Safety and efficacy of N-acetylmannosamine (ManNAc) in patients with GNE myopathy: an open-label phase 2 study.

PURPOSE: To evaluate the safety and efficacy of N-acetylmannosamine (ManNAc) in GNE myopathy, a genetic muscle disease caused by deficiency of the rate-limiting enzyme in N-acetylneuraminic acid (Neu5Ac) biosynthesis. METHODS: We conducted an open-label, phase 2, single-center (NIH, USA) study to evaluate oral ManNAc in 12 patients with GNE myopathy (ClinicalTrials.gov NCT02346461). Primary endpoints were safety and biochemical efficacy as determined by change in plasma Neu5Ac and sarcolemmal sialylation. Clinical efficacy was evaluated using secondary outcome measures as part of study extensions, and a disease progression model (GNE-DPM) was tested as an efficacy analysis method. RESULTS: Most drug-related adverse events were gastrointestinal, and there were no serious adverse events. Increased plasma Neu5Ac (+2,159 nmol/L, p < 0.0001) and sarcolemmal sialylation (p = 0.0090) were observed at day 90 compared to baseline. A slower rate of decline was observed for upper extremity strength (p = 0.0139), lower extremity strength (p = 0.0006), and the Adult Myopathy Assessment Tool (p = 0.0453), compared to natural history. Decreased disease progression was estimated at 12 (γ = 0.61 [95% CI: 0.09, 1.27]) and 18 months (γ = 0.55 [95% CI: 0.12, 1.02]) using the GNE-DPM. CONCLUSION: ManNAc showed long-term safety, biochemical efficacy consistent with the intended mechanism of action, and preliminary evidence clinical efficacy in patients with GNE myopathy.

Characterizing upper limb function in the context of activities of daily living in CLN3 disease.

In CLN3 disease, impairments in motor function are frequently reported to have later onset compared to visual and cognitive decline, but upper limb motor function has yet to be explored in this population. In a cohort of 22 individuals with CLN3, we used a novel application of multiple measures to (1) characterize motor function, particularly of the upper limbs, in activities of daily living (ADLs), and (2) explore associations between motor function and age as well as visual ability, disease severity, and cognitive function, as evaluated by the Unified Batten Disease Rating Scale (UBDRS), a validated CLN3 disease measure. ADLs that required coordination, speed, and fine motor control were particularly challenging for children with CLN3 based on item-level performance across direct assessments (Jebsen-Taylor Hand Function Test [JTHFT] and MyoSet Tools) and caregiver reports (Pediatric Evaluation of Disability Inventory-Computer Adaptive Testing [PEDI-CAT] and Patient-Reported Outcomes Measurement Information System [PROMIS] Pediatric Upper Extremity). Poorer visual ability, disease severity, and cognitive function were associated with worse performance on these measures, whereas age had limited impact. These findings support the need for children with CLN3 to receive skilled clinical evaluation and treatment tailored to their individual needs, particularly in the context of ADLs, as their symptom profile progresses.

Psychosocial Characteristics of Women with a Delayed Diagnosis of Turner Syndrome.

OBJECTIVES: To characterize the psychosocial profiles of adult women diagnosed with Turner syndrome before (early diagnosis) and at or after (late diagnosis) 13 years of age. STUDY DESIGN: Women with Turner syndrome ages 22 and older at evaluation (n = 110) participated in a cross-sectional study at the National Institutes of Health. Researchers performed nonparametric and logistic regression analyses to assess early and late diagnosis cohorts on measures of depression, substance use, and perceptions of competence and identity. RESULTS: Of study participants, 47% received a Turner syndrome diagnosis at or after age 13 years. Median age at diagnosis was 12.0 years (range, 0-43). Covariate-adjusted models revealed that women with late diagnoses had an increased likelihood of developing mild to severe depressive symptoms (OR, 7.36) and a decreased likelihood of being perceived as competent (OR, 0.26). Women with a late diagnosis also exhibited more frequent substance use compared with women with early diagnoses. CONCLUSIONS: These data suggest that Turner syndrome diagnoses received at or after age 13 years may contribute to adverse outcomes related to depression, substance use, and perceptions of competence. Delayed Turner syndrome diagnoses may place women and girls at risk for negative psychosocial development extending into adulthood. These findings indicate it is important for pediatricians to evaluate psychosocial domains in girls with Turner syndrome regularly, particularly among those diagnosed at age 13 years or older. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00006334.

Phase 1 Open-Label Study of Omigapil in Patients With LAMA2- or COL6-Related Dystrophy.

Background and Objectives: Omigapil is a small molecule which inhibits the GAPDH-Siah1-mediated apoptosis pathway. Apoptosis is a pathomechanism underlying the congenital muscular dystrophy subtypes LAMA2-related dystrophy (LAMA2-RD) and COL6-related dystrophy (COL6-RD). Studies of omigapil in the (dyw/dyw) LAMA2-RD mouse model demonstrated improved survival, and studies in the (dy2J/dy2J) LAMA2-RD mouse model and the (Col6a1-/-) COL6-RD mouse model demonstrated decreased apoptosis. Methods: A phase 1 open-label, sequential group, ascending oral dose, cohort study of omigapil in patients with LAMA2-RD or COL6-RD ages 5-16 years was performed (1) to establish the pharmacokinetic (PK) profile of omigapil at a range of doses, (2) to evaluate the safety and tolerability of omigapil at a range of doses, and (3) to establish the feasibility of conducting disease-relevant clinical assessments. Patients were enrolled in cohorts of size 4, with each patient receiving 4 weeks of vehicle run-in and 12 weeks of study drug (at daily doses ranging from 0.02 to 0.08 mg/kg). PK data from each cohort were analyzed before each subsequent dosing cohort was enrolled. A novel, adaptive dose-finding method (stochastic approximation with virtual observation recursion) was used to allow for dose escalation/reduction between cohorts based on PK data. Results: Twenty patients were enrolled at the NIH (LAMA2-RD: N = 10; COL6-RD: N = 10). Slightly greater than dose-proportional increases in systemic exposure to omigapil were seen at doses 0.02-0.08 mg/kg/d. The dose which achieved patient exposure within the pre-established target area under the plasma concentration-vs-time curve (AUC0-24h) range was 0.06 mg/kg/d. In general, omigapil was safe and well tolerated. No consistent changes were seen in the disease-relevant clinical assessments during the duration of the study. Discussion: This study represents the thus far only clinical trial of a therapeutic small molecule for LAMA2-RD and COL6-RD, completed with an adaptive trial design to arrive at dose adjustments. The trial met its primary end point and established that the PK profile of omigapil is suitable for further development in pediatric patients with LAMA2-RD or COL6-RD, the most common forms of congenital muscular dystrophy. While within the short duration of the study disease-relevant clinical assessments did not demonstrate significant changes, this study establishes the feasibility of performing interventional clinical trials in these rare disease patient populations. Classification of Evidence: This study provides Class IV evidence of omigapil in a dose-finding phase 1 study. Trial Registration Information: Clinical Trials NCT01805024.

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. In contrast with the existing quantitative myometry (QMA) setup, the HCR is portable, economical, can be used with any laptop and generates automated command prompts. We demonstrate the feasibility and reliability of HCR device in twenty DM1 individuals and ten age-matched controls; patients returned for follow up within two months. The device showed excellent day to day reproducibility (ICC >0.80) in patients. The HCR device detected myotonia in milder muscle disease and measured longer myotonia duration than QMA indicating enhanced sensitivity for quantifying myotonia in DM1. The reaction time to the relax but not squeeze command was delayed and showed warm up similar to myotonia in DM1. HCR outcomes were correlated with key pinch strength, hand dexterity test, and fat replacement in the MRI of the long finger flexor muscles. Use of the HCR is warranted for grip myotonia and strength measurements in longitudinal observational and interventional studies of DM1.

Brief assessment of motor function: content validity and reliability of the upper extremity gross motor scale.

Content validity and reliability of the Brief Assessment of Motor Function (BAMF) Upper Extremity Gross Motor Scale (UEGMS) were evaluated in this prospective, descriptive study. The UEGMS is one of five BAMF ordinal scales designed for quick documentation of gross, fine, and oral motor skill levels. Designed to be independent of age and diagnosis, it is intended for use for infants through young adults. An expert panel of 17 physical therapists and 13 occupational therapists refined the content by responding to a standard questionnaire comprised of questions, which asked whether each item should be included, is clearly worded, should be reordered higher or lower, is functionally relevant, and is easily discriminated. Ratings of content validity exceeded the criterion except for two items, which may represent different perspectives of physical and occupational therapists. The UEGMS was modified using the quantitative and qualitative feedback from the questionnaires. For reliability, five raters scored videotaped motor performances of 10 children. Coefficients for inter-rater (0.94) and intra-rater (0.95) reliability were high. The results provide evidence of content validity and reliability of the UEGMS for the assessment of UEGM skill.

Differences in activities of daily living performance between long-term pediatric sarcoma survivors and a matched comparison group on standardized testing.

BACKGROUND: In a cross-sectional study examining late effects of pediatric sarcoma therapy, long-term survivors were evaluated on their activities of daily living (ADL) performance. PROCEDURE: Thirty-two persons with Ewing sarcoma family of tumors, rhabdomyosarcoma, and non-rhabdomysarcoma-soft tissue sarcoma enrolled an average of 17 years after treatment. Participants were evaluated using the Assessment of Motor and Process Skills (AMPS) 1, a standardized observational evaluation of ADL task performance. Means and 95% confidence intervals for ADL motor and ADL process ability measures were calculated for four groups: (1) sarcoma survivors, (2) "well" adults matched for age and gender, (3) "well" adults matched for gender that were 10 years older, and (4) "well" adults matched for gender that were 20 years older. RESULTS: ADL motor ability was significantly lower for sarcoma survivors than for the age- and gender-matched comparison group (P < 0.05). There was no significant difference between ADL motor ability of sarcoma survivors and the comparison group 10 years older, but sarcoma survivors had significantly better ADL motor ability (P < 0.05) than the oldest comparison group (20 years older). Sarcoma survivors had significantly worse ADL process ability than the age-matched group (P < 0.05). There was no difference in ADL process ability between the sarcoma survivors and comparison groups that were 10 and 20 years older. CONCLUSIONS: This first report of a clinical evaluation of ADL limitation in pediatric sarcoma survivors treated with intensive multimodal cancer therapy suggests that influences on performance of daily life activities are more common than previously reported.

Lessons and Outcomes of Mobile Acute Care for Elders Consultation in a Veterans Affairs Medical Center.

OBJECTIVE: Describe the implementation and effects of Mobile Acute Care for Elders (MACE) consultation at a Veterans Affairs Medical Center (VAMC). DESIGN: Retrospective cohort analysis. INTERVENTION: Veterans aged 65 or older who were admitted to the medicine service between October 1, 2012, and September 30, 2014, were screened for geriatric syndromes via review of medical records within 48 hours of admission. If the screen was positive, the MACE team offered the admitting team a same-day consultation involving comprehensive geriatric assessment and ongoing collaboration with the admitting team and supportive services to implement patient-centric recommendations for geriatric syndromes. RESULTS: Veterans seen by MACE (n = 421) were compared with those with positive screens but without consultation (n = 372). The two groups did not significantly differ in age, comorbidity, sex, or race. All outcomes (30-day readmission, 30-day mortality, readmission costs) were in the expected direction for patients receiving MACE but did not reach statistical significance. Patients receiving MACE had lower odds of 30-day readmission (11.9% vs 14.8%; odds ratio [OR] = 0.82; 95% confidence interval [CI] = 0.54-1.25; p = .360) and 30-day mortality (5.5% vs 8.6%; OR = 0.64; CI = 0.36-1.12; p = .115), and they had lower 30-day readmission costs (MACE $15,502; CI = $12,242-$19,631; comparison = $18,335; CI = $14,641-$22,962; p = .316) than those who did not receive MACE after adjusting for age and Charlson Comorbidity Index. CONCLUSION: Our MACE consultation model for older veterans with geriatric syndromes leverages the limited supply of clinicians with expertise in geriatrics. Although not statistically significant in this study of 793 subjects, MACE patients had lower odds of 30-day readmission and mortality, and lower readmission costs. J Am Geriatr Soc 67:818-824, 2019.

Upper extremity outcome measures for collagen VI-related myopathy and LAMA2-related muscular dystrophy.

Congenital muscular dystrophy (CMD) comprises a rare group of genetic muscle diseases that present at birth or early during infancy. Two common subtypes of CMD are collagen VI-related muscular dystrophy (COL6-RD) and laminin alpha 2-related dystrophy (LAMA2-RD). Traditional outcome measures in CMD include gross motor and mobility assessments, yet significant motor declines underscore the need for valid upper extremity motor assessments as a clinical endpoint. This study validated a battery of upper extremity measures in these two CMD subtypes for future clinical trials. For this cross-sectional study, 42 participants were assessed over the same 2-5 day period at the National Institutes of Health Clinical Center. All upper extremity measures were correlated with the Motor Function Measure 32 (MFM32). The battery of upper extremity assessments included the Jebsen Taylor Hand Function Test, Quality of Upper Extremity Skills Test (QUEST), hand held dynamometry, goniometry, and MyoSet Tools. Spearman Rho was used for correlations to the MFM32. Pearson was performed to correlate the Jebsen, QUEST, hand-held dynamometry, goniometry and the MyoSet Tools. Correlations were considered significant at the 0.01 level (2-tailed). Significant correlations were found between both the MFM32 and MFM Dimension 3 only (Distal Motor function) and the Jebsen, QUEST, MyoGrip and MyoPinch, elbow flexion/extension ROM and myometry. Additional correlations between the assessments are reported. The Jebsen, the Grasp and Dissociated Movements domains of the QUEST, the MyoGrip and the MyoPinch tools, as well as elbow ROM and myometry were determined to be valid and feasible in this population, provided variation in test items, and assessed a range of difficulty in CMD. To move forward, it will be of utmost importance to determine whether these upper extremity measures are reproducible and sensitive to change over time.

Brief assessment of motor function: content validity and reliability of the oral motor scales.

OBJECTIVE: The Brief Assessment of Motor Function consists of five 0- to 10-point hierarchical scales designed for rapid assessment of gross, fine, and oral motor skills. We describe the development and evaluation of the two Brief Assessment of Motor Function Oral Motor Scales: Oral Motor Articulation and Oral Motor Deglutition. DESIGN: This validation study employed an expert panel of 28 speech-language pathologists, who rated the Brief Assessment of Motor Function Oral Motor Scales items on a scale from 1 to 4 (disagree to agree) to establish content validity. For reliability, oral motor performances of 18 participants (6 mos-20 yrs) were videotaped to represent a wide range of articulation and deglutition capabilities. Four speech-language pathologists, and 1 undergraduate and 10 graduate speech-language pathology students rated the participants' taped samples using the Brief Assessment of Motor Function Oral Motor Scales. RESULTS: All items on the content validity questionnaire had average agreement scores that exceeded criteria, except two, which were not clearly worded; these were clarified. Interrater and intrarater reliability values were 0.997 and 0.986 for the Oral Motor Articulation Scale and 0.977 and 0.997 for the Oral Motor Deglutition Scale. CONCLUSIONS: Expert feedback and reliability procedures suggest that the Brief Assessment of Motor Function Oral Motor Articulation and Deglutition Scales represent the content that they are designed to assess and are reliable for rapid assessment of oral motor skills.

Brief assessment of motor function: content validity and reliability of the fine motor scale.

PURPOSE: The Brief Assessment of Motor Function Fine Motor Scale (FMS) allows rapid assessment, independent of age. This study was done to establish content validity of the FMS and to demonstrate FMS reliability. METHODS: A standard questionnaire ("Disagree" to "Agree," 1-4) was emailed to 28 expert panel members. Ten children with diagnoses including Proteus, Sheldon-Freeman, Smith-Lemli-Opitz, and Smith-Magenis syndromes were videotaped for reliability trials. RESULTS: Expert panel members agreed that all 28 items should be included (means, 3.43-3.89); were functionally relevant (means, 2.93-3.82), were clearly worded (means, 2.71-3.61), and were easily discriminated (means, 3.32-4.0). Kappa values for interrater and intrarater reliability were 0.978 and 0.993, respectively. CONCLUSIONS: Feedback from an expert Panel supported content validity of the Brief Assessment of Motor Function FMS. Kappa values for interrater and intrarater reliability suggest this is a reliable instrument for rapid, objective fine motor assessment.

Treatment late effects in long-term survivors of pediatric sarcoma.

PURPOSE: To assess health and musculoskeletal function in survivors of pediatric sarcomas. PATIENTS AND METHODS: Thirty-two individuals treated for Ewing sarcoma family of tumors (ESFT), rhabdomyosarcoma (RMS), or non-rhabdomyosarcoma soft tissue sarcomas (NR-STS) with multi-modality therapy were enrolled on this cross-sectional study. Median age at the time of therapy was 15.4 years (range 7.1-34.2), median age at the time of analysis was 37.4 years (17.5-55.4), and median duration of time elapsed from completion of therapy was 17.3 years (2.9-32.6). Participants underwent assessments of musculoskeletal functioning, cardiac function, metabolic and lipid analyses, renal and gonadal function, and psychological evaluation. RESULTS: This cohort of sarcoma survivors shows expected locoregional limitations in function of the area affected by sarcoma, and impaired global musculoskeletal functioning as evidenced by limited endurance and limited overall activity levels. The cohort also demonstrated substantial rates of cardiac dysfunction, elevated body fat index, hyperlipidemia, chronic psychological distress, and infertility in men (76%) and premature menopause (49%) in women. CONCLUSION: Sarcoma survivors demonstrate diminished locoregional and global musculoskeletal functioning which likely limit occupational opportunities and socioeconomic health. In addition, the combination of diminished cardiac reserve, limited activity levels, and lipid dysregulation in sarcoma survivors suggests that this population is at increased risk for cardiovascular disease, even many years following completion of sarcoma therapy. Sarcoma survivors may benefit from life long follow-up for cardiovascular disease and from occupational counseling upon completion of therapy.

Functional outcomes and life satisfaction in long-term survivors of pediatric sarcomas.

OBJECTIVES: To describe the inter-relationships among impairments, performance, and disabilities in survivors of pediatric sarcoma and to identify measurements that profile survivors at risk for functional loss. DESIGN: Prospective, cross-sectional. SETTING: Research facility. PARTICIPANTS: Thirty-two participants in National Cancer Institute clinical trials. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Range of motion (ROM), strength, limb volume, grip strength, walk velocity, Assessment of Motor and Process Skills (AMPS); Human Activity Profile (HAP), Sickness Impact Profile (SIP), standard form of the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36); and vocational attitudes and leisure satisfaction. RESULTS: Twenty of 30 survivors tested had moderate or severe loss of ROM; 13 of 31 tested had 90% or less of predicted walk velocity; all of whom had trunk or lower-extremity lesions. Women with decreased ROM (r=.50, P=.06) or strength (r=.74, P=.002) had slow gait velocity. Sixteen of 31 tested were more than 1 standard deviation below normal grip strength. Eighteen had increased limb volume. These 18 had low physical competence (SF-36) (r=-.70, P=.001) and high SIP scores (r=.73, P=.005). AMPS scores were lower than those of the matched normed sample (P<.001). HAP identified 15 of 30 who had moderately or severely reduced activity. Leisure satisfaction was higher in the subjects (P<.001). Eight reported cancer had negatively impacted work and 17 reported that it negatively impacted vocational plans. CONCLUSIONS: Survivors with lower-extremity or truncal lesions and women with decreased ROM and strength likely have slow walk velocity, low exercise tolerance, and high risk for functional loss. They should be identified using ROM, strength, limb volume, and walk time measures.

Changes in neurologic function tests may predict neurotoxicity caused by ixabepilone.

PURPOSE: To investigate baseline factors and neurologic function tests (NFTs) that may predict the development of grade 2 or higher peripheral neuropathy (PN) after treatment with ixabepilone, an epothilone microtubule-stabilizing agent with antitumor activity. PATIENTS AND METHODS: Advanced breast cancer patients were treated with ixabepilone (6 mg/m2) for 5 consecutive days every 3 weeks in a phase II clinical trial. Physical examinations, questionnaires, nerve conduction studies, and NFTs, including the Jebsen Test of Hand Function (JTH) and the Grooved Pegboard Test (GPT), were performed at baseline and during subsequent cycles. RESULTS: Forty-seven patients assessable for PN received a median of five cycles of therapy (range, one to 22 cycles). Nine of these patients developed grade 2 PN, and two developed grade 3 PN, with a median time to onset of 144 days (range, 6 to 189 days). Among these 11 patients, PN resolved in eight patients, with a median of 15 days (range, 6 to 346 days) after onset, but PN did not resolve in three patients during follow-ups at 76, 361, and 746 days after onset. GPT and changes of JTH scores at onset of PN were significantly different between patients with and without PN at comparable follow-up times (P = .006 and P = .002, respectively). Changes in GPT and JTH scores over the first two cycles were often associated with the development of PN by exploratory actuarial analysis. CONCLUSION: Serious ixabepilone-induced neuropathy was relatively rare on the treatment schedule used. NFTs, such as JTH and GPT, may have utility for predicting PN, but further testing is needed.

Motor Skill Development of Children with HIV Infection Measured with the Peabody Developmental Motor Scales.

PURPOSE: Improved health care for pregnant women who are HIV+has minimized complications during delivery and resulted in a measurable cohort of children entering the health care system who are HIV+ with potential for motor disorders. This study was designed to determine how gross and fine motor skills were affected by HIV infection in children aged five years and younger using the Peabody Developmental Motor Scales, and to follow a subsample of these children for one and a half years to determine if their relative skill performances changed over time. METHODS: A sample of 143 children who were HIV+ was evaluated using the Peabody Developmental Motor Scales for their gross and fine motor skills. Their performance scores were compared with the Peabody normative values for age-matched healthy children. A subset of 22 children were reevaluated at six-month intervals (six months; one year;one year six months) to determine if their gross and fine motor skills would change. Raw scores and Peabody Developmental Motor Quotients (DMQ, normalized to the reference population) were calculated. RESULTS: The children who were HIV+ as a group performed below the 50th percentile of the normal reference population. During the one year six month study period, the children who were HIV+improved in raw scores but did not improve in relative (DMQ) scores. The exceptions were the fine motor skill subcategories of "grasping" and "hand use," for which the children who were HIV+performed comparably with the reference population. CONCLUSIONS: Clinicians working with children who are HIV+ should emphasize intervention strategies generally designed to develop all gross motor skills and the specific fine motor skills of "eye-hand coordination" and "manual dexterity."