Diana Castro

Baseline results of the NeuroNEXT spinal muscular atrophy infant biomarker study

This study prospectively assessed putative promising biomarkers for use in assessing infants with spinal muscular atrophy (SMA).

Juvenile myasthenia gravis: a twenty-year experience.

Objective: Juvenile myasthenia gravis (JMG) is an antibody-mediated autoimmune disorder of the neuromuscular junction, at the postsynaptic end plate. JMG presents with fluctuating skeletal muscle weakness and fatigue before the age of 18 years. Very frequently JMG presents with the involvement of the oculomotor muscles, with or without generalized involvement. Methods: We performed a retrospective chart review of patients diagnosed with myasthenia in the pediatric neuromuscular clinics at UT Southwestern, between 1990 and 2010. Osserman classification and the response to therapy scale of Millichap and Dodge were used to compare each patients severity of myasthenia and responsiveness to drugs before the surgery as a baseline and at the last visit, after thymectomy. Results: Fifty-eight patients were included; 29 (50%) were African American, and 34 (58.6%) were female. Age of onset was 11 months to 17 years, and 38 patients (65%) presented as generalized myasthenia gravis. Forty-nine patients (84%) were acetylcholine receptor antibody (AchR-Ab) positive. Of the 32 to undergo thymectomy, 19 subjects (59%) experienced an improved response to B level on the Myasthenia Scale of Millichap and Dodge (good improvement, both objective and subjective, but continuation of drug therapy required in the same or lower dosage) and 75% experienced a drop in Osserman classification by at least 1. Of the 8 individuals who did not show improvement after thymectomy, 4 subjects (50%) underwent repeat thymectomy. They had initially less invasive fluoroscopic or thoracoscopic procedure. Thymic hyperplasia was found in 7 patients (21%) and thymoma in 2. Conclusions: Thymectomy was well tolerated by this group of children. There was clinical improvement after thymectomy in two thirds of the AchR-Ab–positive generalized myasthenia gravis patients. Thymic pathology was seen in less than one third of the patients who underwent thymectomy, with thymic hyperplasia being common. Further studies are necessary to determine whether thymectomy is indicated for all children with generalized JMG. More information about the immunologic, genetic, and molecular differences between patients may determine the best treatment for individual patients.

Spinal Muscular Atrophy: Therapeutic Strategies

Opinion statementSpinal muscular atrophy is caused by mutations in the survival motor neuron 1 (SMN1) gene, leading to the reduction of SMN protein. The loss of alpha motor neurons in the ventral horn of the spinal cord results in progressive paralysis and premature death. There is no current treatment other than symptomatic and supportive care, although over the past decade, there has been an outstanding advancement in understanding the genetics and molecular mechanisms underlying the physiopathology of SMA. The most promising approach, from current trials, is the use of antisense oligonucleotide (ASOs) to redirect SMN2 translation and increase exon 7 inclusion in the majority of the RNA transcript, to increase the production of fully functional SMN protein. Recently, ISIS Pharmaceuticals Inc. (2855 Gazelle Court, Carlsbad CA 92010) reported an interim analysis from a multiple dose study in children with SMA between 2 and 14 years of age, using ASO therapy. The results indicated good tolerability at all dose levels, increases in muscle function in children treated with multiple doses of ISIS-SMNRx, and increase in SMN protein levels in cerebrospinal fluid (CSF) from both single and multiple dose studies. Studies in infants are ongoing in a few centers; soon other institutions may begin enrollment. Infants are fragile and their disease process may differ from the older SMA population. It is not known whether effective drug would best be given to SMA infants or older children. Other promising therapies are still in preclinical phases or early clinical phases. Gene therapy appears to be efficient in improving survival in a severe mouse model of SMA, though a better definition of the route of administration and of the safety profile of the viral vectors is needed before clinical administration is possible.

Congenital muscular dystrophies and congenital myopathies.

Purpose of ReviewThe purpose of this review is to provide information regarding the diagnosis and natural history of some very rare disorders: congenital muscular dystrophies and congenital myopathies. Patients with these conditions share characteristics such as early onset of weakness and severe hypotonia. Other organs such as the brain, eyes, and skin may be involved. Diagnosis depends largely on recognition of phenotype, muscle biopsy, and mutation analysis. Recent FindingsMore than 30 genes have been associated with these diseases, most of which have only been recognized in the past decade. Increasing availability of DNA analysis has been important in decreasing delay in diagnosis. SummaryPatients with congenital muscular dystrophy or congenital myopathy are at high risk of complications including restrictive lung disease, orthopedic deformities, seizures, cardiomyopathy, and malignant hyperthermia. Life expectancy varies with the severity of complications. Having an accurate and specific diagnosis allows the neurologist to carry out anticipatory guidance and appropriate monitoring. New hope exists for experimental treatments for congenital muscular dystrophy and congenital myopathy as our understanding of pathogenesis evolves.

Congenital Myopathies and Muscular Dystrophies

The congenital muscular dystrophies (CMD) and myopathies (CM) are a diverse group of diseases that share features such as early onset of symptoms (in the first year of life), genetic causes, and high risks for restrictive lung disease and orthopedic deformities. Understanding for disease mechanism is available and a fairly well-structured genotype-phenotype correlation for all the CMDs and CMs is now available. To best illustrate the clinical spectrum and diagnostic algorithm for these diseases, this article presents 5 cases, including Ullrich congenital muscular dystrophy, nemaline myopathy, centronuclear myopathy, merosin deficiency congenital muscular dystrophy, and core myopathy.

Characterization of pulmonary function in 10–18 year old patients with Duchenne muscular dystrophy

Pulmonary function loss in patients with Duchenne muscular dystrophy (DMD) is progressive and leads to pulmonary insufficiency. The purpose of this study in 10-18 year old patients with DMD is the assessment of the inter-correlation between pulmonary function tests (PFTs), their reliability and the association with the general disease stage measured by the Brooke score. Dynamic PFTs (peak expiratory flow [PEF], forced vital capacity [FVC], forced expiratory volume in one second [FEV1]) and maximum static airway pressures (MIP, MEP) were prospectively collected from 64 DMD patients enrolled in the DELOS trial (ClinicalTrials.gov, number NCT01027884). Baseline PEF percent predicted (PEF%p) was <80% and patients had stopped taking glucocorticoids at least 12 months prior to study start. At baseline PEF%p, FVC%p and FEV1%p correlated well with each other (Spearmans rho: PEF%p-FVC%p: 0.54; PEF%p-FEV1%p: 0.72; FVC%p-FEV1%p: 0.91). MIP%p and MEP%p correlated well with one another (MIP%p-MEP%p: 0.71) but less well with PEF%p (MIP%p-PEF%p: 0.40; MEP%p-PEF%p: 0.41) and slightly better with FVC%p (MIP%p-FVC%p: 0.59; MEP%p-FVC%p: 0.74). The within-subject coefficients of variation (CV) for successive measures were 6.97% for PEF%p, 6.69% for FVC%p and 11.11% for FEV1%p, indicating that these parameters could be more reliably assessed compared to maximum static airway pressures (CV for MIP%p: 18.00%; MEP%p: 15.73%). Yearly rates of PFT decline (placebo group) were larger in dynamic parameters (PEF%p: -8.9% [SD 2.0]; FVC%p: -8.7% [SD 1.1]; FEV1%p: -10.2% [SD 2.0]) than static airway pressures (MIP%p: -4.5 [SD 1.3]; MEP%p: -2.8 [SD 1.1]). A considerable drop in dynamic pulmonary function parameters was associated with loss of upper limb function (transition from Brooke score category 4 to category 5). In conclusion, these findings expand the understanding of the reliability, correlation and evolution of different pulmonary function measures in DMD patients who are in the pulmonary function decline phase.

Congenital Titinopathy: Comprehensive characterization and pathogenic insights: Congenital Titinopathy

Comprehensive clinical characterization of congenital titinopathy to facilitate diagnosis and management of this important emerging disorder.

Atypical Presentation for Friedreich Ataxia in a Child.

Abstract The classic phenotype of Friedreich ataxia is characterized by dysarthria, progressive limb and trunk ataxia, loss of reflexes, and gait disturbance with the onset of disease before the second decade. Homozygous trinucleotide repeat expansion of GAA in the FXN gene is found in 98% of patients. Two-5% of all patients have a repeat expansion on one allele and a point mutation on the other allele. Atypical phenotype is found in 25% of patients. A 10-year-old boy presented with congenital biliary atresia and progressive gait abnormality. His examination was significant for spastic gait, hyperreflexia, and sensory neuropathy. Genetic testing revealed a compound heterozygous mutation in the FXN gene. The absence of dysarthria and ataxia, retention of reflexes, absence of diabetes, and variable development of cardiomyopathy support a slow progression of disease with compound heterozygous mutation at G130V. Missense mutations are rare causes of Friedreich ataxia that can only be detected by sequencing of the FXN gene. Sequencing of the FXN gene is essential to make an early diagnosis when there is an atypical phenotype.

Phase IIa trial in Duchenne muscular dystrophy shows vamorolone is a first-in-class dissociative steroidal anti-inflammatory drug

ABSTRACT We report a first‐in‐patient study of vamorolone, a first‐in‐class dissociative steroidal anti‐inflammatory drug, in Duchenne muscular dystrophy. This 2‐week, open‐label Phase IIa multiple ascending dose study (0.25, 0.75, 2.0, and 6.0 mg/kg/day) enrolled 48 boys with Duchenne muscular dystrophy (4 to <7 years), with outcomes including clinical safety, pharmacokinetics and pharmacodynamic biomarkers. The study design included pharmacodynamic biomarkers in three contexts of use: 1. Secondary outcomes for pharmacodynamic safety (insulin resistance, adrenal suppression, bone turnover); 2. Exploratory outcomes for drug mechanism of action; 3. Exploratory outcomes for expanded pharmacodynamic safety. Vamorolone was safe and well‐tolerated through the highest dose tested (6.0 mg/kg/day) and pharmacokinetics of vamorolone were similar to prednisolone. Using pharmacodynamic biomarkers, the study demonstrated improved safety of vamorolone versus glucocorticoids as shown by reduction of insulin resistance, beneficial changes in bone turnover (loss of increased bone resorption and decreased bone formation only at the highest dose level), and a reduction in adrenal suppression. Exploratory biomarkers of pharmacodynamic efficacy showed an anti‐inflammatory mechanism of action and a beneficial effect on plasma membrane stability, as demonstrated by a dose‐responsive decrease in serum creatine kinase activity. With an array of pre‐selected biomarkers in multiple contexts of use, we demonstrate the development of the first dissociative steroid that preserves anti‐inflammatory efficacy and decreases steroid‐associated safety concerns. Ongoing extension studies offer the potential to bridge exploratory efficacy biomarkers to clinical outcomes.

Clinical and molecular spectrum of thymidine kinase 2-related mtDNA maintenance defect

Mitochondrial DNA maintenance (mtDNA) defects have a wide range of causes, each with a set of phenotypes that overlap with many other neurological or muscular diseases. Clinicians face the challenge of narrowing down a long list of differential diagnosis when encountered with non-specific neuromuscular symptoms. Biallelic pathogenic variants in the Thymidine Kinase 2 (TK2) gene cause a myopathic form of mitochondrial DNA maintenance defect. Since the first description in 2001, there have been 71 patients reported with 42 unique pathogenic variants. Here we are reporting 11 new cases with 5 novel pathogenic variants. We describe and analyze a total of 82 cases with 47 unique TK2 pathogenic variants in effort to formulate a comprehensive molecular and clinical spectrum of TK2-related mtDNA maintenance disorders.