Multiple-acyl-CoA-dehydrogenase deficiency (MADD) is caused by recessive pathogenic variants in genes encoding the alpha and beta subunits of electron transfer flavoprotein (ETF) and ETF-coenzymeQ oxioreductase. Sunebo and colleagues recently described a MADD cohort, highlighting a paucity of genetic diagnoses and possible association with sertraline. This led us to review all 18 patients known to the West of Scotland adult neurology service who were being treated with riboflavin for a working diagnosis of late-onset MADD. 4/18 (22%) had a single heterozygous likely pathogenic or pathogenic ETFDH variant. Age at onset was 21 to 80y, with mean 52y. 8/18 presented with rhabdomyolysis, all with recognised precipitants. The remainder presented with (sub)acute progressive weakness. Detailed dietary assessments were not undertaken but unhealthy and/or restricted diets were often described. 15/18 (83%) were on sertraline at presentation. 13/18 (72%) had significant increases in C4>C18 acylcarnitines with patterns suggestive of MADD. 2/18 had patterns compatible with MADD or carnitine palmitoyltransferase-2 (CPT-2) deficiency, the latter was excluded genetically. 3/18 has more subtle patterns (C4>C10). For 10 of 14 patients where urine organic acids were analysed, these were suggestive of, or consistent with, MADD. Review of 17 skeletal muscle biopsies revealed abnormal lipid deposition in 15/17, ranging from increased lipid droplet size in a proportion of fibres in 5 cases through to coalescent lipid vacuoles in a majority of fibres in 5 cases. There was no correlation between extent of lipid pathology and age, or presence of ragged-red or COX-deficient fibres. All patients improved clinically and biochemically with riboflavin supplementation, though the extent varied. A late-onset MADD-like condition is much more common in our neurology cohort than primary genetic MADD and is likely multifactorial.

The Glasgow Genomic laboratory offers a 36 gene rhabdomyolysis and metabolic myopathy panel. Test criteria were developed by clinicians but not strictly enforced. Evaluation of 74 consecutive referrals found testing varied according to patients’ Health Board of residence from 0 to 27 patients tested/million population. 6 (8.1%) had definitive diagnoses with likely pathogenic or pathogenic variants (5 RYR1, 1 CAPN3). One had an RYR1 VUS and positive in-vitro contracture test. Clinical details were evaluated in 69 adults. In the two largest Health Boards there were 22.4 patients tested/million population with a pickup rate of definitive genetic diagnoses of 11%, compared with 6.5 tested/million population with a pickup rate of 5% in the rest of Scotland. 60% and 68% respectively fitted test criteria. 32 of 57 cases (56%) referred by clinicians involved in designing the test criteria fitted these, compared with 11 of 12 (92%) other referrals. All 5 probands with RYR1 associated rhabdomyolysis, and 2 relatives with exercise induced pigmenturia, were fit males, with cycling a trigger in all but one. Variant carrying female relatives were asymptomatic or had exercise related myalgia. 4 of 46 non-RYR1 rhabdomyolysis cases were triggered by cycling and 3 by spin classes. One RYR1 associated single rhabdomyolysis case would have been missed by strict application of test criteria, as peak CK was below the 10,000IU/L criterion. However, CK remained elevated, and the investigation pathway suggested referral to a muscle clinic. Persistently elevated CK should be added to test criteria. Both diagnoses (RYR1, CAPN3) in the possible metabolic myopathy group would have been missed if test criteria were adhered to. Variability in clinician awareness and adherence to test criteria likely contribute to the postcode lottery in access to testing. It is unclear why diagnostic pickup varies by patient postcode, and unclear whether the association of RYR1 rhabdomyolysis with cycling is real.

Spectrinopathies represent an emerging theme with overlapping phenotypes ranging from peripheral or central nervous system involvement towards complex syndromic presentations. A total of 60 different reported SPTAN1 mutations is exemplary for this diversity with phenotypes spanning almost the entire neurospectrinopathy spectrum, except myopathic involvement. Through collaboration within the Solve-RD network we identified patients with unsolved progressive distal weakness and unreported SPTAN1 variants. We reached consensus on the interpretation of clinical picture, electrophysiology, muscle MRI and biopsy. Finally, SPTAN1 protein and RNA expression analysis was performed on available muscle biopsy from one of the patients. In total seven index patients, carrying heterozygous SPTAN1 frameshift variants, were included. Three showed autosomal dominant inheritance, three were sporadic and one de novo. All index patients showed early childhood (2-10 years) onset of foot dorsiflexion weakness. Some patients showed distal upper limb weakness (n=4), scoliosis (n=2) and intellectual disability (ID) (n=1). Electrophysiology showed mixed myogenic and neurogenic features. Muscle MRI (n=4) and muscle CT (n=1) showed fatty infiltration of the distal lower limb anterior compartment and/or involvement of the extensor hallucis longus muscle. Muscle biopsy showed dystrophic changes with signs of chronic denervation in three patients. We found proof of a normal protein expression but 40% reduction in SPTAN1 mRNA levels in one patient. We provide evidence for the association of SPTAN1 frameshift variants with childhood onset distal myopathic as well as neurogenic features in seven patients. This finding further extends the established spectrum of SPTAN1 haploinsufficiency associated with a variable penetrance of hereditary motor neuropathy and ID. Overlap between distal myopathic and neurogenic features could be present in other patients and may be overlooked due to phenotypic similarity. Spectrinopathies represent an emerging theme with overlapping phenotypes ranging from peripheral or central nervous system involvement towards complex syndromic presentations. A total of 60 different reported SPTAN1 mutations is exemplary for this diversity with phenotypes spanning almost the entire neurospectrinopathy spectrum, except myopathic involvement. Through collaboration within the Solve-RD network we identified patients with unsolved progressive distal weakness and unreported SPTAN1 variants. We reached consensus on the interpretation of clinical picture, electrophysiology, muscle MRI and biopsy. Finally, SPTAN1 protein and RNA expression analysis was performed on available muscle biopsy from one of the patients. In total seven index patients, carrying heterozygous SPTAN1 frameshift variants, were included. Three showed autosomal dominant inheritance, three were sporadic and one de novo. All index patients showed early childhood (2-10 years) onset of foot dorsiflexion weakness. Some patients showed distal upper limb weakness (n=4), scoliosis (n=2) and intellectual disability (ID) (n=1). Electrophysiology showed mixed myogenic and neurogenic features. Muscle MRI (n=4) and muscle CT (n=1) showed fatty infiltration of the distal lower limb anterior compartment and/or involvement of the extensor hallucis longus muscle. Muscle biopsy showed dystrophic changes with signs of chronic denervation in three patients. We found proof of a normal protein expression but 40% reduction in SPTAN1 mRNA levels in one patient. We provide evidence for the association of SPTAN1 frameshift variants with childhood onset distal myopathic as well as neurogenic features in seven patients. This finding further extends the established spectrum of SPTAN1 haploinsufficiency associated with a variable penetrance of hereditary motor neuropathy and ID. Overlap between distal myopathic and neurogenic features could be present in other patients and may be overlooked due to phenotypic similarity.

Glycogen storage disease type IV (GSD IV) is an autosomal recessive disorder 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. They all had compound heterozygous variants in the GBE1 gene classified as either likely pathogenic or pathogenic, all including the GBE1 c.691+2T>C variant. 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, and the other with talipes and feeding problems. These two cases had presumed antenatal onset of their condition, however unlike most cases with this type of neuromuscular GSD IV described in the literature, they survived until at least toddlerhood. All three cases described developed a similar pattern of axial weakness, proximal upper limb weakness and scapular winging, and much milder proximal lower limb weakness. We review the literature and describe any previously reported cases of neuromuscular GSD IV without polyglucosan bodies on muscle biopsy as well as the reported patterns of muscle weakness. Our cases emphasize that GSD IV should be considered even in the absence of characteristic polyglucosan bodies on muscle biopsy. They also expand the phenotypic spectrum of neuromuscular GSD IV, highlighting that limb girdle weakness and congenital myopathy phenotype can both be caused by mutations in GBE1. Glycogen storage disease type IV (GSD IV) is an autosomal recessive disorder 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. They all had compound heterozygous variants in the GBE1 gene classified as either likely pathogenic or pathogenic, all including the GBE1 c.691+2T>C variant. 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, and the other with talipes and feeding problems. These two cases had presumed antenatal onset of their condition, however unlike most cases with this type of neuromuscular GSD IV described in the literature, they survived until at least toddlerhood. All three cases described developed a similar pattern of axial weakness, proximal upper limb weakness and scapular winging, and much milder proximal lower limb weakness. We review the literature and describe any previously reported cases of neuromuscular GSD IV without polyglucosan bodies on muscle biopsy as well as the reported patterns of muscle weakness. Our cases emphasize that GSD IV should be considered even in the absence of characteristic polyglucosan bodies on muscle biopsy. They also expand the phenotypic spectrum of neuromuscular GSD IV, highlighting that limb girdle weakness and congenital myopathy phenotype can both be caused by mutations in GBE1.

Trendelenberg gait; no contractures were noted.A neuromuscular gene panel test reported as a variant of uncertain significance a novel CFL2 variant (c.449G > A, p.Gluy150Glu, inherited homozygously.Muscle biopsy was performed and revealed the presence of scattered nemaline rods, confirming the mutation as pathogenic.Recent examination (age 10 yr) showed progression of weakness throughout.Neck flexion strength was minimal, and she maintains a posture of next extension.In the legs, hip flexion weakness was pronounced (2/5), with relative preservation of knee flexion (5/5) and extension (4 + /5) but significant ankle dorsiflexion weakness (4-/5).Significant contractures were noted at elbows and knees, and markedly at the ankles.Ultrasound of affected muscles showed a uniform ground-glass appearance.Immunofluorescent analysis showed abnormal CFL-2 distribution, with accumulation within scattered fibers associated with disruption of sarcomeric organization as judged by alpha-actinin staining.CFL-2 expression by western blot results showed a level of 5.6% of normal of a 17 kDa band, but the presence of a 50 kDa band not seen in control muscle; peptide sequencing of this band by mass spectrometry is underway.These results confirm the importance of the C-terminal region to actin organization and suggest the potential of altered CFL-2 self-assembly, providing hypotheses for future studies of CFL-2 structure and function.

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.

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.(c) 2022 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license ( http://creativecommons.org/licenses/by/4.0/ )

Mutations in the CACNA1S gene were recently identified as a new cause of congenital myopathy (CM). To date only a few cases have been described, with limited phenotypic data. We report the clinical, pathological and radiological phenotype in five children with genetically confirmed CACNA1S-CM. →Patients were referred to our national highly specialised service for CM at The Dubowitz Neuromuscular Centre, UK. We conducted retrospective case note analysis. Two patients had recessive inheritance and three autosomal dominant. →Four of five patients (age range 7-18 years) had severe neonatal presentation with foetal akinesia, weakness, hypotonia, contractures, feeding difficulties and respiratory compromise. The 5th patient presented with motor delay in infancy. All five patients had proximal predominant, bulbar and facial weakness but showed spontaneous improvement over time. Ophthalmoplegia was noted in three. Two patients remain non-ambulant. Two developed scoliosis. Two are on nocturnal non-invasive ventilation initiated at age of 5 months and 7 years. All apart from one required nasogastric/gastrostomy feeding up until 2-5 years of age, but all were able to feed orally from age 5 years. One patient had clear history of periodic weakness well responding to Acetazolamide. Two children reported fatigue and limited endurance but no abnormalities of neuromuscular transmission were detected. All muscle biopsies showed fibre size variation and marked slow fibre predominance. Additional findings included mild central nucleation, few central cores and focally accentuated pseudo-dystrophic changes. Three out of the five patients had abnormal lower limb muscle MRI but with no specific muscle pattern. →CACNA1S related myopathy is a recently described form of congenital myopathy and should be considered in cases of undiagnosed dominant and recessive congenital myopathies with phenotypical features presented above.

Faecal incontinence is recognised as a feature of myotonic dystrophy along with other symptoms of bowel dysfunction, but its prevalence is poorly defined. We have surveyed 152 unselected myotonic dystrophy patients. We identified issues with bowel control in 104 (68% of the study population). Forty-eight (32%) reported faecal incontinence in the 4 weeks prior to completion of the questionnaire. Fifty-six patients (37%) reported having to change their lifestyle because of incontinence issues at some point in the prior 4 weeks. This study shows a high frequency of life-changing symptoms in a large unselected, cohort of patients with myotonic dystrophy type 1, and highlights lower gastrointestinal symptoms as an important issue for further research.

We describe a three generation family with multiple members affected by caveolinopathy due to a novel CAV3 mutation c.218A>G (p.Tyr73Cys). The proband presented in the second year of life with a history of neonatal hypotonia, gross motor delay, exercise intolerance, eight-fold elevated CK and absent caveolin 3 immunostaining on biopsy. Now aged ten years, he has only mild muscle weakness but remains severely limited by muscle pain and fatigue. Clinical features in the multiple affected relatives who were subsequently identified illustrate the known intra-familial variability in phenotypes. With the exception of a two-year-old tested predictively, all had muscle hypertrophy and a history of rippling, though the latter could not always be elicited even by experienced clinicians. Several individuals described pre-school exercise intolerance and toe walking, with two having early TA releases. Several had less than two-fold elevations in CK. Muscle MRIs showed hypertrophy, involvement of medial gastrocnemius, particularly the medial aspect, and mild involvement of hamstrings. Sequencing of multiple muscle genes though the Myoseq project and exome sequencing through the deciphering developmental disorders project did not identify a second muscle disorder in the proband to explain his early presentation, however he has a second CAV3 variant c.100G>A (p.Glu34Lys) inherited from his unaffected parent. Functional studies using cell lines for both CAV3 variants showed partial mis-localisation of mutant protein to the Golgi, a recognised feature of pathogenic CAV3 mutations. It is possible that the earlier presentation in the proband results from his compound heterozygosity. This family highlights that caveolinopathy should be considered in pre-school children with exercise intolerance or toe walking combined with muscle hypertrophy, even if CK is only minimally elevated.

The FHL1 gene is located on chromosome Xq26.3. Mutations in this gene have been linked to several X-linked recessive and dominant inherited myopathies and muscular dystrophies. FHL1 encodes the four-and-a-half LIM domains 1 protein (OMIM 300163) which contains a double zinc finger motif and plays a role in protein-protein interaction and cytoskeletal organisation. Here we report 2 patients with mutations in the FHL1 gene that to our knowledge have not been described before. Whole exome sequencing (WES) and data processing were performed by genomics platform at the broad institute of Harvard and MIT. Patient DNA samples (>250 ng) were processed with Illumina exome capture and sequencing technology (human exome target 38 Mb), and data were analysed with the genome analysis tool kit (GATK). Variant calls were uploaded on to the seqr platform. Patient 1 is a 33-year-old female who presented in early adulthood with scapular and proximal upper limb atrophy, joint contractures of the lower limbs, and progressive weakness. Her muscle biopsy shows myopathic and dystrophic features. She has a pathogenic mutation in the FHL1 gene (chrX:135290658, T > A) causing an amino acid change (p.His182Gln). Patient 2 is a 79-year-old male of Black Indian origin with a raised CK (>10x) and a myopathic and dystrophic picture on muscle biopsy. He has scapular winging, contractures, a heart conduction defect, respiratory dysfunction requiring artificial ventilation, and proximal upper and lower muscle weakness. WES revealed the following FHL1 mutation and amino acid change: chrX 135290783 G > C, p.Cys224Ser. Our 2 patients contribute to the growing knowledge of genotype-phenotype correlations in FHL1 mutations.

Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common muscular dystrophies with an estimated prevalence of 1:25.000. Pain is one of the most debilitating symptoms in FSHD patients and it is assumed that it affects negatively both mobility and quality of life (QoL). We aim to describe the characteristics and intensity of pain and QoL in FSHD type 1 patients registered with the UK FSHD Registry. The 416 patients registered were asked to complete questionnaires assessing persistent and recurrent localised pain, together with validated questionnaires (Short-Form McGill questionnaire and the Individualized Neuromuscular Quality of Life Questionnaire (INQoL)). The pain questionnaires were completed by 379 patients; persistent pain was reported by 50% and recurrent localised pain by 43%. Patients with localised pain described it as discomforting (16%) and for persistent pain it was described as discomforting in 19.7% and as distressing in 14.4% of cases. The shoulder was the most affected location for both persistent (40.4%) and localised pain (23.6%). The population with localised pain reported no change in muscle bulk or weakness after the painful episodes. INQoL was completed by 354 patients; the overall mean score was 50.87 where 100 is the greatest impact on QoL. Muscle weakness has the greatest impact (mean 66.32) followed by fatigue (mean 46.89). Activities and body image were the life domains most affected (mean 57.07 and 55.21). QoL is not significantly affected by current age, age of onset of disease or sex. Pain had a moderate impact on QoL (mean 37). INQoL score correlated positively with ambulation (p < 0.001). Score for ambulant patients was 41.6 and non-ambulant patients 61.5. In conclusion patients with FSHD have a high occurrence of pain that is most frequently persistent and has no correlation with ambulation status of the patient. It seems that pain has a moderate impact on QoL. The most affected domains are activities and body image.

Hereditary inclusion body myopathy (IBM) with Paget's disease of the bone (PDB) and frontotemporal dementia (FTD) (IBMPFD) is a rare autosomal dominant disorder due to mutations in the valosin-containing protein gene ( VCP ).1 Pathogenic VCP variants have also been associated with amyotrophic lateral sclerosis2 and other phenotypes including dilated cardiomyopathy and Parkinson's disease. We describe phenotypic and genetic findings of 42 individuals from 21 families with VCP mutations. As our service is the reference laboratory for the UK, we calculated the UK's point prevalence based on the 2011 Census as the number of cases per population. In total, 42 individuals were identified, 23 men and 19 women from 21 kinships (see online supplementary tables S1A, B). Based on our data, the expected point prevalence of IBMPFD in the UK is 0.066/100 000 population. Eighteen unrelated patients harbour a previously described mutation. In addition, three patients from two families harbour two novel variants (c.604G>T, p.G202W in exon 6 and c.1316C>G, p.A439G in exon 11) that are predicted to be pathogenic by in silico analysis (Alamut interpretation software V.2.4) and segregate with disease. Three previously described mutations were identified in exon 5 of the VCP gene. The mutation p.R155H (c.464G>A) was found in 11 families. The mutation p.R191Q (c.572G>A) was found in three unrelated patients, p.R155C (c.463C>T) in two families, and p.R93C (c.277C>T) in two unrelated patients (see online supplementary material genetic analysis and mutation analysis). The mean age of disease onset was …

Mutations affecting skeletal muscle isoforms of the tropomyosin genes may cause nemaline myopathy, cap myopathy, core-rod myopathy, congenital fiber-type disproportion, distal arthrogryposes, and Escobar syndrome. We correlate the clinical picture of these diseases with novel (19) and previously reported (31) mutations of the TPM2 and TPM3 genes. Included are altogether 93 families: 53 with TPM2 mutations and 40 with TPM3 mutations. Thirty distinct pathogenic variants of TPM2 and 20 of TPM3 have been published or listed in the Leiden Open Variant Database (http://www.dmd.nl/). Most are heterozygous changes associated with autosomal-dominant disease. Patients with TPM2 mutations tended to present with milder symptoms than those with TPM3 mutations, DA being present only in the TPM2 group. Previous studies have shown that five of the mutations in TPM2 and one in TPM3 cause increased Ca2+ sensitivity resulting in a hypercontractile molecular phenotype. Patients with hypercontractile phenotype more often had contractures of the limb joints (18/19) and jaw (6/19) than those with nonhypercontractile ones (2/22 and 1/22), whereas patients with the non-hypercontractile molecular phenotype more often (19/22) had axial contractures than the hypercontractile group (7/19). Our in silico predictions show that most mutations affect tropomyosin-actin association or tropomyosin head-to-tail binding.