Update on Inclusion Body Myositis.

PURPOSE OF REVIEW: While sporadic inclusion body myositis (sIBM) is the most common acquired muscle disease after age 50, the pathogenesis of this disease is still poorly understood. In this review, we discuss our current state of knowledge in sIBM and provide an update on our current understanding of its pathophysiology and management. RECENT FINDINGS: Lines of evidence in support of an inflammatory pathogenesis include inflammatory infiltrates in the target organ, NFκB activation, cytokine response, MHC I upregulation, and cN1A antibody. Refractoriness to immunotherapies has led to suggestion of a degenerative pathophysiology. Evidence for impaired protein homeostasis with misfolding burden is coupled with findings of endoplasmic reticulum stress, proteasome dysfunction, and mitochondrial lesion. Recent treatment trials have focused more on correcting the degenerative process or muscle growth rather than controlling the inflammation. There has been growing evidence toward degeneration as the primary process in sIBM. This is consistent with the refractory nature of this disease. Improving our understanding of this disease pathogenesis will propel efforts to find an effective therapy.

Intravenous immunoglobulin in drug and device refractory patients with the symptoms of gastroparesis-an open-label study.

BACKGROUND: Gastroparesis is a complex clinical entity; many aspects of which remain unknown. Although most patients have idiopathic, diabetic, or postsurgical gastroparesis, many are thought to have measurable neuromuscular abnormalities. Immunotherapy has recently been utilized to treat suspected autoimmune gastrointestinal dysmotility. METHODS: Fourteen patients with symptoms of gastroparesis (Gp) who were refractory to drug/device were selected from 443 Gp patients from 2013 to 2015 who were treated at the University of Louisville motility center. All patients underwent a structural and psychiatric evaluation along with detailed psychological and behavioral examination to rule out eating disorders. We performed detailed neuromuscular evaluation and all 14 patients received at least 12 weeks of intravenous immunoglobulin (400 mg/kg infusion weekly). Response was defined subjectively (symptomatic improvement) using standardized IDIOM score system. KEY RESULTS: All 14 patients had serological evidence and/or tissue evidence of immunological abnormality. Post-IVIG therapy, there was a significant improvement in symptoms scores for nausea, vomiting, early satiety, and abdominal pain. CONCLUSIONS AND INFERENCES: Although limited by the absence of placebo group, the data illustrate the role of autoimmunity and neuromuscular evaluation in patients with gastroparesis and support the utility of a diagnostic trial of immunotherapy in an effort to improve therapeutic outcomes for such patients.

Carpal tunnel syndrome in children.

BACKGROUND: Carpal tunnel syndrome or median neuropathy at the wrist is a rare condition in children. Of the reported patients with carpal tunnel syndrome, mucopolysaccharidoses and the mucolipidoses are the most common causes. PATIENTS: We report 13 patients between the ages of 2 and 17 years of age with carpal tunnel syndrome. RESULTS: Mucopolysaccharidoses was the cause in one child. In other children, trauma to the median nerve, malformations of the wrist, brachial plexopathy, obesity, inherited susceptibility to pressure palsies (PMP 22 gene deletion), and family history of median neuropathy at the wrist were identified. All patients had hand pain, numbness, and paresthesias in their hands. The nerve conduction studies showed prolongation of median sensory nerve latency and distal motor latency in median nerve. CONCLUSIONS: Carpal tunnel syndrome occurs in children and a variety of risk factors predispose to its occurrence.

Gastric dysmotility and low serum vitamin D levels in patients with gastroparesis.

Nutritional abnormalities are common in patients with gastroparesis (Gp), a disorder that may affect gastric motility and may delay emptying. The aim of this work was to identify relationships between serum nutrition markers including 25-OH vitamin D and gastric motility measures in Gp patients. We enrolled 59 consecutive gastric motility clinic patients (48 females, 11 males; mean age 44 years; 42 idiopathic; 17 diabetes mellitus) with Gp symptoms. The 25-OH vitamin D levels, for most patients slightly above the lower limit of normal (96.98 nmol/l ± 60.99), were lowest in diabetic range (DM) (75.68 nmol/l ± 34.22) vs. idiopathic (ID) (105.03 nmol/l ± 67.08) gastroparesis patients. First hour GET: one unit increase in 25-OH vitamin D level was associated 0.11% improvement (95% CI -0.22, 0.01 p=0.056) in gastric motility in all patients; this association, although marked in ID Gp patients, (-0.13, CI -0.25, -0.01 p=0.034), was not seen in DM Gp, (0.2, CI -0.45, 0.87, p=0.525). Fourth hour GET: Every unit increase of 25-OH vitamin D was associated with significant improvement in all patients, ( 0.11% CI -0.23, 0.01, p=0.053), and some weak improvement in ID group, (0.11% -0.24, 0.01, p=0.076) and absent in patients with DM (0.03, CI -0.66, 0.72, p=0.932). It is concluded that 25-OH vitamin D levels may influence gastric emptying. Underlying mechanisms for this observation might include the impact of 25-OH vitamin D on the health of the enteric nervous system. 25-OH vitamin D contributions to enteric nerve functions should be explored, particularly where autonomic nervous system comorbidities exist.

Confirmation of the severe phenotypic effect of serine at codon 41 of the superoxide dismutase 1 gene.

INTRODUCTION: A Gly41Ser mutation in the superoxide dismutase 1 gene (SOD1) has been reported to cause a very rapid course of amyotrophic lateral sclerosis (ALS) in a limited number of Italian patients, but a Gly41Asp mutation results in a more benign course. METHODS: Four members of an African American family with autosomal dominant ALS were evaluated clinically over 12 years. Mutation analysis of SOD1 was done on 1 patient. RESULTS: All patients had a pure lower motor neuron syndrome with onset to death in 9-15 months. A Gly41Ser mutation in SOD1 was established. In silico modeling suggested that this mutation can have a more deleterious effect than a Gly41Asp mutation. CONCLUSION: The more rapid course of ALS with the Gly41Ser SOD1 mutation is confirmed in a distinct ethnic group.

Transmission of maternal muscle-specific tyrosine kinase (MuSK) to offspring: report of two cases.

Familial occurrence of myasthenia gravis is uncommon and reports of maternal transmission of muscle-specific tyrosine kinase (MuSK) antibody myasthenia are rarer still. We report two families with maternal transmission of MuSK antibody myasthenia gravis to the offspring by different mechanisms. The first family demonstrates transmission genetic susceptibility of inheriting myasthenia gravis from MuSK antibodies, whereas the second one demonstrates transplacental transmission of MuSK antibodies at birth.

CINRG randomized controlled trial of creatine and glutamine in Duchenne muscular dystrophy.

We tested the efficacy and safety of glutamine (0.6 gm/kg/day) and creatine (5 gm/day) in 50 ambulant boys with Duchenne muscular dystrophy in a 6-month, double-blind, placebo-controlled clinical trial. Drug efficacy was tested by measuring muscle strength manually (34 muscle groups) and quantitatively (10 muscle groups). Timed functional tests, functional parameters, and pulmonary function tests were secondary outcome measures. Although there was no statistically significant effect of either therapy based on manual and quantitative measurements of muscle strength, a disease-modifying effect of creatine in older Duchenne muscular dystrophy and creatine and glutamine in younger Duchenne muscular dystrophy cannot be excluded. Creatine and glutamine were well tolerated.

Tick paralysis.

Tick paralysis results from inoculation of a toxin from tick salivary glands during a blood meal. It is a relatively uncommon neuromuscular disease with a higher prevalence among young girls, although older men who get exposed to ticks may also be affected. It typically presents as an acute ascending paralysis occurring a few days after tick attachment and may result in respiratory failure and death. Patients may report minor sensory symptoms but constitutional signs are usually absent. Deep tendon reflexes are usually hypoactive or absent and ophthalmoplegia and bulbar palsy can occur. Children may be ataxic. Electromyographic studies usually show a variable reduction in the amplitude of compound muscle action potentials but no abnormalities of repetitive nerve stimulation studies. These appear to result from a failure of acetylcholine release at the motor nerve terminal level. There may be subtle abnormalities of motor nerve conduction velocity and sensory action potentials. Removal of the tick results in the very rapid reversal of clinical and physiologic deficits, quicker with North American ticks than with the Ixodes species seen in Australia.

Mitochondrial disorders and ataxia.

Mitochondrial disorders are important causes of progressive ataxia in children. Clinical examination, metabolic studies, imaging studies, muscle biopsies, and mitochondrial DNA studies are required to arrive at a specific diagnosis. There is poor correlation between phenotype and genotype in mitochondrial disorders. Ataxia is a major clinical presentation in Kearns-Sayre syndrome; mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes; myoclonic epilepsy with ragged-red fibers; neurogenic muscle weakness, ataxia, and retinitis pigmentosa; Leigh's syndrome; and coenzyme Q10 deficiency.

Tick paralysis in children: electrophysiology and possibility of misdiagnosis.

The authors report six patients with tick paralysis seen over 5 years. Clinical and electrodiagnostic findings failed to adequately distinguish tick paralysis from Guillain-Barré syndrome in these patients. Finding a tick attached to the scalp or the nape of the neck and removing it resulted in rapid clinical improvement.

Novel mutations in collagen VI genes: expansion of the Bethlem myopathy phenotype.

OBJECTIVE: To investigate the molecular basis of autosomal dominant limb-girdle muscular dystrophy (AD-LGMD) in three large new families. METHODS AND RESULTS: Genome-wide linkage was performed to show that the causative gene in all three families localized to chromosome 21q22.3 (Zmax = 10.3; theta = 0). This region contained the collagen VI alpha1 and alpha2 genes, which have been previously shown to harbor mutations causing a relatively mild congenital myopathy with contractures (Bethlem myopathy). Screening of the collagen VI alpha1 and alpha2 genes revealed novel, causative mutations in each family (COL6A1-K121R, G341D; COL6A2-D620N); two of these mutations were in novel regions of the proteins not previously associated with disease. Collagen VI is a ubiquitously expressed component of connective tissue; however, both limb-girdle muscular dystrophy and Bethlem myopathy patients show symptoms restricted to skeletal muscle. To address the muscle-specific symptoms resulting from collagen VI mutations, the authors studied three patient muscle biopsies at the molecular level (protein expression). A marked reduction of laminin beta1 protein in the myofiber basal lamina in all biopsies was found, although this protein was expressed normally in the neighboring capillary basal laminae. CONCLUSIONS: The authors' studies widen the clinical spectrum of Bethlem myopathy and suggest collagen VI etiology should be investigated in dominant limb-girdle muscular dystrophy. The authors hypothesize that collagen VI mutations lead to muscle-specific defects of the basal lamina, and may explain the muscle-specific symptoms of Bethlem and limb-girdle muscular dystrophy patients with collagen VI mutations.

Sequence variation in GAA repeat expansions may cause differential phenotype display in Friedreich's ataxia.

Friedreich's ataxia, the most common autosomal recessive inherited ataxia, is characterized by progressive gait and limb ataxia. Friedreich's ataxia is known for its occurrence within the first or second decade of life and is associated with hypertrophic cardiomyopathy, and in some cases with diabetes. Genetically, it is identified by the expression of an unstable trinucleotide GAA repeat expansion located in the first intron of the X25 gene on chromosome 9. Two brothers with very late adult-onset ataxia, and their unaffected sister, were examined for the clinical presentation of FA and for the presence of the mutated FA gene. The relationship of the expanded gene sequence to the severity of disease and age of onset were evaluated. Clinical examination revealed that the two brothers had mild ataxia and proprioceptive loss, with age of onset between 60 and 70 years of age. DNA from peripheral blood nucleated cells demonstrated a small homozygous expansion, with approximately 120-130 GAA repeats in the X25 gene in both patients. The expanded repeats were interrupted either with GAAGAG, GAAGGA, or GAAGAAAA sequences. The unaffected sister carried a normal FA genotype with 8-uninterrupted GAA repeat, observed by sequence analysis. In addition, the levels of FA gene transcript in both brothers were relatively lower than that in the unaffected sister. No detectable cardiomyopathy or diabetes was observed. Phenotypic diversity of FA is increasingly expanding. The age of onset and the structure of GAA repeat expansion plays an important role in determining the clinical features and the differential diagnosis of FA. The confirmation of the FA gene mutation in the atypical case, broadens the clinical spectrum of FA, and supports the idea that patients with even a mild form of ataxia of late adult onset should be considered for molecular testing.

Methylation of the FSHD syndrome-linked subtelomeric repeat in normal and FSHD cell cultures and tissues.

Facioscapulohumeral muscular dystrophy (FSHD) has an unusual molecular etiology. In a putatively heterochromatic subtelomeric region of each chromosome 4 homologue (4q35), unaffected individuals have 11 to about 95 tandem copies of a complex 3.3-kb repeat (D4Z4). Most FSHD patients have less than 10 copies at one allelic 4q35. This has been proposed to lead to the loss of heterochromatinization and, thereby, inappropriate gene expression by position effects, explaining the dominant nature of FSHD and the role of a decreased number of copies of D4Z4 at 4q35 but not at 10q26. Consistent with the proposed heterochromatinization of this repeat, by Southern blot analysis, we found that SmaI, MluI, SacII, and EagI sites in D4Z4 are highly methylated in normal and FSHD cell lines and somatic tissues, including skeletal muscle. Like repeated DNA sequences in the juxtacentromeric heterochromatin of chromosomes 1, 9, and 16, D4Z4 was hypomethylated at numerous CpGs in sperm and in cell lines from patients with an unrelated DNA methyltransferase deficiency syndrome (ICF; immunodeficiency, centromeric region instability, facial anomalies) in contrast to its hypermethylation in non-ICF postnatal somatic tissues. Our data on FSHD samples suggest that the disease-associated 4q35 D4Z4 repeats, which constitute a small percentage of the total D4Z4 repeats, are not generally hypomethylated relative to the other repeats of this sequence. However, in individuals not affected with FSHD, the hypermethylation of tandem, high-copy-number D4Z4 repeats might help stabilize heterochromatinization at allelic 4q35 regions just as hypermethylation elsewhere in the genome has been linked to chromatin compaction.

Pediatric patients with undetectable anticonvulsant blood levels: comparison with compliant patients.

Undetectable anticonvulsant blood levels indicate sustained noncompliance (several consecutive doses missed). We compared 91 consecutive outpatients with epilepsy and undetectable anticonvulsant blood levels to 100 patients seen during the same time period, verified as compliant by acceptable serum levels. We hypothesized that pay status, application for Supplemental Security Income, patient age, history of missed appointments, and functional status would differ between compliant and noncompliant patients. We were surprised to find large differences between clinic and insurance patients and between Caucasian and non-Caucasian patients. The 100 compliant patients included 44 Caucasian and 56 non-Caucasian patients, whereas only 9 of 91 noncompliant patients were Caucasian, and only 9 had insurance, compared to 32 compliant patients. Applications for Supplemental Security Income and history of missed appointments were significantly associated with noncompliance, but patient age, seizure type, and seizure control were not. Uninsured Caucasians were more often compliant than non-Caucasians were. Many noncompliant patients had mild epilepsy, which was reportedly doing well. Race and pay status were closely correlated. Several noncompliant females became pregnant, whereas no compliant patients did. Compliant patients were much more likely to be accompanied by a parent or caretaker on clinic visits than noncompliant patients. Noncompliant patients had at least one acceptable subsequent serum level, although 2 patients with intractable epilepsy had undetectable serum levels on three or more occasions. Noncompliance may respond to discussion and advice. We reviewed 124 episodes of undetectable drug levels in the 91 noncompliant patients. Eighteen of these resulted in hospitalization, but in 25 cases, we were told that there had been no seizures since the preceding visit. Many noncompliant patients have infrequent seizures, even if they take little or no medication. Socioeconomic status influences health, life expectancy, and educational success, but it has been claimed to be irrelevant to compliance and adherence issues in epilepsy. Our data and the experience of other centers with childhood diabetes suggest that socioeconomic, racial, and family factors influence compliance or adherence to treatment for many chronic conditions. Educational efforts and support for parents at the start of anticonvulsant treatment may improve compliance. Uninsured patients missed more appointments and were much more likely to be noncompliant than insured patients. Attention to the special problems of Medicaid and minority children is needed.

A novel ryanodine receptor gene mutation causing both cores and rods in congenital myopathy.

BACKGROUND: Central core disease (CCD) and nemaline rod myopathy are generally considered two genetically and histologically distinct disorders. CCD is defined by the presence of well-demarcated round cores within most myofibers. Nemaline rod myopathy is distinguished by the presence of characteristic nemaline bodies within myofibers. The simultaneous occurrence of both cores and rods in the same muscle biopsy has been described, but no gene mutations have been reported yet for this condition. OBJECTIVE: To describe a family containing 16 affected individuals in six generations with an autosomal dominant congenital myopathy that shows clinical and histologic features of both CCD and nemaline myopathy, and to determine the genetic etiology and protein composition of the cores/rods in this family. METHODS AND RESULTS: The results of linkage analyses excluded involvement of the two autosomal dominant nemaline myopathy loci on chromosome 1, but were consistent with a localization of the disease gene at the CCD locus on chromosome 19q13.1 (ryanodine receptor). SSCP analysis and DNA sequencing identified a novel Thr4637Ala mutation in the transmembrane region of the ryanodine receptor protein. Immunofluorescence studies of patient muscle biopsies showed the central cores to stain for ryanodine receptor. CONCLUSIONS: These data suggest that the occurrence of nemaline bodies can be a secondary feature of CCD, and that genetic studies on previously reported core/rod families should be targeted to the ryanodine receptor locus. The results of the immunofluorescence studies suggest that the cores contain excess abnormal ryanodine receptor protein.

Guillian Barré syndrome--recent advances.

Guillian Barré Syndrome (GBS) is an acquired disease of the peripheral nerves that is characterized clinically by rapidly progressing paralysis, areflexia, and albumino-cytological dissociation. It affects both genders, involves people of all ages, is reported worldwide, and in the post-polio era, it is the most common cause of an acute generalized paralysis. The clinical features are distinct and a history and an examination generally lead to a high suspicion of the diagnosis that can then be confirmed by supportive laboratory tests and electrodiagnostic studies. This review discusses the recent advances in understanding of the different variants of GBS such as acute inflammatory demyelinating polyneuropathy (AIDP), acute motor axonal neuropathy (AMAN), acute motor sensory axonal neuropathy (AMSAN), and the Fisher syndrome. The clinical, electrodiagnostic criteria, immunopathogenesis, and management of GBS and its variants are discussed.

Lethal neonatal autosomal recessive axonal sensorimotor polyneuropathy.

Peripheral neuropathy is an uncommon cause of generalized hypotonia and weakness in infancy. It occurs as a part of the clinical syndrome in some neurodegenerative disorders of infancy, but seldom causes respiratory failure or swallowing difficulties. We report a lethal autosomal recessive axonal polyneuropathy with neonatal onset in a large kindred from Northern Mississippi. One patient was studied in detail at our medical center and the information on 12 other affected infants in this large family were gathered from medical records and by interviewing the family members. Patients were symptomatic for the polyneuropathy before birth and died in the first year of life from respiratory complications. Thirteen babies were affected by this clinical phenotype in four generations of this family with a high frequency of consanguinity. Affected babies were of both sexes and were born to healthy consanguineous parents. The clinical phenotype of polyneuropathy in our index patient and other affected babies in this family was similar, and represents a unique form of hereditary neonatal polyneuropathy.