Pompe disease is characterized by a deficiency of acid alpha‐glucosidase that results in muscle weakness and a variable degree of disability. There is an approved therapy based on enzymatic ...replacement that has modified disease progression. Several reports describing muscle magnetic resonance imaging (MRI) features of Pompe patients have been published. Most of the studies have focused on late‐onset Pompe disease (LOPD) and identified a characteristic pattern of muscle involvement useful for the diagnosis. In addition, quantitative MRI studies have shown a progressive increase in fat in skeletal muscles of LOPD over time and they are increasingly considered a good tool to monitor progression of the disease. The studies performed in infantile‐onset Pompe disease patients have shown less consistent changes. Other more sophisticated muscle MRI sequences, such as diffusion tensor imaging or glycogen spectroscopy, have also been used in Pompe patients and have shown promising results.
Objective
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a frequent autoimmune neuropathy with a heterogeneous clinical spectrum. Clinical and experimental evidence suggests that ...autoantibodies may be involved in its pathogenesis, but the target antigens are unknown. Axoglial junction proteins have been proposed as candidate antigens. We examined the reactivity of CIDP patients' sera against neuronal antigens and used immunoprecipitation for antigen unraveling.
Methods
Primary cultures of hippocampal neurons were used to select patients' sera that showed robust reactivity with the cell surface of neurons. The identity of the antigens was established by immunoprecipitation and mass spectrometry, and subsequently confirmed with cell‐based assays, immunohistochemistry with teased rat sciatic nerve, and immunoabsorption experiments.
Results
Four of 46 sera from patients with CIDP reacted strongly against hippocampal neurons (8.6%) and paranodal structures on peripheral nerve. Two patients' sera precipitated contactin‐1 (CNTN1), and 1 precipitated both CNTN1 and contactin‐associated protein 1 (CASPR1). Reactivity against CNTN1 was confirmed in 2 cases, whereas the third reacted only when CNTN1 and CASPR1 were cotransfected. No other CIDP patient or any of the 104 controls with other neurological diseases tested positive. All 3 patients shared common clinical features, including advanced age, predominantly motor involvement, aggressive symptom onset, early axonal involvement, and poor response to intravenous immunoglobulin.
Interpretation
Antibodies against the CNTN1/CASPR1 complex occur in a subset of patients with CIDP who share common clinical features. The finding of this biomarker may help to explain the symptoms of these patients and the heterogeneous response to therapy in CIDP. ANN NEUROL 2013;73:370–380
Objective
The Popeye domain containing 3 (POPDC3) gene encodes a membrane protein involved in cyclic adenosine monophosphate (cAMP) signaling. Besides gastric cancer, no disease association has been ...described. We describe a new muscular dystrophy associated with this gene.
Methods
We screened 1,500 patients with unclassified limb girdle weakness or hyperCKemia for pathogenic POPDC3 variants. Five patients carrying POPDC3 variants were examined by muscle magnetic resonance imaging (MRI), muscle biopsy, and cardiac examination. We performed functional analyses in a zebrafish popdc3 knockdown model and heterologous expression of the mutant proteins in Xenopus laevis oocytes to measure TREK‐1 current.
Results
We identified homozygous POPDC3 missense variants (p.Leu155His, p.Leu217Phe, and p.Arg261Gln) in 5 patients from 3 ethnically distinct families. Variants affected highly conserved residues in the Popeye (p.Leu155 and p.Leu217) and carboxy‐terminal (p.Arg261) domains. The variants were almost absent from control populations. Probands’ muscle biopsies were dystrophic, and serum creatine kinase levels were 1,050 to 9,200U/l. Muscle weakness was proximal with adulthood onset in most patients and affected lower earlier than upper limbs. Muscle MRI revealed fat replacement of paraspinal and proximal leg muscles; cardiac investigations were unremarkable. Knockdown of popdc3 in zebrafish, using 2 different splice‐site blocking morpholinos, resulted in larvae with tail curling and dystrophic muscle features. All 3 mutants cloned in Xenopus oocytes caused an aberrant modulation of the mechano‐gated potassium channel, TREK‐1.
Interpretation
Our findings point to an important role of POPDC3 for skeletal muscle function and suggest that pathogenic variants in POPDC3 are responsible for a novel type of autosomal recessive limb girdle muscular dystrophy. ANN NEUROL 2019;86:832–843
Background and purpose
Distal hereditary motor neuropathies (dHMNs) are a heterogeneous group of disorders characterized by degeneration of the motor component of peripheral nerves. Currently, only ...15% to 32.5% of patients with dHMN are characterized genetically. Additionally, the prevalence of these genetic disorders is not well known. Recently, biallelic mutations in the sorbitol dehydrogenase gene (SORD) have been identified as a cause of dHMN, with an estimated frequency in undiagnosed cases of up to 10%.
Methods
In the present study, we included 163 patients belonging to 108 different families who were diagnosed with a dHMN and who underwent a thorough genetic screening that included next‐generation sequencing and subsequent Sanger sequencing of SORD.
Results
Most probands were sporadic cases (62.3%), and the most frequent age of onset of symptoms was 2 to 10 years (28.8%). A genetic diagnosis was achieved in 37/108 (34.2%) families and 78/163 (47.8%) of all patients. The most frequent cause of distal hereditary motor neuropathies were mutations in HSPB1 (10.4%), GARS1 (9.8%), BICD2 (8.0%), and DNAJB2 (6.7%) genes. In addition, 3.1% of patients were found to be carriers of biallelic mutations in SORD. Mutations in another seven genes were also identified, although they were much less frequent. Eight new pathogenic mutations were detected, and 17 patients without a definite genetic diagnosis carried variants of uncertain significance. The calculated minimum prevalence of dHMN was 2.3 per 100,000 individuals.
Conclusions
This study confirms the genetic heterogeneity of dHMN and that biallelic SORD mutations are a cause of dHMN in different populations.
Distal hereditary motor neuropathies (dHMNs) are rare and genetically heterogeneous diseases. In this study, the diagnosis rate is 47.8%, and the calculated minimum prevalence is at least 2.3 per 100,000 individuals. The most frequent genetic causes of dHMN in our population are mutations in the HSPB1, GARS1, BICD2, and DNAJB2 genes, whereas 3.1% of patients carry biallelic mutations in SORD.
This review aims to discuss the recent results of studies published applying quantitative MRI sequences to large cohorts of patients with neuromuscular diseases.
Quantitative MRI sequences are now ...available to identify and quantify changes in muscle water and fat content. These two components have been associated with acute and chronic injuries, respectively. Studies show that the increase in muscle water is not only reversible if therapies are applied successfully but can also predict fat replacement in neurodegenerative diseases. Muscle fat fraction correlates with muscle function tests and increases gradually over time in parallel with the functional decline of patients with neuromuscular diseases. There are new spectrometry-based sequences to quantify other components, such as glycogen, electrolytes or the pH of the muscle fibre, extending the applicability of MRI to the study of several processes in neuromuscular diseases.
The latest results obtained from the study of long cohorts of patients with various neuromuscular diseases open the door to the use of this technology in clinical trials, which would make it possible to obtain a new measure for assessing the effectiveness of new treatments. The challenge is currently the popularization of these studies and their application to the monitoring of patients in the daily clinic.
Background and purpose
The transition to adult services, and subsequent glucocorticoid management, is critical in adults with Duchenne muscular dystrophy. This study aims (1) to describe treatment, ...functional abilities, respiratory and cardiac status during transition to adulthood and adult stages; and (2) to explore the association between glucocorticoid treatment after loss of ambulation (LOA) and late‐stage clinical outcomes.
Methods
This was a retrospective single‐centre study on individuals with Duchenne muscular dystrophy (≥16 years old) between 1986 and 2022. Logistic regression, Cox proportional hazards models and survival analyses were conducted utilizing data from clinical records.
Results
In all, 112 individuals were included. Mean age was 23.4 ± 5.2 years and mean follow‐up was 18.5 ± 5.5 years. At last assessment, 47.2% were on glucocorticoids; the mean dose of prednisone was 0.38 ± 0.13 mg/kg/day and of deflazacort 0.43 ± 0.16 mg/kg/day. At age 16 years, motor function limitations included using a manual wheelchair (89.7%), standing (87.9%), transferring from a wheelchair (86.2%) and turning in bed (53.4%); 77.5% had a peak cough flow <270 L/min, 53.3% a forced vital capacity percentage of predicted <50% and 40.3% a left ventricular ejection fraction <50%. Glucocorticoids after LOA reduced the risk and delayed the time to difficulties balancing in the wheelchair, loss of hand to mouth function, forced vital capacity percentage of predicted <30% and forced vital capacity <1 L and were associated with lower frequency of left ventricular ejection fraction <50%, without differences between prednisone and deflazacort. Glucocorticoid dose did not differ by functional, respiratory or cardiac status.
Conclusion
Glucocorticoids after LOA preserve late‐stage functional abilities, respiratory and cardiac function. It is suggested using functional abilities, respiratory and cardiac status at transition stages for adult services planning.
The current article provides a brief summary of the clinical approach to congenital and acquired ptosis. An increasing number of publications analyze causes of ptosis or describe diagnostic tests or ...advances in ptosis genetics. The aim of our work is to summarize these findings and provide an updated algorithm for the diagnosis and treatment of patients with ptosis. This review covers important clinical research and studies relevant for neurologists recently published.
Ptosis is a common cause of referral to neuromuscular units. Knowledge of the different causes of this symptom has grown substantially in recent years, from diagnostic tests and genetics studies to potential new therapeutic agents, making it essential to keep up to date on the diagnostic and therapeutic relevance of these contributions.
We emphasize that ptosis should be studied as a complex symptom. Efforts should be made to identify accompanying neurologic or ophthalmologic signs in clinical examination that could lead to a diagnosis. A growing number of diagnostics tests are available in the field, especially in genetics. Meanwhile, surgery continues being the most used therapeutic approach for these patients.
Background
Cushing's syndrome (CS) is associated with skeletal muscle structural and functional impairment which may persist long‐term despite surgical removal of the source of cortisol excess. ...Prevalence of sarcopenia and its impact on Health‐Related‐Quality of Life (HRQoL) in ‘cured’ CS is not known. There is a need to identify easy biomarkers to help the clinicians recognise patients at elevated risk of suffering sustained muscle function.
Patients and Methods
We studied 36 women with CS in remission, and 36 controls matched for age, body mass index, menopausal status, and level of physical activity. We analysed the skeletal muscle mass using dual‐energy X‐ray absorptiometry, muscle fat fraction using two‐point Dixon magnetic resonance imaging and muscle performance and strength using the following tests: hand grip strength, gait speed, timed up and go and 30‐s chair stand. We assessed HRQoL with the following questionnaires: SarQoL, CushingQoL, SF‐36. We calculated the sarcopenia index (SI; serum creatinine/serum cystatin C × 100).
Results
Prevalence of sarcopenia, according to the European Working Group on Sarcopenia in Older People (EWGSOP), was greater in CS as compared with controls (19% vs. 3%; p < .05). Patients with sarcopenia had a lower SarQoL score than those without sarcopenia (61 ± 17 vs. 75 ± 14; p < .05), and scored worse on the items pain, easy bruising and worries on physical appearance (p < .05 for all comparisons) of the CushingQoL questionnaire. Patients with sarcopenia had poorer physical functioning on SF‐36 than those without sarcopenia (60 ± 23 vs. 85 ± 15; p < .01). SI was lower in patients with sarcopenia than those without (71 ± 3 vs. 77 ± 2; p = .032), and was associated with intramuscular fatty infiltration, worse performance on the 30‐s chair stand test, slower gait speed, and worse muscle weakness‐related HRQoL, as measured using the SarQoL questionnaire (p < .05). The optimised cut‐off value for the SI ratio to diagnose sarcopenia was 72, which yielded a sensitivity of 73% and a specificity of 90%.
Conclusions
Sarcopenia is common in patients with CS in long‐term remission, and associated with impaired quality of life. The SI is a potential biomarker allowing clinicians to identify patients at high risk of muscle dysfunction.
Background
Only a few studies have reported muscle imaging data on small cohorts of patients with myotonic dystrophy type 1 (DM1). We aimed to investigate the muscle involvement in a large cohort of ...patients in order to refine the pattern of muscle involvement, to better understand the pathophysiological mechanisms of muscle weakness, and to identify potential imaging biomarkers for disease activity and severity.
Methods
One hundred and thirty‐four DM1 patients underwent a cross‐sectional muscle magnetic resonance imaging (MRI) study. Short tau inversion recovery (STIR) and T1 sequences in the lower and upper body were analyzed. Fat replacement, muscle atrophy and STIR positivity were evaluated using three different scales. Correlations between MRI scores, clinical features and genetic background were investigated.
Results
The most frequent pattern of muscle involvement in T1 consisted of fat replacement of the tongue, sternocleidomastoideus, paraspinalis, gluteus minimus, distal quadriceps and gastrocnemius medialis. Degree of fat replacement at MRI correlated with clinical severity and disease duration, but not with CTG expansion. Fat replacement was also detected in milder/asymptomatic patients. More than 80% of patients had STIR‐positive signals in muscles. Most DM1 patients also showed a variable degree of muscle atrophy regardless of MRI signs of fat replacement. A subset of patients (20%) showed a ‘marbled’ muscle appearance.
Conclusions
Muscle MRI is a sensitive biomarker of disease severity alsofor the milder spectrum of disease. STIR hyperintensity seems to precede fat replacement in T1. Beyond fat replacement, STIR positivity, muscle atrophy and a ‘marbled’ appearance suggest further mechanisms of muscle wasting and weakness in DM1, representing additional outcome measures and therapeutic targets for forthcoming clinical trials.
We refined the pattern of muscle involvement in DM1 by upper and lower body muscle magnetic resonance imaging (MRI), identifying the most frequent pattern of fat replacement and confirming that muscle MRI is a sensitive biomarker of disease burden in DM1. We also observed: STIR‐positive muscles in 80% of patients preceding fat replacement, muscle atrophy in muscles unreplaced by fat, and progeroid muscle appearance supporting a premature muscle senescence. Our findings provide novel insights into the pathophysiological mechanisms of muscle wasting and weakness in DM1, and could represent additional outcome measures and therapeutic targets for forthcoming clinical trials.
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