A study of the phenotypic variability and disease progression in Laing myopathy through the evaluation of muscle imaging.

BACKGROUND: Laing myopathy is characterized by broad clinical and pathological variability. They are limited in number and protocol of study. We aimed to delineate muscle imaging profiles and validate imaging analysis as an outcome measure. METHODS: This was a cross-sectional and longitudinal cohort study. Data from clinical, functional and semi-quantitative muscle imaging (60 magnetic resonance imaging [MRI] and six computed tomography scans) were studied. Hierarchical analysis, graphic heatmap representation and correlation between imaging and clinical data using Bayesian statistics were carried out. RESULTS: The study cohort comprised 42 patients from 13 families harbouring five MYH7 mutations. The cohort had a wide range of ages, age at onset, disease duration, and myopathy extension and Gardner-Medwin and Walton (GMW) functional scores. Intramuscular fat was evident in all but two asymptomatic/pauci-symptomatic patients. Anterior leg compartment muscles were the only affected muscles in 12% of the patients. Widespread extension to the thigh, hip, paravertebral and calf muscles and, less frequently, the scapulohumeral muscles was commonly observed, depicting distinct patterns and rates of progression. Foot muscles were involved in 40% of patients, evolving in parallel to other regions with absence of a disto-proximal gradient. Whole cumulative imaging score, ranging from 0 to 2.9 out of 4, was associated with disease duration and with myopathy extension and GMW scales. Follow-up MRI studies in 24 patients showed significant score progression at a variable rate. CONCLUSIONS: We confirmed that the anterior leg compartment is systematically affected in Laing myopathy and may represent the only manifestation of this disorder. However, widespread muscle involvement in preferential but variable and not distance-dependent patterns was frequently observed. Imaging score analysis is useful to categorize patients and to follow disease progression over time.

Efficacy and tolerability of add-on stiripentol in real-world clinical practice: An observational study in Dravet syndrome and non-Dravet developmental and epileptic encephalopathies.

OBJECTIVE: To assess efficacy and tolerability of stiripentol (STP) as adjunctive treatment in Dravet syndrome and non-Dravet refractory developmental and epileptic encephalopathies (DREEs). METHODS: Retrospective observational study of all children and adults with DREE and prescribed adjunctive STP at Hospital Ruber Internacional from January 2000 to February 2023. Outcomes were retention rate, responder rate (proportion of patients with ≥50% reduction in total seizure frequency relative to baseline), seizure freedom rate, responder rate for status epilepticus, rate of adverse event and individual adverse events, reported at 3, 6, and 12 months and at final visit. Seizure outcomes are reported overall, and for Dravet and non-Dravet subgroups. RESULTS: A total of 82 patients (55 Dravet syndrome and 27 non-Dravet DREE) were included. Median age was 5 years (range 1-59 years), and median age of epilepsy onset was younger in the Dravet group (4.9 [3.6-6] months) than non-Dravet (17.9 [6-42.3], P < 0.001). Median follow-up time STP was 24.1 months (2 years; range 0.3-164 months) and was longer in the Dravet group (35.9 months; range 0.8-164) than non-Dravet (17 months range 0.3-62.3, P < 0.001). At 12 months, retention rate, responder rate and seizure free rate was 68.3% (56/82), 65% [48-77%] and 18% [5.7-29%], respectively. There were no statistically significant differences between groups on these seizure outcomes. Adverse events were reported in 46.3% of patients (38/82), without differences between groups. SIGNIFICANCE: In this population of patients with epileptic and developmental encephalopathies, outcomes with adjunctive STP were similar in patients with non-Dravet DREE to patients with Dravet syndrome.

Clinical, Histological, and Genetic Features of 25 Patients with Autosomal Dominant Progressive External Ophthalmoplegia (ad-PEO)/PEO-Plus Due to TWNK Mutations.

Autosomal dominant mutations in the TWNK gene, which encodes a mitochondrial DNA helicase, cause adult-onset progressive external ophthalmoplegia (PEO) and PEO-plus presentations. In this retrospective observational study, we describe clinical and complementary data from 25 PEO patients with mutations in TWNK recruited from the Hospital 12 de Octubre Mitochondrial Disorders Laboratory Database. The mean ages of onset and diagnosis were 43 and 63 years, respectively. Family history was positive in 22 patients. Ptosis and PEO (92% and 80%) were the most common findings. Weakness was present in 48%, affecting proximal limbs, neck, and bulbar muscles. Exercise intolerance was present in 28%. Less frequent manifestations were cardiac (24%) and respiratory (4%) involvement, neuropathy (8%), ataxia (4%), and parkinsonism (4%). Only 28% had mild hyperCKemia. All 19 available muscle biopsies showed signs of mitochondrial dysfunction. Ten different TWNK mutations were identified, with c.1361T>G (p.Val454Gly) and c.1070G>C (p.Arg357Pro) being the most common. Before definitive genetic confirmation, 56% of patients were misdiagnosed (36% with myasthenia, 20% with oculopharyngeal muscle dystrophy). Accurate differential diagnosis and early confirmation with appropriately chosen complementary studies allow genetic counseling and the avoidance of unnecessary treatments. Thus, mitochondrial myopathies must be considered in PEO/PEO-plus presentations, and particularly, TWNK is an important cause when positive family history is present.