We present three members of an Italian family affected by tubular aggregate myopathy (TAM) and congenital miosis harboring a novel missense mutation in ORAI1. All patients had a mild, late onset TAM revealed by asymptomatic creatine kinase (CK) elevation and congenital miosis consistent with a Stormorken‐like Syndrome, in the absence of thrombocytopathy. Muscle biopsies showed classical histological findings but ultrastructural analysis revealed atypical tubular aggregates (TAs). The whole body muscle magnetic resonance imaging (MRI) showed a similar pattern of muscle involvement that correlated with clinical severity. The lower limbs were more severely affected than the scapular girdle, and thighs were more affected than legs. Molecular analysis revealed a novel c.290C>G (p.S97C) mutation in ORAI1 in all affected patients. Functional assays in both human embryonic kidney (HEK) cells and myotubes showed an increased rate of Ca2+ entry due to a constitutive activation of the CRAC channel, consistent with a ‘gain‐of‐function’ mutation. In conclusion, we describe an Italian family harboring a novel heterozygous c.290C>G (p.S97C) mutation in ORAI1 causing a mild‐ and late‐onset TAM and congenital miosis via constitutive activation of the CRAC channel. Our findings extend the clinical and genetic spectrum of the ORAI1‐related TAM.

We present clinical, histological, muscle imaging and molecular data from 3 patients (proband, his brother and father) of an Italian family affected by tubular aggregate myopathy (TAM). The proband was a 53 years-old woman with cramps and CK elevation. The muscle biopsy of his father, performed when he was 62 years old to investigate an asymptomatic hyperCKemia, revealed a tubular aggregate myopathy at histochemical and ultrastructural levels. The same findings were observed in the muscle biopsy of the brother at the age of 55.

We report a BIN1-related CNM family with unusual clinical phenotype. The proband, a 56-year-old man suffered of lower limbs myalgia since the age of 52. Clinical examination showed short stature, mild symmetric eyelid ptosis without ophthalmoplegia, scapular winging and Achilles tendon retraction. A muscle weakness was not noted. CK levels were up to 350 UI/L. Deltoid muscle biopsy showed nuclear centralization and clustering, deep sarcolemmal invaginations and type 1 fiber hypotrophy. Whole body MRI revealed fatty infiltration of posterior legs compartments, lumbar paraspinal and serratus muscles. Myotonic dystrophy type1 and 2, Pompe disease and MTM1 and DNM2-related CNM were ruled out. By sequencing BIN1, we identified a heterozygous pathogenic mutation [c.107C > A (p.A36E)], and we demonstrate that the mutation strongly impairs the membrane tubulation property of the protein. One affected sister carried the same mutation. Her clinical examination and muscle MRI revealed a similar phenotype. Our findings expand the clinical and genetic spectrum of the autosomal dominant CNM associated with BIN1 mutations.

Here we describe the first case of myotonic dystrophy type 1 (DM1) associated with facio–scapulo–humeral dystrophy (FSHD). From a clinical point of view, the patient displayed a pattern of muscle involvement reminiscent of both disorders, including hand-grip myotonia, facial, axial and distal limbs muscle weakness as well as a bilateral winged scapula associated with atrophy of the pectoralis major muscle and lumbar lordosis; pelvic muscles were mostly spared. An extensive muscle MRI assessment including neck, shoulder, abdominal, pelvic and lower limb muscles documented radiological features typical of DM1 and FSDH. Molecular genetic studies confirmed that the proband carried both a pathologically expanded DMPK allele, inherited from his father, and a de novo shortened D4Z4 repeat fragment at 4q35 locus.

To assess the pattern and degree of involvement of scapular girdle muscles in Facioscapulohumeral muscular dystrophy (FSHD). We standardized an MRI protocol that allowed the identification and evaluation of 14 muscle groups of the neck and upper girdle. 108 FSHD patients were included in the study. The involvement in FSHD was compared with that of limb girdle muscular dystrophies and other myopathies with upper girdle weakness. We were able to identify the most affected and spared muscles in FSHD. Asymmetry was a consistent feature, similarly to what is found in lower limb muscles, and T2-STIR hyperintensities could be detected as well. The pattern of involvement significantly differed from that encountered in other myopathies. Upper girdle imaging is a helpful tool in guiding the clinical diagnosis of FSHD. Moreover, the detailed knowledge of single muscle involvement provides information useful for understanding and following the natural history of the disease and developing rehabilitation protocols. To assess the pattern and degree of involvement of scapular girdle muscles in Facioscapulohumeral muscular dystrophy (FSHD). We standardized an MRI protocol that allowed the identification and evaluation of 14 muscle groups of the neck and upper girdle. 108 FSHD patients were included in the study. The involvement in FSHD was compared with that of limb girdle muscular dystrophies and other myopathies with upper girdle weakness. We were able to identify the most affected and spared muscles in FSHD. Asymmetry was a consistent feature, similarly to what is found in lower limb muscles, and T2-STIR hyperintensities could be detected as well. The pattern of involvement significantly differed from that encountered in other myopathies. Upper girdle imaging is a helpful tool in guiding the clinical diagnosis of FSHD. Moreover, the detailed knowledge of single muscle involvement provides information useful for understanding and following the natural history of the disease and developing rehabilitation protocols.

Background and purposeDuchenne muscular dystrophy carriers represent a rare condition that needs to be recognized because of the possible implications for prenatal diagnosis. Muscle biopsy is currently the diagnostic instrument of choice in sporadic patients. We wanted to verify whether muscle magnetic resonance imaging (MRI) could identify a pattern of involvement suggestive of this condition and whether it was similar to that reported in Duchenne and Becker muscular dystrophy.MethodsEvaluation of pelvic and lower limb MRI scans of 12 dystrophinopathy carriers was performed.ResultsWe found a frequent involvement of the quadratus femoris, gluteus maximus and medius, biceps femoris long head, adductor magnus, vasti and paraspinal muscles, whilst the popliteus, iliopsoas, recti abdominis, sartorius, and gracilis were relatively spared. Asymmetry was a major feature on MRI; it could be detected significantly more often than with sole clinical examination and even in patients without weakness.ConclusionsThe pattern we describe here is similar to that reported in Duchenne and Becker muscular dystrophy, although asymmetry represents a major distinctive feature. Muscle MRI was more sensitive than clinical examination for detecting single muscle involvement and asymmetry. Further studies are needed to verify the consistency of this pattern in larger cohorts and to assess whether muscle MRI can improve diagnostic accuracy in carriers with normal dystrophin staining on muscle biopsy.

Sir, Autosomal recessive spastic ataxia of Charlevoix Saguenay (ARSACS) is an early-onset, slowly progressive spastic ataxia associated with axonal-demyelinating polyneuropathy, hypermyelinated retinal fibers, and, sometimes, with an IQ in the lower normal range 1. MRI studies typically show vermian, cervical, and dorsal spinal cord atrophy, and T2 and FLAIR linear hypointensities in the pons 2. So far, over 70 mutations in SACS have been described, but the significant clinical variability amongst patients – especially in atypical cases described outside Quebec 1 – limits easy genotype–phenotype correlations. Here, we describe two unrelated ARSACS patients from central Italy carrying two novel mutations in SACS (clinico-diagnostic features are summarized in the Table S1). Both patients were born to non-consanguineous parents after a normal delivery. The 26-year-old patient 1, developed since the age of 6 a progressive spastic ataxia, later complicated by other cerebellar signs. Previous gene testing for Friedreich ataxia, MTATP6, and POLG1 mutations was negative. The 28-year-old patient 2 manifested a progressive spastic gait since age 8 years. Her clinical examination documented a spastic ataxic gait with predominant pyramidal signs, hand muscle weakness and atrophy, pes cavus with hammertoes, and other peculiar skeletal abnormalities (Table S1). In both patients, EMG studies documented a mixed polyneuropathy, whereas fundus oculi examination and cognitive tests were normal. Both patients showed the distinctive neuroimaging picture of ARSACS 2, and in addition patient 2 showed the presence of a thin corpus callosum (TCC) (Fig. 1). Given the presence of a TCC and of predominant pyramidal signs, SPG11 and SPG15 were also ruled out in this case. Very interestingly, serial MRI studies performed at ages 23 and 28 years in pt2 did not document significant progression of the cerebellar and pons alterations (Fig. 1). Molecular testing for SACS 1 permitted the molecular confirmation of their disease 3, 4 and detected new gene variants (Table S1). In both cases, a detailed ophthalmologic investigation, including retinal nerve fiber layer (RNFL) assessment by monochromatic photography and ocular coherence tomography (OCT), documented normal optic disc morphology and an enhanced visibility of RNFL; OCT demonstrated increased global RNFL average thickness ranging from 125 to 220 μ (age-matched healthy controls 96 ± 7μ) (Fig. S1). With the detection of two novel SACS mutations (Table S1), this report further broadens the genotypic spectrum of ARSACS. Moreover, our findings highlight specific diagnostic features as indicators strongly suggestive for a clinical suspicion of ARSACS. In particular, OCT studies in both cases described in this work demonstrated increased global RNFL average thickness, confirming recent evidences in ARSACS 5. Thus, it appears safe to suggest that revealing OCT abnormalities early in the diagnostic flowchart of patients with progressive neurodegenerative diseases affecting both pyramidal and cerebellar systems may assist in prioritizing gene analyses. Neuroimaging studies documented in both patients vermian atrophy and tigroid appearance of the pons, and patient 2 also presented a TCC. Such features are not usual in ARSACS 6, 7, whilst it is typical of specific forms of hereditary spastic paraplegias reviewed in 8. However, the coexistence also in this case of typical MRI findings of ARSACS confirms that these ones would also represent other diagnostic indicators for this disorder. Of note, serial MRI studies in patient 2 did not document a significant progression of the neuroradiological features, in agreement with an abnormal developmental mechanism in ARSACS, as hypothesized elsewhere 9. On the other hand, the evidence of a neurological deterioration in ARSACS patients over years suggests that sacsin defects might induce the occurrence of a slow neurodegenerative process as well. Patient 2 also showed distinctive skeletal anomalies (Table S1): this characteristic, already been described in ARSACS 9, suggests investigations in larger cohorts to verify whether it might represent another distinctive feature of ARSACS. Finally, our study further expands the allelic heterogeneity underlying ARSACS. In this regard, it seems reasonable to think that the resulting conformational change of sacsin because of the novel missense in patient 2 might lead to higher quantitative or qualitative protein levels compared to the effects of the truncated mutations in patient 1 and relate to a relatively milder clinical picture (Table S1). Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

The aim of this study was to evaluate pelvis and lower limb muscle MRI scans of 46 patients affected by Becker muscular dystrophy (BMD), subdivided according to disease severity, ranging from clinically asymptomatic patients to patients who had lost ambulation. We found a distinct pattern on muscle imaging characterized by prominent involvement of the gluteus maximus and medius, adductor magnus, biceps femoris long head, semimembranosus and vasti. This pattern was consistent in all the 25 symptomatic patients. Milder changes in the same muscles were found in 13 of the 21 asymptomatic cases. The other 8 asymptomatic patients had a normal scan. The severity of muscle involvement was significantly correlated with age. Our results suggest that a distinct pattern of muscle involvement can be detected in BMD. The early identification of muscle changes in a proportion of asymptomatic patients may be useful as an additional tool in the diagnostic workup.