255th ENMC workshop: Muscle imaging in idiopathic inflammatory myopathies. 15th January, 16th January and 22nd January 2021 - virtual meeting and hybrid meeting on 9th and 19th September 2022 in Hoofddorp, The Netherlands.

The 255th ENMC workshop on Muscle Imaging in Idiopathic Inflammatory myopathies (IIM) aimed at defining recommendations concerning the applicability of muscle imaging in IIM. The workshop comprised of clinicians, researchers and people living with myositis. We aimed to achieve consensus on the following topics: a standardized protocol for the evaluation of muscle images in various types of IIMs; the exact parameters, anatomical localizations and magnetic resonance imaging (MRI) techniques; ultrasound as assessment tool in IIM; assessment methods; the pattern of muscle involvement in IIM subtypes; the application of MRI as biomarker in follow-up studies and clinical trials, and the place of MRI in the evaluation of swallowing difficulty and cardiac manifestations.

Enhanced mitochondrial genome analysis: bioinformatic and long-read sequencing advances and their diagnostic implications.

Introduction: Primary mitochondrial diseases (PMDs) comprise a large and heterogeneous group of genetic diseases that result from pathogenic variants in either nuclear DNA (nDNA) or mitochondrial DNA (mtDNA). Widespread adoption of next-generation sequencing (NGS) has improved the efficiency and accuracy of mtDNA diagnoses; however, several challenges remain.

Areas Covered: In this review, we briefly summarize the current state of the art in molecular diagnostics for mtDNA and consider the implications of improved whole genome sequencing (WGS), bioinformatic techniques, and the adoption of long-read sequencing, for PMD diagnostics.

Muscle MRI in periodic paralysis shows myopathy is common and correlates with intramuscular fat accumulation.

Introduction/aims: The periodic paralyses are muscle channelopathies: hypokalemic periodic paralysis (CACNA1S and SCN4A variants), hyperkalemic periodic paralysis (SCN4A variants), and Andersen-Tawil syndrome (KCNJ2). Both episodic weakness and disabling fixed weakness can occur. Little literature exists on magnetic resonance imaging (MRI) in muscle channelopathies.

Discussion of off-target and tentative genomic findings may sometimes be necessary to allow evaluation of their clinical significance.

We discuss a case where clinical genomic investigation of muscle weakness unexpectedly found a genetic variant that might (or might not) predispose to kidney cancer. We argue that despite its off-target and uncertain nature, this variant should be discussed with the man who had the test, not because it is medical information, but because this discussion would allow the further clinical evaluation that might lead it to becoming so. We argue that while prominent ethical debates around genomics often take 'results' as a starting point and ask questions as to whether to look for and how to react to them, the construction of genomic results is fraught with ethical complexity, although often couched as a primarily technical problem.

Muscle magnetic resonance imaging involvement patterns in nemaline myopathies.

Objective: Characterise the diagnostic and prognostic value of muscle MRI patterns as biomarkers in a genetically heterogeneous nemaline myopathy (NM) patient cohort.

Methods: Modified Mercuri scoring of lower limb MRI in genetically characterised NM patients referred to the highly specialised service for congenital myopathies at Great Ormond Street Hospital. Findings were compared to clinical data and MRI patterns derived from collated published data.

Progressive external ophthalmoplegia.

Progressive external ophthalmoplegia (PEO), characterized by ptosis and impaired eye movements, is a clinical syndrome with an expanding number of etiologically distinct subtypes. Advances in molecular genetics have revealed numerous pathogenic causes of PEO, originally heralded in 1988 by the detection of single large-scale deletions of mitochondrial DNA (mtDNA) in skeletal muscle of people with PEO and Kearns-Sayre syndrome. Since then, multiple point variants of mtDNA and nuclear genes have been identified to cause mitochondrial PEO and PEO-plus syndromes, including mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) and sensory ataxic neuropathy dysarthria ophthalmoplegia (SANDO).

Methods for informing people with amyotrophic lateral sclerosis/motor neuron disease of their diagnosis.

Background: Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), causes increasing physical impairment and disability. People with ALS/MND face huge physical challenges, and the diagnosis can be a source of great psychological distress for both people with ALS/MND and their carers. In such a context, how news of the diagnosis is broken is important.

Incidence and risk factors for patellofemoral dislocation in adults with Charcot-Marie-Tooth disease: An observational study.

Background And Purpose: Patellofemoral (PF) dislocation is frequently encountered in clinical practice among people with Charcot-Marie-Tooth disease (CMT), but the frequency and risk factors for PF dislocation in adults with CMT are unknown. This study aimed to establish the incidence of PF dislocation in adults with CMT and to explore the risk factors associated with PF dislocation.

Methods: This is a cross-sectional study involving adults with a diagnosis of CMT, attending their outpatient clinics at a specialist neuromuscular centre in the United Kingdom.

Advances in methods to analyse cardiolipin and their clinical applications.

Cardiolipin (CL) is a mitochondria-exclusive phospholipid, primarily localised within the inner mitochondrial membrane, that plays an essential role in mitochondrial architecture and function. Aberrant CL content, structure, and localisation have all been linked to impaired mitochondrial activity and are observed in the pathophysiology of cancer and neurological, cardiovascular, and metabolic disorders. The detection, quantification, and localisation of CL species is a valuable tool to investigate mitochondrial dysfunction and the pathophysiological mechanisms underpinning several human disorders.

Revised Hammersmith Scale for spinal muscular atrophy: Inter and intra-rater reliability and agreement.

The Revised Hammersmith Scale (RHS) for Spinal Muscular Atrophy (SMA) was designed as a psychometrically robust clinical outcome assessment to assess physical abilities of patients with type 2 and 3 SMA. The reliability properties of the RHS have not yet been reported. A prospective RHS reliability study was undertaken in a UK cohort of experienced neuromuscular paediatric Physiotherapists.

Integrin α7 Mutations Are Associated With Adult-Onset Cardiac Dysfunction in Humans and Mice.

Background Integrin α7β1 is a major laminin receptor in skeletal and cardiac muscle. In skeletal muscle, integrin α7β1 plays an important role during muscle development and has been described as an important modifier of skeletal muscle diseases. The integrin α7β1 is also highly expressed in the heart, but its precise role in cardiac function is unknown.

Specialist multidisciplinary input maximises rare disease diagnoses from whole genome sequencing.

Diagnostic whole genome sequencing (WGS) is increasingly used in rare diseases. However, standard, semi-automated WGS analysis may overlook diagnoses in complex disorders. Here, we show that specialist multidisciplinary analysis of WGS, following an initial 'no primary findings' (NPF) report, improves diagnostic rates and alters management.

De novo KCNA6 variants with attenuated K 1.6 channel deactivation in patients with epilepsy.

Objective: Mutations in the genes encoding neuronal ion channels are a common cause of Mendelian neurological diseases. We sought to identify novel de novo sequence variants in cases with early infantile epileptic phenotypes and neurodevelopmental anomalies.

Methods: Following clinical diagnosis, we performed whole exome sequencing of the index cases and their parents.

Gene therapy for primary mitochondrial diseases: experimental advances and clinical challenges.

The variable clinical and biochemical manifestations of primary mitochondrial diseases (PMDs), and the complexity of mitochondrial genetics, have proven to be a substantial barrier to the development of effective disease-modifying therapies. Encouraging data from gene therapy trials in patients with Leber hereditary optic neuropathy and advances in DNA editing techniques have raised expectations that successful clinical transition of genetic therapies for PMDs is feasible. However, obstacles to the clinical application of genetic therapies in PMDs remain; the development of innovative, safe and effective genome editing technologies and vectors will be crucial to their future success and clinical approval.

Evidence of nerve hypertrophy in patients with inclusion body myositis on lower limb MRI.

Introduction/aims: Inclusion body myositis (IBM) is a myopathic condition but in some patients has been associated with an axonal length-dependent polyneuropathy. In this study, we quantified the cross-sectional area of the sciatic and tibial nerves in patients with IBM comparing with Charcot-Marie-Tooth disease type 1A (CMT1A) and healthy controls using magnetic resonance neurography (MRN).

Methods: MRN of the sciatic and tibial nerves was performed at 3T using MPRAGE and Dixon acquisitions.