Strokes related to intracranial aneurysm or arteriopathy have been reported in a few patients with late-onset Pompe disease. These reports suggested that cerebral vessel involvement could be an ...underrecognized complication of this disease.
We report cerebral artery involvement in three French patients with late-onset Pompe disease.
The first patient died at age 35 years from complications of a giant fusiform aneurysm of the basilar artery, and her 34-year-old sister showed evidence of dolichoectatic basilar artery on magnetic resonance angiography. A dilative arteriopathy complicated with carotid artery dissection was diagnosed in the third patient, aged 50 years. Two patients are currently being treated with enzyme replacement therapy (alglucosidase alfa), and regular angiographic follow-up showed the absence of progression of vascular abnormalities in one of them.
These observations, combined with previously reported cases, confirm that Pompe disease should be recognized as a predisposing condition to dilative arteriopathy and cerebral aneurysm formation, although the real incidence of these vascular complications remains unknown.
Background and purpose
Our aim was to determine the prognostic value of urine and blood heteroplasmy in patients with the m.3243A>G mutation.
Methods
Adults with the m.3243A>G mutation referred to ...our institution between January 2000 and May 2014 were retrospectively included. The relationship between their baseline clinical characteristics, their mutation load in urine and blood, and major adverse events (MAEs) during follow‐up, defined as medical complications requiring a hospitalization or complicated by death, was studied.
Results
Of the 43 patients (age 45.6 ± 13.3 years) included in the study, 36 patients were symptomatic, including nine with evidence of focal brain involvement, and seven were asymptomatic. Over a 5.5 ± 4.0 year mean follow‐up duration, 14 patients (33%) developed MAEs. Patients with MAEs had a higher mutation load than others in urine (60.1% ± 13.8% vs. 40.6% ± 26.2%, P = 0.01) and in blood (26.9% ± 18.4% vs. 16.0% ± 12.1%, P = 0.03). Optimal cutoff values for the prediction of MAEs were 45% for urine and 35% for blood. In multivariate analysis, mutation load in urine ≥45% odds ratio 25.3; 95% confidence interval (CI) 1.1–567.8; P = 0.04, left ventricular hypertrophy (odds ratio 16.7; 95% CI 1.3– 222.5; P = 0.03) and seizures (odds ratio 48.3; 95% CI 2.5–933; P = 0.01) were associated with MAEs.
Conclusions
Patients with the m.3243A>G mutation are at high risk of MAEs, which can be independently predicted by mutation load in urine ≥45%, a personal history of seizures, and left ventricular hypertrophy.
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Cardiac complications, such as myocardial disease and arrhythmias, are frequent and may be severe in patients with mitochondrial disease. We sought to determine the prevalence and the prognostic ...value of cardiac abnormalities in a series of patients carrying the m.8344 A>G mutation.
We retrospectively collected data concerning a cohort of patients carrying the m.8344A>G mutation. Patients systematically underwent neurologic examination, muscular biopsy, measurement of forced vital capacity, and cardiac evaluation including electrocardiogram, echocardiography, and 24-hour ambulatory electrocardiogram at diagnosis. Neurologic and cardiac evaluations were repeated during follow-up at least every 2 years.
Eighteen patients (mean age 39.3 +/- 17.3 years, 10 women) from 8 families were investigated. Mean follow-up duration was 5.0 +/- 2.7 years. Cardiac abnormalities were identified at diagnosis in 8 patients (44.4%, age 39.1 +/- 17.7 years), including dilated cardiomyopathy in 4, Wolff-Parkinson-White syndrome in 3, incomplete left bundle branch block in 1, and ventricular premature beats in 1. Two additional patients developed left ventricular dysfunction during follow-up and 2 patients died due to heart failure. Subgroup analyses identified early age at disease onset as the only factor significantly associated with myocardial dysfunction.
We identified a high prevalence of ventricular dysfunction and Wolff-Parkinson-White syndrome. Myocardial involvement was associated with an increased risk of cardiac death due to heart failure, suggesting that cardiac investigations should be systematically considered in patients carrying the m.8344A>G mutation.
Background and purpose
To describe a large series of patients with α, β, and γ sarcoglycanopathies (LGMD‐R3, R4, and R5) and study phenotypic correlations and disease progression.
Methods
A ...multicentric retrospective study in four centers in the Paris area collecting neuromuscular, respiratory, cardiac, histologic, and genetic data. The primary outcome of progression was age of loss of ambulation (LoA); disease severity was established according to LoA before or after 18 years of age. Time‐to‐event analysis was performed.
Results
One hundred patients (54 γ‐SG; 41 α‐SG; 5 β‐SG) from 80 families were included. The γ‐SG patients had earlier disease onset than α‐SG patients (5.5 vs. 8 years; p = 0.022) and β‐SG patients (24.4 years). Axial muscle weakness and joint contractures were frequent and exercise intolerance was observed. At mean follow‐up of 22.9 years, 65.3% of patients were wheelchair‐bound (66.7% α‐SG, 67.3% γ‐SG, 40% β‐SG). Dilated cardiomyopathy occurred in all sarcoglycanopathy subtypes, especially in γ‐SG patients (p = 0.01). Thirty patients were ventilated and six died. Absent sarcoglycan protein expression on muscle biopsy and younger age at onset were associated with earlier time to LoA (p = 0.021 and p = 0.002). Age at onset was an independent predictor of both severity and time to LoA (p = 0.0004 and p = 0.009). The α‐SG patients showed genetic heterogeneity, whereas >90% of γ‐SG patients carried the homozygous c.525delT frameshift variant. Five new mutations were identified.
Conclusions
This large multicentric series delineates the clinical spectrum of patients with sarcoglycanopathies. Age at disease onset is an independent predictor of severity of disease and LoA, and should be taken into account in future clinical trials.
This large multicentric Parisian series delineates the clinical spectrum of patients with sarcoglycanopathies. Age at disease onset and absence of sarcoglycan expression on muscle biopsy are predictors of severity of disease and loss of ambulation, and should be taken into account in future clinical trials.
•Dolichol-P-mannose (DPM) synthase plays a role in N-glycosylation and O-mannosylation.•DPM synthase is essential for alpha-dystroglycan O-mannosylation.•Two patients with novel pathogenic variants ...in the DPM3 gene are described.•They exhibited limb-girdle muscular dystrophy and dilated cardiomyopathy.•Abnormal N-glycosylation profile suggestive of CDG-1 was found in both patients.
Deficiency of Dolichol-P-mannose synthase subunit 3 (DPM3) affects the N-glycosylation and O-mannosylation pathways that are respectively involved in congenital disorders of glycosylation (CDG) and alpha-dystroglycanopathies. Herein, we describe novel pathogenic variants in the DPM3 gene in two unrelated male patients. They developed dilated cardiomyopathy in their late teens, limb-girdle muscular dystrophy - one patient in childhood and the other in adulthood. In both patients, next generation sequencing found in the DPM3 gene a heterozygous deletion and a heterozygous pathogenic missense mutation in exon 2 (c.41T>C, p.Leu14Pro). Electrophoresis of serum transferrin found an abnormal N-glycosylation profile suggestive of CDG type 1 (decreased tetrasialotransferrin, increased disialo- and asialotransferrin).
Only two cases of DPM3 gene mutations with limb-girdle muscular dystrophy-dystroglycanopathy have been reported previously. The present study highlights several aspects related to DPM3 gene mutations such as mild to moderately severe limb-girdle muscular dystrophy, dilated cardiomyopathy, and abnormal N-glycosylation profile suggestive of CDG type 1.
Background and purpose
This was a retrospective study to assess the diagnostic value of the non‐ischaemic forearm exercise test in detecting McArdle's disease.
Methods
The study is a retrospective ...diagnostic study over 15 years (1999–2013) on a referred sample of patients suffering from exercise intolerance and various muscle complaints, generally with elevated creatine kinase (CK). In all, 1226 patients underwent the non‐ischaemic forearm exercise test. Blood lactate, ammonia and CK levels were analyzed. DNA analyses and/or muscle biopsies were assessed to confirm the diagnosis of McArdle's disease. The results of 60 volunteers were used to compare with the results of study subjects.
Results
In this cohort, 40 patients were finally diagnosed with McArdle's disease. Absolute values of lactate and ammonia rise were used to discriminate all McArdle patients from healthy patients. A sensitivity and specificity of respectively 100% and 99.7% were calculated. The 24‐h CK level showed no significant difference from the CK level at the day of the test and confirms the safety of the test.
Conclusions
This study has formally assessed the diagnostic value of the non‐ischaemic forearm exercise test in the detection of McArdle's disease. Very high sensitivity and specificity were observed. Furthermore, the test is easy to set up and to perform, it is non‐traumatic and cost effective. It may circumvent a muscle biopsy in McArdle patients presenting the most common mutations. Hence, it is a perfect and safe screening instrument to detect patients with McArdle's disease. Glycogen storage disease type III patients, however, may show similar patterns to McArdle patients.
•The FSHD European Trial Network (FSHD ETN) will have an open membership.•There will be four working groups (WG) on clinical and genetic diagnosis (WG 1), clinical outcome measures (WG2), biomarkers ...(WG 3), and imaging outcome measures (WG4).•Network members will be appointed to reach out to countries not yet connected and to collaborate with the other organizations mentioned above, including the FSHD Clinical Trial Research Network (CTRN).•Network members will contribute to the patient expectations survey FSHD Europe is currently performing.•The network members will promote the use of agreed FSHD Core dataset across all stakeholder groups and registries, with support of TREAT-NMD.
Background and purpose
Pompe disease is a rare inheritable muscle disorder for which enzyme replacement therapy (ERT) has been available since 2006. Uniform criteria for starting and stopping ERT in ...adult patients were developed and reported here.
Methods
Three consensus meetings were organized through the European Pompe Consortium, a network of experts from 11 European countries in the field of Pompe disease. A systematic review of the literature was undertaken to determine the effectiveness of ERT in adult patients on a range of clinical outcome measures and quality of life. A narrative synthesis is presented.
Results
Consensus was reached on how the diagnosis of Pompe disease should be confirmed, when treatment should be started, reasons for stopping treatment and the use of ERT during pregnancy. This was based on expert opinion and supported by the literature. One clinical trial and 43 observational studies, covering a total of 586 individual adult patients, provided evidence of a beneficial effect of ERT at group level. At individual patient level, the response to treatment varied, but factors associated with a patient's response to ERT were not described in many studies. Eleven observational studies focused on more severely affected patients, suggesting that ERT can also be beneficial in these patients. There are no studies on the effects of ERT in pre‐symptomatic patients.
Conclusions
This is the first European consensus recommendation for starting and stopping ERT in adult patients with Pompe disease, based on the extensive experience of experts from different countries.
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