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BackgroundLAMA2-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.ObjectiveTo investigate the diagnostic utility of muscle imaging in LAMA2-RD using whole-body magnetic resonance imaging (WBMRI).Results27 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.ConclusionWBMRI in LAMA2-RD shows a homogeneous pattern of brain and muscle imaging, representing a supportive diagnostic tool.

Retinitis pigmentosa (RP) is the most common inherited retinal disease (IRD) and is characterized by photoreceptor degeneration and progressive vision loss. We report 4 patients presenting with RP from 3 unrelated families with variants in TBC1D32, which to date has never been associated with an IRD. To validate TBC1D32 as a putative RP causative gene, we combined Xenopus in vivo approaches and human induced pluripotent stem cell-derived (iPSC-derived) retinal models. Our data showed that TBC1D32 was expressed during retinal development and that it played an important role in retinal pigment epithelium (RPE) differentiation. Furthermore, we identified a role for TBC1D32 in ciliogenesis of the RPE. We demonstrated elongated ciliary defects that resulted in disrupted apical tight junctions, loss of functionality (delayed retinoid cycling and altered secretion balance), and the onset of an epithelial-mesenchymal transition-like phenotype. Last, our results suggested photoreceptor differentiation defects, including connecting cilium anomalies, that resulted in impaired trafficking to the outer segment in cones and rods in TBC1D32 iPSC-derived retinal organoids. Overall, our data highlight a critical role for TBC1D32 in the retina and demonstrate that TBC1D32 mutations lead to RP. We thus identify TBC1D32 as an IRD-causative gene.

Background Congenital bilateral vocal cord paralysis is a rare occurrence. Approximately half the cases are associated with a major comorbidity, usually neurological, neuromuscular or malformative. Case presentation In a male newborn, respiratory distress syndrome and stridor were observed immediately following birth. The cause was bilateral vocal cord paralysis in the adducted position. Neuroradiological investigation revealed a unilateral discontinuity between the upper pons and the right medulla oblongata. Hypoplasia of the right posterior hemiarches of C1-C2 and the right exo-occipital bone was observed, as was a small clivus. MR angiography showed the absence of the distal right vertebral artery, with hypoplasia and parietal irregularities of the proximal segments. Respiratory autonomy was not obtained despite endoscopic laser cordotomy, corticosteroid therapy and nasal continuous positive airway pressure. The infant died at the age of 4 weeks after treatment was limited to comfort care. Conclusions A medullary lesion is an exceptional cause of congenital bilateral vocal cord paralysis. The strictly unilateral neurological and vascular defect and the absence of associated intracranial or extracranial malformation make this clinical case unique and suggest a disruptive mechanism. This case also highlights the help provided by advanced neuroimaging techniques, i.e. fibre tracking using diffusion tensor imaging, in the decision-making process.

We present the phenotype of an infant with the largest ATN1 CAG expansion reported to date (98 repeats). He presented at 4 months with developmental delay, poor eye contact, acquired microcephaly, failure to thrive. He progressively developed dystonia‐parkinsonism with paroxysmal oromandibular and limbs dyskinesia and fatal outcome at 17 months. Cerebral MRI disclosed globus pallidus T2‐WI hyperintensities and brain atrophy. Molecular analysis was performed post‐mortem following the diagnosis of dentatorubral–pallidoluysian atrophy (DRPLA) in his symptomatic father. Polyglutamine expansion defects should be considered when neurodegenerative genetic disease is suspected even in infancy and parkinsonism can be a presentation of infantile‐onset DRPLA.

The aim of this study was to analyze patients from two distinct families with a novel distal titinopathy phenotype associated with exactly the same CNV in the TTN gene. We used an integrated strategy combining deep phenotyping and complete molecular analyses in patients. The CNV is the most proximal out‐of‐frame TTN variant reported and leads to aberrant splicing transcripts leading to a frameshift. In this case, the dominant effect would be due to dominant‐negative and/or haploinsufficiency. Few CNV in TTN have been reported to date. Our data represent a novel phenotype–genotype association and provides hypotheses for its dominant effects.

The cochlear aqueduct (CA) is a bony canal located at the base of the scala tympani of the cochlea. It connects the inner ear perilymph fluid to the cerebrospinal fluid of the posterior cerebral fossa. Its function is not well understood, as it seems to be patent in only a fraction of adult patients. Indirect observations argue in favor of the CA being more patent in children. To study the CA morphology in children, we performed a retrospective single-center study of 85 high-resolution temporal bone computed tomography (hrCT) scans of children with a mean age of 3.23 ± 3.07 years (13 days of life up to 18 years), and compared them with a group of 22 adult hrCT (mean age of 24.01 ± 3.58 years). The CA morphology measurements included its total length, its funnel (wider intracranial portion) length and width and its type (indicating its radiological patency), according to a previously published classification. The dimensions of the CA were significantly smaller in children compared with adults for the axial length (10.37 ± 2.58 versus 14.63 ± 2.40 mm, respectively, p < 0,001) and the funnel length (3.94 ± 1.59 versus 6.01 ± 1.77 mm, respectively, p < 0,001). The funnel width tended to be smaller but the difference was not significant: 3.49 ± 1,33 versus 3.89 ± 1.07 mm, p = 0,22. The repartition of types of CA was also statistically different. The CA appeared to be more identifiable in the children population. Type 1 (CA visible along its entire course) accounted for 42% (36/85) of children and only 5% (1/22) of adults, type 2 (visible in the medial two thirds) for 30% (25/85) versus 31% (7/22), type 3 (not visible completely along the medial two thirds) for 27% (23/85) versus 50% (11/22). Finally, type 4 (undetectable) was found in only 1% (1/85) of children and 14% (3/22) of adults (p < 0,001). Our study showed significant postnatal growth of the length of the CA, which was more rapid before the age of 2, and slowed after 6 years of age. Its width increased less, with children older than 2 years presenting a similar width to adults. The CA was more identifiable in hrCT in children, arguing for a more permeable tract. The number of completely ossified CA was significantly lower in the children population. These findings highlight the differences between the CA morphology in adults and children and raise the question of differences in function. Moreover, these differences may impact the pharmacodynamics of drugs or vectors delivered into the pediatric inner ear. Further studies are required, both on the anatomy of temporal bones and on the function of the CA in children.

Homozygous mutations in MAG, encoding the myelin‐associated glycoprotein, a transmembrane component of the myelin sheath, have been associated with SPG 75 recessive spastic paraplegia. Here, we report the first patient with two compound heterozygous novel MAG mutations (p.A151V and p.S373R) and early developmental delay with a progressive complex phenotype characterized by spastic paraplegia, peripheral sensorimotor neuropathy, intellectual disability, and sensorial dysfunctions with severe optic atrophy and hearing involvement. Brain imaging showed progressive global cerebellar atrophy. We propose that complex hereditary spastic paraplegia, with axonal and demyelinating polyneuropathy, sensorial impairment and intellectual disability might suggest MAG mutations.

Autophagy is a cellular process through which toxic aggregates, pathogens, and damaged organelles are disposed of and essential metabolites recycled. This study challenges the belief that a core autophagy protein is indispensable.

The cochlear aqueduct (CA) is a bony canal located at the base of the scala tympani of the cochlea. It connects the inner ear perilymph fluid to the cerebrospinal fluid of the posterior cerebral fossa. Its function is not well understood, as it seems to be patent in only a fraction of adult patients. Indirect observations argue in favor of the CA being more patent in children. To study the CA morphology in children, we performed a retrospective single-center study of 85 high-resolution temporal bone computed tomography (hrCT) scans of children with a mean age of 3.23 ± 3.07 years (13 days of life up to 18 years), and compared them with a group of 22 adult hrCT (mean age of 24.01 ± 3.58 years). The CA morphology measurements included its total length, its funnel (wider intracranial portion) length and width and its type (indicating its radiological patency), according to a previously published classification. The dimensions of the CA were significantly smaller in children compared with adults for the axial length (10.37 ± 2.58 versus 14.63 ± 2.40 mm, respectively, p  < 0,001) and the funnel length (3.94 ± 1.59 versus 6.01 ± 1.77 mm, respectively, p  < 0,001). The funnel width tended to be smaller but the difference was not significant: 3.49 ± 1,33 versus 3.89 ± 1.07 mm, p  = 0,22. The repartition of types of CA was also statistically different. The CA appeared to be more identifiable in the children population. Type 1 (CA visible along its entire course) accounted for 42% (36/85) of children and only 5% (1/22) of adults, type 2 (visible in the medial two thirds) for 30% (25/85) versus 31% (7/22), type 3 (not visible completely along the medial two thirds) for 27% (23/85) versus 50% (11/22). Finally, type 4 (undetectable) was found in only 1% (1/85) of children and 14% (3/22) of adults ( p  < 0,001). Our study showed significant postnatal growth of the length of the CA, which was more rapid before the age of 2, and slowed after 6 years of age. Its width increased less, with children older than 2 years presenting a similar width to adults. The CA was more identifiable in hrCT in children, arguing for a more permeable tract. The number of completely ossified CA was significantly lower in the children population. These findings highlight the differences between the CA morphology in adults and children and raise the question of differences in function. Moreover, these differences may impact the pharmacodynamics of drugs or vectors delivered into the pediatric inner ear. Further studies are required, both on the anatomy of temporal bones and on the function of the CA in children.