Introduction:Arthrogryposis is characterized by the presence of multiple contractures at birth and can be caused by pathogenic variants in TTN (Titin). Exons and variants that are not expressed in one of the three major isoforms of titin are referred to as “metatranscript-only” and have been considered to be only expressed during fetal development. Recently, the metatranscript-only variant (c.39974-11T>G) in TTN with a second truncating TTN variant has been linked to arthrogryposis multiplex congenita and myopathy. Methods: Via exome sequencing we identified the TTN c.39974-11T>G splice variant in trans with one of three truncating variants (p.Arg8922*, p.Lys32998Asnfs*63), p.Tyr10345*) in five individuals from three families. Clinical presentation and muscle ultrasound as well as MRI images were analyzed. Results: All five patients presented with generalized muscular hypotonia, reduced muscle bulk and congenital contractures most prominently affecting the upper limbs and distal joints. Muscular hypotonia persisted and contractures improved over time. One individual, the recipient twin in the setting of twin-to-twin transfusion syndrome, died from severe cardiac hypertrophy one day after birth. Ultrasound and MRI imaging studies revealed a recognizable pattern of muscle involvement with striking fibrofatty involvement in the hamstrings and calves, and relative sparing of the femoral adductors and anterior segment of the thighs. Conclusion:The recurrent TTN c.39974-11T>G variant consistently causes congenital arthrogryposis and persisting myopathy providing evidence that the metatranscript-only 213-217 exons impact muscle elasticity during early development and beyond. There is a recognizable pattern of muscle involvement, which is distinct from other myopathies and provides valuable clues for diagnostic worku
ObjectiveFHL1‐related reducing body myopathy is an ultra‐rare, X‐linked dominant myopathy. In this cross‐sectional study, we characterize skeletal muscle ultrasound, muscle MRI, and cardiac MRI findings in FHL1‐related reducing body myopathy patients.MethodsSeventeen patients (11 male, mean age 35.4, range 12–76 years) from nine independent families with FHL1‐related reducing body myopathy underwent clinical evaluation, muscle ultrasound (n = 11/17), and lower extremity muscle MRI (n = 14/17), including Dixon MRI (n = 6/17). Muscle ultrasound echogenicity was graded using a modified Heckmatt scale. T1 and STIR axial images of the lower extremity muscles were evaluated for pattern and distribution of abnormalities. Quantitative analysis of intramuscular fat fraction was performed using the Dixon MRI images. Cardiac studies included electrocardiogram (n = 15/17), echocardiogram (n = 17/17), and cardiac MRI (n = 6/17). Cardiac muscle function, T1 maps, T2‐weighted black blood images, and late gadolinium enhancement patterns were analyzed.ResultsMuscle ultrasound showed a distinct pattern of increased echointensity in skeletal muscles with a nonuniform, multifocal, and “geographical” distribution, selectively involving the deeper fascicles of muscles such as biceps and tibialis anterior. Lower extremity muscle MRI showed relative sparing of gluteus maximus, rectus femoris, gracilis, and lateral gastrocnemius muscles and an asymmetric and multifocal, “geographical” pattern of T1 hyperintensity within affected muscles. Cardiac studies revealed mild and nonspecific abnormalities on electrocardiogram and echocardiogram with unremarkable cardiac MRI studies.InterpretationSkeletal muscle ultrasound and muscle MRI reflect the multifocal aggregate formation in muscle in FHL1‐related reducing body myopathy and are practical and informative tools that can aid in diagnosis and monitoring of disease progression.
Collagen XII-related disorders (COLXII-RD) are a heterogenous group of disorders with overlapping symptoms involving both connective tissue and muscle, clinically manifesting with hyperlaxity, contractures, and weakness of variable clinical severity. Biallelic loss-of-function (LOF), as well as dominantly acting variants in COL12A1 , have been recognized to cause COLXII-RD, with the disease severity being notably more severe in patients with recessive LOF COLXII-RD. While additional dominant cases have now been reported, fewer cases of the presumed more severe recessive COLXII-RD have been documented. Here, we present detailed clinical, immunohistochemical and imaging data on seven additional patients from six families, with biallelic pathogenic variants in COL12A1. In line with the initial report, four patients present with a consistent severe congenital phenotype, with significant myopathic muscle involvement on imaging and severe weakness with minimal attainment of motor skills, respiratory insufficiency, scoliosis, dysphagia and poor weight gain requiring G-tube feeds. In contrast, the remaining three patients manifest a milder phenotype, presenting with congenital hypotonia and hyperlaxity with subsequent steady improvement, acquisition of motor skills such as independent ambulation and muscle imaging consistent with diffuse mild muscle involvement and preferential involvement of the rectus femoris. Gum hypertrophy was a notable finding at birth across the disease severity spectrum. Cardiac valvular involvement was observed in three patients, while one patient from a consanguineous family presented with hypertrophic cardiomyopathy. Respiratory insufficiency was present in the severely affected patients. This cohort of patients thus expands the clinical spectrum associated with biallelic variants in COL12A1 to now also include a milder overlap phenotype of muscle and connective tissue disease. This series reviews the clinical presentation, immunostaining, muscle imaging, and explores the genotypephenotype correlations for recessive COLXII-RD and thus highlights a still novel recognizable overlap syndrome.
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