Leigh syndrome: an adult presentation of a paediatric disease.

A previously healthy 27-year-old man was admitted to the acute neurology ward with events involving his face, throat and upper limb, which video telemetry later confirmed were refractory focal seizures. He also had progressive pyramidal features, dysarthria and ataxia. MR scans of the brain identified progressive bilateral basal ganglia abnormalities, consistent with Leigh syndrome. However, extensive laboratory and genetic panels did not give a unifying diagnosis. A skeletal muscle biopsy showed no histopathological abnormalities on routine stains. Sequencing of the entire mitochondrial genome in skeletal muscle identified a well-characterised pathogenic variant (m.10191T>C in MT-ND3; NC_012920.1) at 85% heteroplasmy in skeletal muscle. We discuss the clinical and molecular diagnosis of an adult presenting with Leigh syndrome, which is more commonly a paediatric presentation of mitochondrial disease, and how early recognition of a mitochondrial cause is important to support patient care.

The West of Scotland Cohort of Mitochondrial Individuals with the m.3243A>G Variant: Variations in Phenotypes and Predictors of Disease Severity.

BACKGROUND: The m.3243A>G variant is the commonest mitochondrial (mt) DNA pathogenic variant and a frequent cause of mitochondrial disease. Individuals present with a variety of clinical manifestations from diabetes to neurological events resembling strokes. Due to this, patients are commonly cared for by a multidisciplinary team. OBJECTIVES: This project aimed to identify patients with confirmed mt.3243A>G-related mitochondrial disease attending the Muscle Clinic at Queen Elizabeth University Hospital in Glasgow. We explored potential correlates between clinical phenotypes and mtDNA heteroplasmy levels, HbA1c levels, body mass index, and specific clinical manifestations. We investigated if there were discrepancies between non-neurological speciality labelling in clinical records and individuals' phenotypes. METHODS: Data were gathered from the West of Scotland electronic records. Phenotypes were ascertained by a clinician with expertise in mitochondrial disorders. Statistical analyses were applied to study relationships between tissue heteroplasmy, HbA1c and clinical phenotypes including body mass index (BMI). RESULTS: Forty-six individuals were identified from 31 unrelated pedigrees. Maternally inherited diabetes and deafness was the prominent syndromic phenotype (48%). A significant association was found between overall number of symptoms and bowel dysmotility (p < 0.01). HbA1c was investigated as a predictor of severity with potential association seen. Although used widely as a prognosticator, neither corrected blood nor urine mtDNA heteroplasmy levels were associated with increased number of symptoms. In 74.1% of records, syndromic phenotypes were incorrectly used by non-neurological specialities. CONCLUSIONS: This m.3243 A > G patient cohort present with marked clinical heterogeneity. Urine and blood heteroplasmy levels are not reliable predictors of disease severity. HbA1c may be a novel predictor of disease severity with further research required to investigate this association. We infer that prognosis may be worse in patients with low BMIs and in those with bowel dysmotility. These results underscore a multidisciplinary approach and highlight a problem with inaccurate use of the existing nomenclature.

Analysis of muscle magnetic resonance imaging of a large cohort of patient with VCP-mediated disease reveals characteristic features useful for diagnosis.

BACKGROUND: The diagnosis of patients with mutations in the VCP gene can be complicated due to their broad phenotypic spectrum including myopathy, motor neuron disease and peripheral neuropathy. Muscle MRI guides the diagnosis in neuromuscular diseases (NMDs); however, comprehensive muscle MRI features for VCP patients have not been reported so far. METHODS: We collected muscle MRIs of 80 of the 255 patients who participated in the "VCP International Study" and reviewed the T1-weighted (T1w) and short tau inversion recovery (STIR) sequences. We identified a series of potential diagnostic MRI based characteristics useful for the diagnosis of VCP disease and validated them in 1089 MRIs from patients with other genetically confirmed NMDs. RESULTS: Fat replacement of at least one muscle was identified in all symptomatic patients. The most common finding was the existence of patchy areas of fat replacement. Although there was a wide variability of muscles affected, we observed a common pattern characterized by the involvement of periscapular, paraspinal, gluteal and quadriceps muscles. STIR signal was enhanced in 67% of the patients, either in the muscle itself or in the surrounding fascia. We identified 10 diagnostic characteristics based on the pattern identified that allowed us to distinguish VCP disease from other neuromuscular diseases with high accuracy. CONCLUSIONS: Patients with mutations in the VCP gene had common features on muscle MRI that are helpful for diagnosis purposes, including the presence of patchy fat replacement and a prominent involvement of the periscapular, paraspinal, abdominal and thigh muscles.

Glycogen storage disease type IV without detectable polyglucosan bodies: importance of broad gene panels.

Glycogen storage disease type IV (GSD IV) is caused by mutations in the glycogen branching enzyme 1 (GBE1) gene and is characterized by accumulation of polyglucosan bodies in liver, muscle and other tissues. We report three cases with neuromuscular forms of GSD IV, none of whom had polyglucosan bodies on muscle biopsy. The first case had no neonatal problems and presented with delayed walking. The other cases presented at birth: one with arthrogryposis, hypotonia, and respiratory distress, the other with talipes and feeding problems. All developed a similar pattern of axial weakness, proximal upper limb weakness and scapular winging, and much milder proximal lower limb weakness. Our cases expand the phenotypic spectrum of neuromuscular GSD IV, highlight that congenital myopathy and limb girdle weakness can be caused by mutations in GBE1, and emphasize that GSD IV should be considered even in the absence of characteristic polyglucosan bodies on muscle biopsy.

Immune-Mediated Neuropathies: Pathophysiology and Management.

Dysfunction of the immune system can result in damage of the peripheral nervous system. The immunological mechanisms, which include macrophage infiltration, inflammation and proliferation of Schwann cells, result in variable degrees of demyelination and axonal degeneration. Aetiology is diverse and, in some cases, may be precipitated by infection. Various animal models have contributed and helped to elucidate the pathophysiological mechanisms in acute and chronic inflammatory polyradiculoneuropathies (Guillain-Barre Syndrome and chronic inflammatory demyelinating polyradiculoneuropathy, respectively). The presence of specific anti-glycoconjugate antibodies indicates an underlying process of molecular mimicry and sometimes assists in the classification of these disorders, which often merely supports the clinical diagnosis. Now, the electrophysiological presence of conduction blocks is another important factor in characterizing another subgroup of treatable motor neuropathies (multifocal motor neuropathy with conduction block), which is distinct from Lewis-Sumner syndrome (multifocal acquired demyelinating sensory and motor neuropathy) in its response to treatment modalities as well as electrophysiological features. Furthermore, paraneoplastic neuropathies are also immune-mediated and are the result of an immune reaction to tumour cells that express onconeural antigens and mimic molecules expressed on the surface of neurons. The detection of specific paraneoplastic antibodies often assists the clinician in the investigation of an underlying, sometimes specific, malignancy. This review aims to discuss the immunological and pathophysiological mechanisms that are thought to be crucial in the aetiology of dysimmune neuropathies as well as their individual electrophysiological characteristics, their laboratory features and existing treatment options. Here, we aim to present a balance of discussion from these diverse angles that may be helpful in categorizing disease and establishing prognosis.

Masseter muscle volume as a disease marker in adult-onset myotonic dystrophy type 1.

The advent of clinical trials in myotonic dystrophy type 1 (DM1) necessitates the identification of reliable outcome measures to quantify different disease manifestations using minimal number of assessments. In this study, clinical correlations of mean masseter volume (mMV) were explored to evaluate its potential as a marker of muscle involvement in adult-onset DM1 patients. We utilised data from a preceding study, pertaining to 39 DM1 patients and 20 age-matched control participants. In this study participants had undergone MRI of the brain, completed various clinical outcome measures and had CTG repeats measured by small-pool PCR. Manual segmentation of masseter muscles was performed by a single rater to estimate mMV. The masseter muscle was atrophied in DM1 patients when compared to controls (p<0.001). Significant correlations were found between mMV and estimated progenitor allele length (p = 0.001), modal allele length (p = 0.003), disease duration (p = 0.009) and and the Muscle Impairment Rating Scale (p = 0.008). After correction for lean body mass, mMV was also inversely correlated with self-reported myotonia (p = 0.014). This study demonstrates that changes in mMV are sensitive in reflecting the underlying disease process. Quantitative MRI methods demonstrate that data concerning both central and peripheral disease could be acquired from MR brain imaging studies in DM1 patients.

Genotype-phenotype correlations in valosin-containing protein disease: a retrospective muticentre study.

BACKGROUND: Valosin-containing protein (VCP) disease, caused by mutations in the VCP gene, results in myopathy, Paget's disease of bone (PBD) and frontotemporal dementia (FTD). Natural history and genotype-phenotype correlation data are limited. This study characterises patients with mutations in VCP gene and investigates genotype-phenotype correlations. METHODS: Descriptive retrospective international study collecting clinical and genetic data of patients with mutations in the VCP gene. RESULTS: Two hundred and fifty-five patients (70.0% males) were included in the study. Mean age was 56.8±9.6 years and mean age of onset 45.6±9.3 years. Mean diagnostic delay was 7.7±6 years. Symmetric lower limb weakness was reported in 50% at onset progressing to generalised muscle weakness. Other common symptoms were ventilatory insufficiency 40.3%, PDB 28.2%, dysautonomia 21.4% and FTD 14.3%. Fifty-seven genetic variants were identified, 18 of these no previously reported. c.464G>A (p.Arg155His) was the most frequent variant, identified in the 28%. Full time wheelchair users accounted for 19.1% with a median time from disease onset to been wheelchair user of 8.5 years. Variant c.463C>T (p.Arg155Cys) showed an earlier onset (37.8±7.6 year) and a higher frequency of axial and upper limb weakness, scapular winging and cognitive impairment. Forced vital capacity (FVC) below 50% was as risk factor for being full-time wheelchair user, while FVC <70% and being a full-time wheelchair user were associated with death. CONCLUSION: This study expands the knowledge on the phenotypic presentation, natural history, genotype-phenotype correlations and risk factors for disease progression of VCP disease and is useful to improve the care provided to patient with this complex disease.

Morbidity and mortality associated with gastrointestinal dysfunction in neuromuscular disease: a single-centre case series.

Gastrointestinal dysfunction in neuromuscular disease is associated with significant morbidity and mortality. It is often underreported despite its prevalence in this cohort. There are a number of issues reported, with gastrointestinal dysmotility and intestinal pseudo-obstruction carrying a poor outcome. We present a case-series of six patients attending a single-centre specialist muscle clinic with a confirmed diagnosis of a neuromuscular disorder (Duchenne muscular dystrophy, mitochondrial disorders, and desmin-related myopathy) and problematic gastrointestinal dysfunction. We advocate prompt recognition and early management, as part of the multi-disciplinary team, to prevent clinical deterioration.

Clinical and neuroradiological correlates of sleep in myotonic dystrophy type 1.

Abnormalities of sleep are common in myotonic dystrophy type 1 (DM1), but few previous studies have combined polysomnography with detailed clinical measures and brain imaging. In the present study, domiciliary polysomnography, symptom questionnaires and cognitive evaluation were undertaken in 39 DM1-affected individuals. Structural brain MRI was completed in those without contra-indication (n = 32). Polysomnograms were adequate for analysis in 36 participants. Sleep efficiency was reduced, and sleep architecture altered in keeping with previous studies. Twenty participants (56%) had moderate or severe sleep-disordered breathing (apnoea-hypopnoea index [AHI] ≥ 15). In linear modelling, apnoeas were positively associated with increasing age and male sex. AHI ≥ 15 was further associated with greater daytime pCO2 and self-reported physical impairment, somnolence and fatigue. Percentage REM sleep was inversely associated with cerebral grey matter volume, stage 1 sleep was positively associated with occipital lobe volume and stage 2 sleep with amygdala volume. Hippocampus volume was positively correlated with self-reported fatigue and somnolence. Linear relationships were also observed between measures of sleep architecture and cognitive performance. Findings broadly support the hypothesis that changes in sleep architecture and excessive somnolence in DM1 reflect the primary disease process in the central nervous system.

FXR1-related congenital myopathy: expansion of the clinical and genetic spectrum.

BACKGROUND: Biallelic pathogenic variants in FXR1 have recently been associated with two congenital myopathy phenotypes: a severe form associated with hypotonia, long bone fractures, respiratory insufficiency and infantile death, and a milder form characterised by proximal muscle weakness with survival into adulthood. OBJECTIVE: We report eight patients from four unrelated families with biallelic pathogenic variants in exon 15 of FXR1. METHODS: Whole exome sequencing was used to detect variants in FXR1. RESULTS: Common clinical features were noted for all patients, which included proximal myopathy, normal serum creatine kinase levels and diffuse muscle atrophy with relative preservation of the quadriceps femoris muscle on muscle imaging. Additionally, some patients with FXR1-related myopathy had respiratory involvement and required bilevel positive airway pressure support. Muscle biopsy showed multi-minicores and type I fibre predominance with internalised nuclei. CONCLUSION: FXR1-related congenital myopathy is an emerging entity that is clinically recognisable. Phenotypic variability associated with variants in FXR1 can result from differences in variant location and type and is also observed between patients homozygous for the same variant, rendering specific genotype-phenotype correlations difficult. Our work broadens the phenotypic spectrum of FXR1-related congenital myopathy.

Forecasting stroke-like episodes and outcomes in mitochondrial disease.

In this retrospective, multicentre, observational cohort study, we sought to determine the clinical, radiological, EEG, genetics and neuropathological characteristics of mitochondrial stroke-like episodes and to identify associated risk predictors. Between January 1998 and June 2018, we identified 111 patients with genetically determined mitochondrial disease who developed stroke-like episodes. Post-mortem cases of mitochondrial disease (n = 26) were identified from Newcastle Brain Tissue Resource. The primary outcome was to interrogate the clinico-radiopathological correlates and prognostic indicators of stroke-like episode in patients with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome (MELAS). The secondary objective was to develop a multivariable prediction model to forecast stroke-like episode risk. The most common genetic cause of stroke-like episodes was the m.3243A>G variant in MT-TL1 (n = 66), followed by recessive pathogenic POLG variants (n = 22), and 11 other rarer pathogenic mitochondrial DNA variants (n = 23). The age of first stroke-like episode was available for 105 patients [mean (SD) age: 31.8 (16.1)]; a total of 35 patients (32%) presented with their first stroke-like episode ≥40 years of age. The median interval (interquartile range) between first and second stroke-like episodes was 1.33 (2.86) years; 43% of patients developed recurrent stroke-like episodes within 12 months. Clinico-radiological, electrophysiological and neuropathological findings of stroke-like episodes were consistent with the hallmarks of medically refractory epilepsy. Patients with POLG-related stroke-like episodes demonstrated more fulminant disease trajectories than cases of m.3243A>G and other mitochondrial DNA pathogenic variants, in terms of the frequency of refractory status epilepticus, rapidity of progression and overall mortality. In multivariate analysis, baseline factors of body mass index, age-adjusted blood m.3243A>G heteroplasmy, sensorineural hearing loss and serum lactate were significantly associated with risk of stroke-like episodes in patients with the m.3243A>G variant. These factors informed the development of a prediction model to assess the risk of developing stroke-like episodes that demonstrated good overall discrimination (area under the curve = 0.87, 95% CI 0.82-0.93; c-statistic = 0.89). Significant radiological and pathological features of neurodegeneration were more evident in patients harbouring pathogenic mtDNA variants compared with POLG: brain atrophy on cranial MRI (90% versus 44%, P < 0.001) and reduced mean brain weight (SD) [1044 g (148) versus 1304 g (142), P = 0.005]. Our findings highlight the often idiosyncratic clinical, radiological and EEG characteristics of mitochondrial stroke-like episodes. Early recognition of seizures and aggressive instigation of treatment may help circumvent or slow neuronal loss and abate increasing disease burden. The risk-prediction model for the m.3243A>G variant can help inform more tailored genetic counselling and prognostication in routine clinical practice.

The phenotypic and genotypic features of a Scottish cohort with McArdle disease.

This retrospective study evaluated the phenotypic and genotypic features of 14 patients with McArdle disease attending the West of Scotland adult muscle clinic. Although all patients experienced exercise-induced cramps, exercise intolerance and hyperCKaemia, only 71% (n = 10) experienced the second wind phenomenon, rhabdomyolysis and/or myoglobinuria. We observed a high rate of fixed muscle weakness (50%; n = 7), coronary artery disease (36%; n = 5), and psychological comorbidity (50%; n = 7). Although 79% had symptom onset in the first decade of life, the mean age at presentation and at genetic diagnosis was 43.8 years and 47.7 years, respectively. 93% had at least one copy of the common PYGM pathogenic variant, c.148C > T, p.(Arg50*), with 50% (n = 7) of the cohort being homozygous. Our cohort highlights the phenotypic variability seen in McArdle disease and underscores the potential for late-onset presentations. It emphasises the need for improved awareness and recognition of this condition amongst neurologists, rheumatologists and general physicians. A history of exercise intolerance and second wind phenomenon may not always be volunteered by the patient, underscoring the need to ask specific questions in clinic to extrapolate the relevant symptoms in this patient cohort.

A DM1 patient with CCG variant repeats: Reaching the diagnosis.

We report the case of a male patient presenting in his 50s with ptosis, facial and distal limb muscle weakness, clinical and electrical myotonia, and a prior history of cataract extraction. He had a dominant family history in keeping with a similar phenotype. Myotonic dystrophy type 1 was clinically suspected. Triplet-primed polymerase chain reaction in a diagnostic laboratory did not identify a typical CTG repeat expansion on two separate blood samples. However, subsequent genetic testing on a research basis identified a heterozygous repeat expansion containing CCG variant repeats. Our case highlights the point that variant repeats are not detectable on triplet-primed polymerase chain reaction and result in a milder phenotype of myotonic dystrophy. It is crucial to maintain a high clinical index of suspicion of this common neuromuscular condition.

Making sense of missense variants in TTN-related congenital myopathies.

Mutations in the sarcomeric protein titin, encoded by TTN, are emerging as a common cause of myopathies. The diagnosis of a TTN-related myopathy is, however, often not straightforward due to clinico-pathological overlap with other myopathies and the prevalence of TTN variants in control populations. Here, we present a combined clinico-pathological, genetic and biophysical approach to the diagnosis of TTN-related myopathies and the pathogenicity ascertainment of TTN missense variants. We identified 30 patients with a primary TTN-related congenital myopathy (CM) and two truncating variants, or one truncating and one missense TTN variant, or homozygous for one TTN missense variant. We found that TTN-related myopathies show considerable overlap with other myopathies but are strongly suggested by a combination of certain clinico-pathological features. Presentation was typically at birth with the clinical course characterized by variable progression of weakness, contractures, scoliosis and respiratory symptoms but sparing of extraocular muscles. Cardiac involvement depended on the variant position. Our biophysical analyses demonstrated that missense mutations associated with CMs are strongly destabilizing and exert their effect when expressed on a truncating background or in homozygosity. We hypothesise that destabilizing TTN missense mutations phenocopy truncating variants and are a key pathogenic feature of recessive titinopathies that might be amenable to therapeutic intervention.

A Practical Approach to Managing Patients With Myasthenia Gravis-Opinions and a Review of the Literature.

When the diagnosis of myasthenia gravis (MG) has been secured, the aim of management should be prompt symptom control and the induction of remission or minimal manifestations. Symptom control, with acetylcholinesterase inhibitors such as pyridostigmine, is commonly employed. This may be sufficient in mild disease. There is no single universally accepted treatment regimen. Corticosteroids are the mainstay of immunosuppressive treatment in patients with more than mild MG to induce remission. Immunosuppressive therapies, such as azathioprine are prescribed in addition to but sometimes instead of corticosteroids when background comorbidities preclude or restrict the use of steroids. Rituximab has a role in refractory MG, while plasmapheresis and immunoglobulin therapy are commonly prescribed to treat MG crisis and in some cases of refractory MG. Data from the MGTX trial showed clear evidence that thymectomy is beneficial in patients with acetylcholine receptor (AChR) antibody positive generalized MG, up to the age of 65 years. Minimally invasive thymectomy surgery including robotic-assisted thymectomy surgery has further revolutionized thymectomy and the management of MG. Ocular MG is not life-threatening but can be significantly disabling when diplopia is persistent. There is evidence to support early treatment with corticosteroids when ocular motility is abnormal and fails to respond to symptomatic treatment. Treatment needs to be individualized in the older age-group depending on specific comorbidities. In the younger age-groups, particularly in women, consideration must be given to the potential teratogenicity of certain therapies. Novel therapies are being developed and trialed, including ones that inhibit complement-induced immunological pathways or interfere with antibody-recycling pathways. Fatigue is common in MG and should be duly identified from fatigable weakness and managed with a combination of physical therapy with or without psychological support. MG patients may also develop dysfunctional breathing and the necessary respiratory physiotherapy techniques need to be implemented to alleviate the patient's symptoms of dyspnoea. In this review, we discuss various facets of myasthenia management in adults with ocular and generalized disease, including some practical approaches and our personal opinions based on our experience.

Brain Structural Features of Myotonic Dystrophy Type 1 and their Relationship with CTG Repeats.

BACKGROUND: Few adequately-powered studies have systematically evaluated brain morphology in adult-onset myotonic dystrophy type 1 (DM1). OBJECTIVE: The goal of the present study was to determine structural brain differences between individuals with and without adult-onset DM1 in a multi-site, case-controlled cohort. We also explored correlations between brain structure and CTG repeat length. METHODS: Neuroimaging data was acquired in 58 unaffected individuals (29 women) and 79 individuals with DM1 (50 women). CTG repeat length, expressed as estimated progenitor allele length (ePAL), was determined by small pool PCR. Statistical models were adjusted for age, sex, site, and intracranial volume (ICV). RESULTS: ICV was reduced in DM1 subjects compared with controls. Accounting for the difference in ICV, the DM1 group exhibited smaller volume in frontal grey and white matter, parietal grey matter as well as smaller volume of the corpus callosum, thalamus, putamen, and accumbens. In contrast, volumes of the hippocampus and amygdala were significantly larger in DM1. Greater ePAL was associated with lower volumes of the putamen, occipital grey matter, and thalamus. A positive ePAL association was observed for amygdala volume and cerebellar white matter. CONCLUSIONS: Smaller ICV may be a marker of aberrant neurodevelopment in adult-onset DM1. Volumetric analysis revealed morphological differences, some associated with CTG repeat length, in structures with plausible links to key DM1 symptoms including cognitive deficits and excessive daytime somnolence. These data offer further insights into the basis of CNS disease in DM1, and highlight avenues for further work to identify therapeutic targets and imaging biomarkers.

Guidelines for single fiber EMG.

This document is the consensus of international experts on the current status of Single Fiber EMG (SFEMG) and the measurement of neuromuscular jitter with concentric needle electrodes (CNE - CN-jitter). The panel of authors was chosen based on their particular interests and previous publications within a specific area of SFEMG or CN-jitter. Each member of the panel was asked to submit a section on their particular area of interest and these submissions were circulated among the panel members for edits and comments. This process continued until a consensus was reached. Donald Sanders and Erik Stålberg then edited the final document.

Outcome Measures for Central Nervous System Evaluation in Myotonic Dystrophy Type 1 May Be Confounded by Deficits in Motor Function or Insight.

Background: Central nervous system involvement in myotonic dystrophy type 1 (DM1) is associated with cognitive deficits, impaired social performance and excessive somnolence, which greatly impact quality of life. With the advent of clinical trials in DM1, there is a pressing need to identify outcome measures for quantification of central symptoms that are feasible and valid. In this context, we sought to evaluate neuropsychological and self-reported measures currently recommended by expert consensus, with particular reference to their specificity for central nervous system involvement in a moderate-sized DM1 cohort. Methods: Forty-five adults with DM1 and 20 controls completed neuropsychology assessments and symptom questionnaires. Those without contraindication also underwent MRI brain, from which global gray matter volume and white matter lesion volume were quantified. CTG repeat was measured by small pool PCR, and was screened for the presence of variant repeat sequences. Results: The neuropsychology test battery was well tolerated and detected impairment across various domains in the DM1 group vs. controls. Large effect sizes in the Stroop and Trail Making Tests were however attenuated by correction for basic speed, which could be influenced by dysarthria and upper limb weakness, respectively. Low mood was strongly associated with increased self-reporting of central symptoms, including cognitive impairment. Conversely, self-reported cognitive impairment did not generally predict poorer performance in neuropsychology assessments, and there was a trend toward greater self-reporting of low mood and cognitive problems in those with milder white matter change on MRI. Global gray matter volume correlated with performance in several neuropsychology assessments in a multivariate model with age and sex, while white matter lesion volume was associated with executive dysfunction reported by a proxy. Screening for variant repeats was positive in three individuals, who reported mild muscle symptoms. Conclusions: Identification of outcome measures with good specificity for brain involvement in DM1 is challenging, since complex cognitive assessments may be compromised by peripheral muscle weakness and self-reported questionnaires may be influenced by mood and insight. This highlights the need for further large, longitudinal studies to identify and validate objective measures, which may include imaging biomarkers and cognitive measures not influenced by motor speed.

ECEL1 gene related contractural syndrome: Long-term follow-up and update on clinical and pathological aspects.

Autosomal recessive mutations in the ECEL1 gene have recently been associated with a wide phenotypic spectrum including severe congenital contractural syndromes and distal arthrogryposis type 5D (DA5D). Here, we describe four novel families with ECEL1 gene mutations, reporting 15 years of follow-up for four patients and detailed muscle pathological description for three individuals. In particular, we observed mild myopathic features, prominent core-like areas in one individual, and presence of nCAM positive fibres in three patients from 2 unrelated families suggesting a possible problem with innervation. Our findings expand current knowledge concerning the phenotypic and pathological spectrum associated with ECEL1 gene mutations and may suggest novel insights regarding the underlying pathomechanism of the disease.