Carmen Paradas

LONG-TERM OUTCOME IN CHRONIC INFLAMMATORY DEMYELINATING POLYNEUROPATHY PATIENTS TREATED WITH INTRAVENOUS IMMUNOGLOBULIN: A RETROSPECTIVE STUDY

Introduction: The objective of this retrospective study was to describe the short‐ and long‐term patterns of IVIg use, safety, and response to treatment in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). Methods: Response to therapy was defined as an improvement of ≥1 point on the modified Rankin score at short‐ and mid‐term visits. Patient status at long term was classified as remission, stability, or non‐responder. Results: Eighty‐six patients were included; 60.5% responded at short term and 54.6% at mid‐term. At long term, 25.6% of patients were in remission, 65.1% were stable, and 9.3% were non‐responders. The only variable associated with remission was a better response during the first 6 months of follow‐up. Conclusions: A significant percentage of patients did not require any additional drugs in the long term. This suggests that treatment effect or disease outcome may be stable over time, and treatment regimens should therefore be individualized to avoid overtreatment. Muscle Nerve 48: 870–876, 2013

TK2 mutation presenting as indolent myopathy.

Recessive mutations in the TK2 gene typically cause fatal infantile mitochondrial DNA (mtDNA) depletion syndromes (MDS).1–3 However, the progression of weakness may vary,4 as shown by recently described adult patients with late-onset myopathy.5,6 To date, only 5 adult patients with TK2-related MDS have been reported. Herein, we describe a man who had several unusual features. Clinically, he was weak as a child but sought medical attention as an adult. At the molecular level, multiple mtDNA deletions in muscle were more prominent than mtDNA depletion.

Prognostic value of X-chromosome inactivation in symptomatic female carriers of dystrophinopathy

BackgroundBetween 8% and 22% of female carriers of DMD mutations exhibit clinical symptoms of variable severity. Development of symptoms in DMD mutation carriers without chromosomal rearrangements has been attributed to skewed X-chromosome inactivation (XCI) favouring predominant expression of the DMD mutant allele. However the prognostic use of XCI analysis is controversial. We aimed to evaluate the correlation between X-chromosome inactivation and development of clinical symptoms in a series of symptomatic female carriers of dystrophinopathy.MethodsWe reviewed the clinical, pathological and genetic features of twenty-four symptomatic carriers covering a wide spectrum of clinical phenotypes. DMD gene analysis was performed using MLPA and whole gene sequencing in blood DNA and muscle cDNA. Blood and muscle DNA was used for X-chromosome inactivation (XCI) analysis thought the AR methylation assay in symptomatic carriers and their female relatives, asymptomatic carriers as well as non-carrier females.ResultsSymptomatic carriers exhibited 49.2% more skewed XCI profiles than asymptomatic carriers. The extent of XCI skewing in blood tended to increase in line with the severity of muscle symptoms. Skewed XCI patterns were found in at least one first-degree female relative in 78.6% of symptomatic carrier families. No mutations altering XCI in the XIST gene promoter were found.ConclusionsSkewed XCI is in many cases familial inherited. The extent of XCI skewing is related to phenotype severity. However, the assessment of XCI by means of the AR methylation assay has a poor prognostic value, probably because the methylation status of the AR gene in muscle may not reflect in all cases the methylation status of the DMD gene.

1α,25(OH)2-Vitamin D3 Increases Dysferlin Expression in vitro and in a Human Clinical Trial

Dysferlinopathies are a heterogenous group of autosomal recessive inherited muscular dystrophies caused by mutations in DYSF gene. Dysferlin is expressed mainly in skeletal muscle and in monocytes and patients display a severe reduction or absence of protein in both tissues. Vitamin D3 promotes differentiation of the promyelocytic leukemia HL60 cells. We analyzed the effect of vitamin D3 on dysferlin expression in vitro using HL60 cells, monocytes and myotubes from controls and carriers of a single mutation in DYSF. We also performed an observational study with oral vitamin D3 in a cohort of 21 carriers. Fifteen subjects were treated for 1 year and dysferlin expression in monocytes was analysed before and after treatment. Treatment with vitamin D3 increased expression of dysferlin in vitro. The effect of vitamin D3 was mediated by both a nongenomic pathway through MEK/ERK and a genomic pathway involving binding of vitamin D3 receptor to the dysferlin promoter. Carriers treated with vitamin D3 had significantly increased expression of dysferlin in monocytes compared with nontreated carriers (P < 0.05). These findings will have important therapeutic implications since a combination of different molecular strategies together with vitamin D3 uptake could increase dysferlin expression to nonpathological protein levels.Dysferlinopathies are a heterogenous group of autosomal recessive inherited muscular dystrophies caused by mutations in DYSF gene. Dysferlin is expressed mainly in skeletal muscle and in monocytes and patients display a severe reduction or absence of protein in both tissues. Vitamin D3 promotes differentiation of the promyelocytic leukemia HL60 cells. We analyzed the effect of vitamin D3 on dysferlin expression in vitro using HL60 cells, monocytes and myotubes from controls and carriers of a single mutation in DYSF. We also performed an observational study with oral vitamin D3 in a cohort of 21 carriers. Fifteen subjects were treated for 1 year and dysferlin expression in monocytes was analysed before and after treatment. Treatment with vitamin D3 increased expression of dysferlin in vitro. The effect of vitamin D3 was mediated by both a nongenomic pathway through MEK/ERK and a genomic pathway involving binding of vitamin D3 receptor to the dysferlin promoter. Carriers treated with vitamin D3 had significantly increased expression of dysferlin in monocytes compared with nontreated carriers (P < 0.05). These findings will have important therapeutic implications since a combination of different molecular strategies together with vitamin D3 uptake could increase dysferlin expression to nonpathological protein levels.

The Clinical Outcome Study for dysferlinopathy: An international multicenter study

Objective: To describe the baseline clinical and functional characteristics of an international cohort of 193 patients with dysferlinopathy. Methods: The Clinical Outcome Study for dysferlinopathy (COS) is an international multicenter study of this disease, evaluating patients with genetically confirmed dysferlinopathy over 3 years. We present a cross-sectional analysis of 193 patients derived from their baseline clinical and functional assessments. Results: There is a high degree of variability in disease onset, pattern of weakness, and rate of progression. No factor, such as mutation class, protein expression, or age at onset, accounted for this variability. Among patients with clinical diagnoses of Miyoshi myopathy or limb-girdle muscular dystrophy, clinical presentation and examination was not strikingly different. Respiratory impairment and cardiac dysfunction were observed in a minority of patients. A substantial delay in diagnosis was previously common but has been steadily reducing, suggesting increasing awareness of dysferlinopathies. Conclusions: These findings highlight crucial issues to be addressed for both optimizing clinical care and planning therapeutic trials in dysferlinopathy. This ongoing longitudinal study will provide an opportunity to further understand patterns and variability in disease progression and form the basis for trial design.

Quantifiable diagnosis of muscular dystrophies and neurogenic atrophies through network analysis

BackgroundThe diagnosis of neuromuscular diseases is strongly based on the histological characterization of muscle biopsies. However, this morphological analysis is mostly a subjective process and difficult to quantify. We have tested if network science can provide a novel framework to extract useful information from muscle biopsies, developing a novel method that analyzes muscle samples in an objective, automated, fast and precise manner.MethodsOur database consisted of 102 muscle biopsy images from 70 individuals (including controls, patients with neurogenic atrophies and patients with muscular dystrophies). We used this to develop a new method, Neuromuscular DIseases Computerized Image Analysis (NDICIA), that uses network science analysis to capture the defining signature of muscle biopsy images. NDICIA characterizes muscle tissues by representing each image as a network, with fibers serving as nodes and fiber contacts as links.ResultsAfter a ‘training’ phase with control and pathological biopsies, NDICIA was able to quantify the degree of pathology of each sample. We validated our method by comparing NDICIA quantification of the severity of muscular dystrophies with a pathologist’s evaluation of the degree of pathology, resulting in a strong correlation (R = 0.900, P <0.00001). Importantly, our approach can be used to quantify new images without the need for prior ‘training’. Therefore, we show that network science analysis captures the useful information contained in muscle biopsies, helping the diagnosis of muscular dystrophies and neurogenic atrophies.ConclusionsOur novel network analysis approach will serve as a valuable tool for assessing the etiology of muscular dystrophies or neurogenic atrophies, and has the potential to quantify treatment outcomes in preclinical and clinical trials.

Rules of tissue packing involving different cell types: human muscle organization

Natural packed tissues are assembled as tessellations of polygonal cells. These include skeletal muscles and epithelial sheets. Skeletal muscles appear as a mosaic composed of two different types of cells: the “slow” and “fast” fibres. Their relative distribution is important for the muscle function but little is known about how the fibre arrangement is established and maintained. In this work we capture the organizational pattern in two different healthy muscles: biceps brachii and quadriceps. Here we show that the biceps brachii muscle presents a particular arrangement, based on the different sizes of slow and fast fibres. By contrast, in the quadriceps muscle an unbiased distribution exists. Our results indicate that the relative size of each cellular type imposes an intrinsic organization into natural tessellations. These findings establish a new framework for the analysis of any packed tissue where two or more cell types exist.

Teenage exercise is associated with earlier symptom onset in dysferlinopathy: a retrospective cohort study

Dysferlinopathy, an autosomal recessive muscular dystrophy caused by DYSF mutations, demonstrates a variable phenotype and progression rate, with symptom onset ranging from first to eighth decade and some patients requiring wheelchairs for mobility within 10 years, with others remaining minimally affected.1 Dysferlinopathy populations have previously been described as having an unusually high level of presymptomatic sporting ability.2 We hypothesised that this activity could be related to subsequent disease progression and investigated the hypothesis using data from the Jain Foundation’s Clinical Outcomes Study (COS) of 202 patients with dysferlinopathy.1 Data were used from 182 of the 202 patients enrolled in the Jain COS; 10 dropped out and did not give permission to use their data and 10 did not fully complete the exercise questionnaire. The questionnaire used in the screening visits (online supplementary information) between 6 November 2012 and 19 March 2015 asked about the type, level and frequency of all physical activity prior to symptom onset. Self-reported age of first symptoms, first wheelchair use and full-time wheelchair use was taken from screening questionnaires. Exercises were classified based on metabolic equivalents (METs) as moderate (MET 3–6) or vigorous (MET >6) (online supplementary table 1).3 Participants were coded, based on the maximum frequency of activity reported between ages 10 and 18 years, as 0—no physical activity; 1—vigorous activity occasionally/monthly, or moderate activity once weekly; 2— moderate activity multiple times per week or vigorous activity once weekly; and 3—vigorous activity multiple times per week. ### Supplementary file 1 [jnnp-2017-317329-SP1.pdf] ### Statistical analysis Age of symptom onset was compared by analysis of variance (ANOVA) with least squares means for individual group differences. Risk of symptom onset, occasional wheelchair use and full-time wheelchair requirement over time were compared for exercise groups 1, 2 and 3 against group 0 using Cox proportional hazards regression. Proportional hazards assumption was violated …

A novel MYH7 founder mutation causing Laing distal myopathy in Southern Spain

MYH7 gene mutations are associated with wide clinical and genetic heterogeneity. We report a novel founder mutation in MYH7 in Southern Spain (Andalucía). We studied two index patients and 24 family members from two apparently independent families by physical examination, serum creatine-kinase, muscle MRI, sequencing studies and genetic linkage analysis. Sixteen individuals were heterozygous for a (p.R1560P) variant in the MYH7 gene. Haplotype was consistent with a common ancestor for the two families. The patients displayed the classic Laing distal myopathy phenotype, with hanging first toe as the initial presentation, even in mildly affected patients who declared themselves asymptomatic, although neck flexor weakness was revealed as an early sign in some cases. MRI showed that the sartorius was the first muscle involved, even in two out of three asymptomatic carriers. Our findings support the novel variant p.R1560P in MYH7 as a founder mutation in Andalucía. The early involvement of the sartorius muscle in MRI may be useful as an indicator of affection status.

Muscle imaging in laminopathies: synthesis study identifies meaningful muscles for follow-up: Muscle MRI progression in LMNA

Introduction: Particular fibroadipose infiltration patterns have been recently described by muscle imaging in congenital and later onset forms of LMNA‐related muscular dystrophies (LMNA‐RD). Methods: Scores for fibroadipose infiltration of 23 lower limb muscles in 34 patients with LMNA‐RD were collected from heat maps of 2 previous studies. Scoring systems were homogenized. Relationships between muscle infiltration and disease duration and age of onset were modeled with random forests. Results: The pattern of infiltration differs according to disease duration but not to age of disease onset. The muscles whose progression best predicts disease duration were semitendinosus, biceps femoris long head, gluteus medius, and semimembranosus. Discussion: In LMNA‐RD, our synthetic analysis of lower limb muscle infiltration did not find major differences between forms with different ages of onset but allowed the identification of muscles with characteristic infiltration during disease progression. Monitoring of these specific muscles by quantitative MRI may provide useful imaging biomarkers in LMNA‐RD. Muscle Nerve 58:812–817, 2018