Anoctamin-5 related muscle disease: clinical and genetic findings in a large European cohort.

Anoctamin-5 related muscle disease is caused by biallelic pathogenic variants in the anoctamin-5 gene (ANO5) and shows variable clinical phenotypes: limb-girdle muscular dystrophy type 12 (LGMD-R12), distal muscular dystrophy type 3 (MMD3), pseudometabolic myopathy or asymptomatic hyperCKaemia. In this retrospective, observational, multicentre study we gathered a large European cohort of patients with ANO5-related muscle disease to study the clinical and genetic spectrum and genotype-phenotype correlations. We included 234 patients from 212 different families, contributed by 15 centres from 11 European countries. The largest subgroup was LGMD-R12 (52.6%), followed by pseudometabolic myopathy (20.5%), asymptomatic hyperCKaemia (13.7%) and MMD3 (13.2%). In all subgroups, there was a male predominance, except for pseudometabolic myopathy. Median age at symptom onset of all patients was 33 years (range 23-45 years). The most frequent symptoms at onset were myalgia (35.3%) and exercise intolerance (34.1%), while at last clinical evaluation most frequent symptoms and signs were proximal lower limb weakness (56.9%) and atrophy (38.1%), myalgia (45.1%) and atrophy of the medial gastrocnemius muscle (38.4%). Most patients remained ambulatory (79.4%). At last evaluation, 45.9% of patients with LGMD-R12 additionally had distal weakness in the lower limbs and 48.4% of patients with MMD3 also showed proximal lower limb weakness. Age at symptom onset did not differ significantly between males and females. However, males had a higher risk of using walking aids earlier (P = 0.035). No significant association was identified between sportive versus non-sportive lifestyle before symptom onset and age at symptom onset nor any of the motor outcomes. Cardiac and respiratory involvement that would require treatment occurred very rarely. Ninety-nine different pathogenic variants were identified in ANO5 of which 25 were novel. The most frequent variants were c.191dupA (p.Asn64Lysfs*15) (57.7%) and c.2272C>T (p.Arg758Cys) (11.1%). Patients with two loss-of function variants used walking aids at a significantly earlier age (P = 0.037). Patients homozygous for the c.2272C>T variant showed a later use of walking aids compared to patients with other variants (P = 0.043). We conclude that there was no correlation of the clinical phenotype with the specific genetic variants, and that LGMD-R12 and MMD3 predominantly affect males who have a significantly worse motor outcome. Our study provides useful information for clinical follow up of the patients and for the design of clinical trials with novel therapeutic agents.

Three novel FHL1 variants cause a mild phenotype of Emery-Dreifuss muscular dystrophy.

Emery-Dreifuss muscular dystrophy (EDMD) is a hereditary muscle disease, characterized by the clinical triade of early-onset joint contractures, progressive muscle weakness, and cardiac involvement. Pathogenic variants in FHL1 can cause a rare X-linked recessive form of EDMD, type 6. We report three men with novel variants in FHL1 leading to EDMD6. The onset of muscle symptoms was in late adulthood and muscle weakness was not prominent in either of the patients. All patients had hypertrophic cardiomyopathy and one of them also had cardiac arrhythmias. Western blot performed on muscle biopsies from two of the patients showed no FHL1 protein expression. We predict that the variant in the third patient also leads to the absence of FHL1 protein. Complete loss of all FHL1 isoforms combined with mild muscle involvement supports the hypothesis that loss of all FHL1 isoforms is more benign than the cytotoxic effects of expressed FHL1 protein with pathogenic missense variants.

Nutritional Interventions for Patients with Mitochondrial POLG-Related Diseases: A Systematic Review on Efficacy and Safety.

Ketogenic diet is recommended as a treatment to reduce seizure frequency in patients with intractable epilepsy. The evidence and safety results are sparse for diet interventions in patients with pathogenic polymerase gamma (POLG) variants and intractable epilepsy. The aim of this systematic review is to summarize the efficacy of diet treatment on seizure frequency, clinical symptoms, and potential deleterious effect of liver involvement in patients with mitochondrial diseases caused by pathogenic POLG variants. Literature was searched in PubMed, Embase; and Cochrane in April 2022; no filter restrictions were imposed. The reference lists of retrieved studies were checked for additional literature. Eligibility criteria included verified pathogenic POLG variant and diet treatment. Overall, 880 studies were identified, providing eight case-reports representing nine patients eligible for inclusion. In eight of nine cases, clinical symptoms were improved; six out of nine cases reported improvements in seizure frequency. However, increasing levels of liver enzymes after initiating ketogenic diet were found in four of the nine cases, with one case revealing decreased levels of liver enzymes after initiating long-chain triglyceride restriction. Viewed together, the studies imply that ketogenic diet can have a positive impact on seizure frequency, but may induce progression of liver impairment in patients with pathogenic POLG variants.

Muscle biopsy and MRI findings in ANO5-related myopathy.

INTRODUCTION/AIMS: Mutations in the anoctamin 5 (ANO5) gene are a common cause of muscular dystrophy. We aimed to investigate whether inflammatory changes in muscle are present in patients with ANO5 myopathy when assessed by muscle biopsy and muscle magnetic resonance imaging (MRI). METHODS: Adults with pathogenic variations in ANO5 known to cause muscular dystrophy were included in our study. Muscle biopsies of pelvic and lower extremity muscles were reviewed retrospectively. Muscle MR short-tau inversion recovery (STIR) images of a subset of these patients were obtained prospectively. RESULTS: Muscle biopsies from 24 patients were reviewed. MR STIR images were performed in 17 of these patients. We found inflammatory changes in muscle biopsies of three patients and MRI revealed hyperintense signals on STIR images in 14 of 17 patients. DISCUSSION: In this study, we found that muscle edema is very common in patients with ANO5 myopathy and that some patients have inflammatory changes in muscle biopsies. Further studies are needed to determine whether the STIR+ lesions reflect inflammation.

Does continuous electroencephalography influence therapeutic decisions in neurocritical care?

OBJECTIVES: In the neurocritical care unit (neuro-ICU), the impact of continuous EEG (cEEG) on therapeutic decisions and prognostication, including outcome prediction using the Status Epilepticus Severity Score (STESS), is poorly investigated. We studied to what extent cEEG contributes to treatment decisions, and how this relates to clinical outcome and the use of STESS in neurocritical care. METHODS: We included patients admitted to the neuro-ICU or neurological step-down unit of a tertiary referral hospital between 05/2013 and 06/2015. Inclusion criteria were ≥20 h of cEEG monitoring and age ≥15 years. Exclusion criteria were primary epileptic and post-cardiac arrest encephalopathies. RESULTS: Ninety-eight patients met inclusion criteria, 80 of which had status epilepticus, including 14 with super-refractory status. Median length of cEEG monitoring was 50 h (range 21-374 h). Mean STESS was lower in patients with favorable outcome 1 year after discharge (modified Rankin Scale [mRS] 0-2) compared to patients with unfavorable outcome (mRS 3-6), albeit not statistically significant (mean STESS 2.3 ± 2.1 vs 3.6 ± 1.7, p = 0.09). STESS had a sensitivity of 80%, a specificity of 42%, and a negative predictive value of 93% for outcome. cEEG results changed treatment decisions in 76 patients, including escalation of antiepileptic treatment in 65 and reduction in 11 patients. CONCLUSION: Status Epilepticus Severity Score had a high negative predictive value but low sensitivity, suggesting that STESS should be used cautiously. Of note, cEEG results altered clinical decision-making in three of four patients, irrespective of the presence or absence of status epilepticus, confirming the clinical value of cEEG in neurocritical care.

Quality of life in hypokalemic periodic paralysis - a survey.

Primary hypokalemic periodic paralysis (HypoPP) is a skeletal muscle channelopathy most commonly caused by pathogenic variants in the calcium channel gene, CACNA1S. HypoPP can present with attacks of paralysis and/or permanent muscle weakness. Previous studies have shown that patients with HypoPP can have impaired quality of life (QoL). In this cross-sectional study, we aimed to describe the QoL in patients with HypoPP caused by pathogenic variants in CACNA1S using The Individualized Neuromuscular Quality of Life (INQoL) questionnaire, a validated tool to measure the QoL of patients with neuromuscular diseases (higher score, worse QoL). We showed that muscle weakness and fatigue were the symptoms with the greatest impact on participants' lives and that "activities", in the life domain of the INQoL, was most affected by HypoPP. Furthermore, we showed that the total INQoL score increased with age. Low QoL was primarily driven by progressive permanent muscle weakness and not attacks of paralysis, although half of the participants reported that attacks of paralysis challenged their daily life. The results suggest that special attention should be given to muscle weakness and fatigue in patients with HypoPP.

Effect of strength training on functional outcomes and strength in patients with polyneuropathy: A scoping review.

Introduction: Polyneuropathy (PNP) is a chronic progressive disease that over time can lead to damage of sensory, motor and/or autonomic peripheral nerves. Symptoms vary from predominantly sensory to severe sensorimotor affection both proximally and distally. This can result in considerable functional impairments that affect activities of daily living. In other neurological patients, strength training has shown to improve strength and functional outcomes. Since medical treatment only exists for very few percentages of the underlying causes it is obvious to consider if strength training could be a potential treatment for functional impairments. To date little is known on the effect of strength training in patients with PNP. Aim: The aim of this scoping review was to summarize research on strength training and outcomes on physical function in patients with PNP. Methods: We systematically searched five data bases; Pubmed, Embase, Cinahl, Cochrane library and Web of science. Studies on strength training (load ≥70% of 1RM) in patients with PNP were included. The search was carried out in November 2022. Results: 362 articles were screened by title and abstract, 101 articles were full text screened. Eight studies were included. Patients with Charcot-Marie-Tooth (CMT), chronic inflammatory polyneuropathy (CIDP) and diabetic polyneuropathy (DPN) were represented in the studies (five RCTs, two case-series, and one cross-over trial). The methodological quality ranged from fair-poor in seven studies, one study reached good quality. Results from the studies indicated that strength training in CMT, CIDP and DPN may improve strength. However, various outcomes were used to evaluate strength training, so direct comparisons were difficult. Discussion: In this scoping review we summarized research on strength training and outcomes evaluated in interventions in patients with PNP. Eight studies were included, they indicated that strength training may be beneficial for patients with PNP. However, due to low methodological strength of most studies a recommendation for patients with PNP cannot be made. Thus, the low number of studies with relatively low quality, where various functional outcomes were used, underscores the importance of future studies to evaluate the effect of strength training on relevant functional outcomes and strength in patients with PNP.

Hypokalemic periodic paralysis: a 3-year follow-up study.

BACKGROUND AND OBJECTIVES: Primary hypokalemic periodic paralysis (HypoPP) is an inherited channelopathy most commonly caused by mutations in CACNA1S. HypoPP can present with different phenotypes: periodic paralysis (PP), permanent muscle weakness (PW), and mixed weakness (MW) with both periodic and permanent weakness. Little is known about the natural history of HypoPP. METHODS: In this 3-year follow-up study, we used the MRC scale for manual muscle strength testing and whole-body muscle MRI (Mercuri score) to assess disease progression in individuals with HypoPP-causing mutations in CACNA1S. RESULTS: We included 25 men (mean age 43 years, range 18-76 years) and 12 women (mean age 42 years, range 18-76 years). Two participants were asymptomatic, 21 had PP, 12 MW, and two PW. The median number of months between baseline and follow-up was 42 (range 26-52). Muscle strength declined in 11 patients during follow-up. Four of the patients with a decline in muscle strength had no attacks of paralysis during follow-up, and two of these patients had never had attacks of paralysis. Fat replacement of muscles increased in 27 patients during follow-up. Eight of the patients with increased fat replacement had no attacks of paralysis during follow-up, and two of these patients had never had attacks of paralysis. DISCUSSION: The study demonstrates that HypoPP can be a progressive myopathy in both patients with and without attacks of paralysis.

Humoral immune response to COVID-19 vaccine in patients with myasthenia gravis.

We investigated the humoral response to the Pfizer-BioNTech COVID-19 (BNT162b2) vaccine in patients with myasthenia gravis on or off immunosuppressants and compared this to the response in healthy individuals. The SARS-CoV-2 IgG response and neutralizing capacity were measured in 83 patients (57 on immunosuppressants) and 332 healthy controls at baseline, three weeks, and two and six months after the vaccine. We found that the proportion of positive humoral response was lower in patients on immunosuppressants vs. controls at three weeks and two months (p ≤ 0.001), but not at six months post-vaccination (p = 0.379).

Case report: A novel variant in SLC25A46 causing sensorimotor polyneuropathy and optic atrophy.

SLC25A46 is a mitochondrial protein involved in mitochondrial dynamics. Recently, bi-allelic variants have been identified as a pathogenic cause in a spectrum of neurological syndromes. We report a novel homozygous SLC25A46 variant in two siblings, originating from Iraq. Both presented with optic atrophy and varying neurological symptoms. The neurological examination and nerve conduction studies were consistent with sensorimotor polyneuropathy, one having mild polyneuropathy and the other pronounced polyneuropathy. The cases illustrate the disease spectrum and provide substantial information to the knowledge of polyneuropathy caused by SLC25A46 variants. It further highlights the diagnostic potentials of whole exome sequencing which can improve future understanding of disease mechanisms.

[Paroxystic dyskinesia].

This is a case report of a patient, who was diagnosed with epilepsy (atypical infantile convulsions) at the age of one year and unspecific myopathy at the age of three years. At the age of 25 years, the patient was referred to a neuromuscular clinic due to myopathy, but the diagnose was changed to atypical infantile convulsions with seizures in adulthood and paroxysmal choreoathetosis due to a pathogenic variant c.970G>A, p. (Gly324Arg) in the PRRT2 gene.

Autophagy is affected in patients with hypokalemic periodic paralysis: an involvement in vacuolar myopathy?

Hypokalemic periodic paralysis is an autosomal dominant, rare disorder caused by variants in the genes for voltage-gated calcium channel CaV1.1 (CACNA1S) and NaV1.4 (SCN4A). Patients with hypokalemic periodic paralysis may suffer from periodic paralysis alone, periodic paralysis co-existing with permanent weakness or permanent weakness alone. Hypokalemic periodic paralysis has been known to be associated with vacuolar myopathy for decades, and that vacuoles are a universal feature regardless of phenotype. Hence, we wanted to investigate the nature and cause of the vacuoles. Fourteen patients with the p.R528H variation in the CACNA1S gene was included in the study. Histology, immunohistochemistry and transmission electron microscopy was used to assess general histopathology, ultrastructure and pattern of expression of proteins related to muscle fibres and autophagy. Western blotting and real-time PCR was used to determine the expression levels of proteins and mRNA of the proteins investigated in immunohistochemistry. Histology and transmission electron microscopy revealed heterogenous vacuoles containing glycogen, fibrils and autophagosomes. Immunohistochemistry demonstrated autophagosomes and endosomes arrested at the pre-lysosome fusion stage. Expression analysis showed a significant decrease in levels of proteins an mRNA involved in autophagy in patients, suggesting a systemic effect. However, activation level of the master regulator of autophagy gene transcription, TFEB, did not differ between patients and controls, suggesting competing control over autophagy gene transcription by nutritional status and calcium concentration, both controlling TFEB activity. The findings suggest that patients with hypokalemic periodic paralysis have disrupted autophagic processing that contribute to the vacuoles seen in these patients.

Permanent muscle weakness in hypokalemic periodic paralysis.

OBJECTIVE: To map the phenotypic spectrum in 55 individuals with mutations in CACNA1S known to cause hypokalemic periodic paralysis (HypoPP) using medical history, muscle strength testing, and muscle MRI. METHODS: Adults with a mutation in CACNA1S known to cause HypoPP were included. Medical history was obtained. Muscle strength and MRI assessments were performed. RESULTS: Fifty-five persons were included. Three patients presented with permanent muscle weakness and never attacks of paralysis. Seventeen patients presented with a mixed phenotype of periodic paralysis and permanent weakness. Thirty-one patients presented with the classical phenotype of periodic attacks of paralysis and no permanent weakness. Four participants were asymptomatic. Different phenotypes were present in 9 of 18 families. All patients with permanent weakness had abnormal replacement of muscle by fat on MRI. In addition, 20 of 35 participants with no permanent weakness had abnormal fat replacement of muscle on MRI. The most severely affected muscles were the paraspinal muscles, psoas, iliacus, the posterior muscles of the thigh and gastrocnemius, and soleus of the calf. Age was associated with permanent weakness and correlated with severity of weakness and fat replacement of muscle on MRI. CONCLUSIONS: Our results show that phenotype in individuals with HypoPP-causing mutations in CACNA1S varies from asymptomatic to periodic paralysis with or without permanent muscle weakness or permanent weakness as sole presenting picture. Variable phenotypes are found within families. Muscle MRI reveals fat replacement in patients with no permanent muscle weakness, suggesting a convergence of phenotype towards a fixed myopathy with aging.

Validation of Repeated Endothelial Function Measurements Using EndoPAT in Stroke.

BACKGROUND: Decreased endothelial function (EF) may be a prognostic marker for stroke. Measuring pharmacological effects on EF may be of interest in the development of personalized medicine for stroke prevention. In this study, we assessed the reliability of repeated EF measurements using a pulse amplitude tonometry technology in acute stroke patients. Similarly, reliability was tested in healthy subjects devoid of vascular disease to estimate reactivity and reliability in a younger non-stroke population. MATERIALS AND METHODS: EF was assessed using the EndoPAT2000 in 20 healthy volunteers (men 50%, mean age 35.85 ± 3.47 years) and 21 stroke patients (men 52%, mean age 66.38 ± 2.85 years, and mean NIHSS 4.09 ± 0.53) under standardized conditions. EF was measured as the reactive hyperemia index (RHI), logarithm of RHI (lnRHI), and Framingham RHI (fRHI). Measurements were separated by 1.5 and 24 h to assess same-day and day-to-day reliability, respectively. RESULTS: Fair to moderate correlations of measurements [intraclass correlation coefficient (ICC)same-day 0.29 and ICCday-to-day 0.52] were detected in healthy subjects. In stroke patients, we found moderate to substantial correlation of both same-day and day-to-day repeated measurements (ICCsame-day 0.40 and ICCday-to-day 0.62). fRHI compared with RHI and lnRHI showed best reliability. CONCLUSION: Repeated measurements of fRHI in stroke patients show moderate reliability on same-day and substantial on day-to-day measurements. Likewise, in healthy subjects there was substantial reliability on day-to-day measurement, but only moderate on same-day measurements. In general, day-to-day correlation of repeated EF measurements was far better than that of same-day measurements, which ranged from poor to moderate depending on the specific outcome measure of EF. A possible carryover effect should be considered if same-day repeated testing of drug effects is applied in future studies.

[Inflammation as part of cerebral amyloid angiopathy disguised as a tumour].

A male with probable cerebral amyloid angiopathy (CAA)-related inflammation presented with headache and subacute hemi-paresis. After admission he developed a disturbance of consciousness and a CT brain scan showed oedema with significant midline shift. He was treated with corticosteroids with prompt clinical improvement. A MR brain scan after treatment showed confluent T2-weighted lesions, microbleeds and regression of oedema. The patient was discharged in habitual status. During withdrawal of corticosteroids he showed clinical and radiological signs of relapsing CAA-related inflammation.