Variants in DTNA cause a mild, dominantly inherited muscular dystrophy.

DTNA encodes α-dystrobrevin, a component of the macromolecular dystrophin-glycoprotein complex (DGC) that binds to dystrophin/utrophin and α-syntrophin. Mice lacking α-dystrobrevin have a muscular dystrophy phenotype, but variants in DTNA have not previously been associated with human skeletal muscle disease. We present 12 individuals from four unrelated families with two different monoallelic DTNA variants affecting the coiled-coil domain of α-dystrobrevin. The five affected individuals from family A harbor a c.1585G > A; p.Glu529Lys variant, while the recurrent c.1567_1587del; p.Gln523_Glu529del DTNA variant was identified in the other three families (family B: four affected individuals, family C: one affected individual, and family D: two affected individuals). Myalgia and exercise intolerance, with variable ages of onset, were reported in 10 of 12 affected individuals. Proximal lower limb weakness with onset in the first decade of life was noted in three individuals. Persistent elevations of serum creatine kinase (CK) levels were detected in 11 of 12 affected individuals, 1 of whom had an episode of rhabdomyolysis at 20 years of age. Autism spectrum disorder or learning disabilities were reported in four individuals with the c.1567_1587 deletion. Muscle biopsies in eight affected individuals showed mixed myopathic and dystrophic findings, characterized by fiber size variability, internalized nuclei, and slightly increased extracellular connective tissue and inflammation. Immunofluorescence analysis of biopsies from five affected individuals showed reduced α-dystrobrevin immunoreactivity and variably reduced immunoreactivity of other DGC proteins: dystrophin, α, ß, δ and γ-sarcoglycans, and α and ß-dystroglycans. The DTNA deletion disrupted an interaction between α-dystrobrevin and syntrophin. Specific variants in the coiled-coil domain of DTNA cause skeletal muscle disease with variable penetrance. Affected individuals show a spectrum of clinical manifestations, with severity ranging from hyperCKemia, myalgias, and exercise intolerance to childhood-onset proximal muscle weakness. Our findings expand the molecular etiologies of both muscular dystrophy and paucisymptomatic hyperCKemia, to now include monoallelic DTNA variants as a novel cause of skeletal muscle disease in humans.

Loss of tubulin deglutamylase CCP1 causes infantile-onset neurodegeneration.

A set of glutamylases and deglutamylases controls levels of tubulin polyglutamylation, a prominent post-translational modification of neuronal microtubules. Defective tubulin polyglutamylation was first linked to neurodegeneration in the Purkinje cell degeneration (pcd) mouse, which lacks deglutamylase CCP1, displays massive cerebellar atrophy, and accumulates abnormally glutamylated tubulin in degenerating neurons. We found biallelic rare and damaging variants in the gene encoding CCP1 in 13 individuals with infantile-onset neurodegeneration and confirmed the absence of functional CCP1 along with dysregulated tubulin polyglutamylation. The human disease mainly affected the cerebellum, spinal motor neurons, and peripheral nerves. We also demonstrate previously unrecognized peripheral nerve and spinal motor neuron degeneration in pcd mice, which thus recapitulated key features of the human disease. Our findings link human neurodegeneration to tubulin polyglutamylation, entailing this post-translational modification as a potential target for drug development for neurodegenerative disorders.

Upper motor neuron signs and early onset gait abnormalities in young children with bi-allelic VWA1 variants.

Bi-allelic loss-of-function variants in Von Willebrand factor type A (VWA1) were recently discovered to lead to an early onset motor neuropathy or neuromyopathy. What makes this discovery particularly notable is the high frequency of one of the VWA1 (NM_022834.5) founder variants, c.62_71dup (p.Gly25ArgfsTer74), which nears 0.01% in European populations, and suggests that there may be a wide spectrum of disease features and severity. Here, we report two cases from nonconsanguineous families in North America that presented in early childhood with lower extremity weakness and prominent foot deformities, and were found to carry bi-allelic variants in VWA1. We draw focus to upper motor neuron signs and abnormal gait phenotypes as presenting symptoms in VWA1-related disorder and expand the clinical and molecular spectrum.

Developing outcome measures of disease activity in pediatric myasthenia.

INTRODUCTION: Pediatric myasthenia encompasses juvenile myasthenia gravis (JMG) and congenital myasthenic syndrome (CMS), which are chronic disorders with fluctuating symptoms amenable to medical therapy. Disease activity and treatment response may be difficult to assess, but, unlike adults, outcome measures have not been developed in children. METHODS: The study was performed in children (0-18 years of age) at the neuromuscular center of a pediatric hospital over a 3-year period. Patients were recruited prospectively as part of their routine clinical care. Demographic data, diagnosis (JMG/CMS), and the following scales were recorded at each visit: Myasthenia Gravis Foundation of America (MGFA) class, Myasthenia Gravis Composite (MGC), and Pediatric Myasthenia-Quality of Life 15 (PM-QOL15). RESULTS: Thirty-three patients (24 JMG, 9 CMS) were included in the study, 22 had two or more visits. We established known-groups validity of the MGC and PM-QOL15 scores as compared with the MGFA class. To establish concurrent validity, we constructed a receiver-operating characteristic curve and calculated threshold values of MGC and PM-QOL15 with optimal sensitivity and specificity for identifying a patient with more severe (MGFA III or higher) disease. Finally, we demonstrated the concordance between the MGC and PM-QOL15 by their statistically significant positive Pearson and Spearman correlations. DISCUSSION: Our study suggests that MGC and PM-QOL15 are important disease outcome measures in pediatric myasthenia that are easy to administer and provide reliable assessment of disease activity in the clinic setting. Further studies are needed to validate their use for pediatric clinical research trials.

Update on Muscular Dystrophies with Focus on Novel Treatments and Biomarkers.

PURPOSE OF REVIEW: Muscular dystrophies are a heterogeneous group of inherited muscular disorders characterized by progressive muscle weakness and in many cases cardiac and respiratory muscle involvement. Historically, these disorders are considered incurable with grave prognoses. The genes responsible for most muscular dystrophies are known, and early diagnosis is achievable with proper clinical recognition and advanced genetic testing. This article reviews recent advances in the development of novel treatments and biomarkers in the realm of muscular dystrophies commonly encountered in pediatric population. RECENT FINDINGS: The therapeutic landscape of muscular dystrophies has changed with the development of new approved treatments for Duchenne muscular dystrophy (DMD), the most common and severe muscular dystrophy. This has paved the way for the development of novel therapeutic strategies for not only DMD but also other muscular dystrophies. This article reviews recent advances in the development of novel treatments and biomarkers in the realm of muscular dystrophies commonly encountered in pediatric population.

Neuralgic amyotrophy in children.

INTRODUCTION: Neuralgic amyotrophy (NA) is characterized by the clinical triad of pain, muscle weakness/atrophy, and sensory symptoms. METHODS: We retrospectively identified children (≤18 years old) over the course of 15 years (2003-2017) at a single pediatric center. RESULTS: We included 22 patients (8 females and 14 males, 6-18 years old); pain was the presenting manifestation in all of them. Clinical weakness involving the periscapular muscles was observed in 16 patients and scapular winging in 13 patients. Two patients had preceding viral infection. Electromyography was performed in 21 patients: sensory nerve abnormalities were detected in 5, and neurogenic changes were most commonly observed in the serratus anterior muscle. Treatment was mainly supportive, although 4 patients received immunotherapy. Persistent pain and residual motor deficits were observed in more than half of the patients at follow-up. DISCUSSION: NA is rare in children but clinicians should be aware of this entity to avoid delays in diagnosis. In our series, presentation was similar to that seen in adults. Muscle Nerve 57: 932-936, 2018.

Reliability of a novel ultrasound system for gray-scale analysis of muscle.

INTRODUCTION: Ultrasound is increasingly used as an adjunct in the diagnosis of neuromuscular disease by measuring muscle thickness and echointensity (EI). Reproducibility is limited because of variations in scanning technique and proprietary algorithms that alter EI values. METHODS: We developed a standardized scanning protocol and a portable machine without any postimaging processing. Ten subjects underwent scanning of 6 muscles by 3 sonographers on 2 separate days. One of the sonographers repeated the protocol with 4 different machine/transducer combinations. Gray-scale values were measured from each image with the use of a region of interest (ROI) box. RESULTS: Combined intraclass correlation coefficients were 0.92 (intra-rater), 0.88 (inter-rater), and 0.96 (inter-system). The biceps had the highest variability (coefficient of variance [COV] 12.7%), and the medial gastrocnemius had the lowest variability (COV 7.4%). CONCLUSIONS: We demonstrate excellent reliability of a reproducible ultrasound system for gray-scale analysis of muscle that has potential applicability as a screening tool for neuromuscular disease. Muscle Nerve 56: 408-412, 2017.

Clinical and laboratory findings of 21 patients with radiation-induced myopathy.

BACKGROUND: Limited data are available on radiation-induced myopathy (RIM) in adult cancer survivors. METHODS: We retrospectively reviewed the clinical, electrophysiological, serological, radiological and pathological findings of patients with RIM seen in the neurology clinic over a 11-year period (2002-2013). RESULTS: Out of 251 patients with radiotherapy-induced neuromuscular complications, 21 had RIM (11 men and 10 women). Cancers included: Hodgkin's lymphoma (13), non-Hodgkin's lymphoma (one), pinealoblastoma (one), tongue (two), nasopharyngeal (one), thyroid (one) and testicular cancer (two). Various radiotherapy protocols were used but all patients received neck and upper torso radiation. The mean latency between radiation exposure and onset of RIM was 15 years (range 2-45 years). The most common presentation was head drop (43%) followed by neck pain (38%). Axial (86%) and periscapular (81%) muscle weakness and atrophy were frequent findings. Two patients died in follow-up from hypercapnic respiratory failure secondary to neuromuscular weakness. Serum creatine kinase values were usually normal or slightly elevated. EMG revealed predominantly myopathic changes in the axial and periscapular muscles. Half of the muscle biopsies (6/12) showed myopathic changes; increased connective tissue elements were observed in seven of eight muscle biopsies performed in the irradiated field; and mitochondrial dysfunction in two. CONCLUSIONS: RIM is a potential long-term neuromuscular adverse effect of radiation exposure in Hodgkin's disease and other types of cancer manifesting predominantly as head drop and can be fatal due to neuromuscular respiratory failure. Improved radiotherapy protocols might reduce the risk of RIM and other radiation-induced neuromuscular complications.

Camptocormia as presenting manifestation of a spectrum of myopathic disorders.

INTRODUCTION: Camptocormia is the involuntary flexion of the thoracolumbar spine leading to an abnormal posture. METHODS: We retrospectively identified patients with myopathy who manifested with camptocormia and were seen in our neuromuscular clinic. The diagnosis of myopathy was based on myopathic electromyographic changes, often accompanied by 1 or more of the following: elevated creatine kinase (CK); myopathic histopathological findings; and genetic confirmation. RESULTS: Fifty-two patients were identified; 35 had symptoms limited to camptocormia, but were found to have additional weakness of facial (8 patients), neck (11 patients), and limb muscles (17 patients). CK values were normal or mildly to moderately elevated. MRI/CT of the spine showed paraspinal muscle atrophy and fat replacement. Facioscapulohumeral muscular dystrophy and sporadic inclusion body myositis were the most commonly identified myopathies in this cohort. CONCLUSIONS: Despite the difficulty in characterizing the myopathy in patients with camptocormia, a definitive diagnosis was possible in 54% of cases. The pattern of associated extra-axial weakness may provide clues to the diagnosis.

Inclusion-body myositis presenting with facial diplegia.

INTRODUCTION: The hallmark clinical presentation of inclusion-body myositis (IBM) is slowly progressive weakness that characteristically affects the quadriceps and finger and wrist finger flexor muscles. Facial weakness can also occur, but it is typically mild and not a prominent finding. METHODS: We describe the clinical features, laboratory investigations, and muscle biopsy findings in a 58-year old man who presented with a 6-year history of marked progressive symmetrical facial weakness. Examination also showed shoulder abduction and hip extensor weakness. RESULTS: The patient's serum creatine kinase level was 655 U/L, and electromyography showed fibrillation potentials and myopathic motor unit potentials. A biopsy specimen of the left biceps muscle was pathognomonic for IBM. CONCLUSIONS: This patient did not have a typical presentation for IBM but rather fulfilled the pathological criteria for IBM. To our knowledge, facial diplegia has not been reported previously as a presenting manifestation of IBM.

Single-institution Series of Hirayama Disease in North America.

STUDY DESIGN: A retrospective chart review. OBJECTIVE: The aims of this study were to review pathophysiology, workup, and treatment for Hirayama disease (HD); and to assess outcomes from a single institution. SUMMARY OF BACKGROUND DATA: HD is a rare, painless, cervical myelopathy with distal upper extremity weakness, muscle wasting, and spinal cord atrophy. Disease progression-a consequence of repeat flexion injury-occurs up to 5 years from the initial diagnosis. METHODS: Single-institution review of pediatric HD patients from 2010 to 2020. RESULTS: Patients (n=10 male, n=2 female) presented in the second decade (14-20 y) with painless progressive distal upper extremity weakness and atrophy without sensory loss. Electromyography (n=12) demonstrated denervation in C7-T1 myotomes and flexion/extension magnetic resonance imaging showed focal cord atrophy and anterior displacement of the posterior dura with epidural enhancement in flexion. Treatment included observation and external orthoses (n=9) and anterior cervical discectomy with fusion (n=3). One of the 9 patients managed conservatively experienced further deterioration; no patient who underwent anterior cervical discectomy with fusion progressed. CONCLUSIONS: Patients with HD require a multidisciplinary approach to diagnosis and treatment to preserve function. Treatment is preventive and aims to minimize flexion injury by inhibiting motion across involved joints. First-line management is avoidance of neck flexion and use of rigid orthosis; in cases of failed conservative management and/or rapid clinical deterioration, surgical fixation can be offered.

Effects of HMGCR deficiency on skeletal muscle development.

Pathogenic variants in HMGCR were recently linked to a limb-girdle muscular dystrophy (LGMD) phenotype. The protein product HMG CoA reductase (HMGCR) catalyzes a key component of the cholesterol synthesis pathway. The two other muscle diseases associated with HMGCR, statin-associated myopathy (SAM) and autoimmune anti-HMGCR myopathy, are not inherited in a Mendelian pattern. The mechanism linking pathogenic variants in HMGCR with skeletal muscle dysfunction is unclear. We knocked down Hmgcr in mouse skeletal myoblasts, knocked down hmgcr in Drosophila, and expressed three pathogenic HMGCR variants (c.1327C>T, p.Arg443Trp; c.1522_1524delTCT, p.Ser508del; and c.1621G>A, p.Ala541Thr) in Hmgcr knockdown mouse myoblasts. Hmgcr deficiency was associated with decreased proliferation, increased apoptosis, and impaired myotube fusion. Transcriptome sequencing of Hmgcr knockdown versus control myoblasts revealed differential expression involving mitochondrial function, with corresponding differences in cellular oxygen consumption rates. Both ubiquitous and muscle-specific knockdown of hmgcr in Drosophila led to lethality. Overexpression of reference HMGCR cDNA rescued myotube fusion in knockdown cells, whereas overexpression of the pathogenic variants of HMGCR cDNA did not. These results suggest that the three HMGCR-related muscle diseases share disease mechanisms related to skeletal muscle development.

Noncovalent template-assisted mimicry of multiloop protein surfaces: assembling discontinuous and functional domains.

We report here a novel noncovalent synthetic strategy for template-assembled de novo protein design. In this approach, a peptide was first conjugated with two oligoguanosine strands via click chemistry and the conjugates were then self-assembled in the presence of metal ions. G-quadruplex formation directs two peptide strands to assemble on one face of the scaffold and form an adjacent two loop surface. This approach can be used to rapidly prepare multiple two-loop structures with both homo- and heterosequences.

Supramolecular dendrimers: convenient synthesis by programmed self-assembly and tunable thermoresponsivity.

We report here the noncovalent synthesis of thermosensitive dendrimers. Short oligoguanosine strands were linked to the focal point of a dendron by using "click chemistry", and quadruplex formation was used to drive the self-assembly process in the presence of metal ions. The dynamic nature of these noncovalent assemblies can be exploited to create combinatorial libraries of dendrimers as demonstrated by the co-assembly of two components. These supramolecular dendrimers showed thermoresponsive behavior that can be tuned by varying the templating cations or the number of guanines in the oligonucleotide strand.

Neurological complications following pediatric liver transplant.

OBJECTIVE: We studied neurological complications (NCs) after liver transplantation (LT) in children. METHODS: We performed an institutional review board-approved retrospective review of patients with LT ≤21 years during a period of 30 years (1980-2010). NCs were classified as early (within 3 months post-LT) and delayed (beyond 3 months post-LT). RESULTS: Of 65 children with LT, 20 (30.7%) had NCs; 16 were girls. Mean age was 11.8±5.9 years. Early NCs were found in 13.8% (9/65) of the patients: seizures in 7 and encephalopathy in 2. Abnormal neuroimaging findings were posterior reversible leukoencephalopathy syndrome (1), intracranial hemorrhage (1), mild cerebral edema (1), and bilateral basal ganglia T1W hyperintensities in magnetic resonance imaging (1). On follow-up, there were 3 deaths (unrelated to NCs). One with intracranial hemorrhage had residual hemiparesis and was taking a long-term antiepileptic drug. Late NCs are found in 16.9% (11/65) of the patients: seizures in 4, headache in 4, encephalopathy in 3 (1 had seizures in addition), and paresthesias caused by possible small-fiber neuropathy in 1. Abnormal neuroimaging findings were hypoxic-ischemic encephalopathy (1), encephalomalacia caused by old hemorrhage (1), and hyperintensity of the posterior periventricular white matter in magnetic resonance imaging (1). On follow-up, all of the patients survived; 1 had papilledema with secondary optic atrophy requiring optic nerve sheath fenestration and 1 needed long-term antiepileptic drug. CONCLUSIONS: NCs are common in children after LT, seizures being the most common. In contrary to the previous studies, we found delayed complications more often than early complications. Early detection and appropriate management of NCs is important.

Generalized anhidrosis in a child following presumptive H1N1 influenza.

We report an 8-year-old girl who developed generalized anhidrosis following presumptive H1N1 infection. Pure autonomic dysfunction is an unusual complication following H1N1 infection and specially generalized anhidrosis without other autonomic dysfunction have not been reported before.

Deep brain stimulation in children with dystonia: experience from a tertiary care center.

OBJECTIVE: To investigate the efficacy and safety of deep brain stimulation (DBS) of the globus pallidus internus (GPi) in children with dystonia. METHODS: Retrospective chart review of patients (≤21 years) with dystonia who underwent GPi DBS. Outcome measures were assessed by the Burke-Fahn-Marsden Dystonia Rating (BFMDR) movement and disability scales pre- and post-DBS. RESULTS: Eight patients underwent DBS; mean age of onset was 7.5 ± 4.8 years (7 were male). Mean age at DBS was 14.1 ± 4.6 years. Etiology of dystonia was primary in 6 patients and secondary in 2. There was significant improvement of BFMDR movement as well as BFMDR disability scales in 6 patients with primary dystonia with modest improvement in those scales in 2 patients with secondary dystonia. Hardware-related problems were observed in 2 and infection was noted in 1. CONCLUSIONS: GPi DBS is an effective and safe therapy in pediatric patients with primary as well as selected cases of secondary dystonia.

Electromyography in infants: experience from a pediatric neuromuscular center.

Electromyography plays a pivotal role in diagnosing neuromuscular disorders. The purpose of this study was to investigate the role of electromyography in infants. We performed a retrospective study of the infants who underwent electromyography from 2003 to 2017 and recorded demographic profile, indication, electrodiagnostic findings, and final diagnosis from the follow-up data. 179 studies were completed; electromyography was abnormal in 109 (60.9%) patients. The most common referral indication was hypotonia followed by birth trauma related injuries and rule out neuromuscular disorders. The most common electrodiagnostic diagnosis was localized to muscles followed by plexus and motor neurons. Among the patients with normal electromyography, the most common diagnosis was due to myopathies. Electromyography plays an important role in the workup of neuromuscular disorders in infants though with increased utilization of genetic testing we observed a declining trend in the number of electromyography performed in the latter half the study.

Diagnostic capabilities of nanopore long-read sequencing in muscular dystrophy.

Many individuals with muscular dystrophies remain genetically undiagnosed despite clinical diagnostic testing, including exome sequencing. Some may harbor previously undetected structural variants (SVs) or cryptic splice sites. We enrolled 10 unrelated families: nine had muscular dystrophy but lacked complete genetic diagnoses and one had an asymptomatic DMD duplication. Nanopore genomic long-read sequencing identified previously undetected pathogenic variants in four individuals: an SV in DMD, an SV in LAMA2, and two single nucleotide variants in DMD that alter splicing. The DMD duplication in the asymptomatic individual was in tandem. Nanopore sequencing may help streamline genetic diagnostic approaches for muscular dystrophy.