failure (HMERF) is caused by titin A-band mutations in exon 344 and considered quite rare. Respiratory insufficiency is an early symptom. A collection of families and patients with muscle disease suggestive of HMERF was clinically and genetically studied. METHODS: Altogether 12 new families with 19 affected patients and diverse nationalities were studied. Most of the patients were investigated using targeted next-generation sequencing; Sanger sequencing was applied in some of the patients and available family members. Histological data and muscle MRI findings were evaluated. RESULTS: Three families had several family members studied while the rest were single patients. Most patients had distal and proximal muscle weakness together with respiratory insufficiency. Five heterozygous TTN A-band mutations were identified of which two were novel. Also with the novel mutations the muscle pathology and imaging findings were compatible with the previous reports of HMERF. CONCLUSIONS: Our collection of 12 new families expands mutational spectrum with two new mutations identified. HMERF is not that rare and can be found worldwide, but maybe underdiagnosed. Diagnostic process seems to be complex as this study shows with mostly single patients without clear dominant family history.

Interpreting Genetic Variants in Titin in Patients With Muscle Disorders.

Importance: Mutations in the titin gene (TTN) cause a wide spectrum of genetic diseases. The interpretation of the numerous rare variants identified in TTN is a difficult challenge given its large size. Objective: To identify genetic variants in titin in a cohort of patients with muscle disorders. Design, Setting, and Participants: In this case series, 9 patients with titinopathy and 4 other patients with possibly disease-causing variants in TTN were identified. Titin mutations were detected through targeted resequencing performed on DNA from 504 patients with muscular dystrophy, congenital myopathy, or other skeletal muscle disorders. Patients were enrolled from 10 clinical centers in April 2012 to December 2013. All of them had not received a diagnosis after undergoing an extensive investigation, including Sanger sequencing of candidate genes. The data analysis was performed between September 2013 and January 2017. Sequencing data were analyzed using an internal custom bioinformatics pipeline. Main Outcomes and Measures: The identification of novel mutations in the TTN gene and novel patients with titinopathy. We performed an evaluation of putative causative variants in the TTN gene, combining genetic, clinical, and imaging data with messenger RNA and/or protein studies. Results: Of the 9 novel patients with titinopathy, 5 (55.5%) were men and the mean (SD) age at onset was 25 (15.8) years (range, 0-46 years). Of the 4 other patients (3 men and 1 woman) with possibly disease-causing TTN variants, 2 (50%) had a congenital myopathy and 2 (50%) had a slowly progressive distal myopathy with onset in the second decade. Most of the identified mutations were previously unreported. However, all the variants, even the already described mutations, require careful clinical and molecular evaluation of probands and relatives. Heterozygous truncating variants or unique missense changes are not sufficient to make a diagnosis of titinopathy. Conclusions and Relevance: The interpretation of TTN variants often requires further analyses, including a comprehensive evaluation of the clinical phenotype (deep phenotyping) as well as messenger RNA and protein studies. We propose a specific workflow for the clinical interpretation of genetic findings in titin.

Enhancing clinical decisions about care through a pre-consultation sheet that captures patients' views on their health conditions and treatments: A qualitative study in the field of chronic pain.

OBJECTIVE: This study examined whether and how a pre-consultation sheet (PCS) that captures patients' views on their condition and treatments can facilitate doctors in identifying targets for medical advice. METHODS: A PCS in the form of a list of questions was developed and implemented in chronic pain consultations. Its value was examined through video-recordings and post-consultation interviews with doctors and patients. RESULTS: Doctors reported that the PCS helped them identify topics that required further discussion with patients, unexpected information, patients' expectations on outcomes, and their attitudes and beliefs about treatments. Patients reported that the PCS helped them collect and structure their views, reduced their anxiety regarding the encounter, and created a setting in which they felt heard. CONCLUSION: The PCS captures patients' views that are valuable in helping doctors identify targets of intervention. It focuses on aspects that matter to patients and that enrich information sharing beyond medical records. PRACTICE IMPLICATIONS: Addressing patients' views on health conditions and treatments facilitates doctors and patients in defining targets for intervention. It assists doctors in tailoring their advice and helps patients present their case. A PCS seems to be a feasible and acceptable instrument to support doctors and patients in this information sharing.

Maintenance of Wakefulness Test scores and driving performance in sleep disorder patients and controls.

OBJECTIVE: Sleepiness at the wheel is a risk factor for traffic accidents. Past studies have demonstrated the validity of the Maintenance of Wakefulness Test (MWT) scores as a predictor of driving impairment in untreated patients with obstructive sleep apnea syndrome (OSAS), but there is limited information on the validity of the maintenance of wakefulness test by MWT in predicting driving impairment in patients with hypersomnias of central origin (narcolepsy or idiopathic hypersomnia). The aim of this study was to compare the MWT scores with driving performance in sleep disorder patients and controls. METHODS: 19 patients suffering from hypersomnias of central origin (9 narcoleptics and 10 idiopathic hypersomnia), 17 OSAS patients and 14 healthy controls performed a MWT (4×40-minute trials) and a 40-minute driving session on a real car driving simulator. Participants were divided into 4 groups defined by their MWT sleep latency scores. The groups were pathological (sleep latency 0-19 min), intermediate (20-33 min), alert (34-40 min) and control (>34 min). The main driving performance outcome was the number of inappropriate line crossings (ILCs) during the 40 minute drive test. RESULTS: Patients with pathological MWT sleep latency scores (0-19 min) displayed statistically significantly more ILC than patients from the intermediate, alert and control groups (F (3, 46)=7.47, p<0.001). INTERPRETATION: Pathological sleep latencies on the MWT predicted driving impairment in patients suffering from hypersomnias of central origin as well as in OSAS patients. MWT is an objective measure of daytime sleepiness that appears to be useful in estimating the driving performance in sleepy patients.

Pilot trial of clenbuterol in spinal and bulbar muscular atrophy.

OBJECTIVE: To test the efficacy and tolerability of clenbuterol in patients with spinal and bulbar muscular atrophy (SBMA). METHODS: Twenty patients with a diagnosis of SBMA were given oral clenbuterol (0.04 mg/d) for 12 months. The primary efficacy end point was the change from baseline of the walking distance covered in 6 minutes at 12 months. Secondary end points included the change over time in muscle strength assessed with the Medical Research Council scale, the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R), and forced vital capacity values. Safety was assessed by a series of laboratory and instrumental tests, as well as reporting of adverse events. RESULTS: Sixteen patients completed the study. There was a significant and sustained increase in walking distance covered in 6 minutes and forced vital capacity between the baseline and the 12-month assessments (p < 0.001). No differences were recorded in Medical Research Council or ALSFRS-R scores between baseline and follow-up assessments. Serious side effects, including those on heart function, were absent. A significant increase in serum creatine kinase levels was observed. CONCLUSIONS: Our findings suggest a positive effect of clenbuterol on SBMA disease progression. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that clenbuterol is effective in improving motor function in SBMA.

Myotonia congenita: novel mutations in CLCN1 gene and functional characterizations in Italian patients.

Myotonia congenita is an autosomal dominantly or recessively inherited muscle disorder causing impaired muscle relaxation and variable degrees of permanent muscle weakness, abnormal currents linked to the chloride channel gene (CLCN1) encoding the chloride channel on skeletal muscle membrane. We describe 12 novel mutations: c.1606G>C (p.Val536Leu), c.2533G>A (p.Gly845Ser), c.2434C>T (p.Gln812X), c.1499T>G (p.E500X), c.1012C>T (p.Arg338X), c.2403+1G>A, c.2840T>A (p.Val947Glu), c.1598C>T (p.Thr533Ile), c.1110delC, c.590T>A (p.Ile197Arg), c.2276insA Fs800X, c.490T>C (p.Trp164Arg) in 22 unrelated Italian patients. To further understand the functional outcome of selected missense mutations (p.Trp164Arg, p.Ile197Arg and p.Gly845Ser, and the previously reported p.Gly190Ser) we characterized the biophysical properties of mutant ion channels in tsA cell model. In the physiological range of muscle membrane potential, all the tested mutations, except p.Gly845Ser, reduced the open probability, increased the fast and slow components of deactivation and affected pore properties. This suggests a decrease in macroscopic chloride currents impairing membrane potential repolarization and causing hyperexcitability in muscle membranes. Detailed clinical features are given of the 8 patients characterized by cell electrophysiology. These data expand the spectrum of CLCN1 mutations and may contribute to genotype-phenotype correlations. Furthermore, we provide insights into the fine protein structure of ClC-1 and its physiological role in the maintenance of membrane resting potential.

The novel mitochondrial tRNAAsn gene mutation m.5709T>C produces ophthalmoparesis and respiratory impairment.

Although mutations in mitochondrial tRNAs constitute the most common mtDNA defect, the presence of pathological variants in mitochondrial tRNA(Asn) is extremely rare. We were able to identify a novel mtDNA tRNA(Asn) gene pathogenic mutation associated with a myopathic phenotype and a previously unreported respiratory impairment. Our proband is an adult woman with ophthalmoparesis and respiratory impairment. Her muscle biopsy presented several cytochrome c oxidase-negative (COX-) fibres and signs of mitochondrial proliferation (ragged red fibres). Sequence analysis of the muscle-derived mtDNA revealed an m.5709T>C substitution, affecting mitochondrial tRNA(Asn) gene. Restriction-fragment length polymorphism analysis of the mutation in isolated muscle fibres showed that a threshold of at least 91.9% mutated mtDNA results in the COX deficiency phenotype. The new phenotype further increases the clinical spectrum of mitochondrial diseases caused by mutations in the tRNA(Asn) gene.