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... 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...
Research Interests:
Research Interests:
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... 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.
Research Interests:
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... 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...
Research Interests:
Research Interests: Psychology, Locomotion, Adolescent, Medicine, Physical Medicine and Rehabilitation, and 15 moreActivities of Daily Living, Humans, Child, Female, Computerized Adaptive Testing, Male, Infant, Caregivers, Rasch Model, Reproducibility of Results, Disabled Persons, Mobility limitation, Disability Evaluation, Child preschool, and Medical and Health Sciences
Research Interests:
Research Interests:
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... 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.
Research Interests:
Research Interests:
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... 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.
Research Interests:
Research Interests:
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... 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. ...
Research Interests:
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... 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...
Research Interests:
Research Interests:
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... 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.
Research Interests:
Research Interests:
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... 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.
Research Interests:
Research Interests:
Research Interests:
Research Interests:
REFERENCES 1. Kang PB, Gooch CL, McDermott MP, Darras BT, Finkel RS, Yang ML, et al. The motor neuron response to SMN1 deficiency in spinal muscular atrophy. Muscle Nerve 2014;49:636–644. 2. Swoboda KJ, Prior TW, Scott CB, McNaught TP,... more
REFERENCES 1. Kang PB, Gooch CL, McDermott MP, Darras BT, Finkel RS, Yang ML, et al. The motor neuron response to SMN1 deficiency in spinal muscular atrophy. Muscle Nerve 2014;49:636–644. 2. Swoboda KJ, Prior TW, Scott CB, McNaught TP, Wride MC, Reyna SP, et al. Natural history of denervation in SMA: relation to age, SMN2 copy number, and function. Ann Neurol 2005;57:704–712. 3. Finkel RS. Electrophysiological and motor function scale association in a pre-symptomatic infant with spinal muscular atrophy type I. Neuromuscul Disord 2013;23:112–115. 4. Tapia JC, Wylie JD, Kasthuri N, Hayworth KJ, Schalek R, Berger DR, et al. Pervasive synaptic branch removal in the mammalian neuromuscular system at birth. Neuron 2012;74:816–829. 5. Barry JA, Ribchester RR. Persistent polyneuronal innervation in partially denervated rat muscle after reinnervation and recovery from prolonged nerve conduction block. J Neurosci 1995;15:6327–6339.
Research Interests:
To define this genetic syndrome. The constellation of infantile epilepsy, acquired microcephaly and hypoglychorrachia is characteristic of glucose transporter type 1 (Glut1) deficiency syndrome, a prototype neurometabolic disorder caused... more
To define this genetic syndrome. The constellation of infantile epilepsy, acquired microcephaly and hypoglychorrachia is characteristic of glucose transporter type 1 (Glut1) deficiency syndrome, a prototype neurometabolic disorder caused by inheritable mutations in the gene SLC2A1. All known mutations reduce the function of Glut1 in the blood brain barrier and thus limit brain glucose availability. As the cerebral metabolic rate for glucose increases during infancy, patients become gradually symptomatic, a phenomenon that underscores the importance of early diagnosis via lumbar puncture and treatment, which has meet with some success in ameliorating several --but not all-- features of the disease. The increasing number of mild phenotypic variants being described, owing to the improved awareness of the disease, has led to the consideration of Glut1 deficiency in the diagnosis of infantile seizures, mental retardation, familial epilepsy and movement disorders.
Research Interests:
Research Interests:
Research Interests:
Research Interests:
Research Interests:
Research Interests:
Impaired mobility and fatigue are common in ambulatory spinal muscular atrophy (SMA) patients. The 6-minute walk test (6MWT) is a reliable measure of fatigue in SMA patients. To further evaluate fatigue, we used quantitative gait analysis... more
Impaired mobility and fatigue are common in ambulatory spinal muscular atrophy (SMA) patients. The 6-minute walk test (6MWT) is a reliable measure of fatigue in SMA patients. To further evaluate fatigue, we used quantitative gait analysis during the 6MWT. Nine subjects with SMA and 9 age- and gender-matched, healthy controls were evaluated. Gait parameters of speed and dynamic balance were correlated with 6MWT distance. Performance during the first and last 25 meters of the 6MWT was compared. Speed-related gait parameters and support base correlated with 6MWT distance. Walking performance was worse for SMA patients. The deterioration in stride length during the 6MWT was greater in SMA patients than in controls. Gait analysis detects fatigue, and the decrement in stride length may reflect selective muscle involvement in SMA. Further understanding of the mechanisms underlying fatigue may suggest additional targets for future therapeutic interventions.
Research Interests:
Individuals with spinal muscular atrophy (SMA) type 3 are able to walk but they have weakness, gait impairments and fatigue. Our primary study objective was to examine longitudinal changes in the six-minute walk test (6MWT) and to... more
Individuals with spinal muscular atrophy (SMA) type 3 are able to walk but they have weakness, gait impairments and fatigue. Our primary study objective was to examine longitudinal changes in the six-minute walk test (6MWT) and to evaluate whether age and SMA type 3 subtype are associated with decline in ambulatory function. Data from three prospective natural history studies were used. Seventy-three participants who performed the 6MWT more than once, at least 6 months apart, were included; follow-up ranged from 0.5-9 years. Only data from patients who completed the 6MWT were included. The mean age of the participants was 13.5 years (range 2.6-49.1), with 52 having disease onset before age 3 years (type 3A). At baseline, type 3A participants walked a shorter distance on average (257.1 m) than type 3B participants (390.2 m) (difference = 133.1 m, 95% confidence interval [CI] 71.8-194.3, p < 0.001). Distance walked was weakly associated with age (r = 0.25, p = 0.04). Linear mixed e...
Research Interests:
Training methodology was established to optimize reliability of outcome measures in the nusinersen clinical trials. The Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND), Hammersmith Functional... more
Training methodology was established to optimize reliability of outcome measures in the nusinersen clinical trials. The Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND), Hammersmith Functional Motor Scale Expanded (HFMSE), and Revised Upper Limb (RULM) were primary or secondary outcomes. Video review, quarterly conference calls, and item scoring checks supported evaluator competence. Baseline and screening along with video review established intra and inter-rater reliability. Inter and intra-rater reliability were both excellent. Intraclass correlation coefficients (ICC) ranged between 0.906-0.994 across initial training meetings and 0.824-0.996 across annual retraining meetings. This was similar for CHOP INTEND (ICC = 0.824-0.951), HFMSE (ICC = 0.981-0.996), and RULM (ICC = 0.966-0.990). Intra-rater reliability for the CHOP INTEND, HFMSE, and RULM were ICC = 0.895 (95% CI: 0.852-0.926; n = 116), ICC = 0.959 (95% CI: 0.942-0.971; n = 125),...
Research Interests:
PurposeTo determine feasibility and utility of newborn screening for spinal muscular atrophy (SMA) in New York State.MethodsWe validated a multiplex TaqMan real-time quantitative polymerase chain reaction assay using dried blood spots for... more
PurposeTo determine feasibility and utility of newborn screening for spinal muscular atrophy (SMA) in New York State.MethodsWe validated a multiplex TaqMan real-time quantitative polymerase chain reaction assay using dried blood spots for SMA. From January 2016 to January 2017, we offered, consented, and screened 3,826 newborns at three hospitals in New York City and tested newborns for the deletion in exon 7 of SMN1.ResultsNinety-three percent of parents opted in for SMA screening. Overall the SMA carrier frequency was 1.5%. We identified one newborn with a homozygous SMN1 deletion and two copies of SMN2, which strongly suggests the severe type 1 SMA phenotype. The infant was enrolled in the NURTURE clinical trial and was first treated with Spinraza at age 15 days. She is now age 12 months, meeting all developmental milestones, and free of any respiratory issues.ConclusionOur pilot study demonstrates the feasibility of population-based screening, the acceptance by families, and the...
Research Interests:
Spinal muscular atrophy is an autosomal recessive neuromuscular disorder that is caused by an insufficient level of survival motor neuron (SMN) protein. Nusinersen is an antisense oligonucleotide drug that modifies pre-messenger RNA... more
Spinal muscular atrophy is an autosomal recessive neuromuscular disorder that is caused by an insufficient level of survival motor neuron (SMN) protein. Nusinersen is an antisense oligonucleotide drug that modifies pre-messenger RNA splicing of the SMN2 gene and thus promotes increased production of full-length SMN protein. We conducted a randomized, double-blind, sham-controlled, phase 3 efficacy and safety trial of nusinersen in infants with spinal muscular atrophy. The primary end points were a motor-milestone response (defined according to results on the Hammersmith Infant Neurological Examination) and event-free survival (time to death or the use of permanent assisted ventilation). Secondary end points included overall survival and subgroup analyses of event-free survival according to disease duration at screening. Only the first primary end point was tested in a prespecified interim analysis. To control the overall type I error rate at 0.05, a hierarchical testing strategy was...
Research Interests:
To describe a characteristic paroxysmal eye-head movement disorder that occurs in infants with Glut1 deficiency syndrome (Glut1 DS). We retrospectively reviewed the medical charts of 101 patients with Glut1 DS to obtain clinical data... more
To describe a characteristic paroxysmal eye-head movement disorder that occurs in infants with Glut1 deficiency syndrome (Glut1 DS). We retrospectively reviewed the medical charts of 101 patients with Glut1 DS to obtain clinical data about episodic abnormal eye movements and analyzed video recordings of 18 eye movement episodes from 10 patients. A documented history of paroxysmal abnormal eye movements was found in 32/101 patients (32%), and a detailed description was available in 18 patients, presented here. Episodes started before age 6 months in 15/18 patients (83%), and preceded the onset of seizures in 10/16 patients (63%) who experienced both types of episodes. Eye movement episodes resolved, with or without treatment, by 6 years of age in 7/8 patients with documented long-term course. Episodes were brief (usually <5 minutes). Video analysis revealed that the eye movements were rapid, multidirectional, and often accompanied by a head movement in the same direction. Eye move...
Research Interests:
Haploinsufficiency of the SLC2A1 gene and paucity of its translated product, the glucose transporter-1 (Glut1) protein, disrupt brain function and cause the neurodevelopmental disorder, Glut1 deficiency syndrome (Glut1 DS). There is... more
Haploinsufficiency of the SLC2A1 gene and paucity of its translated product, the glucose transporter-1 (Glut1) protein, disrupt brain function and cause the neurodevelopmental disorder, Glut1 deficiency syndrome (Glut1 DS). There is little to suggest how reduced Glut1 causes cognitive dysfunction and no optimal treatment for Glut1 DS. We used model mice to demonstrate that low Glut1 protein arrests cerebral angiogenesis, resulting in a profound diminution of the brain microvasculature without compromising the blood-brain barrier. Studies to define the temporal requirements for Glut1 reveal that pre-symptomatic, AAV9-mediated repletion of the protein averts brain microvasculature defects and prevents disease, whereas augmenting the protein late, during adulthood, is devoid of benefit. Still, treatment following symptom onset can be effective; Glut1 repletion in early-symptomatic mutants that have experienced sustained periods of low brain glucose nevertheless restores the cerebral mi...
Research Interests:
Nusinersen is a 2&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;-O-methoxyethyl phosphorothioate-modified antisense drug being developed to treat spinal muscular atrophy. Nusinersen is... more
Nusinersen is a 2&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;-O-methoxyethyl phosphorothioate-modified antisense drug being developed to treat spinal muscular atrophy. Nusinersen is specifically designed to alter splicing of SMN2 pre-mRNA and thus increase the amount of functional survival motor neuron (SMN) protein that is deficient in patients with spinal muscular atrophy. This open-label, phase 2, escalating dose clinical study assessed the safety and tolerability, pharmacokinetics, and clinical efficacy of multiple intrathecal doses of nusinersen (6 mg and 12 mg dose equivalents) in patients with infantile-onset spinal muscular atrophy. Eligible participants were of either gender aged between 3 weeks and 7 months old with onset of spinal muscular atrophy symptoms between 3 weeks and 6 months, who had SMN1 homozygous gene deletion or mutation. Safety assessments included adverse events, physical and neurological examinations, vital signs, clinical laboratory tests, cerebrospinal fluid laboratory tests, and electrocardiographs. Clinical efficacy assessments included event free survival, and change from baseline of two assessments of motor function: the motor milestones portion of the Hammersmith Infant Neurological Exam-Part 2 (HINE-2) and the Children&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) motor function test, and compound motor action potentials. Autopsy tissue was analysed for target engagement, drug concentrations, and pharmacological activity. HINE-2, CHOP-INTEND, and compound motor action potential were compared between baseline and last visit using the Wilcoxon signed-rank test. Age at death or permanent ventilation was compared with natural history using the log-rank test. The study is registered at ClinicalTrials.gov, number NCT01839656. 20 participants were enrolled between May 3, 2013, and July 9, 2014, and assessed through to an interim analysis done on Jan 26, 2016. All participants experienced adverse events, with 77 serious adverse events reported in 16 participants, all considered by study investigators not related or unlikely related to the study drug. In the 12 mg dose group, incremental achievements of motor milestones (p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0·0001), improvements in CHOP-INTEND motor function scores (p=0·0013), and increased compound muscle action potential amplitude of the ulnar nerve (p=0·0103) and peroneal nerve (p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0·0001), compared with baseline, were observed. Median age at death or permanent ventilation was not reached and the Kaplan-Meier survival curve diverged from a published natural history case series (p=0·0014). Analysis of autopsy tissue from patients exposed to nusinersen showed drug uptake into motor neurons throughout the spinal cord and neurons and other cell types in the brainstem and other brain regions, exposure at therapeutic concentrations, and increased SMN2 mRNA exon 7 inclusion and SMN protein concentrations in the spinal cord. Administration of multiple intrathecal doses of nusinersen showed acceptable safety and tolerability, pharmacology consistent with its intended mechanism of action, and encouraging clinical efficacy. Results informed the design of an ongoing, sham-controlled, phase 3 clinical study of nusinersen in infantile-onset spinal muscular atrophy. Ionis Pharmaceuticals, Inc and Biogen.
Research Interests:
Research Interests:
CoQ10 deficiency has been recently described in tissues of a patient with GLUT1 deficiency syndrome. Here, we investigated patients and mice with GLUT1 deficiency in order to determine whether low CoQ is a recurrent biochemical feature of... more
CoQ10 deficiency has been recently described in tissues of a patient with GLUT1 deficiency syndrome. Here, we investigated patients and mice with GLUT1 deficiency in order to determine whether low CoQ is a recurrent biochemical feature of this disorder, to justify CoQ10 supplementation as therapeutic option.CoQ10 levels were investigated in plasma, white blood cells, and skin fibroblasts of 16 patients and healthy controls and in the brain, cerebellum, liver, kidney, muscle, and plasma of 4-month-old GLUT1 mutant and control mice.CoQ10 levels in plasma did not show any difference compared with controls. Since most of the patients studied were on a ketogenic diet, which can alter CoQ10 content in plasma, we also analyzed white blood cells and cultured skin fibroblasts. Again, we found no differences. In mice, we found slightly reduced CoQ in the cerebellum, likely an epiphenomenon, and activity of the mitochondrial respiratory chain enzymes was normal.Our data from GLUT1 deficiency p...
Research Interests:
1. Most mammalian muscles consist of a mixture of different muscle fiber types. 2. We analyzed various muscles with different percentages of slow and fast fibers in addition to other organs of rat for enzyme activities of beta-oxidation... more
1. Most mammalian muscles consist of a mixture of different muscle fiber types. 2. We analyzed various muscles with different percentages of slow and fast fibers in addition to other organs of rat for enzyme activities of beta-oxidation and the purine nucleotide cycle (PNC). 3. According to the content of slow-twitch fibers all enzymes of beta-oxidation were high in activity whereas enzymes of the purine nucleotide cycle were low. 4. Amongst all enzymes of beta-oxidation, crotonase showed the highest activity. 5. In heart muscle, enzyme activities of beta-oxidation were even higher than in m. soleus which consists almost exclusively of slow-twitch type I fibers. 6. Measurements of all three enzymes involved in the purine nucleotide cycle revealed high activities in muscles predominantly composed of fast-twitch fibers. 7. It was always adenylate deaminase which revealed the highest activity. 8. Heart muscle showed low activities for enzymes of PNC.
Research Interests:
Opinion statement – •Mitochondrial diseases are disorders of energy metabolism that include defects of pyruvate metabolism, Krebs cycle, respiratory chain (RC), and fatty acid oxidation (FAO). – •Treatment of pyruvate metabolism,... more
Opinion statement – •Mitochondrial diseases are disorders of energy metabolism that include defects of pyruvate metabolism, Krebs cycle, respiratory chain (RC), and fatty acid oxidation (FAO). – •Treatment of pyruvate metabolism, Krebs cycle, and RC disorders is, in general, disappointing. Therapeutic approaches consist of electron acceptors, enzyme activators, vitamins, coenzymes, free-radical scavengers, dietary measures, and supportive therapy. These treatment assumptions
Research Interests:
Research Interests:
Introduction: Nemaline myopathy (NM) is a congenital neuromuscular disorder often characterized by hypotonia, facial weakness, skeletal muscle weakness, and the presence of rods on muscle biopsy. A rare form of nemaline myopathy known as... more
Introduction: Nemaline myopathy (NM) is a congenital neuromuscular disorder often characterized by hypotonia, facial weakness, skeletal muscle weakness, and the presence of rods on muscle biopsy. A rare form of nemaline myopathy known as Amish Nemaline Myopathy has only been seen in a genetically isolated cohort of Old Order Amish patients who may additionally present with tremors in the first 2-3 months of life. Methods: We describe an Hispanic male diagnosed with nemaline myopathy histopathologically and subsequently confirmed by next generation gene sequencing. Results: Direct sequencing revealed that he is homozygous for a pathogenic nonsense variant c.323C&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;G (p.S108X) in exon 9 of the TNNT1 gene. Conclusions: This report describes a novel pathogenic variant in the TNNT1 gene and represents a nemaline myopathy-causing variant in the TNNT1 gene outside of the Old Order Amish and Dutch ancestry. Muscle Nerve, 2015.
Research Interests:
Research Interests:
Research Interests:
... from Novartis.” But on another website (http://www.princetoncme.com/public/ 2004-79-4/) I found the following disclosure: “Ilo E. Leppik, MD: Honoraria/Consultant/Speaker/Grant– Abbott Laboratories, AstraZeneca, Athena, Bristol-Myers... more
... from Novartis.” But on another website (http://www.princetoncme.com/public/ 2004-79-4/) I found the following disclosure: “Ilo E. Leppik, MD: Honoraria/Consultant/Speaker/Grant– Abbott Laboratories, AstraZeneca, Athena, Bristol-Myers Squibb, Carter-Wallace, Cephalon, Ciba ...