Expression of LIM domain-binding 3 (LDB3), a striated muscle Z-band alternatively spliced PDZ-motif protein in the nervous system.

LIM domain-binding 3 (LDB3) is a member of the Enigma family of PDZ-LIM proteins. LDB3 has been reported as a striated muscle-specific Z-band alternatively spliced protein that plays an important role in mechanosensory actin cytoskeleton remodeling. This study shows that LDB3 is broadly expressed in the central and peripheral nervous system of human and mouse.

Simple and economical HandClench Relaxometer device for reliable and sensitive measurement of grip myotonia in myotonic dystrophy.

Grip myotonia and weakness are attractive treatment response biomarkers in clinical trials of myotonic dystrophy type 1 (DM1). There is a need to develop simple, patient-friendly and reproducible methods of quantifying grip myotonia in multisite trial settings. We designed a HandClench Relaxometer (HCR) that measures grip myotonia and strength.

Brief assessment of cognitive function in myotonic dystrophy: Multicenter longitudinal study using computer-assisted evaluation.

Introduction/aims: Myotonic dystrophy type 1 (DM1) is known to affect cognitive function, but the best methods to assess central nervous system involvement in multicenter studies have not been determined. In this study our primary aim was to evaluate the potential of computerized cognitive tests to assess cognition in DM1.

Methods: We conducted a prospective, longitudinal, observational study of 113 adults with DM1 at six sites.

Improving the efficacy of exome sequencing at a quaternary care referral centre: novel mutations, clinical presentations and diagnostic challenges in rare neurogenetic diseases.

Background: We used a multimodal approach including detailed phenotyping, whole exome sequencing (WES) and candidate gene filters to diagnose rare neurological diseases in individuals referred by tertiary neurology centres.

Methods: WES was performed on 66 individuals with neurogenetic diseases using candidate gene filters and stringent algorithms for assessing sequence variants. Pathogenic or likely pathogenic missense variants were interpreted using in silico prediction tools, family segregation analysis, previous publications of disease association and relevant biological assays.

Myopathy associated LDB3 mutation causes Z-disc disassembly and protein aggregation through PKCα and TSC2-mTOR downregulation.

Mechanical stress induced by contractions constantly threatens the integrity of muscle Z-disc, a crucial force-bearing structure in striated muscle. The PDZ-LIM proteins have been proposed to function as adaptors in transducing mechanical signals to preserve the Z-disc structure, however the underlying mechanisms remain poorly understood. Here, we show that LDB3, a well-characterized striated muscle PDZ-LIM protein, modulates mechanical stress signaling through interactions with the mechanosensing domain in filamin C, its chaperone HSPA8, and PKCα in the Z-disc of skeletal muscle.

Skeletal Muscle Magnetic Resonance Biomarkers in GNE Myopathy.

Objective: To characterize muscle involvement and evaluate disease severity in patients with GNE myopathy using skeletal muscle MRI and proton magnetic resonance spectroscopy (H-MRS).

Methods: Skeletal muscle imaging of the lower extremities was performed in 31 patients with genetically confirmed GNE myopathy, including T1-weighted and short tau inversion recovery (STIR) images, T1 and T2 mapping, and H-MRS. Measures evaluated included longitudinal relaxation time (T1), transverse relaxation time (T2), and H-MRS fat fraction (FF).

Cardiac MRI identifies valvular and myocardial disease in a subset of ANO5-related muscular dystrophy patients.

Patients with bi-allelic loss-of-function mutations in the gene ANO5 most commonly present with muscular dystrophy. In some studies, patients with ANO5-related dystrophy (ANO5-RD) had evidence of mild cardiac abnormalities; however, cardiac magnetic resonance imaging (MRI) has not been used for myocardial characterization. Ten patients with genetically confirmed ANO5-RD were enrolled in a phenotyping study to better characterize cardiac involvement.

Intracellular calcium leak as a therapeutic target for RYR1-related myopathies.

RYR1 encodes the type 1 ryanodine receptor, an intracellular calcium release channel (RyR1) on the skeletal muscle sarcoplasmic reticulum (SR). Pathogenic RYR1 variations can destabilize RyR1 leading to calcium leak causing oxidative overload and myopathy. However, the effect of RyR1 leak has not been established in individuals with RYR1-related myopathies (RYR1-RM), a broad spectrum of rare neuromuscular disorders.

Improved Criteria for the Classification of Titin Variants in Inherited Skeletal Myopathies.

Background: Extensive genetic screening results in the identification of thousands of rare variants that are difficult to interpret. Because of its sheer size, rare variants in the titin gene (TTN) are detected frequently in any individual. Unambiguous interpretation of molecular findings is almost impossible in many patients with myopathies or cardiomyopathies.

Consensus-based care recommendations for adults with myotonic dystrophy type 1.

Purpose Of Review: Myotonic dystrophy type 1 (DM1) is a severe, progressive genetic disease that affects between 1 in 3,000 and 8,000 individuals globally. No evidence-based guideline exists to inform the care of these patients, and most do not have access to multidisciplinary care centers staffed by experienced professionals, creating a clinical care deficit.

Recent Findings: The Myotonic Dystrophy Foundation (MDF) recruited 66 international clinicians experienced in DM1 patient care to develop consensus-based care recommendations.

Novel Variants in Individuals with -Related Congenital Myopathies: Genetic, Laboratory, and Clinical Findings.

The ryanodine receptor 1-related congenital myopathies (-RM) comprise a spectrum of slow, rare neuromuscular diseases. Affected individuals present with a mild-to-severe symptomatology ranging from proximal muscle weakness, hypotonia and joint contractures to scoliosis, ophthalmoplegia, and respiratory involvement. Although there is currently no FDA-approved treatment for RM, our group recently conducted the first clinical trial in this patient population (NCT02362425).

Holistic segmentation of the lung in cine MRI.

Duchenne muscular dystrophy (DMD) is a childhood-onset neuromuscular disease that results in the degeneration of muscle, starting in the extremities, before progressing to more vital areas, such as the lungs. Respiratory failure and pneumonia due to respiratory muscle weakness lead to hospitalization and early mortality. However, tracking the disease in this region can be difficult, as current methods are based on breathing tests and are incapable of distinguishing between muscle involvements.

Charcot-Marie-Tooth Disease type 4C: Novel mutations, clinical presentations, and diagnostic challenges.

Introduction: This study analyzes and describes atypical presentations of Charcot-Marie-Tooth disease type 4C (CMT4C).

Methods: We present clinical and physiologic features of 5 patients with CMT4C caused by biallelic private mutations of SH3TC2.

Results: All patients manifested scoliosis, and nerve conduction study indicated results in the demyelinating range.

Respiratory magnetic resonance imaging biomarkers in Duchenne muscular dystrophy.

Objective: To examine the diaphragm and chest wall dynamics with cine breathing magnetic resonance imaging (MRI) in ambulatory boys with Duchenne muscular dystrophy (DMD) without respiratory symptoms and controls.

Methods: In 11 DMD boys and 15 controls, cine MRI of maximal breathing was recorded for 10 sec. The lung segmentations were done by an automated pipeline based on a Holistically-Nested Network model (HNN method).

Skeletal muscle water T as a biomarker of disease status and exercise effects in patients with Duchenne muscular dystrophy.

The purpose of this study was to examine exercise effects on muscle water T in patients with Duchenne muscular dystrophy (DMD). In 12 DMD subjects and 19 controls, lower leg muscle fat (%) was measured by Dixon and muscle water T and R (1/T) by the tri-exponential model. Muscle water R was measured again at 3 hours after an ankle dorsiflexion exercise.

Expression and Purification of ZASP Subdomains and Clinically Important Isoforms: High-Affinity Binding to G-Actin.

Z-disc-associated, alternatively spliced, PDZ motif-containing protein (ZASP) is a principal component of the sarcomere. The three prevalent isoforms of ZASP in skeletal muscle are generated by alternative splicing of exons 9 and 10. The long isoforms, either having (ZASP-L) or lacking exon 10 (ZASP-LΔex10), include an N-terminal PDZ domain, an actin-binding region (ABR) with a conserved motif (ZM), and three C-terminal LIM domains.

Upper arm and cardiac magnetic resonance imaging in Duchenne muscular dystrophy.

We analyzed quantitative maps of and relaxation times and muscle fat fraction measurements in magnetic resonance imaging of the upper arm skeletal muscles and heart in ambulatory boys with Duchenne muscular dystrophy and age-range-matched healthy volunteer boys. The cardiac-optimized sequences detected fatty infiltration and edema in the upper arm skeletal muscles but not the myocardium in these Duchenne muscular dystrophy boys who had normal ejection fraction. Imaging the heart and skeletal muscle using the same magnetic resonance imaging methods during a single scan may be useful in assessing relative disease status and therapeutic response in clinical trials of Duchenne muscular dystrophy.

Quantifying disease activity in fatty-infiltrated skeletal muscle by IDEAL-CPMG in Duchenne muscular dystrophy.

The purpose of this study was to explore the use of iterative decomposition of water and fat with echo asymmetry and least-squares estimation Carr-Purcell-Meiboom-Gill (IDEAL-CPMG) to simultaneously measure skeletal muscle apparent fat fraction and water T (T) in patients with Duchenne muscular dystrophy (DMD). In twenty healthy volunteer boys and thirteen subjects with DMD, thigh muscle apparent fat fraction was measured by Dixon and IDEAL-CPMG, with the IDEAL-CPMG also providing T as a measure of muscle inflammatory activity. A subset of subjects with DMD was followed up during a 48-week clinical study.

Divalent cation-responsive myotonia and muscle paralysis in skeletal muscle sodium channelopathy.

We report a patient with paramyotonia congenita/hyperkalemic periodic paralysis due to Nav1.4 I693T mutation who had worsening of myotonia and muscle weakness in the setting of hypomagnesemia and hypocalcemia with marked recovery after magnesium administration. Computer simulations of the effects of the I693T mutation were introduced in the muscle fiber model by both hyperpolarizing shifts in the Nav1.

Results of a two-year pilot study of clinical outcome measures in collagen VI- and laminin alpha2-related congenital muscular dystrophies.

Potential therapies are currently under development for two congenital muscular dystrophy (CMD) subtypes: collagen VI-related muscular dystrophy (COL6-RD) and laminin alpha 2-related dystrophy (LAMA2-RD). However, appropriate clinical outcome measures to be used in clinical trials have not been validated in CMDs. We conducted a two-year pilot study to evaluate feasibility, reliability, and validity of various outcome measures, particularly the Motor Function Measure 32, in 33 subjects with COL6-RD and LAMA2-RD.

Atypical presentation of GNE myopathy with asymmetric hand weakness.

GNE myopathy is a rare autosomal recessive muscle disease caused by mutations in GNE, the gene encoding the rate-limiting enzyme in sialic acid biosynthesis. GNE myopathy usually manifests in early adulthood with distal myopathy that progresses slowly and symmetrically, first involving distal muscles of the lower extremities, followed by proximal muscles with relative sparing of the quadriceps. Upper extremities are typically affected later in the disease.

Lysosomal abnormalities in hereditary spastic paraplegia types SPG15 and SPG11.

Objective: Hereditary spastic paraplegias (HSPs) are among the most genetically diverse inherited neurological disorders, with over 70 disease loci identified (SPG1-71) to date. SPG15 and SPG11 are clinically similar, autosomal recessive disorders characterized by progressive spastic paraplegia along with thin corpus callosum, white matter abnormalities, cognitive impairment, and ophthalmologic abnormalities. Furthermore, both have been linked to early-onset parkinsonism.