Darryl C De Vivo - Academia.edu (original) (raw)
Papers by Darryl C De Vivo
The field of pediatric neuromuscular disorders has continued to expand scientifically since the e... more The field of pediatric neuromuscular disorders has continued to expand scientifically since the era of molecular neurogenetics began in the mid-1980s. The rapid changes in the field may be overwhelming to busy, practicing clinicians on a day-to-day basis. The dramatic advances in DNA diagnostics have added to the complexity of a challenging clinical field and have left physicians occasionally uncertain about the relative indications for traditional tests such as EMG and muscle biopsy. Clearly, all these diagnostic tests remain useful, and it is up to the modern clinician to make informed decisions, after the initial clinical evaluation, to facilitate an accurate biomolecular diagnosis as quickly and as economically as possible. Older children and their families are increasingly aware of these extraordinary advances through their own access to the Internet, and they challenge us to remain informed and updated. They wait impatiently for us to translate these scientific achievements in...
Epilepsia Open, 2020
This is an open access article under the terms of the Creative Commons Attribution License, which... more This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Spinal Muscular Atrophy
Oxford Medicine Online, 2017
Spinal muscular atrophy (SMA) is a common, inherited, pediatric motor neuron disorder caused by i... more Spinal muscular atrophy (SMA) is a common, inherited, pediatric motor neuron disorder caused by insufficient SMN protein. As of yet, there is no good treatment for the disease. SMA has an incidence of ~1 in 10,000 newborns carrier frequency of 1 in 50, making it the most common inherited cause of infant mortality. Patients with severe SMA, or Werdnig-Hoffman disease, typically manifest weakness during the first 6 months of life. Such patients are so debilitated that they never sit independently, frequently succumbing to the disease before age 2 years. A much milder form of SMA, Kugelberg-Welander disease, with onset after 18 months of age, often during childhood and characterized by prolonged ambulation and a normal life expectancy, was described in 1956. In 1995 mutations in a novel gene, Survival of Motor Neuron 1 (SMN1), were determined to be the specific cause of SMA.
Analysis of Gait Disturbance in Glut 1 Deficiency Syndrome
Journal of child neurology, Jan 10, 2016
Anticipating potential therapies for Glut 1 deficiency syndrome (Glut1DS) emphasizes the need for... more Anticipating potential therapies for Glut 1 deficiency syndrome (Glut1DS) emphasizes the need for effective clinical outcome measures. The 6-minute walk test is a well-established outcome measure that evaluates walking ability in neurological diseases. Twenty-one children with Glut 1 deficiency syndrome and 21 controls performed the 6-minute walk test. Fatigue was determined by comparing distance walked in the first and sixth minutes. Gait was analyzed by stride length, velocity, cadence, base of support, and percentage time in double support. Independent sample t-tests examined differences between group. Repeated-measures analysis of variance evaluated gait parameters over time. Glut 1 deficiency syndrome patients walked less (P < .05), had slower velocities (P < .0001), had shorter stride lengths (P < .0001), spent more time in double support (P < .001), and had increasing variability in base of support (P = .009). Glut 1 deficiency syndrome patients have impaired moto...
Muscle & Nerve, 2016
We evaluated the suitability of a caregiver-reported functional measure, the Pediatric Evaluation... more We evaluated the suitability of a caregiver-reported functional measure, the Pediatric Evaluation of Disability Inventory-Computer Adaptive Test (PEDI-CAT), for children and young adults with spinal muscular atrophy (SMA). Methods: PEDI-CAT Mobility and Daily Activities domain item banks were administered to 58 caregivers of children and young adults with SMA. Rasch analysis was used to evaluate test properties across SMA types. Results: Unidimensional content for each domain was confirmed. The PEDI-CAT was most informative for Type III SMA, with ability levels distributed close to 0.00 logits in both domains. It was less informative for Types I and II SMA, especially for mobility skills. Item and person abilities were not distributed evenly across all types. Conclusions: The PEDI-CAT may be used to measure functional performance in SMA, but additional items are needed to identify small changes in function and best represent the abilities of all types of SMA.
Annals of Clinical and Translational Neurology, 2021
We explored the benefits of triheptanoin as a treatment for Short Chain Enoyl Co-A Hydratase (SCE... more We explored the benefits of triheptanoin as a treatment for Short Chain Enoyl Co-A Hydratase (SCEH) deficiency. One child with early onset, severe SCEH Deficiency was treated with triheptanoin, an odd chain oil with anapleurotic properties, for 37 months. Blood and urine chemistry safety measures, motor skills assessment, physical exam, and neurological assessment were monitored over a 27 month period. Modest sustained gains in motor skills, attention, muscle bulk, and strength were observed without any significant adverse effects. Triheptanoin appears to be a promising effective treatment for SCEH Deficiency.
Table 1. [Molecular Genetic Testing Used in Glut1 DS]
University of Washington, Seattle, Mar 1, 2018
Hypotonia–cystinuria 2p21 deletion syndrome: Intrafamilial variability of clinical expression
Annals of Clinical and Translational Neurology, 2021
Two siblings presented similarly with congenital hypotonia, lactic acidosis, and failure to thriv... more Two siblings presented similarly with congenital hypotonia, lactic acidosis, and failure to thrive. Later in childhood, the brother developed cystinuria and nephrolithiasis whereas the older sister suffered from cystinuria and chronic neurobehavioral disturbances. Biopsied muscle studies demonstrated deficient cytochrome c oxidase activities consistent with a mitochondrial disease. Whole exome sequencing (WES), however, revealed a homozygous 2p21 deletion involving two contiquous genes, SLC3A1 (deletion of exons 2‐10) and PREPL (deletion of exons 2‐14). The molecular findings were consistent with the hypotonia–cystinuria 2p21 deletion syndrome, presenting similarly in infancy with mitochondrial dysfunction but diverging later in childhood and displaying intrafamilial phenotypic variability.
Journal of Inherited Metabolic Disease, 2003
Cerebral hyperemia, stroke, and transfusion in sickle cell disease
Neurology, 1989
To investigate cerebral hemodynamics in sickle cell disease (SCD), we used the 133Xenon inhalatio... more To investigate cerebral hemodynamics in sickle cell disease (SCD), we used the 133Xenon inhalation technique of quantifying cerebral blood flow (CBF) in 67 patients. Clinical examinations and cerebral magnetic resonance imaging also were performed in all patients. Compared with age-matched healthy controls, CBF was elevated by 68% in patients, and inversely related to hematocrit. An experimental index of cerebral blood volume, pr4, was also elevated in the patients in a similar manner. Cerebral blood volume was positively correlated to CBF in SCD patients but not in controls. History of stroke and current neurologic symptoms were associated with lower flow and higher cerebral blood volume. Transfusion therapy reduced the hyperemia, the reduction being greater than expected by hematocrit elevation alone. These findings document a vasodilatory hyperemia in SCD. This dilatation may be a risk factor for ischemic distal-field infarctions, as visualized by MRI, due to a limitation of cerebrovascular reserve capacity.
Annals of Clinical and Translational Neurology, 2021
Objective: To estimate muscle oxygen uptake and quantify fatigue during exercise in ambulatory in... more Objective: To estimate muscle oxygen uptake and quantify fatigue during exercise in ambulatory individuals with spinal muscular atrophy (SMA) and healthy controls. Methods: Peak aerobic capacity (VO 2peak) and workload (W peak) were measured by cardiopulmonary exercise test (CPET) in 19 ambulatory SMA patients and 16 healthy controls. Submaximal exercise (SME) at 40% W peak was performed for 10 minutes. Change in vastus lateralis deoxygenated hemoglobin, measured by near-infrared spectroscopy, determined muscle oxygen uptake (DHHb) at rest and during CPET and SME. Dual energy X-ray absorptiometry assessed fat-free mass (FFM%). Fatigue was determined by percent change in workload or distance in the first compared to the last minute of SME (Fatigue SME) and six-minute walk test (Fatigue 6MWT), respectively. Results: DHHb-PEAK, DHHb-SME, VO 2peak , W peak , FFM%, and 6MWT distance were lower (P < 0.001), and Fatigue 6MWT and Fatigue SME were higher (P < 0.001) in SMA compared to controls. DHHb-PEAK correlated with FFM% (r = 0.50) and VO 2peak (r = 0.41) only in controls. Only in SMA, Fatigue 6MWT was inversely correlated with W peak (r = À0.69), and Fatigue SME was inversely correlated with FFM% (r = À0.55) and VO 2peak (r = À0.69). Interpretation: This study provides further support for muscle mitochondrial dysfunction in SMA patients. During exercise, we observed diminished muscle oxygen uptake but no correlation with aerobic capacity or body composition. We also observed increased fatigue which correlated with decreased aerobic capacity, workload, and body composition. Understanding the mechanisms underlying diminished muscle oxygen uptake and increased fatigue during exercise in SMA may identify additional therapeutic targets that rescue symptomatic patients and mitigate their residual disease burden.
Ambulatory function and fatigue in nusinersen-treated children with spinal muscular atrophy. (P2.322)
Neurology, 2018
Objective: To examine distance walked and fatigue during the six minute walk test (6MWT) in nusin... more Objective: To examine distance walked and fatigue during the six minute walk test (6MWT) in nusinersen-treated children with spinal muscular atrophy (SMA). Background: Individuals with milder SMA phenotypes are able to walk but weakness causes gait impairments and reduced endurance. Assessments of walking ability are clinically relevant in this population. The 6MWT is a valid and reliable functional outcome measure that captures weakness and fatigue in SMA patients. Design/Methods: Two multicenter, open-label clinical trials with nusinersen enrolled patients with SMA types 2 and 3, ages 2–15 years. CS2 (NCT01703988) was an 85-day (+168-day follow up [FU]) phase 1b/2a, multiple ascending dose (3, 6, 9 or 12 mg) study, where participants had an option to continue. After a varying treatment break, CS2 patients were enrolled later in the ongoing 533-day (+182-day FU) CS12 (NCT02052791, 12 mg dose) extension study. We evaluated change in 6MWT distance and fatigue over 253 and 1050 days. ...
Early-onset cerebellar ataxia due to novel mutations in ACO2 (P2.224)
Neurology, 2015
OBJECTIVE: To report a patient with ACO2 mutation and early onset cerebellar ataxia without retin... more OBJECTIVE: To report a patient with ACO2 mutation and early onset cerebellar ataxia without retinal involvement BACKGROUND: Inherited ataxias are a group of heterogeneous disorders affecting children and adults. In almost half of the patients, the genetic cause of the disorder is unknown. ACO2 mutations have been reported in individuals from two unrelated families who presented at 2-6 months of age with truncal hypotonia, seizures, and ophthalmologic abnormalities. The course was severe with profound psychomotor retardation and progressive visual loss. CASE REPORT: We report a 3-year-old boy, born of an uncomplicated pregnancy. Family history is unremarkable. The boy had difficulties sitting and was not able to sit until 14 months. Walking ability is impaired for the presence of motor dyspraxia and he is able to walk only with bilateral support. He also present delayed speech and language development. RESULTS: Neurological examination evidenced a prominent cerebellar involvement wit...
Annals of Clinical and Translational Neurology, 2021
Objective: We report longitudinal data from 144 type III SMA pediatric and adult patients treated... more Objective: We report longitudinal data from 144 type III SMA pediatric and adult patients treated with nusinersen as part of an international effort. Methods: Patients were assessed using Hammersmith Functional Motor Scale Expanded (HFMSE), Revised Upper Limb Module (RULM), and 6-Minute Walk Test (6MWT) with a mean follow-up of 1.83 years after nusinersen treatment. Results: Over 75% of the 144 patients had a 12-month follow-up. There was an increase in the mean scores from baseline to 12 months on both HFMSE (1.18 points, p = 0.004) and RULM scores (0.58 points, p = 0.014) but not on the 6MWT (mean difference = 6.65 m, p = 0.33). When the 12-month HFMSE changes in the treated cohort were compared to an external cohort of untreated patients, in all untreated patients older than 7 years, the mean changes were always negative, while always positive in the treated ones. To reduce a selection bias, we also used a multivariable analysis. On the HFMSE scale, age, gender, baseline value, and functional status contributed significantly to the changes, while the number of SMN2 copies did not contribute. The effect of these variables was less obvious on the RULM and 6MWT. Interpretation: Our results expand the available data on the
Neurology: Clinical Practice, 2020
Funding information and disclosures are provided at the end of the article. Full disclosure form ... more Funding information and disclosures are provided at the end of the article. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp.
Pediatric physical therapy : the official publication of the Section on Pediatrics of the American Physical Therapy Association, Jul 1, 2018
To quantitatively describe passive lower extremity range of motion in participants with spinal mu... more To quantitatively describe passive lower extremity range of motion in participants with spinal muscular atrophy (SMA) types 2 and 3, and to establish preliminary thresholds to identify individuals at risk for performing poorly on disease-specific motor function outcome measures. Eighty participants with SMA types 2 and 3, enrolled in an international multicenter natural history study, were evaluated with lower extremity range of motion testing and the Hammersmith Functional Motor Scale-Expanded. A hip extension joint angle of -7.5° or less for SMA type 2 and 0° or less for SMA type 3 identified diminished motor ability with good sensitivity. For knee extension, a joint angle of -9.0° or less for SMA type 2 or 0° or less for SMA type 3 was similarly sensitive. Minimal hip and knee joint contractures were associated with diminished motor ability. Clinical trial designs should consider the effect of contractures on motor function.
Muscle & Nerve, 2017
Introduction: Gait impairment is common in spinal muscular atrophy (SMA) and is described using c... more Introduction: Gait impairment is common in spinal muscular atrophy (SMA) and is described using clinical assessments and instrumented walkways. Continuous over-ground walking has not been studied. Methods: Nine SMA participants completed the 6-minute walk test (6MWT) and 10-meter walk/ run wearing instrumented footwear (SoleSound). Data were simultaneously collected using a reference system (GAITRite). The root-mean-square error (RMSE) indicated criterion validity. The decrease in walking speed represented fatigue. Foot loading patterns were evaluated using force sensors. Results: The RMSE for stride time, length, and velocity ranged from 1.3% to 1.7%. Fatigue was 11.6 6 9.1%, which corresponded to an average deceleration of 0.37 6 0.28 mm/s 2. Participants spent most of their stance without heel contact. Forefoot contact occurred early in the gait cycle. Conclusions: These results suggest that footwear-based devices are an alternative to specialized equipment for gait assessment. Better understanding of gait disturbances should inform ongoing treatment efforts and provide a more sensitive outcome measure.
Child Neurology Open, 2016
Dystonia is often associated with the symmetrical basal ganglia lesions of Leigh syndrome. Howeve... more Dystonia is often associated with the symmetrical basal ganglia lesions of Leigh syndrome. However, it has also been associated with mitochondrial ND mutations, with or without Leber hereditary optic neuropathy. The m.14459G>A mutation in ND6 causes dystonia with or without familial Leber hereditary optic neuropathy. We report heteroplasmic 14459G>A mutations in 2 unrelated children with nonmaternally inherited generalized dystonia and showing bilateral magnetic resonance imaging lesions in nucleus pallidus and putamen. Both children have reached their teenage years, and they are intellectually active, despite their motor problems.
Neuromuscular Disorders, 2016
The aim of this retrospective multicentric study was to assess developmental milestones longitudi... more The aim of this retrospective multicentric study was to assess developmental milestones longitudinally in type I SMA infants using the Hammersmith Infant Neurological Examination. Thirty-three type I SMA infants, who classically do not achieve the ability to sit unsupported, were included in the study. Our results confirmed that all patients had a score of 0 out of a scale of 4 on items assessing sitting, rolling, crawling, standing or walking. A score of more than 0 was only achieved in three items: head control (n = 13), kicking (n = 15) and hand grasp (n = 18). In these items, the maximal score achieved was 1 out of a scale of 4, indicating only partial achievement of the milestone. Infants with symptom onset after 6 months of age had longer preservation of a score of 1 when compared to those with onset before 6 months of age. Our results suggest that even when current standards of care are applied, developmental milestones are rarely even partially achieved as part of natural history in type I SMA infants. No infants in this study achieved a major milestone such as rolling over, or sitting independently, which would therefore represent robust outcomes in future interventional trials.
The field of pediatric neuromuscular disorders has continued to expand scientifically since the e... more The field of pediatric neuromuscular disorders has continued to expand scientifically since the era of molecular neurogenetics began in the mid-1980s. The rapid changes in the field may be overwhelming to busy, practicing clinicians on a day-to-day basis. The dramatic advances in DNA diagnostics have added to the complexity of a challenging clinical field and have left physicians occasionally uncertain about the relative indications for traditional tests such as EMG and muscle biopsy. Clearly, all these diagnostic tests remain useful, and it is up to the modern clinician to make informed decisions, after the initial clinical evaluation, to facilitate an accurate biomolecular diagnosis as quickly and as economically as possible. Older children and their families are increasingly aware of these extraordinary advances through their own access to the Internet, and they challenge us to remain informed and updated. They wait impatiently for us to translate these scientific achievements in...
Epilepsia Open, 2020
This is an open access article under the terms of the Creative Commons Attribution License, which... more This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Spinal Muscular Atrophy
Oxford Medicine Online, 2017
Spinal muscular atrophy (SMA) is a common, inherited, pediatric motor neuron disorder caused by i... more Spinal muscular atrophy (SMA) is a common, inherited, pediatric motor neuron disorder caused by insufficient SMN protein. As of yet, there is no good treatment for the disease. SMA has an incidence of ~1 in 10,000 newborns carrier frequency of 1 in 50, making it the most common inherited cause of infant mortality. Patients with severe SMA, or Werdnig-Hoffman disease, typically manifest weakness during the first 6 months of life. Such patients are so debilitated that they never sit independently, frequently succumbing to the disease before age 2 years. A much milder form of SMA, Kugelberg-Welander disease, with onset after 18 months of age, often during childhood and characterized by prolonged ambulation and a normal life expectancy, was described in 1956. In 1995 mutations in a novel gene, Survival of Motor Neuron 1 (SMN1), were determined to be the specific cause of SMA.
Analysis of Gait Disturbance in Glut 1 Deficiency Syndrome
Journal of child neurology, Jan 10, 2016
Anticipating potential therapies for Glut 1 deficiency syndrome (Glut1DS) emphasizes the need for... more Anticipating potential therapies for Glut 1 deficiency syndrome (Glut1DS) emphasizes the need for effective clinical outcome measures. The 6-minute walk test is a well-established outcome measure that evaluates walking ability in neurological diseases. Twenty-one children with Glut 1 deficiency syndrome and 21 controls performed the 6-minute walk test. Fatigue was determined by comparing distance walked in the first and sixth minutes. Gait was analyzed by stride length, velocity, cadence, base of support, and percentage time in double support. Independent sample t-tests examined differences between group. Repeated-measures analysis of variance evaluated gait parameters over time. Glut 1 deficiency syndrome patients walked less (P < .05), had slower velocities (P < .0001), had shorter stride lengths (P < .0001), spent more time in double support (P < .001), and had increasing variability in base of support (P = .009). Glut 1 deficiency syndrome patients have impaired moto...
Muscle & Nerve, 2016
We evaluated the suitability of a caregiver-reported functional measure, the Pediatric Evaluation... more We evaluated the suitability of a caregiver-reported functional measure, the Pediatric Evaluation of Disability Inventory-Computer Adaptive Test (PEDI-CAT), for children and young adults with spinal muscular atrophy (SMA). Methods: PEDI-CAT Mobility and Daily Activities domain item banks were administered to 58 caregivers of children and young adults with SMA. Rasch analysis was used to evaluate test properties across SMA types. Results: Unidimensional content for each domain was confirmed. The PEDI-CAT was most informative for Type III SMA, with ability levels distributed close to 0.00 logits in both domains. It was less informative for Types I and II SMA, especially for mobility skills. Item and person abilities were not distributed evenly across all types. Conclusions: The PEDI-CAT may be used to measure functional performance in SMA, but additional items are needed to identify small changes in function and best represent the abilities of all types of SMA.
Annals of Clinical and Translational Neurology, 2021
We explored the benefits of triheptanoin as a treatment for Short Chain Enoyl Co-A Hydratase (SCE... more We explored the benefits of triheptanoin as a treatment for Short Chain Enoyl Co-A Hydratase (SCEH) deficiency. One child with early onset, severe SCEH Deficiency was treated with triheptanoin, an odd chain oil with anapleurotic properties, for 37 months. Blood and urine chemistry safety measures, motor skills assessment, physical exam, and neurological assessment were monitored over a 27 month period. Modest sustained gains in motor skills, attention, muscle bulk, and strength were observed without any significant adverse effects. Triheptanoin appears to be a promising effective treatment for SCEH Deficiency.
Table 1. [Molecular Genetic Testing Used in Glut1 DS]
University of Washington, Seattle, Mar 1, 2018
Hypotonia–cystinuria 2p21 deletion syndrome: Intrafamilial variability of clinical expression
Annals of Clinical and Translational Neurology, 2021
Two siblings presented similarly with congenital hypotonia, lactic acidosis, and failure to thriv... more Two siblings presented similarly with congenital hypotonia, lactic acidosis, and failure to thrive. Later in childhood, the brother developed cystinuria and nephrolithiasis whereas the older sister suffered from cystinuria and chronic neurobehavioral disturbances. Biopsied muscle studies demonstrated deficient cytochrome c oxidase activities consistent with a mitochondrial disease. Whole exome sequencing (WES), however, revealed a homozygous 2p21 deletion involving two contiquous genes, SLC3A1 (deletion of exons 2‐10) and PREPL (deletion of exons 2‐14). The molecular findings were consistent with the hypotonia–cystinuria 2p21 deletion syndrome, presenting similarly in infancy with mitochondrial dysfunction but diverging later in childhood and displaying intrafamilial phenotypic variability.
Journal of Inherited Metabolic Disease, 2003
Cerebral hyperemia, stroke, and transfusion in sickle cell disease
Neurology, 1989
To investigate cerebral hemodynamics in sickle cell disease (SCD), we used the 133Xenon inhalatio... more To investigate cerebral hemodynamics in sickle cell disease (SCD), we used the 133Xenon inhalation technique of quantifying cerebral blood flow (CBF) in 67 patients. Clinical examinations and cerebral magnetic resonance imaging also were performed in all patients. Compared with age-matched healthy controls, CBF was elevated by 68% in patients, and inversely related to hematocrit. An experimental index of cerebral blood volume, pr4, was also elevated in the patients in a similar manner. Cerebral blood volume was positively correlated to CBF in SCD patients but not in controls. History of stroke and current neurologic symptoms were associated with lower flow and higher cerebral blood volume. Transfusion therapy reduced the hyperemia, the reduction being greater than expected by hematocrit elevation alone. These findings document a vasodilatory hyperemia in SCD. This dilatation may be a risk factor for ischemic distal-field infarctions, as visualized by MRI, due to a limitation of cerebrovascular reserve capacity.
Annals of Clinical and Translational Neurology, 2021
Objective: To estimate muscle oxygen uptake and quantify fatigue during exercise in ambulatory in... more Objective: To estimate muscle oxygen uptake and quantify fatigue during exercise in ambulatory individuals with spinal muscular atrophy (SMA) and healthy controls. Methods: Peak aerobic capacity (VO 2peak) and workload (W peak) were measured by cardiopulmonary exercise test (CPET) in 19 ambulatory SMA patients and 16 healthy controls. Submaximal exercise (SME) at 40% W peak was performed for 10 minutes. Change in vastus lateralis deoxygenated hemoglobin, measured by near-infrared spectroscopy, determined muscle oxygen uptake (DHHb) at rest and during CPET and SME. Dual energy X-ray absorptiometry assessed fat-free mass (FFM%). Fatigue was determined by percent change in workload or distance in the first compared to the last minute of SME (Fatigue SME) and six-minute walk test (Fatigue 6MWT), respectively. Results: DHHb-PEAK, DHHb-SME, VO 2peak , W peak , FFM%, and 6MWT distance were lower (P < 0.001), and Fatigue 6MWT and Fatigue SME were higher (P < 0.001) in SMA compared to controls. DHHb-PEAK correlated with FFM% (r = 0.50) and VO 2peak (r = 0.41) only in controls. Only in SMA, Fatigue 6MWT was inversely correlated with W peak (r = À0.69), and Fatigue SME was inversely correlated with FFM% (r = À0.55) and VO 2peak (r = À0.69). Interpretation: This study provides further support for muscle mitochondrial dysfunction in SMA patients. During exercise, we observed diminished muscle oxygen uptake but no correlation with aerobic capacity or body composition. We also observed increased fatigue which correlated with decreased aerobic capacity, workload, and body composition. Understanding the mechanisms underlying diminished muscle oxygen uptake and increased fatigue during exercise in SMA may identify additional therapeutic targets that rescue symptomatic patients and mitigate their residual disease burden.
Ambulatory function and fatigue in nusinersen-treated children with spinal muscular atrophy. (P2.322)
Neurology, 2018
Objective: To examine distance walked and fatigue during the six minute walk test (6MWT) in nusin... more Objective: To examine distance walked and fatigue during the six minute walk test (6MWT) in nusinersen-treated children with spinal muscular atrophy (SMA). Background: Individuals with milder SMA phenotypes are able to walk but weakness causes gait impairments and reduced endurance. Assessments of walking ability are clinically relevant in this population. The 6MWT is a valid and reliable functional outcome measure that captures weakness and fatigue in SMA patients. Design/Methods: Two multicenter, open-label clinical trials with nusinersen enrolled patients with SMA types 2 and 3, ages 2–15 years. CS2 (NCT01703988) was an 85-day (+168-day follow up [FU]) phase 1b/2a, multiple ascending dose (3, 6, 9 or 12 mg) study, where participants had an option to continue. After a varying treatment break, CS2 patients were enrolled later in the ongoing 533-day (+182-day FU) CS12 (NCT02052791, 12 mg dose) extension study. We evaluated change in 6MWT distance and fatigue over 253 and 1050 days. ...
Early-onset cerebellar ataxia due to novel mutations in ACO2 (P2.224)
Neurology, 2015
OBJECTIVE: To report a patient with ACO2 mutation and early onset cerebellar ataxia without retin... more OBJECTIVE: To report a patient with ACO2 mutation and early onset cerebellar ataxia without retinal involvement BACKGROUND: Inherited ataxias are a group of heterogeneous disorders affecting children and adults. In almost half of the patients, the genetic cause of the disorder is unknown. ACO2 mutations have been reported in individuals from two unrelated families who presented at 2-6 months of age with truncal hypotonia, seizures, and ophthalmologic abnormalities. The course was severe with profound psychomotor retardation and progressive visual loss. CASE REPORT: We report a 3-year-old boy, born of an uncomplicated pregnancy. Family history is unremarkable. The boy had difficulties sitting and was not able to sit until 14 months. Walking ability is impaired for the presence of motor dyspraxia and he is able to walk only with bilateral support. He also present delayed speech and language development. RESULTS: Neurological examination evidenced a prominent cerebellar involvement wit...
Annals of Clinical and Translational Neurology, 2021
Objective: We report longitudinal data from 144 type III SMA pediatric and adult patients treated... more Objective: We report longitudinal data from 144 type III SMA pediatric and adult patients treated with nusinersen as part of an international effort. Methods: Patients were assessed using Hammersmith Functional Motor Scale Expanded (HFMSE), Revised Upper Limb Module (RULM), and 6-Minute Walk Test (6MWT) with a mean follow-up of 1.83 years after nusinersen treatment. Results: Over 75% of the 144 patients had a 12-month follow-up. There was an increase in the mean scores from baseline to 12 months on both HFMSE (1.18 points, p = 0.004) and RULM scores (0.58 points, p = 0.014) but not on the 6MWT (mean difference = 6.65 m, p = 0.33). When the 12-month HFMSE changes in the treated cohort were compared to an external cohort of untreated patients, in all untreated patients older than 7 years, the mean changes were always negative, while always positive in the treated ones. To reduce a selection bias, we also used a multivariable analysis. On the HFMSE scale, age, gender, baseline value, and functional status contributed significantly to the changes, while the number of SMN2 copies did not contribute. The effect of these variables was less obvious on the RULM and 6MWT. Interpretation: Our results expand the available data on the
Neurology: Clinical Practice, 2020
Funding information and disclosures are provided at the end of the article. Full disclosure form ... more Funding information and disclosures are provided at the end of the article. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp.
Pediatric physical therapy : the official publication of the Section on Pediatrics of the American Physical Therapy Association, Jul 1, 2018
To quantitatively describe passive lower extremity range of motion in participants with spinal mu... more To quantitatively describe passive lower extremity range of motion in participants with spinal muscular atrophy (SMA) types 2 and 3, and to establish preliminary thresholds to identify individuals at risk for performing poorly on disease-specific motor function outcome measures. Eighty participants with SMA types 2 and 3, enrolled in an international multicenter natural history study, were evaluated with lower extremity range of motion testing and the Hammersmith Functional Motor Scale-Expanded. A hip extension joint angle of -7.5° or less for SMA type 2 and 0° or less for SMA type 3 identified diminished motor ability with good sensitivity. For knee extension, a joint angle of -9.0° or less for SMA type 2 or 0° or less for SMA type 3 was similarly sensitive. Minimal hip and knee joint contractures were associated with diminished motor ability. Clinical trial designs should consider the effect of contractures on motor function.
Muscle & Nerve, 2017
Introduction: Gait impairment is common in spinal muscular atrophy (SMA) and is described using c... more Introduction: Gait impairment is common in spinal muscular atrophy (SMA) and is described using clinical assessments and instrumented walkways. Continuous over-ground walking has not been studied. Methods: Nine SMA participants completed the 6-minute walk test (6MWT) and 10-meter walk/ run wearing instrumented footwear (SoleSound). Data were simultaneously collected using a reference system (GAITRite). The root-mean-square error (RMSE) indicated criterion validity. The decrease in walking speed represented fatigue. Foot loading patterns were evaluated using force sensors. Results: The RMSE for stride time, length, and velocity ranged from 1.3% to 1.7%. Fatigue was 11.6 6 9.1%, which corresponded to an average deceleration of 0.37 6 0.28 mm/s 2. Participants spent most of their stance without heel contact. Forefoot contact occurred early in the gait cycle. Conclusions: These results suggest that footwear-based devices are an alternative to specialized equipment for gait assessment. Better understanding of gait disturbances should inform ongoing treatment efforts and provide a more sensitive outcome measure.
Child Neurology Open, 2016
Dystonia is often associated with the symmetrical basal ganglia lesions of Leigh syndrome. Howeve... more Dystonia is often associated with the symmetrical basal ganglia lesions of Leigh syndrome. However, it has also been associated with mitochondrial ND mutations, with or without Leber hereditary optic neuropathy. The m.14459G>A mutation in ND6 causes dystonia with or without familial Leber hereditary optic neuropathy. We report heteroplasmic 14459G>A mutations in 2 unrelated children with nonmaternally inherited generalized dystonia and showing bilateral magnetic resonance imaging lesions in nucleus pallidus and putamen. Both children have reached their teenage years, and they are intellectually active, despite their motor problems.
Neuromuscular Disorders, 2016
The aim of this retrospective multicentric study was to assess developmental milestones longitudi... more The aim of this retrospective multicentric study was to assess developmental milestones longitudinally in type I SMA infants using the Hammersmith Infant Neurological Examination. Thirty-three type I SMA infants, who classically do not achieve the ability to sit unsupported, were included in the study. Our results confirmed that all patients had a score of 0 out of a scale of 4 on items assessing sitting, rolling, crawling, standing or walking. A score of more than 0 was only achieved in three items: head control (n = 13), kicking (n = 15) and hand grasp (n = 18). In these items, the maximal score achieved was 1 out of a scale of 4, indicating only partial achievement of the milestone. Infants with symptom onset after 6 months of age had longer preservation of a score of 1 when compared to those with onset before 6 months of age. Our results suggest that even when current standards of care are applied, developmental milestones are rarely even partially achieved as part of natural history in type I SMA infants. No infants in this study achieved a major milestone such as rolling over, or sitting independently, which would therefore represent robust outcomes in future interventional trials.