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D M Escolar,
L P Hache,
P R Clemens,
A Cnaan,
C M McDonald,
V Viswanathan,
A J Kornberg,
T E Bertorini,
Y Nevo, T Lotze, [......],
M M Ryan,
E Monasterio,
J W Day,
A Zimmerman,
A Arrieta,
E Henricson,
J Mayhew,
J Florence,
F Hu,
A M Connolly
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ABSTRACT: To perform a double-blind, randomized study comparing efficacy and safety of daily and weekend prednisone in boys with Duchenne muscular dystrophy (DMD).
A total of 64 boys with DMD who were between 4 and 10 years of age were randomized at 1 of 12 centers of the Cooperative International Neuromuscular Research Group. Efficacy and safety of 2 prednisone schedules (daily 0.75 mg/kg/day and weekend 10 mg/kg/wk) were evaluated over 12 months.
Equivalence was met for weekend and daily dosing of prednisone for the primary outcomes of quantitative muscle testing (QMT) arm score and QMT leg score. Secondary strength scores for QMT elbow flexors also showed equivalence between the 2 treatment groups. Overall side effect profiles of height and weight, bone density, cataract formation, blood pressure, and behavior, analyzed at 12 months, did not differ between weekend and daily dosing of prednisone.
Weekend dosing of prednisone is equally beneficial to the standard daily dosing of prednisone. Analysis of side effect profiles demonstrated overall tolerability of both dosing regimens.
This study provides Class I evidence that weekend prednisone dosing is as safe and effective as daily prednisone in preserving muscle strength and preventing body mass index increases in boys with DMD over a 12-month period.
Neurology 08/2011; 77(5):444-52. · 8.31 Impact Factor
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S U Dhar,
F Scaglia,
F-Y Li,
L Smith,
B A Barshop,
C M Eng,
R H Haas,
J V Hunter, T Lotze,
B Maranda,
M Willis,
J E Abdenur,
E Chen,
W O'Brien,
L-J C Wong
[show abstract]
[hide abstract]
ABSTRACT: Guanidinoacetate methyltransferase (GAMT) deficiency is a disorder of creatine biosynthesis, characterized by excessive amounts of guanidinoacetate in body fluids, deficiency of creatine in the brain, and presence of mutations in the GAMT gene. We present here 8 new patients with GAMT deficiency along with their clinical, biochemical and molecular data. The age at diagnosis of our patients ranges from 0 to 14 years. The age of onset of seizures usually ranges from infancy to 3 years. However, one of our patients developed seizures at age 5; progressing to myoclonic epilepsy at age 8 years and another patient has not developed seizures at age 17 years. Five novel mutations were identified: c.37ins26 (p.G13PfsX38), c.403G>T (p.D135Y), c.507_521dup15 (p.C169_S173dup), c.402C>G (p.Y134X) and c.610_611delAGinsGAA (p.R204EfsX63). Six patients had the c.327G>A (last nucleotide of exon 2) splice-site mutation which suggests that this is one of the most common mutations in the GAMT gene, second only to the known Portuguese founder mutation, c.59G>C (p.W20S). Our data suggests that the clinical presentation can be variable and the diagnosis may be overlooked due to unawareness of this disorder. Therefore, GAMT deficiency should be considered in the differential diagnosis of progressive myoclonic epilepsy as well as in unexplained developmental delay or regression with dystonia, even if the patient has no history of seizures. As more patients are reported, the prevalence of GAMT deficiency will become known and guidelines for prenatal diagnosis, newborn screening, presymptomatic testing and treatment, will need to be formulated.
Molecular Genetics and Metabolism 12/2008; 96(1):38-43. · 3.19 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Acute disseminated encephalomyelitis (ADEM) is typically a monophasic demyelinating disorder. However, a clinical presentation consistent with ADEM can also be the first manifestation of multiple sclerosis (MS), particularly in children. Quantitative analyses of MRI images from children with monophasic ADEM have yet to be compared with those from children with MS, and MRI criteria capable of distinguishing ADEM from MS at onset have yet to be derived.
A retrospective analysis of MRI scans obtained at first attack from 28 children subsequently diagnosed with MS and 20 children with ADEM was performed. T2/fluid-attenuated inversion recovery hyperintense lesions were quantified and categorized according to location, description, and size. T1-weighted images before and after administration of gadolinium were evaluated for the presence of black holes and for gadolinium enhancement. Mean lesion counts and qualitative features were compared between groups and analyzed to create a proposed diagnostic model.
Total lesion number did not differentiate ADEM from MS, but periventricular lesions were more frequent in children with MS. Combined quantitative and qualitative analyses led to the following criteria to distinguish MS from ADEM: any two of 1) absence of a diffuse bilateral lesion pattern, 2) presence of black holes, and 3) presence of two or more periventricular lesions. Using these criteria, MS patients at first attack could be distinguished from monophasic ADEM patients with an 81% sensitivity and a 95% specificity.
MRI diagnostic criteria are proposed that may be useful in differentiating children experiencing the first attack of multiple sclerosis from those with monophasic acute disseminated encephalomyelitis.
Neurology 12/2008; 72(11):968-73. · 8.31 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: MRI diagnostic criteria have not yet been adopted for pediatric multiple sclerosis (MS). MRI plays a pivotal role in supporting the diagnosis of MS in adults. We sought to quantitatively define the MRI features of pediatric MS, to determine features that distinguish MS from nondemyelinating relapsing childhood neurologic disorders, and to propose MRI criteria for lesion dissemination in space in children with MS.
A retrospective analysis of MRI scans from 38 children with clinically definite MS and 45 children with nondemyelinating diseases with relapsing neurologic deficits (migraine, systemic lupus erythematosus) was performed. For each scan, T2/FLAIR hyperintense lesions were quantified and categorized according to location and size. Mean lesion counts in specific locations were compared between groups to derive diagnostic criteria. Validation of the proposed criteria was performed using MRI scans from a second independent MS cohort (n = 21).
MRI lesion location and size categories differed between children with MS and nondemyelinating controls with a medium to large effect size for most variables. The presence of at least two of the following-five or more lesions, two or more periventricular lesions, or one brainstem lesion-distinguished MS from other nondemyelinating disease controls with 85% sensitivity and 98% specificity.
We propose modifications to the currently established McDonald MRI criteria for lesion dissemination in space that will enhance the diagnostic accuracy of these criteria for multiple sclerosis in children.
Neurology 12/2008; 72(11):961-7. · 8.31 Impact Factor
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A McKeon,
V A Lennon, T Lotze,
S Tenenbaum,
J M Ness,
M Rensel,
N L Kuntz,
J P Fryer,
H Homburger,
J Hunter,
B G Weinshenker,
K Krecke,
C F Lucchinetti,
S J Pittock
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[hide abstract]
ABSTRACT: In adult patients, autoantibodies targeting the water channel aquaporin-4 (AQP4) are a biomarker for a spectrum of CNS inflammatory demyelinating disorders with predilection for optic nerves and spinal cord (neuromyelitis optica [NMO]). Here we describe the neurologic, serologic, and radiographic findings associated with CNS AQP4 autoimmunity in childhood.
A total of 88 consecutive seropositive children were identified through service evaluation for NMO-IgG. Sera of 75 were tested for coexisting autoantibodies. Clinical information was available for 58.
Forty-two patients (73%) were non-Caucasian, and 20 (34%) had African ethnicity. Median age at symptom onset was 12 years (range 4-18). Fifty-seven (98%) had attacks of either optic neuritis (n = 48; 83%) or transverse myelitis (n = 45; 78%), or both. Twenty-six (45%) had episodic cerebral symptoms (encephalopathy, ophthalmoparesis, ataxia, seizures, intractable vomiting, or hiccups). Thirty-eight (68%) had brain MRI abnormalities, predominantly involving periventricular areas (in descending order of frequency): the medulla, supratentorial and infratentorial white matter, midbrain, cerebellum, thalamus, and hypothalamus. Additional autoantibodies were detected in 57 of 75 patients (76%), and 16 of 38 (42%) had a coexisting autoimmune disorder recorded (systemic lupus erythematosus, Sjögren syndrome, juvenile rheumatoid arthritis, Graves disease). Attacks were recurrent in 54 patients (93%; median follow-up, 12 months). Forty-three of 48 patients (90%) had residual disability: 26 (54%) visual impairment and 21 (44%) motor deficits (median Expanded Disability Status Scale 4.0 at 12 months).
Aquaporin-4 autoimmunity is a distinctive recurrent and widespread inflammatory CNS disease in children.
Neurology 08/2008; 71(2):93-100. · 8.31 Impact Factor
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ABSTRACT: While many methods have been proposed for detecting disease outbreaks from pre-diagnostic data, their performance is usually not well understood. In this paper, we describe the relationship between forecast accuracy and the detection accuracy of a method. We argue that most existing temporal detection methods for biosurveillance can be characterized as a forecasting component coupled with a monitoring/detection component. We show that improved forecasting results in improved detection and we quantify the relationship between forecast accuracy and detection metrics under different scenarios. The forecast accuracy can then be used to rate an algorithm's expected performance in detecting outbreaks. Simulation is used to compare empirical performance with theoretical results; we also show examples with authentic biosurveillance data.
Technologies for Homeland Security, 2008 IEEE Conference on; 06/2008
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[hide abstract]
ABSTRACT: The paroxysmal dyskinesias (PxDs) are involuntary, intermittent movement disorders manifested by dystonia, chorea, athetosis, ballismus or any combination of these hyperkinetic disorders. Paroxysmal kinesigenic dyskinesia (PKD), one of the four main types of PxD, involves sudden attacks of dyskinesias induced by voluntary movements. PKD most commonly occurs sporadically or as an autosomal-dominant familial trait with variable penetrance. Many causes of secondary PKD are being recognized. The exact pathophysiology of the PxDs awaits further elucidation, although basal ganglia dysfunction appears to play a major role. Although the precise gene remains unknown, genetic linkage studies have isolated loci on chromosome 16, which colocalizes with the locus for familial infantile convulsions and paroxysmal choreoathetosis in some studies. The episodic nature of PKD and its relationship with other episodic diseases, such as epilepsy, migraine, and episodic ataxia, suggests channelopathy as a possible underlying etiology. PKD may remit spontaneously, but it also responds well to anticonvulsants as well as some other agents.
Seminars in Pediatric Neurology 04/2003; 10(1):68-79. · 1.65 Impact Factor
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S.U. Dhar,
F. Scaglia,
F.-Y. Li,
L. Smith,
B.A. Barshop,
C.M. Eng,
R.H. Haas,
J.V. Hunter, T. Lotze,
B. Maranda,
M. Willis,
J.E. Abdenur,
E. Chen,
W. O’Brien,
L-J.C. Wong
[show abstract]
[hide abstract]
ABSTRACT: Guanidinoacetate methyltransferase (GAMT) deficiency is a disorder of creatine biosynthesis, characterized by excessive amounts of guanidinoacetate in body fluids, deficiency of creatine in the brain, and presence of mutations in the GAMT gene. We present here 8 new patients with GAMT deficiency along with their clinical, biochemical and molecular data. The age at diagnosis of our patients ranges from 0 to 14 years. The age of onset of seizures usually ranges from infancy to 3 years. However, one of our patients developed seizures at age 5; progressing to myoclonic epilepsy at age 8 years and another patient has not developed seizures at age 17 years. Five novel mutations were identified: c.37ins26 (p.G13PfsX38), c.403G > T (p.D135Y), c.507_521dup15 (p.C169_S173dup), c.402C > G (p.Y134X) and c.610_611delAGinsGAA (p.R204EfsX63). Six patients had the c.327G > A (last nucleotide of exon 2) splice-site mutation which suggests that this is one of the most common mutations in the GAMT gene, second only to the known Portuguese founder mutation, c.59G > C (p.W20S). Our data suggests that the clinical presentation can be variable and the diagnosis may be overlooked due to unawareness of this disorder. Therefore, GAMT deficiency should be considered in the differential diagnosis of progressive myoclonic epilepsy as well as in unexplained developmental delay or regression with dystonia, even if the patient has no history of seizures. As more patients are reported, the prevalence of GAMT deficiency will become known and guidelines for prenatal diagnosis, newborn screening, presymptomatic testing and treatment, will need to be formulated.
Molecular Genetics and Metabolism.
