[End of life perspectives: a systematic survey of patients with amyotrophic lateral sclerosis].

Background: Amyotrophic lateral sclerosis (ALS) is a disease that still has to be primarily treated symptomatically or palliatively. It is therefore all the more important, in addition to initiating treatment, such as percutaneous endoscopic gastrostomy (PEG), noninvasive ventilation therapy (NIVT) and invasive ventilation therapy via tracheotomy (IVT), to discuss the possible termination of these measures early on.

Question: What is the importance of advance directives for those affected and where are possible deficits in therapy planning for the end of life?

Material And Method: Between March 2017 and January 2019 patients with a clinically confirmed diagnosis of ALS at six treatment centers were asked to fill out a questionnaire.

Different Patterns of Autoantibody Secretion by Peripheral Blood Mononuclear Cells in Autoimmune Nodopathies.

Background And Objectives: Autoimmune nodopathies with antibodies against the paranodal proteins show a distinct phenotype of a severe sensorimotor neuropathy. In some patients, complete remission can be achieved after treatment with rituximab whereas others show a chronic course. For optimal planning of treatment, predicting the course of disease and therapeutic response is crucial.

5qSMA: standardised retrospective natural history assessment in 268 patients with four copies of SMN2.

Newborn screening for 5qSMA offers the potential for early, ideally pre-symptomatic, therapeutic intervention. However, limited data exist on the outcomes of individuals with 4 copies of SMN2, and there is no consensus within the SMA treatment community regarding early treatment initiation in this subgroup. To provide evidence-based insights into disease progression, we performed a retrospective analysis of 268 patients with 4 copies of SMN2 from the SMArtCARE registry in Germany, Austria and Switzerland.

Improvements in Walking Distance during Nusinersen Treatment - A Prospective 3-year SMArtCARE Registry Study.

Background And Objectives: Disease progression in patients with spinal muscular atrophy (SMA) has changed dramatically within the past years due to the approval of three different disease-modifying treatments. Nusinersen was the first drug to be approved for the treatment of SMA patients. Clinical trials provided data from infants with SMA type 1 and children with SMA type 2, but there is still insufficient evidence and only scarcely reported long-term experience for nusinersen treatment in ambulant patients.

FLNC-Associated Myofibrillar Myopathy: New Clinical, Functional, and Proteomic Data.

Objective: To determine whether a new indel mutation in the dimerization domain of filamin C (FLNc) causes a hereditary myopathy with protein aggregation in muscle fibers, we clinically and molecularly studied a German family with autosomal dominant myofibrillar myopathy (MFM).

Methods: We performed mutational analysis in 3 generations, muscle histopathology, and proteomic studies of IM protein aggregates. Functional consequences of the mutation were investigated with interaction and transfection studies and biophysics molecular analysis.

A form of muscular dystrophy associated with pathogenic variants in JAG2.

JAG2 encodes the Notch ligand Jagged2. The conserved Notch signaling pathway contributes to the development and homeostasis of multiple tissues, including skeletal muscle. We studied an international cohort of 23 individuals with genetically unsolved muscular dystrophy from 13 unrelated families.

Novel variants broaden the phenotypic spectrum of PLEKHG5-associated neuropathies.

Background And Purpose: Pathogenic variants in PLEKHG5 have been reported to date to be causative in three unrelated families with autosomal recessive intermediate Charcot-Marie-Tooth disease (CMT) and in one consanguineous family with spinal muscular atrophy (SMA). PLEKHG5 is known to be expressed in the human peripheral nervous system, and previous studies have shown its function in axon terminal autophagy of synaptic vesicles, lending support to its underlying pathogenetic mechanism. Despite this, there is limited knowledge of the clinical and genetic spectrum of disease.

De Novo and Inherited Variants in GBF1 are Associated with Axonal Neuropathy Caused by Golgi Fragmentation.

Distal hereditary motor neuropathies (HMNs) and axonal Charcot-Marie-Tooth neuropathy (CMT2) are clinically and genetically heterogeneous diseases characterized primarily by motor neuron degeneration and distal weakness. The genetic cause for about half of the individuals affected by HMN/CMT2 remains unknown. Here, we report the identification of pathogenic variants in GBF1 (Golgi brefeldin A-resistant guanine nucleotide exchange factor 1) in four unrelated families with individuals affected by sporadic or dominant HMN/CMT2.

Effect of High-Caloric Nutrition on Survival in Amyotrophic Lateral Sclerosis.

Objective: Weight loss has been identified as a negative prognostic factor in amyotrophic lateral sclerosis, but there is no evidence regarding whether a high-caloric diet increases survival. Therefore, we sought to evaluate the efficacy of a high-caloric fatty diet (HCFD) for increasing survival.

Methods: A 1:1 randomized, placebo-controlled, parallel-group, double-blinded trial (LIPCAL-ALS study) was conducted between February 2015 and September 2018.

Prognostic factors in ALS: a comparison between Germany and China.

Objective: Several independent prognostic factors, such as age of onset, type of onset, body mass index (BMI), and progression rate have been identified for amyotrophic lateral sclerosis (ALS) in Caucasians. The aim of this study was to identify such factors in Chinese patients and to compare their impact with German patients.

Methods: Comparison of prognostic factors was based on two hospital-based registries.

Targeted sequencing with expanded gene profile enables high diagnostic yield in non-5q-spinal muscular atrophies.

Spinal muscular atrophies (SMAs) are a heterogeneous group of disorders characterized by muscular atrophy, weakness, and hypotonia due to suspected lower motor neuron degeneration (LMND). In a large cohort of 3,465 individuals suspected with SMA submitted for SMN1 testing to our routine diagnostic laboratory, 48.8% carried a homozygous SMN1 deletion, 2.

Frequent genes in rare diseases: panel-based next generation sequencing to disclose causal mutations in hereditary neuropathies.

Hereditary neuropathies comprise a wide variety of chronic diseases associated to more than 80 genes identified to date. We herein examined 612 index patients with either a Charcot-Marie-Tooth phenotype, hereditary sensory neuropathy, familial amyloid neuropathy, or small fiber neuropathy using a customized multigene panel based on the next generation sequencing technique. In 121 cases (19.

Lifetime exercise intolerance with lactic acidosis as key manifestation of novel compound heterozygous ACAD9 mutations causing complex I deficiency.

We report a 36-year-old female having lifetime exercise intolerance and lactic acidosis with nausea associated with novel compound heterozygous Acyl-CoA dehydrogenase 9 gene (ACAD9) mutations (p.Ala390Thr and p.Arg518Cys).

Oculopharyngeal muscular dystrophy as a rare cause of dysphagia.

Oculopharyngeal muscular dystrophy (OPMD) is a rare cause for late-onset dysphagia. OPMD normally follows an autosomal dominant inheritance. Herein we describe a rare case of an autosomal recessive inheritance of OPMD.

Percutaneous endoscopic gastrostomy in amyotrophic lateral sclerosis: a prospective observational study.

Weight loss is increasingly considered as a negative prognostic marker in amyotrophic lateral sclerosis (ALS). Despite the critical importance of nutritional issues in ALS, and the common use of percutaneous endoscopic gastrostomy (PEG), there is a general lack of knowledge on peri-interventional treatment, optimal parameters of enteral nutrition, its timing during disease progression and its potential disease-modifying effects in ALS patients. Here we report the results of a multi-center prospective study of percutaneous endoscopic gastrostomy (PEG) in ALS.

ANO5 gene analysis in a large cohort of patients with anoctaminopathy: confirmation of male prevalence and high occurrence of the common exon 5 gene mutation.

Limb girdle muscular dystrophy type 2L or anoctaminopathy is a condition mainly characterized by adult onset proximal lower limb muscular weakness and raised CK values, due to recessive ANO5 gene mutations. An exon 5 founder mutation (c.191dupA) has been identified in most of the British and German LGMD2L patients so far reported.

Treatment of dysferlinopathy with deflazacort: a double-blind, placebo-controlled clinical trial.

Background: Dysferlinopathies are autosomal recessive disorders caused by mutations in the dysferlin (DYSF) gene encoding the dysferlin protein. DYSF mutations lead to a wide range of muscular phenotypes, with the most prominent being Miyoshi myopathy (MM) and limb girdle muscular dystrophy type 2B (LGMD2B).

Methods: We assessed the one-year-natural course of dysferlinopathy, and the safety and efficacy of deflazacort treatment in a double-blind, placebo-controlled cross-over trial.

Muscle MRI findings in limb girdle muscular dystrophy type 2L.

Limb girdle muscular dystrophy type 2L (LGMD2L) is an adult-onset slowly progressive muscular dystrophy associated with recessive mutations in the ANO5 gene. We analysed the muscle MRI pattern in a cohort of 25 LGMD2L patients in order to understand the extent and progression of muscle pathology in LGM2L and assess if muscle MRI might help in the diagnostic work-up of these patients. Our results showed a homogeneous pattern of muscle pathology on muscle MRI, with a predominant involvement of the posterior compartment muscles in both the thighs and calves.

A randomized, double blind, placebo-controlled trial of pioglitazone in combination with riluzole in amyotrophic lateral sclerosis.

Background: Pioglitazone, an oral anti-diabetic that stimulates the PPAR-gamma transcription factor, increased survival of mice with amyotrophic lateral sclerosis (ALS).

Methods/principal Findings: We performed a phase II, double blind, multicentre, placebo controlled trial of pioglitazone in ALS patients under riluzole. 219 patients were randomly assigned to receive 45 mg/day of pioglitazone or placebo (one: one allocation ratio).

Clinical and neuropathological findings in patients with TACO1 mutations.

We have recently identified mutations in the translation activator of cytochrome c oxidase 1 (TACO1) gene, leading to cytochrome c oxidase (COX) deficiency. Here, we report the clinical and neuroimaging findings of five members of a big consanguinous family homozygous for c.472insC in TACO1.

Health-related quality of life in ALS, myasthenia gravis and facioscapulohumeral muscular dystrophy.

Neuromuscular disorders are rare diseases with a chronic and debilitating course. Unfortunately, data on the health-related quality of life (HRQoL) in neuromuscular diseases are limited. The objective of this multicentre cross-sectional study was to compare the HRQoL in patients with amyotrophic lateral sclerosis (ALS), facioscapulohumeral muscular dystrophy (FSHD) and myasthenia gravis (MG) and to identify the determinants of the HRQoL in these diseases.