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Objective Mutations in the genes encoding the extracellular matrix protein collagen VI (ColVI) cause a spectrum of disorders with variable inheritance including Ullrich congenital muscular dystrophy, Bethlem myopathy, and intermediate phenotypes. We extensively characterized, at the clinical, cellular, and molecular levels, 49 patients with onset in the first 2 years of life to investigate genotype‐phenotype correlations. Methods Patients were classified into 3 groups: early‐severe (18%), moderate‐progressive (53%), and mild (29%). ColVI secretion was analyzed in patient‐derived skin fibroblasts. Chain‐specific transcript levels were quantified by quantitative reverse transcriptase polymerase chain reaction (qRT‐PCR), and mutation identification was performed by sequencing of complementary DNA. Results ColVI secretion was altered in all fibroblast cultures studied. We identified 56 mutations, mostly novel and private. Dominant de novo mutations were detected in 61% of the cases. Importantly, mutations causing premature termination codons (PTCs) or in‐frame insertions strikingly destabilized the corresponding transcripts. Homozygous PTC‐causing mutations in the triple helix domains led to the most severe phenotypes (ambulation never achieved), whereas dominant de novo in‐frame exon skipping and glycine missense mutations were identified in patients of the moderate‐progressive group (loss of ambulation). Interpretation This work emphasizes that the diagnosis of early onset ColVI myopathies is arduous and time‐consuming, and demonstrates that quantitative RT‐PCR is a helpful tool for the identification of some mutation‐bearing genes. Moreover, the clinical classification proposed allowed genotype‐phenotype relationships to be explored, and may be useful in the design of future clinical trials. ANN NEUROL 2010;68:511–520

Background Tubular aggregate myopathies (TAMs) are muscle disorders characterised by abnormal accumulations of densely packed single-walled or doublewalled membrane tubules in muscle fibres. Recently, STIM1, encoding a major calcium sensor of the endoplasmic reticulum, was identified as a TAM gene. Methods The present study aims to define the clinical, histological and ultrastructural phenotype of tubular aggregate myopathy and to assess the STIM1 mutation spectrum. Results We describe six new TAM families harbouring one known and four novel STIM1 mutations. All identified mutations are heterozygous missense mutations affecting highly conserved amino acids in the calcium-binding EFhand domains, demonstrating the presence of a mutation hot spot for TAM. We show that the mutations induce constitutive STIM1 clustering, strongly suggesting that calcium sensing and consequently calcium homoeostasis is impaired. Histological and ultrastructural analyses define a common picture with tubular aggregates labelled with Gomori trichrome and Nicotinamide adenine dinucleotide (NADH) tetrazolium reductase, substantiating their endoplasmic reticulum origin. The aggregates were observed in both fibre types and were often accompanied by nuclear internalisation and fibre size variability. The phenotypical spectrum ranged from childhood onset progressive muscle weakness and elevated creatine kinase levels to adultonset myalgia without muscle weakness and normal CK levels. Conclusions The present study expands the phenotypical spectrum of STIM1-related tubular aggregate myopathy. STIM1 should therefore be considered for patients with tubular aggregate myopathies involving either muscle weakness or myalgia as the first and predominant clinical sign.

Objectives-To compare the diagnosis and prognosis of extracranial versus intracranial vertebral artery dissections without intracerebral haemorrhage. Methods-Twenty two vertebral artery dissections were defined by intra-arterial angiography and classified in two groups: group 1, nine extracranial dissections (seven patients) and group 2, 13 intracranial dissections (nine patients), involving the basilar artery in five cases. Bilateral dissections were found in 38% of the population. Before angiography, all the patients had been investigated by continuous wave Doppler, colour coded Doppler, and transcranial Doppler. Mean follow up was 44 months. Results-The two most important symptoms of both dissections (81% of patients) were unbearable pain preceding stroke and progressive onset of stroke within a few hours. Severe ultrasonic abnormalities were present in 94% of the patients whereas specific ultrasonic signs (segmental dilation with eccentric channel) were rare (19%) in both groups. Major strokes and brainstem strokes represented respectively 67% and 78% in intracranial versus 43% and 29% in extracranial dissections. Severe sequelae (permanent disabling motor or cerebellar deficit) were more often associated with intracranial (44%) than with extracranial dissections (14%). No recurrence of dissection and no cerebral haemorrhage were found under heparin. Significant factors of poor outcome (P< 0.05) were the initial severity of the stroke and the bilateral location of dissections. Conclusion-The combination of a pain and a progressive onset of the stroke, corroborated by ultrasonic findings, could have helped to recognise most of these types of dissections. Intracranial dissections have a poorer prognosis than extracranial dissections.

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