ABSTRACT Background and Objectives Spinocerebellar ataxias (SCA) represent a clinically and genetically heterogeneous group of progressive neurodegenerative diseases with prominent cerebellar atrophy. Recently, a novel pathogenic repeat expansion in intron 1 of FGF14 was identified, causing adult‐onset SCA (SCA27B). We aimed to determine the proportion of our unsolved adult‐onset ataxia cohort harboring this expansion using several technologies, and to characterize the phenotypic presentation within our population. Methods Individuals presenting with adult‐onset ataxia (> 30 years old) and negative previous genetic testing were selected from the Care4Rare patient repository. Affected individuals were from all ethnicities, and 90% had a family history suggestive of dominant ataxia, representing 19 of the 23 families included. We used multiple tools (PCR, long‐read genome sequencing and optical genome mapping (OGM)) to identify the pathogenic GAA repeat in FGF14. Results Of the 23 families included in this study, 65.2% harbored a pathogenic GAA expansion in FGF14. Individuals of French‐Canadian descent (FC) represented most of our cohort and had a 64.7% diagnostic yield. Affected individuals presented with gaze‐evoked nystagmus, gait ataxia, cerebellar dysarthria, and early episodic features. The GAA expansion in FGF14 was visible by OGM in all individuals tested. Interpretation Our diagnostic yield demonstrates this expansion may be the most common cause of adult‐onset SCA in dominant families of FC ancestry. Our FC participants have a phenotype distinct from previously published FC patients, with gaze‐evoked nystagmus being the most common eye anomaly. From a diagnostic standpoint, the pathogenic GAA repeat can be identified by OGM, but additional tests are required to complement the interpretation.

Idiopathic inflammatory myopathies (IIMs) are rare disorders characterized by inflammation of skeletal muscle, which can result in fatty replacement of muscle, muscle atrophy, and subsequent weakness. Therapeutic advancements have improved clinical outcomes but impose an economic impact on healthcare systems. We aimed to summarize the direct and indirect costs associated with IIMs in a systematic review (PROSPERO Registration #CRD42023443143). Electronic databases (MEDLINE, Embase, CINAHL, and Scopus) were systematically searched for full-length articles (excluding case reports) reporting costs specific to patients diagnosed with an IIM, published between database inception and April 19, 2023. Direct cost categories included inpatient, outpatient, medication, home/long-term care, and durable medical equipment such as mobility and respiratory aids. Indirect costs included lost productivity. Eligibility criteria were met by 21 of the 3,193 unique titles identified. Costs are expressed in 2023 United States of America dollars, with adjustments for differences in purchasing power applied to currency conversions. As no study reported on all cost categories, annualized cost of IIM per patient was estimated by calculating the mean cost per category, and then adding the means of the different cost categories. By this method, IIM was estimated to cost $52,210 per patient per year. Proportional contributions by category were lost productivity (0.278), outpatient care (0.214), medications (0.171), inpatient care (0.161), home/long-term care (0.122), and durable medical equipment (0.053). Newer findings with intravenous immunoglobulin considered first line therapy for IIM demonstrated markedly higher annual medication costs per patient, upwards of $33,900 compared to an average of $3,908 ± $1,042 in older studies. Future cost-effectiveness studies require updated cost-of-illness studies reflecting the evolving sub-classification and treatment options for IIM, and should consider the impact of IIM on patients and their families.

Inclusion body myositis (IBM) is an idiopathic muscle disorder primarily affecting adults above the age of 50. IBM is characterized by weakness in the knee extensor and deep finger flexor muscles due to muscle atrophy and fibroadipose replacement. Dynamometry and manual muscle testing are commonly used to assess patient muscle strength, while magnetic resonance imaging and electromyography studies identify the patterns of muscle atrophy and motor unit potentials. Although the underlying pathophysiological mechanisms of IBM are still unknown, common histopathological markers include rimmed vacuoles and inclusions. The immune system is also largely implicated in pathogenesis, as skeletal muscle in IBM overexpresses major histocompatibility complex I (MHC-I), and cluster of differentiation (CD) 8+ T-cells, and features endomysial inflammation. Antibodies to the cytosolic 5'-nucleotidase 1A (cN1A) protein have been associated with IBM but have low sensitivity and specificity. As many classic features of IBM present only in advanced stages of disease, there are substantial challenges to the diagnosis and monitoring of IBM progression in its early stages. Identifying early diagnostic biomarkers and new biomarker signatures associated with IBM disease progression is necessary for clinical trial readiness.

Inclusion body myositis is an idiopathic inflammatory myopathy. Whether its cause is primarily autoimmune or degenerative is debated. Its prevalence is 18 per 100 000 people, higher than dermatomyositis or amyotrophic lateral sclerosis (ALS). Inclusion body myositis predominantly affects males (3:1

[Voir la version anglaise de l'article ici : www.cmaj.ca/lookup/doi/10.1503/cmaj.231815][1] La myosite à inclusions est une myopathie inflammatoire idiopathique. Son étiologie, qu'elle soit essentiellement d'origine auto-immune ou dégénérative, fait toujours l'objet de débats. La pré

BACKGROUND:Oculopharyngeal muscular dystrophy (OPMD) is a rare, late-onset, slowly progressive neuromuscular disorder characterized by ptosis, dysphagia, and proximal limb weakness. Emerging clinical trials require rapidly accessible and sensitive biomarkers to evaluate OPMD disease progression and potential response to future treatments. OBJECTIVE:This cross-sectional study was designed to identify candidate circulating protein and imaging biomarkers of OPMD severity for future use in clinical trials. METHODS:Twenty-five individuals with OPMD (age 63.3 ± 10.5 years; GCN copy number of 13 in PABPN1) were assessed using the 7k SOMAScan assay to profile the plasma proteome, and MRI to quantify replacement of muscle by fat. OPMD severity was first categorized using the clinical presence/absence of limb weakness, and protein signals were considered distinguishing if they differed by more than 30% between subgroups and had statistically significant P-values after correcting for multiple comparisons. Distinguishing proteins were contrasted with age-matched controls (n = 10). OPMD severity was also treated as a continuous variable using fat fraction of the soleus muscle, and proteins were considered distinguishing if the slope of relationship between protein signal and soleus fat fraction differed significantly from zero after correcting for multiple comparisons. Pathway analyses were conducted using Metascape and the Database for Annotation, Visualization, and Integrated Discovery webtools. RESULTS:Eighteen plasma proteins distinguished OPMD on both indicators of severity. Pathway analyses identified skeletal muscle tissue, phagocytosis/engulfment, and extracellular matrix organization as enriched ontology clusters in OPMD with limb weakness. The most distinguishing plasma protein signals (ACTN2, MYOM2, CA3, APOBEC2, MYL3, and PDLIM3) were over 200% higher in OPMD with limb weakness than OPMD without limb weakness as well as controls, and correlated strongly with percent of fatty replacement of soleus (r = 0.89 ± 0.04). CONCLUSIONS:The candidate biomarkers identified contribute to the ongoing search for sensitive and accessible biomarkers of OPMD progression, prognosis, and monitoring.

AbstractObjectivesPatients with refractory myasthenia gravis (MG) have few treatment options. Autologous hematopoietic stem cell transplantation (HSCT) has been used to treat immune diseases; however, its use in the treatment of MG is not broadly considered. Our objective is to report on the efficacy and safety of HSCT in refractory MG.MethodsTwenty‐one patients who underwent HSCT for MG were retrospectively reviewed. All patients had severe MG refractory to multiple therapies. Stem cells were mobilized with cyclophosphamide and granulocyte colony‐stimulating factor. The grafts were depleted of immune cells by selecting CD34+ cells. HSCT conditioning consisted of high‐dose cytoreductive therapy and anti‐thymocyte globulin. The primary efficacy outcome was achieving clinically stable remission or minimal manifestations without treatment and remaining as such until most recent follow‐up.ResultsThe median time from MG diagnosis to HSCT was 4.0 years. The primary outcome was reached in 16 of 18 evaluable patients (89%) at a median of 1.7 years and maintained with a median follow‐up of 6.7 years (range 1.0–21.9 years). Three patients were not evaluable for the primary outcome: one due to confounding illness and two died within 12 months of transplant. The transplant‐related mortality at 100 days was 9.5%. Two late deaths occurred, with uncertain relation to the HSCT.InterpretationAfter HSCT for refractory MG, most patients achieved sustained disease remission. However, HSCT‐related mortality in medically complex MG patients may be high. Prospective studies investigating the efficacy and safety of HSCT in the treatment of refractory MG are warranted.

Oculopharyngeal muscular dystrophy (OPMD) is a genetic muscle disease causing ptosis, severe swallowing difficulties and progressive limb weakness, although atypical presentations may be difficult to diagnose. Sensitive biomarkers of disease progression in OPMD are needed to enable more effective clinical trials. This study was designed to test the feasibility of using MRI to aid OPMD diagnosis and monitor OPMD progression. Twenty-five subjects with Dixon whole-body muscle MRI were enrolled: 10 patients with genetically confirmed OPMD, 10 patients with non-OPMD muscular dystrophies, and 5 controls. Using the MRI Dixon technique, muscle fat replacement was evaluated in the tongue, serratus anterior, lumbar paraspinal, adductor magnus, and soleus muscles using quantitative and semi-quantitative rating methods. Changes were compared with muscle strength testing, dysphagia severity, use of gait aids, and presence of dysarthria. Quantitative MRI scores of muscle fat replacement in the tongue could differentiate OPMD from other muscular dystrophies and from controls. Moreover, fat fraction in the tongue correlated with clinical severity of dysphagia. This study provides preliminary support for the use of Dixon-based quantitative MRI images as outcome measures for monitoring disease progression in clinical trials and provides rationale for future prospective studies aimed at methodological refinement and covariate identification.

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See article on pages 558‐561 in volume 66, Issue 5, November issue .

Oculopharyngeal muscular dystrophy (OPMD) is a rare, primarily autosomal dominant, late onset muscular dystrophy commonly presenting with ptosis, dysphagia, and subsequent weakness of proximal muscles. Although OPMD diagnosis can be confirmed with high confidence by genetic testing, the slow progression of OPMD poses a significant challenge to clinical monitoring and a barrier to assessing the efficacy of treatments during clinical trials. Accordingly, there is a pressing need for more sensitive measures of OPMD progression, particularly those which do not require a muscle biopsy. This review provides an overview of progress in OPMD biomarkers from clinical assessment, quantitative imaging, histological assessments, and genomics, as well as hypothesis-generating "omics" approaches. The ongoing search for biomarkers relevant to OPMD progression needs an integrative, longitudinal approach combining validated and experimental approaches which may include clinical, imaging, demographic, and biochemical assessment methods. A multi-omics approach to biochemical biomarker discovery could help provide context for differences found between individuals with varying levels of disease activity and provide insight into pathomechanisms and prognosis of OPMD.

Background and ObjectivesCoenzyme Q(10) (CoQ(10)) is an important electron carrier and antioxidant. The COQ7 enzyme catalyzes the hydroxylation of 5-demethoxyubiquinone-10 (DMQ(10)), the second-to-last step in the CoQ(10) biosynthesis pathway. We report a consanguineous family presenting with a hereditary motor neuropathy associated with a homozygous c.1A > G p.? variant of COQ7 with abnormal CoQ(10) biosynthesis.MethodsAffected family members underwent clinical assessments that included nerve conduction testing, histologic analysis, and MRI. Pathogenicity of the COQ7 variant was assessed in cultured fibroblasts and skeletal muscle using a combination of immunoblots, respirometry, and quinone analysis.ResultsThree affected siblings, ranging from 12 to 24 years of age, presented with a severe length-dependent motor neuropathy with marked symmetric distal weakness and atrophy with normal sensation. Muscle biopsy of the quadriceps revealed chronic denervation pattern. An MRI examination identified moderate to severe fat infiltration in distal muscles. Exome sequencing demonstrated the homozygous COQ7 c.1A > G p.? variant that is expected to bypass the first 38 amino acid residues at the n-terminus, initiating instead with methionine at position 39. This is predicted to cause the loss of the cleavable mitochondrial targeting sequence and 2 additional amino acids, thereby preventing the incorporation and subsequent folding of COQ7 into the inner mitochondrial membrane. Pathogenicity of the COQ7 variant was demonstrated by diminished COQ7 and CoQ(10) levels in muscle and fibroblast samples of affected siblings but not in the father, unaffected sibling, or unrelated controls. In addition, fibroblasts from affected siblings had substantial accumulation of DMQ(10), and maximal mitochondrial respiration was impaired in both fibroblasts and muscle.DiscussionThis report describes a new neurologic phenotype of COQ7-related primary CoQ(10) deficiency. Novel aspects of the phenotype presented by this family include pure distal motor neuropathy involvement, as well as the lack of upper motor neuron features, cognitive delay, or sensory involvement in comparison with cases of COQ7-related CoQ(10) deficiency previously reported in the literature.

ABSTRACT: Background and Objective: The prevalence and role of the motor band sign (MBS) remain unclear in motor neuron disease. We report the frequency of MBS in amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS), its correlation with clinical upper motor neuron (UMN) signs, and prognostic value in ALS. Methods: We conducted a retrospective study of ALS, PLS, and controls with retrievable MRI between 2010 and 2018. We compared the frequencies of MBS across the three groups, and studied correlation between susceptibility-weighted MRI measurements in primary motor cortices and contralateral UMN features. Clinical outcomes were compared between ALS with and without MBS. Results: Thirteen ALS, 5 PLS, and 10 controls were included (median age 60 years, IQR 54–66 years; 14/28 males). MBS was present in 9/13 (69.2%, 95% CI 38.9–89.6%) and 4/5 (80.0%, 95% CI 29.9–99.0%) of ALS and PLS, respectively, and none in controls. 2/13 (15.4%, 95% CI 2.7–46.3%) ALS and 3/5 (60.0%, 95% CI 17.0–92.7%) PLS had MBS in the absence of corticospinal T2/FLAIR hyperintensity sign. Susceptibility measurements in left motor cortices had a significantly positive correlation with contralateral UMN signs in ALS (τ b = 0.628, p = 0.03). Similar but nonsignificant trends was observed for right motor cortices in ALS (τ b = 0.516, p = 0.07). There were no significant differences in mRS at last follow-up, mortality, or time from symptom onset to last follow-up between ALS patients with and without MBS. Conclusions: We provide limited evidence that MBS and susceptibility quantification measurements in motor cortices may serve as surrogate markers of UMN involvement in motor neuron disease.

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Background and Objectives The human genome contains ∼20,000 genes, each of which has its own set of complex regulatory systems to govern precise expression in each developmental stage and cell type. Here, we report a female patient with congenital weakness, respiratory failure, skeletal dysplasia, contractures, short stature, intellectual delay, respiratory failure, and amenorrhea who presented to Medical Genetics service with no known cause for her condition. Methods Whole-exome and whole-genome sequencing were conducted, as well as investigational functional studies to assess the effect of SOX8 variant. Results The patient was found to have biallelic SOX8 variants (NM_014587.3:c.422+5G>C; c.583dup p.(His195ProfsTer11)). SOX8 is a transcriptional regulator, which is predicted to be imprinted (expressed from only one parental allele), but this has not yet been confirmed. We provide evidence that while SOX8 was maternally expressed in adult-derived fibroblasts and lymphoblasts, it was biallelically expressed in other cell types and therefore suggest that biallelic variants are associated with this recessive condition. Functionally, we showed that the paternal variant had the capacity to affect mRNA splicing while the maternal variant resulted in low levels of a truncated protein, which showed decreased binding at and altered expression of SOX8 targets. Discussion Our findings associate SOX8 variants with this novel condition, highlight how complex genome regulation can complicate novel disease-gene identification, and provide insight into the molecular pathogenesis of this disease.

Primary acetylcholine receptor deficiency is the most common subtype of congenital myasthenic syndrome, resulting in reduced amount of acetylcholine receptors expressed at the muscle endplate and impaired neuromuscular transmission. AChR deficiency is caused mainly by pathogenic variants in the ε-subunit of the acetylcholine receptor encoded by CHRNE, although pathogenic variants in other subunits are also seen. We report the clinical and molecular features of 13 patients from nine unrelated kinships with acetylcholine receptor deficiency harbouring the CHRNA1 variant NM_001039523.3:c.257G>A (p.Arg86His) in homozygosity or compound heterozygosity. This variant results in the inclusion of an alternatively-spliced evolutionary exon (P3A) that causes expression of a non-functional acetylcholine receptor α-subunit. We compare the clinical findings of this group to the other cases of acetylcholine receptor deficiency within our cohort. We report differences in phenotype, highlighting a predominant pattern of facial and distal weakness in adulthood, predominantly in the upper limbs, which is unusual for acetylcholine receptor deficiency syndromes, and more in keeping with slow-channel syndrome or distal myopathy. Finally, we stress the importance of including alternative exons in variant analysis to increase the probability of achieving a molecular diagnosis.

Background Myotonic dystrophy type 1 (DM1) is a hereditary muscular dystrophy affecting ∼2.1–14.3/100,000 adults. Cardiac manifestations of DM1 include conduction disorders and rarely cardiomyopathies. DM1 increases the risk of obstetric complications, however, little is known about the relationship between pregnancy and cardiomyopathy in DM1 due to disease rarity. Case A 23-year-old with DM1 developed cardiomyopathy during pregnancy. Despite initial medical stabilization, she subsequently developed multiple spontaneous coronary artery dissections postpartum, worsening cardiomyopathy and multiorgan failure. She died 5 months postpartum. Conclusion Though cardiomyopathy and arterial dissection are both known complications of pregnancy, this case suggests individuals with myotonic dystrophy type 1 may be at heightened risk for cardiac disease during the peripartum period. Physicians caring for women with suspected or proven DM1 should offer counseling and be alerted to the risk of cardiac complications with pregnancy and in the peripartum period. Pregnant and peripartum women with DM1 are likely to benefit from more frequent assessments of cardiac function including echocardiograms and early institution of heart failure management protocols when symptoms of cardiomyopathy present.