The FLNC Ala1186Val Variant Linked to Cytoplasmic Body Myopathy and Cardiomyopathy Causes Protein Instability.

Filamin C-related disorders include myopathies and cardiomyopathies linked to variants in the FLNC gene. Filamin C belongs to a family of actin-binding proteins involved in sarcomere stability. This study investigates the pathogenic impact of the FLNC c.3557C > T (p.Ala1186Val) pathogenic variant associated with an early-onset cytoplasmic body myopathy and cardiomyopathy in three unrelated patients. We performed clinical imaging and myopathologic and genetic characterization of three patients with an early-onset myopathy and cardiomyopathy. Bioinformatics analysis, variant interpretation, and protein structure analysis were performed to validate and assess the effects of the filamin C variant. All patients presented with a homogeneous clinical phenotype marked by a severe contractural myopathy, leading to loss of gait. There was prominent respiratory involvement and restrictive or hypertrophic cardiomyopathies. The Ala1186Val variant is located in the interstrand loop involved in intradomain stabilization and/or interdomain interactions with neighbor Ig-like domains. 3D modeling highlights local structural changes involving nearby residues and probably impacts the protein stability, causing protein aggregation in the form of cytoplasmic bodies. Myopathologic studies have disclosed the prominent aggregation and upregulation of the aggrephagy-associated proteins LC3B and p62. As a whole, the Ala1186Val variant in the FLNC gene provokes a severe myopathy with contractures, respiratory involvement, and cardiomyopathy due to protein aggregation in patients' muscles.

Diagnostic interest of whole-body MRI in early- and late-onset LAMA2 muscular dystrophies: a large international cohort.

BACKGROUND: LAMA2-related muscular dystrophy (LAMA2-RD) encompasses a group of recessive muscular dystrophies caused by mutations in the LAMA2 gene, which codes for the alpha-2 chain of laminin-211 (merosin). Diagnosis is straightforward in the classic congenital presentation with no ambulation and complete merosin deficiency in muscle biopsy, but is far more difficult in milder ambulant individuals with partial merosin deficiency. OBJECTIVE: To investigate the diagnostic utility of muscle imaging in LAMA2-RD using whole-body magnetic resonance imaging (WBMRI). RESULTS: 27 patients (2-62 years, 21-80% with acquisition of walking ability and 6 never ambulant) were included in an international collaborative study. All carried two pathogenic mutations, mostly private missense changes. An intronic variant (c.909 + 7A > G) was identified in all the Chilean cases. Three patients (two ambulant) showed intellectual disability, epilepsy, and brain structural abnormalities. WBMRI T1w sequences or T2 fat-saturated images (Dixon) revealed abnormal muscle fat replacement predominantly in subscapularis, lumbar paraspinals, gluteus minimus and medius, posterior thigh (adductor magnus, biceps femoris, hamstrings) and soleus. This involvement pattern was consistent for both ambulant and non-ambulant patients. The degree of replacement was predominantly correlated to the disease duration, rather than to the onset or the clinical severity. A "COL6-like sandwich sign" was observed in several muscles in ambulant adults, but different involvement of subscapularis, gluteus minimus, and medius changes allowed distinguishing LAMA2-RD from collagenopathies. The thigh muscles seem to be the best ones to assess disease progression. CONCLUSION: WBMRI in LAMA2-RD shows a homogeneous pattern of brain and muscle imaging, representing a supportive diagnostic tool.

Minimally Invasive Fusionless Surgery for Scoliosis in Spinal Muscular Atrophy: Long-term Follow-up Results in a Series of 59 Patients.

BACKGROUND: Treatment of spinal muscular atrophy (SMA) scoliosis has evolved in the last decade, with the emergence of fusionless surgical techniques that allow correction of the deformity before the end of growth spurt. These techniques are expected to delay definitive spine fusion and preserve trunk growth. PURPOSE: The aim was to evaluate long-term clinical, radiologic, and respiratory outcomes of a minimally invasive fusionless surgery (MIFLS) in SMA scoliosis. METHODS: All children affected with SMA scoliosis who underwent MIFLS in our department from 2011 to 2019 were included. The instrumentation consisted in a bilateral sliding rod construct from T1 to the sacrum, anchored proximally by double-hook claws and distally by iliosacral screws. Clinical, genetic, respiratory and radiographic data were retrospectively reviewed. A patient's satisfaction survey was performed. RESULTS: A total of 59 children with genetic confirmation of SMA (9SMA1c, 47SMA2, and 3SMA3) underwent MIFLS at a mean age of 11±1.9 years. All of them were nonwalker at the time of surgery. Twenty-six were treated with intrathecal Nusinersen. Mean follow-up was 5.2 years (2 to 9.6 y). Mean major coronal curve improved from 79±15 to 41±16 degrees and pelvic obliquity decreased from 24±11 to 5.9±4 degrees. Mean space available for lung improved from 77% to 93%. Mechanical or infectious complications occurred in 9 patients, with removal of the implant in 1. 6 children required unplanned surgeries. Postoperative bracing was needed in 13 children. Mean gain weight 3 years after the first surgery was 6 kg. 91.5% of patients had a positive satisfaction of the surgery. There was no significant impact in respiratory function postoperatively. Only 30 children required rod lengthening procedures, with a mean interval between procedures of 1.9 years (0.5 to 3.7 y). No arthrodesis was required at last follow-up in any patient. CONCLUSION: Bipolar MIFLS in SMA preserves spinal and thoracic growth without interference with respiratory function. It provides a significant correction of spinal deformity and pelvic obliquity, having a reduced rate of complications. The correction of spinal deformity was maintained at long term, not requiring definitive fusion at the end of growth. LEVEL OF EVIDENCE: Level IV.

Assessment of respiratory muscles and motor function in children with SMA treated by nusinersen.

INTRODUCTION: Nusinersen is associated with an improvement in motor function in children with spinal muscular atrophy (SMA) but data on respiratory muscles strength are scarce. Respiratory muscles performance and lung function were evaluated in children with SMA 1c and 2 after six injections of nusinersen (M14). Results from patients with SMA2 were compared with data of age-matched historical controls. Motor function tests (MFM and HINE-2) were assessed at baseline and M14 in the treated patients. RESULTS: Sixteen children (2 SMA Type 1c and 14 SMA Type 2), mean age 9.4 ± 2.3 years, were included. The data of 14 historical SMA 2 controls (mean age 9.3 ± 1.9 years) were gathered. The strength of the global inspiratory muscles of SMA 2 treated with nusinersen, assessed on maximal static inspiratory pressure, forced vital capacity, and esophageal pressure during a maximal sniff was significantly better compared with historical controls (p < .05). A significant improvement in MFM and HINE-2 was observed in the patients with 16 SMA treated with nusinersen after 14 months as compared with baseline. CONCLUSION: In children with SMA Type 2, respiratory muscle performance was significantly better after six injections of nusinersen as compared with age-matched SMA Type 2 historical controls.

A novel neuromuscular form of glycogen storage disease type IV with arthrogryposis, spinal stiffness and rare polyglucosan bodies in muscle.

Glycogen storage disease type IV (GSD IV) is an autosomal recessive disorder causing polyglucosan storage in various tissues. Neuromuscular forms present with fetal akinesia deformation sequence, lethal myopathy, or mild hypotonia and weakness. A 3-year-old boy presented with arthrogryposis, motor developmental delay, weakness, and rigid spine. Whole body MRI revealed fibroadipose muscle replacement but sparing of the sartorius, gracilis, adductor longus and vastus intermedialis muscles. Polyglucosan bodies were identified in muscle, and GBE1 gene analysis revealed two pathogenic variants. We describe a novel neuromuscular GSD IV phenotype and confirm the importance of muscle morphological studies in early onset neuromuscular disorders.

New human-specific brain landmark: the depth asymmetry of superior temporal sulcus.

Identifying potentially unique features of the human cerebral cortex is a first step to understanding how evolution has shaped the brain in our species. By analyzing MR images obtained from 177 humans and 73 chimpanzees, we observed a human-specific asymmetry in the superior temporal sulcus at the heart of the communication regions and which we have named the "superior temporal asymmetrical pit" (STAP). This 45-mm-long segment ventral to Heschl's gyrus is deeper in the right hemisphere than in the left in 95% of typical human subjects, from infanthood till adulthood, and is present, irrespective of handedness, language lateralization, and sex although it is greater in males than in females. The STAP also is seen in several groups of atypical subjects including persons with situs inversus, autistic spectrum disorder, Turner syndrome, and corpus callosum agenesis. It is explained in part by the larger number of sulcal interruptions in the left than in the right hemisphere. Its early presence in the infants of this study as well as in fetuses and premature infants suggests a strong genetic influence. Because this asymmetry is barely visible in chimpanzees, we recommend the STAP region during midgestation as an important phenotype to investigate asymmetrical variations of gene expression among the primate lineage. This genetic target may provide important insights regarding the evolution of the crucial cognitive abilities sustained by this sulcus in our species, namely communication and social cognition.

Organising white matter in a brain without corpus callosum fibres.

Isolated corpus callosum dysgenesis (CCD) is a congenital malformation which occurs during early development of the brain. In this study, we aimed to identify and describe its consequences beyond the lack of callosal fibres, on the morphology, microstructure and asymmetries of the main white matter bundles with diffusion imaging and fibre tractography. Seven children aged between 9 and 13 years old and seven age- and gender-matched control children were studied. First, we focused on bundles within the mesial region of the cerebral hemispheres: the corpus callosum, Probst bundles and cingulum which were selected using a conventional region-based approach. We demonstrated that the Probst bundles have a wider connectivity than the previously described rostrocaudal direction, and a microstructure rather distinct from the cingulum but relatively close to callosal remnant fibres. A sigmoid bundle was found in two partial ageneses. Second, the corticospinal tract, thalamic radiations and association bundles were extracted automatically via an atlas of adult white matter bundles to overcome bias resulting from a priori knowledge of the bundles' anatomical morphology and trajectory. Despite the lack of callosal fibres and the colpocephaly observed in CCD, all major white matter bundles were identified with a relatively normal morphology, and preserved microstructure (i.e. fractional anisotropy, mean diffusivity) and asymmetries. Consequently the bundles' organisation seems well conserved in brains with CCD. These results await further investigations with functional imaging before apprehending the cognition variability in children with isolated dysgenesis.