Chiara Marini-Bettolo

Complex phenotypes associated with STIM1 mutations in both coiled coil and EF-hand domains

Dominant mutations in STIM1 are a cause of three allelic conditions: tubular aggregate myopathy, Stormorken syndrome (a complex phenotype including myopathy, hyposplenism, hypocalcaemia and bleeding diathesis), and a platelet dysfunction disorder, York platelet syndrome. Previous reports have suggested a genotype-phenotype correlation with mutations in the N-terminal EF-hand domain associated with tubular aggregate myopathy, and a common mutation at p.R304W in a coiled coil domain associated with Stormorken syndrome. In this study individuals with STIM1 variants were identified by exome sequencing or STIM1 direct sequencing, and assessed for neuromuscular, haematological and biochemical evidence of the allelic disorders of STIM1. STIM1 mutations were investigated by fibroblast calcium imaging and 3D modelling. Six individuals with STIM1 mutations, including two novel mutations (c.262A>G (p.S88G) and c.911G>A (p.R304Q)), were identified. Extra-neuromuscular symptoms including thrombocytopenia, platelet dysfunction, hypocalcaemia or hyposplenism were present in 5/6 patients with mutations in both the EF-hand and CC domains. 3/6 patients had psychiatric disorders, not previously reported in STIM1 disease. Review of published STIM1 patients (n = 49) confirmed that neuromuscular symptoms are present in most patients. We conclude that the phenotype associated with activating STIM1 mutations frequently includes extra-neuromuscular features such as hypocalcaemia, hypo-/asplenia and platelet dysfunction regardless of mutation domain.

Sleepiness and Sleep-related Breathing Disorders in Myotonic Dystrophy and Responses to Treatment: A Prospective Cohort Study

OBJECTIVE We conducted prospective assessments in people with myotonic dystrophy type 1 (DM1) with daytime sleepiness, provided targeted therapies and assessed response. METHODS Patients had overnight sleep assessments. Treatment with continuous positive airway pressure (CPAP) for OSA, non-invasive ventilation (NIV) for respiratory failure, modafinil for excessive daytime sleepiness were commenced. RESULTS 120 people were studied: mean age 46.9 years (SD 13.2, range 18-74), body mass index 27.9 kg/m2 (7.2, 16-53), Epworth Sleepiness Score (ESS) 13.1 (4.7, 2-24). Twenty one people (18% of group) had OSA: mean age 49.6, BMI 31.1, ESS 14.3, ODI 22, pO2 11.3, pCO2 5.4. All were offered CPAP; seven continued with benefit but 14 had intolerance or no benefit. Thirty-three people (27%) had respiratory failure and abnormal sleep study: mean age 51.5, BMI 31.3, ESS 13.9, ODI 22.9, pO2 8.7, pCO2 6.8. All were offered NIV; 12 continued with benefit but 18 had intolerance or no benefit, 1 died and 2 declined commencement. Thirty-six people (30%) had predominantly sleepiness: mean age 44.8, BMI 24.6, ESS 14.1, ODI 9.2, pO2 11.7, pCO2 5.4. All were offered modafinil; 12 continued this with benefit but 10 had intolerance or no benefit, one was unkeen to start, 11 did not attend further clinic and two had other sleep disorders. Comparing means of treatment responders to non-responders showed no significant difference in any variable, except ESS: 15.9 vs.11.9 respectively, p < 0.0001. CONCLUSIONS Causes of sleepiness are variable in DM1, but include obstructive sleep apnoea, respiratory failure and sleepiness with a normal sleep study; 29% of this studied cohort benefited from targeted sleep therapies.

Benign and malignant tumors in the UK myotonic dystrophy patient registry

In light of recent evidence indicating that cancer is part of the myotonic dystrophy (DM) phenotype, we assessed the prevalence of benign and malignant tumors among 220 patients enrolled in the UK Myotonic Dystrophy Patient Registry and evaluated factors associated with their development.

Recessive mutations in the kinase ZAK cause a congenital myopathy with fibre type disproportion

Congenital myopathies define a heterogeneous group of neuromuscular diseases with neonatal or childhood hypotonia and muscle weakness. The genetic cause is still unknown in many patients, precluding genetic counselling and better understanding of the physiopathology. To identify novel genetic causes of congenital myopathies, exome sequencing was performed in three consanguineous families. We identified two homozygous frameshift mutations and a homozygous nonsense mutation in the mitogen-activated protein triple kinase ZAK. In total, six affected patients carry these mutations. Reverse transcription polymerase chain reaction and transcriptome analyses suggested nonsense mRNA decay as a main impact of mutations. The patients demonstrated a generalized slowly progressive muscle weakness accompanied by decreased vital capacities. A combination of proximal contractures with distal joint hyperlaxity is a distinct feature in one family. The low endurance and compound muscle action potential amplitude were strongly ameliorated on treatment with anticholinesterase inhibitor in another patient. Common histopathological features encompassed fibre size variation, predominance of type 1 fibre and centralized nuclei. A peculiar subsarcolemmal accumulation of mitochondria pointing towards the centre of the fibre was a novel histological hallmark in one family. These findings will improve the molecular diagnosis of congenital myopathies and implicate the mitogen-activated protein kinase (MAPK) signalling as a novel pathway altered in these rare myopathies.

MEGF10 related myopathies: A new case with adult onset disease with prominent respiratory failure and review of reported phenotypes

Recessive mutations in MEGF10 (multiple epidermal growth factor 10) have been reported in a severe early onset disorder named Early Myopathy, Areflexia, Respiratory Distress and Dysphagia, and a milder form with cores in the muscle biopsy; and a possible genotype-phenotype correlation determining the clinical presentation has been suggested. We undertook exome sequencing in a 66 year old male with a 20 year history of progressive proximal and distal weakness of upper and lower limbs, facial weakness and dysphagia, who developed respiratory failure requiring ventilation while still ambulant in his 50s. Muscle biopsy demonstrated myopathic changes with aggregation of myofibrillar proteins. Mutations in MEGF10 were identified: a novel essential splice site (c.1426+1G>T) and a novel missense variant (c.352T>C, p.(Cys118Arg)). We performed a detailed review of all reported MEGF10 cases (n = 20), and confirmed the presence of a genotype-phenotype correlation, namely that with ≥1 null mutation onset of respiratory dysfunction occurs in the first year of life, whereas with 2 missense mutations, respiratory dysfunction occurs at 10 years old or much later, as in the patient reported here. Our findings expand the phenotype of MEGF10 mutations to include onset in the 5th decade, and discuss the spectrum of MEGF10 related disease.

Survival patterns and cancer determinants in families with myotonic dystrophy type 1

Research indicates that patients with myotonic dystrophy type 1 (DM1) are at increased risk of cancer and early death. Family data may provide insights given DM1 phenotypic heterogeneity, the broad range of non‐muscular manifestations and the usual delays in the diagnosis of DM1.

The UK Myotonic Dystrophy Patient Registry

An opportunity for patients with Myotonic Dystrophy type 1 to participate in clinical trials and obtain the best possible care The UK Myotonic Dystrophy Patient Registry is managed by TREAT-NMD a network which brings together scientists, healthcare professionals, pharmaceutical companies and patient organisations to create the infrastructure to ensure that new therapies reach patients as quickly as possible.