Phase II Open Label Study of Valproic Acid in Spinal Muscular Atrophy

UNLABELLED:Preliminary in vitro and in vivo studies with valproic acid (VPA) in cell lines and patients with spinal muscular atrophy (SMA) demonstrate increased expression of SMN, supporting the possibility of therapeutic benefit. We performed an open label trial of VPA in 42 subjects with SMA to assess safety and explore potential outcome measures to help guide design of future controlled clinical trials. Subjects included 2 SMA type I ages 2-3 years, 29 SMA type II ages 2-14 years and 11 type III ages 2-31 years, recruited from a natural history study. VPA was well-tolerated and without evident hepatotoxicity. Carnitine depletion was frequent and temporally associated with increased weakness in two subjects. Exploratory outcome measures included assessment of gross motor function via the modified Hammersmith Functional Motor Scale (MHFMS), electrophysiologic measures of innervation including maximum ulnar compound muscle action potential (CMAP) amplitudes and motor unit number estimation (MUNE), body composition and bone density via dual-energy X-ray absorptiometry (DEXA), and quantitative blood SMN mRNA levels. Clear decline in motor function occurred in several subjects in association with weight gain; mean fat mass increased without a corresponding increase in lean mass. We observed an increased mean score on the MHFMS scale in 27 subjects with SMA type II (p<or=0.001); however, significant improvement was almost entirely restricted to participants <5 years of age. Full length SMN levels were unchanged and Delta7SMN levels were significantly reduced for 2 of 3 treatment visits. In contrast, bone mineral density (p<or=0.0036) and maximum ulnar CMAP scores (p<or=0.0001) increased significantly. CONCLUSIONS:While VPA appears safe and well-tolerated in this initial pilot trial, these data suggest that weight gain and carnitine depletion are likely to be significant confounding factors in clinical trials. This study highlights potential strengths and limitations of various candidate outcome measures and underscores the need for additional controlled clinical trials with VPA targeting more restricted cohorts of subjects. TRIAL REGISTRATION:ClinicalTrials.gov

SMA CARNI-VAL Trial Part I: Double-Blind, Randomized, Placebo-Controlled Trial of L-Carnitine and Valproic Acid in Spinal Muscular Atrophy

Valproic acid (VPA) has demonstrated potential as a therapeutic candidate for spinal muscular atrophy (SMA) in vitro and in vivo.Two cohorts of subjects were enrolled in the SMA CARNIVAL TRIAL, a non-ambulatory group of "sitters" (cohort 1) and an ambulatory group of "walkers" (cohort 2). Here, we present results for cohort 1: a multicenter phase II randomized double-blind intention-to-treat protocol in non-ambulatory SMA subjects 2-8 years of age. Sixty-one subjects were randomized 1:1 to placebo or treatment for the first six months; all received active treatment the subsequent six months. The primary outcome was change in the modified Hammersmith Functional Motor Scale (MHFMS) score following six months of treatment. Secondary outcomes included safety and adverse event data, and change in MHFMS score for twelve versus six months of active treatment, body composition, quantitative SMN mRNA levels, maximum ulnar CMAP amplitudes, myometry and PFT measures.At 6 months, there was no difference in change from the baseline MHFMS score between treatment and placebo groups (difference = 0.643, 95% CI = -1.22-2.51). Adverse events occurred in >80% of subjects and were more common in the treatment group. Excessive weight gain was the most frequent drug-related adverse event, and increased fat mass was negatively related to change in MHFMS values (p = 0.0409). Post-hoc analysis found that children ages two to three years that received 12 months treatment, when adjusted for baseline weight, had significantly improved MHFMS scores (p = 0.03) compared to those who received placebo the first six months. A linear regression analysis limited to the influence of age demonstrates young age as a significant factor in improved MHFMS scores (p = 0.007).This study demonstrated no benefit from six months treatment with VPA and L-carnitine in a young non-ambulatory cohort of subjects with SMA. Weight gain, age and treatment duration were significant confounding variables that should be considered in the design of future trials.Clinicaltrials.gov NCT00227266

Genetic analysis and natural history of Charcot-Marie-Tooth disease CMTX1 due to GJB1 variants

Charcot-Marie-Tooth disease (CMT) due to GJB1 variants (CMTX1) is the second most common form of CMT. It is an X-linked disorder characterised by progressive sensory and motor neuropathy with males affected more severely than females. Many reported GJB1 variants remain classified as variants of uncertain significance (VUS). In this large, international, multicentre study we prospectively collected demographic, clinical and genetic data on patients with CMT associated with GJB1 variants. Pathogenicity for each variant was defined using adapted American College of Medical Genetics criteria. Baseline and longitudinal analyses were conducted to study genotype-phenotype correlations, to calculate longitudinal change using the CMT Examination Score (CMTES), to compare males versus females, and pathogenic/likely pathogenic (P/LP) variants versus VUS. We present 387 patients from 295 families harbouring 154 variants in GJB1. Of these, 319 patients (82.4%) were deemed to have P/LP variants, 65 had VUS (16.8%) and 3 benign variants (0.8%; excluded from analysis); an increased proportion of patients with P/LP variants compared with using ClinVar's classification (74.6%). Male patients (166/319, 52.0%, P/LP only) were more severely affected at baseline. Baseline measures in patients with P/LP variants and VUS showed no significant differences, and regression analysis suggested the disease groups were near identical at baseline. Genotype-phenotype analysis suggested c.-17G>A produces the most severe phenotype of the five most common variants, and missense variants in the intracellular domain are less severe than other domains. Progression of disease was seen with increasing CMTES over time up to 8 years follow-up. Standard response mean (SRM), a measure of outcome responsiveness, peaked at 3 years with moderate responsiveness (change in CMTES (ΔCMTES) = 1.3 ± 2.6, p = 0.00016, SRM = 0.50). Males and females progressed similarly up to 8 years, but baseline regression analysis suggested that over a longer period, females progress more slowly. Progression was most pronounced for mild phenotypes (CMTES = 0-7; 3-year ΔCMTES = 2.3 ± 2.5, p = 0.001, SRM = 0.90). Enhanced variant interpretation has yielded an increased proportion of GJB1 variants classified as P/LP and will aid future variant interpretation in this gene. Baseline and longitudinal analysis of this large cohort of CMTX1 patients describes the natural history of the disease including the rate of progression; CMTES showed moderate responsiveness for the whole group at 3 years and higher responsiveness for the mild group at 3, 4 and 5 years. These results have implications for patient selection for upcoming clinical trials

SMA CARNI-VAL TRIAL PART II: A Prospective, Single-Armed Trial of L-Carnitine and Valproic Acid in Ambulatory Children with Spinal Muscular Atrophy

Multiple lines of evidence have suggested that valproic acid (VPA) might benefit patients with spinal muscular atrophy (SMA). The SMA CARNIVAL TRIAL was a two part prospective trial to evaluate oral VPA and l-carnitine in SMA children. Part 1 targeted non-ambulatory children ages 2–8 in a 12 month cross over design. We report here Part 2, a twelve month prospective, open-label trial of VPA and L-carnitine in ambulatory SMA children.This study involved 33 genetically proven type 3 SMA subjects ages 3–17 years. Subjects underwent two baseline assessments over 4–6 weeks and then were placed on VPA and L-carnitine for 12 months. Assessments were performed at baseline, 3, 6 and 12 months. Primary outcomes included safety, adverse events and the change at 6 and 12 months in motor function assessed using the Modified Hammersmith Functional Motor Scale Extend (MHFMS-Extend), timed motor tests and fine motor modules. Secondary outcomes included changes in ulnar compound muscle action potential amplitudes (CMAP), handheld dynamometry, pulmonary function, and Pediatric Quality of Life Inventory scores.Twenty-eight subjects completed the study. VPA and carnitine were generally well tolerated. Although adverse events occurred in 85% of subjects, they were usually mild and transient. Weight gain of 20% above body weight occurred in 17% of subjects. There was no significant change in any primary outcome at six or 12 months. Some pulmonary function measures showed improvement at one year as expected with normal growth. CMAP significantly improved suggesting a modest biologic effect not clinically meaningful.This study, coupled with the CARNIVAL Part 1 study, indicate that VPA is not effective in improving strength or function in SMA children. The outcomes used in this study are feasible and reliable, and can be employed in future trials in SMA

Frizzle Frazzled

An otherwise healthy 12-year-old boy originally from Palestine was referred for refractory papilledema secondary to familial IIH. He has a history of fully accommodative esotropia with onset age 2-3. At age 9, elevated optic nerves prompted a neuro-ophthalmic referral. Best corrected visual acuities were subnormal at 20/60 OU. Optic disc drusen were confirmed on fundus autofluorescence but superimposed by papilledema with obscuration of the retinal vessels OD>OS. MRI findings were consistent with elevated intracranial pressure (Figure 1). Lumber puncture showed normal spinal fluid constituents and an opening pressure of 24 cm H2O. He was diagnosed with familial idiopathic intracranial hypertension because his 9-year-old sister presented at the same time with similar neuro-ophthalmic findings and headaches that resolved after lumbar puncture. Oral acetazolamide 375 mg TID (15 mg/kg/day) improved the optic nerve appearance and his visual acuity on follow up. Subsequently, gains in visual acuity reverted to baseline, and his disc appearance worsened. OCT of the macula showed abnormal foveal contour and intraretinal fluid, felt consistent with refractory papilledema. Repeat opening pressure read 26 cm H2O. A second opinion was obtained for consideration of optic nerve sheath fenestration. Subnormal visual acuities of 20/50 OD and 20/40 OS with best correction of +14.00sphere OD and +13.25+0.50x090 OS were noted. Goldmann perimetry showed constricted fields OU with an enlarged blind spot OD and a superonasal defect OS (Figure 2). Examination showed normal anterior segments, 2+ vitreous cells, and nerve fiber layer thickening with blurred optic disc margins and blunted foveal reflexes OU (Figure 3). Scattered, faint tessellated pigmentary changes were noted throughout the mid-peripheral retinae. The patient was discontinued from acetazolamide under consideration of an alternative diagnosis. Fluorescein angiography subsequently showed no leakage from the optic nerve heads but window defects in the inferonasal mid-periphery. A confirmatory diagnostic test was obtained

Frizzle Frazzled

An otherwise healthy 12-year-old boy originally from Palestine was referred for refractory papilledema secondary to familial IIH. He has a history of fully accommodative esotropia with onset age 2-3. At age 9, elevated optic nerves prompted a neuro-ophthalmic referral. Best corrected visual acuities were subnormal at 20/60 OU. Optic disc drusen were confirmed on fundus autofluorescence but superimposed by papilledema with obscuration of the retinal vessels OD>OS. MRI findings were consistent with elevated intracranial pressure (Figure 1). Lumber puncture showed normal spinal fluid constituents and an opening pressure of 24 cm H2O. He was diagnosed with familial idiopathic intracranial hypertension because his 9-year-old sister presented at the same time with similar neuro-ophthalmic findings and headaches that resolved after lumbar puncture. Oral acetazolamide 375 mg TID (15 mg/kg/day) improved the optic nerve appearance and his visual acuity on follow up. Subsequently, gains in visual acuity reverted to baseline, and his disc appearance worsened. OCT of the macula showed abnormal foveal contour and intraretinal fluid, felt consistent with refractory papilledema. Repeat opening pressure read 26 cm H2O. A second opinion was obtained for consideration of optic nerve sheath fenestration. Subnormal visual acuities of 20/50 OD and 20/40 OS with best correction of +14.00sphere OD and +13.25+0.50x090 OS were noted. Goldmann perimetry showed constricted fields OU with an enlarged blind spot OD and a superonasal defect OS (Figure 2). Examination showed normal anterior segments, 2+ vitreous cells, and nerve fiber layer thickening with blurred optic disc margins and blunted foveal reflexes OU (Figure 3). Scattered, faint tessellated pigmentary changes were noted throughout the mid-peripheral retinae. The patient was discontinued from acetazolamide under consideration of an alternative diagnosis. Fluorescein angiography subsequently showed no leakage from the optic nerve heads but window defects in the inferonasal mid-periphery. A confirmatory diagnostic test was obtained

Gene transfer into skeletal muscles by isogenic myoblasts

NRC publication: Ye

Frizzle Frazzled

An otherwise healthy 12-year-old boy originally from Palestine was referred for refractory papilledema secondary to familial IIH. He has a history of fully accommodative esotropia with onset age 2-3. At age 9, elevated optic nerves prompted a neuro-ophthalmic referral. Best corrected visual acuities were subnormal at 20/60 OU. Optic disc drusen were confirmed on fundus autofluorescence but superimposed by papilledema with obscuration of the retinal vessels OD>OS. MRI findings were consistent with elevated intracranial pressure (Figure 1). Lumber puncture showed normal spinal fluid constituents and an opening pressure of 24 cm H2O. He was diagnosed with familial idiopathic intracranial hypertension because his 9-year-old sister presented at the same time with similar neuro-ophthalmic findings and headaches that resolved after lumbar puncture. Oral acetazolamide 375 mg TID (15 mg/kg/day) improved the optic nerve appearance and his visual acuity on follow up. Subsequently, gains in visual acuity reverted to baseline, and his disc appearance worsened. OCT of the macula showed abnormal foveal contour and intraretinal fluid, felt consistent with refractory papilledema. Repeat opening pressure read 26 cm H2O. A second opinion was obtained for consideration of optic nerve sheath fenestration. Subnormal visual acuities of 20/50 OD and 20/40 OS with best correction of +14.00sphere OD and +13.25+0.50x090 OS were noted. Goldmann perimetry showed constricted fields OU with an enlarged blind spot OD and a superonasal defect OS (Figure 2). Examination showed normal anterior segments, 2+ vitreous cells, and nerve fiber layer thickening with blurred optic disc margins and blunted foveal reflexes OU (Figure 3). Scattered, faint tessellated pigmentary changes were noted throughout the mid-peripheral retinae. The patient was discontinued from acetazolamide under consideration of an alternative diagnosis. Fluorescein angiography subsequently showed no leakage from the optic nerve heads but window defects in the inferonasal mid-periphery. A confirmatory diagnostic test was obtained

Toxicity of replication-defective adenoviral recombinants in dissociated cultures of nervous tissue

NRC publication: Ye