E-Health & Innovation to Overcome Barriers in Neuromuscular Diseases. Report from the 1st eNMD Congress: Nice, France, March 22-23, 2019.

By definition, neuromuscular diseases are rare and fluctuating in terms of symptoms; patients are often lately diagnosed, do not have enough information to understand their condition and be proactive in their management. Usually, insufficient resources or services are available, leading to patients' social burden. From a medical perspective, the rarity of such diseases leads to the unfamiliarity of the medical staff and caregiver and an absence of consensus in disease assessment, treatment, and management. Innovations have to be developed in response to patients' and physicians' unmet needs.It is vital to improve several aspects of patients' quality of life with a better comprehension of their disease, simplify their management and follow-up, help their caregiver, and reduce the social and economic burden for living with a rare debilitating disease. Database construction regrouping patients' data and symptoms according to specific country registration on data privacy will be critical in establishing a clear consensus on neuromuscular disease treatment.Clinicians also need technological innovations to help them recognize neuromuscular diseases, find the best therapeutic approach based on medical consensus, and tools to follow patients' states regularly. Diagnosis also has to be improved by implementing automated systems to analyze a considerable amount of data, representing a significant step forward to accelerate the diagnosis and the patients' follow up. Further, the development of new tools able to precisely measure specific outcomes reliably is of the matter of importance in clinical trials to assess the efficacy of a newly developed compound.In this context, creation of an expert community is essential to communicate and share ideas. To this end, 97 clinicians, healthcare professionals, researchers, and representatives of private companies from 9 different countries met to discuss the new perspective and challenges to develop and implement innovative tools in the field of neuromuscular diseases.

A novel neuromuscular syndrome associated with clenbuterol-tainted heroin.

BACKGROUND: Clenbuterol is a potent, long-acting beta-adrenergic agonist that has been reported as an adulterant of heroin. We describe an atypical syndrome in five users of clenbuterol-tainted heroin. METHODS: All cases were referred to a regional Poison Control Center. Urine and blood were analyzed using gas and liquid chromatography as well as mass spectrometry. CASE SERIES: Five heroin users presented with a syndrome characterized by muscular spasm, tremor, hyperreflexia, and elevated serum creatine phosphokinase concentrations. All patients lacked findings of acute clenbuterol toxicity but tested positive for clenbuterol and negative for strychnine and a battery of common potential adulterants. CONCLUSIONS: We report five cases of a novel neuromuscular syndrome in users of clenbuterol-adulterated heroin. It is unclear whether these reactions represent an atypical response to clenbuterol or another unidentified contaminant.

D-2-hydroxyglutaric aciduria with cerebral, vascular, and muscular abnormalities in a 14-year-old boy.

D-2-Hydroxyglutaric Aciduria is a rare metabolic disorder that can cause injury to the brain and other organs. This case report concerns a 14-year-old boy showing irritability and typical signs of pyloric stenosis early postnatally. From the age of 3 months he had epilepsy. He was mentally retarded, hypotonic with preserved reflexes, and dystonic. The features were dysmorphic with elongated head and high arched palate. Cardiomegaly with aortic insufficiency was diagnosed. Magnetic resonance imaging of the brain revealed atrophy, reduced periventricular white matter, and multiple bilateral aneurysms of the middle cerebral arteries. The boy died at the age of 14 years. Autopsy confirmed the white-matter reduction of the cerebral hemispheres as well as the arterial aneurysms of the middle cerebral arteries. Lesions of a few leptomeningeal and cerebral microvessels and of the renal and pulmonary arteries were also found. There were bilateral infarcts of the kidneys and signs of cardiomyopathy with noncompensated left ventricular failure. Signs of myopathy were evident. The clinical and postmortem findings imply a disseminated mesenchymal process.

Excretion of porphyrins and porphyrin precursors during neuromuscular paralysis produced by dithiobiuret.

Urinary excretion of porphyrin precursors delta-aminolevulinic acid (ALA) and porphobilinogen (PBG) and total porphyrins was measured during intoxication of rats with 2,4-dithiobiuret (DTB), a chemical which produces delayed-onset neuromuscular weakness, in an attempt to ascertain whether or not DTB poisoning in the rat would serve as an animal model of the neurologic symptoms of acute intermittent porphyria. Daily administration of DTB (1 mg/kg/day, i.p.) produced flaccid skeletal muscle weakness first detected after 4 to 5 days of treatment. Onset of skeletal muscle weakness was associated with a significant increase in urinary excretion of ALA. The excretion of PBG and total porphyrin was also increased; however, the increase was not significant. The increase in porphyrins and porphyrin precursors was due to increased urine output which coincided with the onset of neuromuscular weakness; urinary concentrations of ALA, PBG, and porphyrins were not increased by DTB. Measurements of free-erythrocyte protoporphyrin, taken after 7 days of DTB treatment, indicated a significant elevation of free erythrocyte protoporphyrin concentration. The pattern of alterations in the heme precursors associated with DTB-induced paralysis in rats is quite different from that observed in humans afflicted with acute intermittent porphyria. Therefore, we conclude that DTB-induced paralysis in the rat does not represent an accurate animal model of acute intermittent porphyria.

Excretion of total and muscular N tau-methylhistidine and creatinine in muscle diseases.

The daily urinary excretions of N tau-methylhistidine and creatinine from 52 adult patients were measured under standardized conditions. The ratio of N tau-methylhistidine to creatinine excretion was calculated on the basis of the total and muscle-specific excretion rates and correlated to the clinical status of the patients. In patients with muscular diseases and in those with diseases of the central nervous system, the total daily excretion of both metabolites was about 30% lower than in controls. The muscle-specific ratio in patients with diseases of the central nervous system and patients with muscular diseases was not different from that observed in controls. Only in patients with neurogenic atrophies was the ratio elevated, so that it was more than twice the control value. The ratio of excreted N tau-methylhistidine/creatinine is only valid as an indicator of myofibrillar protein breakdown after correction for the contribution of nonskeletal muscle tissues to the urinary excretion.

Proteins in the urine associated with Duchenne muscular dystrophy and other neuromuscular diseases.

1. Up to 200 protein staining spots could be detected on two-dimensional electrophoresis of urine from healthy persons. Other minor spots were occasionally present. 2. Although the electropherograms exhibited constant characteristic features some variation in protein pattern was observed between individuals and with a given individual at different times. 3. Two additional proteins, spots C and D, were consistently present in urine from boys with Duchenne muscular dystrophy. Spot C was also present in the urine of about 60% of obligatory carriers of this dystrophy. 4. The protein responsible for spot C had a molecular weight of 26000 and an isoelectric point of 5.3. 5. Spot C was also detected in the urine of patients with other neuromuscular conditions. Neither spot C nor spot D could be detected in the urine of patients with physical disabilities other than those of neuromuscular origin. 6. It is concluded that the urinary excretion of spot C, and probably of spot D, is a consequence of muscle damage and that their detection has potential as a diagnostic tool.

A protein in urine associated with muscle disease and muscle damage.

Analysis of the protein composition of human urine by high-resolution two-dimensional electrophoresis showed that several features are associated with neuromuscular diseases, the best defined being the appearance in the urine of a small amount of a protein that migrates on the electropherogram as a characteristic spot (spot C). This spot consists of a protein of apparent molecular weight 26 000 and isoelectric point 5.3. The spot was usually present in the urine of patients suffering from diseases in which the musculature was directly affected but was rarely found in other patients and normal subjects. The protein responsible for spot C appears to be an index of muscle damage caused by a number of conditions. Attempts are being made to isolate enough of the protein to permit its identification.

Decrease of 3-methylhistidine and increase of NG,NG-dimethylarginine in the urine of patients with muscular dystrophy.

The amounts of 3-methylhistidine, N epsilon,N epsilon-dimethyllysine, N epsilon, N epsilon, N epsilon-trimethyllysine, NG,NG-dimethylarginine, and NG,N'G-dimethylarginine were determined in the urine specimens of healthy subjects and patients of corresponding ages with Duchenne, limb-girdle, and congenital types of muscular dystrophy, and motor neuron diseases. The amount of excretion of 3-methylhistidine decreased and that of NG,NG-dimethylarginine increased significantly in Duchenne and limb-girdle types of muscular dystrophy, but not in diseases with neurogenic muscular atrophy. The decrease of 3-methylhistidine was observed consistently throughout the course of the Duchenne type of muscular dystrophy. The amounts of the other methylamino acids both in myogenic and neurogenic myopathies were not different from those in healthy subjects.

3-Methylhistidine excretion as an index of myofibrillar protein catabolism in neuromuscular disease.

Myofibrillar protein catabolism has been calculated in a variety of neuromuscular diseases from the amount of 3-methylhistidine excreted in the urine. It was found to be significantly raised in Duchenne type muscular dystrophy, motor neurone disease, polymyositis, and thyrotoxic myopathy. In Becker type muscular dystrophy the level was slightly raised. It was normal in scapuloperoneal and limb girdle dystrophy, dystrophia myotonica, extrapyramidal disease, and multiple sclerosis. It was significantly decreased in hypothyroid myopathy.

[Pathogenesis of creatinuria and aminoaciduria in neuromuscular diseases]. / K patogenezu kreatinurii i aminoatsidurii pri nervno-myshechnykh zabolevaniiakh.

By introducing inhibitors of phosphodiestherase and adenylacyclase the authors studied the role of cyclic AMP in the pathogenesis of creatinuria and aminoaciduria in neuro-muscular diseases. It was demonstrated that in patients with Duchenne myopathy creatinuria and aminoaciduria were possibly due to a deop of nucleotide level in the muscles. And on the contrary in cases of Erb's and Landouzy-Dejerine myopathy the changes of nitrogen metabolism are due to an increased content of cyclic AMP. These data may be used for differential diagnosis of myopathy.