Publications by authors named "Ksenija Gorni"

20 Publications

  • Page 1 of 1

Risdiplam-Treated Infants with Type 1 Spinal Muscular Atrophy versus Historical Controls.

N Engl J Med 2021 07;385(5):427-435

From the Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston (B.T.D.); the Developmental Neurology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan (R.M., G.B.), and the Center of Translational and Experimental Myology, IRCCS Istituto Giannina Gaslini, Genoa (C.B.) - both in Italy; the Department of Developmental Neurology, Medical University of Gdańsk, Gdańsk, Poland (M.M.-B.); the Paediatric Gait Analysis Service of New South Wales, the Children's Hospital at Westmead and the University of Sydney, Sydney (K.R.); the Department of Pediatrics, Peking University First Hospital, Beijing (H.X.), and Children's Hospital of Fudan University, Shanghai (Y.W.) - both in China; the Department of Neurology, Faculdade de Medicina, Universidade de São Paulo, São Paulo (E.Z.); the Dubowitz Neuromuscular Centre, National Institute for Health Research Great Ormond Street Hospital Biomedical Research Centre, University College London Great Ormond Street Institute of Child Health, and Great Ormond Street Hospital for Children NHS Foundation Trust, London (G.B.), Roche Products, Welwyn Garden City (M.E.-K.), and the Muscular Dystrophy UK Oxford Neuromuscular Centre, the Department of Paediatrics, University of Oxford, Oxford (L.S.) - all in the United Kingdom; Russian Children Neuromuscular Center, Veltischev Clinical Pediatric Research Institute, Pirogov Russian National Research Medical University, Moscow (D.V.); Pharma Development, Safety (M.G.), Product Development Medical Affairs - Neuroscience and Rare Disease (K.G., P.F.), and Pharma Development Neurology (R.S.S.), F. Hoffmann-La Roche, and Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel (O.K., H.K.) - both in Basel, Switzerland; the Division of Child Neurology, Centre de Références des Maladies Neuromusculaires, the Department of Pediatrics, University Hospital Liege, University of Liege, Liege, Belgium (L.S.); and I-Motion, Institut de Myologie, Assistance Publique Hôpitaux de Paris, Hôpital Armand Trousseau, Paris (L.S.).

Background: Type 1 spinal muscular atrophy (SMA) is a progressive neuromuscular disease characterized by an onset at 6 months of age or younger, an inability to sit without support, and deficient levels of survival of motor neuron (SMN) protein. Risdiplam is an orally administered small molecule that modifies pre-messenger RNA splicing and increases levels of functional SMN protein in blood.

Methods: We conducted an open-label study of risdiplam in infants with type 1 SMA who were 1 to 7 months of age at enrollment. Part 1 of the study (published previously) determined the dose to be used in part 2 (reported here), which assessed the efficacy and safety of daily risdiplam as compared with no treatment in historical controls. The primary end point was the ability to sit without support for at least 5 seconds after 12 months of treatment. Key secondary end points were a score of 40 or higher on the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND; range, 0 to 64, with higher scores indicating better motor function), an increase of at least 4 points from baseline in the CHOP-INTEND score, a motor-milestone response as measured by Section 2 of the Hammersmith Infant Neurological Examination (HINE-2), and survival without permanent ventilation. For the secondary end points, comparisons were made with the upper boundary of 90% confidence intervals for natural-history data from 40 infants with type 1 SMA.

Results: A total of 41 infants were enrolled. After 12 months of treatment, 12 infants (29%) were able to sit without support for at least 5 seconds, a milestone not attained in this disorder. The percentages of infants in whom the key secondary end points were met as compared with the upper boundary of confidence intervals from historical controls were 56% as compared with 17% for a CHOP-INTEND score of 40 or higher, 90% as compared with 17% for an increase of at least 4 points from baseline in the CHOP-INTEND score, 78% as compared with 12% for a HINE-2 motor-milestone response, and 85% as compared with 42% for survival without permanent ventilation (P<0.001 for all comparisons). The most common serious adverse events were pneumonia, bronchiolitis, hypotonia, and respiratory failure.

Conclusions: In this study involving infants with type 1 SMA, risdiplam resulted in higher percentages of infants who met motor milestones and who showed improvements in motor function than the percentages observed in historical cohorts. Longer and larger trials are required to determine the long-term safety and efficacy of risdiplam in infants with type 1 SMA. (Funded by F. Hoffmann-La Roche; FIREFISH ClinicalTrials.gov number, NCT02913482.).
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http://dx.doi.org/10.1056/NEJMoa2102047DOI Listing
July 2021

Prognostic Factors and Treatment-Effect Modifiers in Spinal Muscular Atrophy.

Clin Pharmacol Ther 2021 Mar 31. Epub 2021 Mar 31.

Division of Child Neurology Reference Center for Neuromuscular Disease, Department of Pediatrics, Centre Hospitalier Régional de Références des Maladies Neuromusculaires, University Hospital Liège & University of La Citadelle, Liège, Belgium.

Spinal muscular atrophy (SMA) is a rare, progressive neuromuscular disease characterized by loss of motor neurons and muscle atrophy. Untreated infants with type 1 SMA do not achieve major motor milestones, and death from respiratory failure typically occurs before 2 years of age. Individuals with types 2 and 3 SMA exhibit milder phenotypes and have better functional and survival outcomes. Herein, a systematic literature review was conducted to identify factors that influence the prognosis of types 1, 2, and 3 SMA. In untreated infants with type 1 SMA, absence of symptoms at birth, a later symptom onset, and a higher survival of motor neuron 2 (SMN2) copy number are all associated with increased survival. Disease duration, age at treatment initiation, and, to a lesser extent, baseline function were identified as potential treatment-modifying factors for survival, emphasizing that early treatment with disease-modifying therapies (DMT) is essential in type 1 SMA. In patients with types 2 and 3 SMA, factors considered prognostic of changes in motor function were SMN2 copy number, age, and ambulatory status. Individuals aged 6-15 years were particularly vulnerable to developing complications (scoliosis and progressive joint contractures) which negatively influence functional outcomes and may also affect the therapeutic response in patients. Age at the time of treatment initiation emerged as a treatment-effect modifier on the outcome of DMTs. Factors identified in this review should be considered prior to designing or analyzing studies in an SMA population, conducting population matching, or summarizing results from different studies on the treatments for SMA.
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http://dx.doi.org/10.1002/cpt.2247DOI Listing
March 2021

Risdiplam in Type 1 Spinal Muscular Atrophy.

N Engl J Med 2021 03 24;384(10):915-923. Epub 2021 Feb 24.

From the Dubowitz Neuromuscular Centre, National Institute for Health Research Great Ormond Street Hospital Biomedical Research Centre, Great Ormond Street Institute of Child Health University College London, and Great Ormond Street Hospital Trust, London (G.B.), Roche Products, Welwyn Garden City (M.E.-K.), and the Muscular Dystrophy UK Oxford Neuromuscular Centre, Department of Paediatrics, University of Oxford, Oxford (L.S.) - all in the United Kingdom; the Developmental Neurology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan (G.B., R.M.), and the Pediatric Neurology Institution, Catholic University and Nemo Pediatrico, Fondazione Policlinico Gemelli IRCCS, Rome (E.M.); the Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston (B.T.D.); the Department of Neurology, Stanford University, Palo Alto, CA (J.W.D.); Centre de Référence des Maladies Neuromusculaires, Queen Fabiola Children's University Hospital, Université Libre de Bruxelles, Brussels (N.D.), the Neuromuscular Reference Center, Universitair Ziekenhuis Gent, Ghent (N.D.), and the Division of Child Neurology, Centre de Références des Maladies Neuromusculaires, Department of Pediatrics, University Hospital Liege and University of Liege, Liege (L.S.) - all in Belgium; the Division of Pediatric Neurology, University Children's Hospital Basel (A.K.), Pharma Development Safety (M.G.), Product Development Medical Affairs-Neuroscience and Rare Disease (K.G., P.F.), and Pharma Development Neurology (R.S.S.), F. Hoffmann-La Roche, and Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel (O.K., H.K., T.S.), Basel, and Pediatric Neurology, Inselspital, University of Bern, Bern (A.K.) - both in Switzerland; the Discipline of Physiotherapy, Faculty of Medicine and Health, University of Sydney, Sydney (K.R.); and I-Motion, Hôpital Armand Trousseau, Paris (L.S.).

Background: Type 1 spinal muscular atrophy is a rare, progressive neuromuscular disease that is caused by low levels of functional survival of motor neuron (SMN) protein. Risdiplam is an orally administered, small molecule that modifies pre-messenger RNA splicing and increases levels of functional SMN protein.

Methods: We report the results of part 1 of a two-part, phase 2-3, open-label study of risdiplam in infants 1 to 7 months of age who had type 1 spinal muscular atrophy, which is characterized by the infant not attaining the ability to sit without support. Primary outcomes were safety, pharmacokinetics, pharmacodynamics (including the blood SMN protein concentration), and the selection of the risdiplam dose for part 2 of the study. Exploratory outcomes included the ability to sit without support for at least 5 seconds.

Results: A total of 21 infants were enrolled. Four infants were in a low-dose cohort and were treated with a final dose at month 12 of 0.08 mg of risdiplam per kilogram of body weight per day, and 17 were in a high-dose cohort and were treated with a final dose at month 12 of 0.2 mg per kilogram per day. The baseline median SMN protein concentrations in blood were 1.31 ng per milliliter in the low-dose cohort and 2.54 ng per milliliter in the high-dose cohort; at 12 months, the median values increased to 3.05 ng per milliliter and 5.66 ng per milliliter, respectively, which represented a median of 3.0 times and 1.9 times the baseline values in the low-dose and high-dose cohorts, respectively. Serious adverse events included pneumonia, respiratory tract infection, and acute respiratory failure. At the time of this publication, 4 infants had died of respiratory complications. Seven infants in the high-dose cohort and no infants in the low-dose cohort were able to sit without support for at least 5 seconds. The higher dose of risdiplam (0.2 mg per kilogram per day) was selected for part 2 of the study.

Conclusions: In infants with type 1 spinal muscular atrophy, treatment with oral risdiplam led to an increased expression of functional SMN protein in the blood. (Funded by F. Hoffmann-La Roche; ClinicalTrials.gov number, NCT02913482.).
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http://dx.doi.org/10.1056/NEJMoa2009965DOI Listing
March 2021

Natural history of Type 2 and 3 spinal muscular atrophy: 2-year NatHis-SMA study.

Ann Clin Transl Neurol 2021 02 24;8(2):359-373. Epub 2020 Dec 24.

Institute of Myology, GH Pitié Salpêtrière, Paris, France.

Objective: To characterize the natural history of spinal muscular atrophy (SMA) over 24 months using innovative measures such as wearable devices, and to provide evidence for the sensitivity of these measures to determine their suitability as endpoints in clinical trials.

Methods: Patients with Type 2 and 3 SMA (N = 81) with varied functional abilities (sitters, nonsitters, nonambulant, and ambulant) who were not receiving disease-modifying treatment were assessed over 24 months: motor function (Motor Function Measure [MFM]), upper limb strength (MyoGrip, MyoPinch), upper limb activity (ActiMyo ), quantitative magnetic resonance imaging (fat fraction [FF ] mapping and contractile cross-sectional area [C-CSA]), pulmonary function (forced vital capacity [FVC], peak cough flow, maximum expiratory pressure, maximum inspiratory pressure, and sniff nasal inspiratory pressure), and survival of motor neuron (SMN) protein levels.

Results: MFM32 scores declined significantly over 24 months, but not 12 months. Changes in upper limb activity could be detected over 6 months and continued to decrease significantly over 12 months, but not 24 months. Upper limb strength decreased significantly over 12 and 24 months. FVC declined significantly over 12 months, but not 24 months. FF increased over 12 and 24 months, although not with statistical significance. A significant increase in C-CSA was observed at 12 but not 24 months. Blood SMN protein levels were stable over 12 and 24 months.

Interpretation: These data demonstrate that the MFM32, MyoGrip, MyoPinch, and ActiMyo enable the detection of a significant decline in patients with Type 2 and 3 SMA over 12 or 24 months.
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http://dx.doi.org/10.1002/acn3.51281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886049PMC
February 2021

Long-term follow-up of patients with type 2 and non-ambulant type 3 spinal muscular atrophy (SMA) treated with olesoxime in the OLEOS trial.

Neuromuscul Disord 2020 12 5;30(12):959-969. Epub 2020 Nov 5.

Neuroscience Product Development, F. Hoffmann-La Roche Ltd, Basel, Switzerland.

In a previous Phase 2 study, olesoxime had a favorable safety profile. Although the primary endpoint was not met, analyses suggested that olesoxime might help in the maintenance of motor function in patients with Types 2/3 SMA. This open-label extension study (OLEOS) further characterizes the safety, tolerability and efficacy of olesoxime over longer therapy durations. In OLEOS, no new safety risks were identified. Compared to matched natural history data, patients treated with olesoxime demonstrated small, non-significant changes in motor function over 52 weeks. Motor function scores were stable for 52 weeks but declined over the remainder of the study. The greatest decline in motor function was seen in patients ≤15 years old, and those with Type 2 SMA had faster motor function decline versus those with Type 3 SMA. Previous treatment with olesoxime in the Phase 2 study was not protective of motor function in OLEOS. Respiratory outcomes were stable in patients with Type 3 SMA >15 years old but declined in patients with Type 2 SMA and in patients with Type 3 SMA ≤15 years old. Overall, with no stabilization of functional measures observed over 130 weeks, OLEOS did not support significant benefit of olesoxime in patients with SMA.
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http://dx.doi.org/10.1016/j.nmd.2020.10.008DOI Listing
December 2020

Risdiplam treatment has not led to retinal toxicity in patients with spinal muscular atrophy.

Ann Clin Transl Neurol 2021 01 24;8(1):54-65. Epub 2020 Nov 24.

Neuro-Ophthalmology Center, Ophthalmology Department, IRCCS Istituto Auxologico Italiano, Milan, Italy.

Objective: Evaluation of ophthalmologic safety with focus on retinal safety in patients with spinal muscular atrophy (SMA) treated with risdiplam (EVRYSDI®), a survival of motor neuron 2 splicing modifier associated with retinal toxicity in monkeys. Risdiplam was approved recently for the treatment of patients with SMA, aged ≥ 2 months in the United States, and is currently under Health Authority review in the EU.

Methods: Subjects included patients with SMA aged 2 months-60 years enrolled in the FIREFISH, SUNFISH, and JEWELFISH clinical trials for risdiplam. Ophthalmologic assessments, including functional assessments (age-appropriate visual acuity and visual field) and imaging (spectral domain optical coherence tomography [SD-OCT], fundus photography, and fundus autofluorescence [FAF]), were conducted at baseline and every 2-6 months depending on study and assessment. SD-OCT, FAF, fundus photography, and threshold perimetry were evaluated by an independent, masked reading center. Adverse events (AEs) were reported throughout the study.

Results: A total of 245 patients receiving risdiplam were assessed. Comprehensive, high-quality, ophthalmologic monitoring assessing retinal structure and visual function showed no retinal structural or functional changes. In the youngest patients, SD-OCT findings of normal retinal maturation were observed. AEs involving eye disorders were not suggestive of risdiplam-induced toxicity and resolved with ongoing treatment.

Interpretation: Extensive ophthalmologic monitoring conducted in studies in patients with SMA confirmed that risdiplam does not induce ophthalmologic toxicity in pediatric or adult patients with SMA at the therapeutic dose. These results suggest that safety ophthalmologic monitoring is not needed in patients receiving risdiplam, as also reflected in the United States Prescribing Information for risdiplam.
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http://dx.doi.org/10.1002/acn3.51239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818230PMC
January 2021

Assessment of the validity and reliability of the 32-item Motor Function Measure in individuals with Type 2 or non-ambulant Type 3 spinal muscular atrophy.

PLoS One 2020 18;15(9):e0238786. Epub 2020 Sep 18.

Department of Pediatric Physical Medicine and Rehabilitation, Hôpital Mère Enfant, CHU-Lyon, Lyon University, Lyon, France.

The 32-item Motor Function Measure (MFM32) is an assessment of motor function, and its measurement properties were established in a broad neuromuscular disease population. This study sought to investigate the reliability, validity, and ability to detect change of MFM32 in individuals with Type 2 and non-ambulant Type 3 spinal muscular atrophy (SMA). Data were used from the Phase 2 study assessing the efficacy and safety of olesoxime. A total of 110 individuals with Type 2 or 3 SMA were included in the analyses. Test-retest reliability (intraclass-correlation coefficient in global impression-defined stable individuals), internal consistency (Cronbach's alpha), convergent validity (Spearman rank order correlations with other measures), known-groups validity (analysis of covariance comparing Hammersmith Functional Motor Scale -defined groups), and ability to detect change (analysis of covariance comparing global impression-defined groups) were calculated. Strong evidence of test-retest reliability (intraclass-correlation coefficient = 0.93-0.95), internal consistency (Cronbach's alpha = 0.89), convergent validity (Hammersmith Functional Motor Scale: rho = 0.87; forced vital capacity: rho = 0.61), known-groups validity (all p<0.0001), and ability to detect change (all p<0.001) were demonstrated. These results provide evidence of the MFM32's measurement properties, supporting its use in longitudinal research in individuals with Type 2 and non-ambulant Type 3 SMA.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0238786PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7500661PMC
November 2020

Validity and Reliability of the 32-Item Motor Function Measure in 2- to 5-Year-Olds with Neuromuscular Disorders and 2- to 25-Year-Olds with Spinal Muscular Atrophy.

Neurol Ther 2020 Dec 27;9(2):575-584. Epub 2020 Aug 27.

Department of Pediatric Physical Medicine and Rehabilitation, Hôpital Mère Enfant, Centre Hospitalier Universitaire (CHU) de Lyon-Lyon University, Lyon, France.

Introduction: To investigate the validity and reliability of the 32-item Motor Function Measure (MFM32) in individuals with neuromuscular disorders (NMD), including spinal muscular atrophy (SMA), aged 2-5 years, and in non-ambulant individuals with Types 2 or 3 SMA, aged 2-25 years.

Methods: Test-retest reliability (intraclass correlation coefficient [ICC]), internal consistency (Cronbach's alpha [α]), convergent validity (Spearman rank-order correlations), and known-groups validity (analysis of covariance comparing groups defined by the Clinical Global Impression of Severity [CGI-S] scale and Vignos grade) were calculated. The analysis was performed on a dataset provided by Hospices Civils De Lyon, extracted from the multinational MFM32 database. A total of 165 individuals were included in the analyses, of whom 84 were in the NMD group (aged 2-5 years) and 81 were in the SMA group (aged 2-25 years).

Results: Strong evidence of test-retest reliability (ICC: 2- to 5-years' population = 0.94-0.95; 2- to 25-years' population = 0.97), internal consistency (Cronbach's α: 2- to 5-years' population = 0.96; 2- to 25-years' population = 0.95), convergent validity (2- to 5-years' population: CGI-S rho = - 0.84, Vignos grade rho = - 0.79; 2- to 25-years' population: CGI-S rho = - 0.49), and known-groups validity (all P < 0.001) were demonstrated.

Conclusions: These analyses provide supportive evidence of the validity and reliability of the MFM32 in younger individuals with NMDs, aged 2-5 years, and in non-ambulant individuals with Types 2 or 3 SMA, aged 2-25 years, supporting the use of the MFM32 across a wide age range.
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http://dx.doi.org/10.1007/s40120-020-00206-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606363PMC
December 2020

The CINRG Becker Natural History Study: Baseline characteristics.

Muscle Nerve 2020 09 24;62(3):369-376. Epub 2020 Jul 24.

Children's National Medical Center, Washington, DC, USA.

We performed an observational, natural history study of males with in-frame dystrophin gene deletions causing Becker muscular dystrophy (BMD). A prospective natural history study collected longitudinal medical, strength, and timed function assessments. Eighty-three participants with genetically confirmed BMD were enrolled (age range 5.6-75.4 years). Lower extremity function and the percentage of participants who retained ambulation declined across the age span. The largest single group of participants had in-frame deletions that corresponded to an out-of-frame deletion treated with an exon 45 skip to restore the reading frame. This group of 54 participants showed similarities in baseline motor functional assessments when compared to the group of all others in the study. A prospective natural history cohort with in-frame dystrophin gene deletions offers the potential to contribute to clinical trial readiness for BMD and to analyze therapeutic benefit of exon skipping for Duchenne muscular dystrophy.
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http://dx.doi.org/10.1002/mus.27011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7520226PMC
September 2020

Genetic Modifiers of Duchenne Muscular Dystrophy and Dilated Cardiomyopathy.

PLoS One 2015 29;10(10):e0141240. Epub 2015 Oct 29.

Neuromuscular Center, Department of Neuroscience, University of Padova, Padova, Italy.

Objective: Dilated cardiomyopathy (DCM) is a major complication and leading cause of death in Duchenne muscular dystrophy (DMD). DCM onset is variable, suggesting modifier effects of genetic or environmental factors. We aimed to determine if polymorphisms previously associated with age at loss of independent ambulation (LoA) in DMD (rs28357094 in the SPP1 promoter, rs10880 and the VTTT/IAAM haplotype in LTBP4) also modify DCM onset.

Methods: A multicentric cohort of 178 DMD patients was genotyped by TaqMan assays. We performed a time-to-event analysis of DCM onset, with age as time variable, and finding of left ventricular ejection fraction < 50% and/or end diastolic volume > 70 mL/m2 as event (confirmed by a previous normal exam < 12 months prior); DCM-free patients were censored at the age of last echocardiographic follow-up.

Results: Patients were followed up to an average age of 15.9 ± 6.7 years. Seventy-one/178 patients developed DCM, and median age at onset was 20.0 years. Glucocorticoid corticosteroid treatment (n = 88 untreated; n = 75 treated; n = 15 unknown) did not have a significant independent effect on DCM onset. Cardiological medications were not administered before DCM onset in this population. We observed trends towards a protective effect of the dominant G allele at SPP1 rs28357094 and recessive T allele at LTBP4 rs10880, which was statistically significant in steroid-treated patients for LTBP4 rs10880 (< 50% T/T patients developing DCM during follow-up [n = 13]; median DCM onset 17.6 years for C/C-C/T, log-rank p = 0.027).

Conclusions: We report a putative protective effect of DMD genetic modifiers on the development of cardiac complications, that might aid in risk stratification if confirmed in independent cohorts.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0141240PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4626372PMC
June 2016

Benefits of glucocorticoids in non-ambulant boys/men with Duchenne muscular dystrophy: A multicentric longitudinal study using the Performance of Upper Limb test.

Neuromuscul Disord 2015 Oct 17;25(10):749-53. Epub 2015 Jul 17.

IRCCS Eugenio Medea, Bosisio Parini, Italy.

The aim of this study was to establish the possible effect of glucocorticoid treatment on upper limb function in a cohort of 91 non-ambulant DMD boys and adults of age between 11 and 26 years. All 91 were assessed using the Performance of Upper Limb test. Forty-eight were still on glucocorticoid after loss of ambulation, 25 stopped steroids at the time they lost ambulation and 18 were GC naïve or had steroids while ambulant for less than a year. At baseline the total scores ranged between 0 and 74 (mean 41.20). The mean total scores were 47.92 in the glucocorticoid group, 36 in those who stopped at loss of ambulation and 30.5 in the naïve group (p < 0.001). The 12-month changes ranged between -20 and 4 (mean -4.4). The mean changes were -3.79 in the glucocorticoid group, -5.52 in those who stopped at loss of ambulation and -4.44 in the naïve group. This was more obvious in the patients between 12 and 18 years and at shoulder and elbow levels. Our findings suggest that continuing glucocorticoids throughout teenage years and adulthood after loss of ambulation appears to have a beneficial effect on upper limb function.
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http://dx.doi.org/10.1016/j.nmd.2015.07.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4597096PMC
October 2015

Prevalence of congenital muscular dystrophy in Italy: a population study.

Neurology 2015 Mar 4;84(9):904-11. Epub 2015 Feb 4.

From the Departments of Paediatrics and Neurology (A.G., F.B., G.T., M. Monforte, E.R., M.P., E.M.), Catholic University, Rome; Unit of Neuromuscular and Neurodegenerative Disorders (A.D., G.T., E.B.), Department of Neurosciences, Bambino Gesù Children's Hospital, Rome; Pediatric Neurology and Neuromuscular Disease and Immunology Unit (I.M., M. Mora, L.M.), Istituto Neurologico Besta, Milan; Department of Neurosciences, Psychiatry and Anaesthesiology (S.M.), University of Messina; Neuromuscular Disease Unit (C.B., C.M.), G. Gaslini Institute, Genoa; Department of Neurosciences (E.P.), University of Padua, Italy; Department of Developmental Neuroscience and Molecular Medicine Neuromuscular Unit (G.A., R.B., F.M.S.), Stella Maris Institute, Pisa; Department of Neurological Sciences (F. Magri, G.P.C.), IRCCS Ospedale Maggiore Policlinico, University of Milan; Child Neurology and Psychiatry Unit (A.B.), IRCCS C. Mondino Foundation; Neuromuscular and Rare Diseases Unit (M. Moggio), IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Dino Ferrari Center, Milano; Child Neurology and Psychiatry Unit (A.P.), IRCCS Istituto delle Scienze Neurologiche di Bologna, Bellaria Hospital, Bologna; Cardiomiologia e Genetica Medica (R.P., L.P.), Dipartimento di Medicina Sperimentale Seconda Università di Napoli; Neuromuscular Center (T.M.), S.G. Battista Hospital, University of Turin; Centro Nemo (K.G.), Milan; Neuromuscular Unit (M.V.), Nigrisoli Hospital, Bologna; Section of Medical Genetics (F.G., A.F.), Department of Experimental and Diagnostic Medicine, Ferrara, Italy; and Dubowitz Neuromuscular Centre (F. Muntoni), UCL Institute of Child Health & Great Ormond Street Hospital for Children, London, UK.

Objective: We provide a nationwide population study of patients with congenital muscular dystrophy in Italy.

Methods: Cases were ascertained from the databases in all the tertiary referral centers for pediatric neuromuscular disorders and from all the genetic diagnostic centers in which diagnostic tests for these forms are performed.

Results: The study includes 336 patients with a point prevalence of 0.563 per 100,000. Mutations were identified in 220 of the 336 (65.5%). The cohort was subdivided into diagnostic categories based on the most recent classifications on congenital muscular dystrophies. The most common forms were those with α-dystroglycan glycosylation deficiency (40.18%) followed by those with laminin α2 deficiency (24.11%) and collagen VI deficiency (20.24%). The forms of congenital muscular dystrophy related to mutations in SEPN1 and LMNA were less frequent (6.25% and 5.95%, respectively).

Conclusions: Our study provides for the first time comprehensive epidemiologic information and point prevalence figures for each of the major diagnostic categories on a large cohort of congenital muscular dystrophies. The study also reflects the diagnostic progress in this field with an accurate classification of the cases according to the most recent gene discoveries.
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http://dx.doi.org/10.1212/WNL.0000000000001303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351663PMC
March 2015

The 6 minute walk test and performance of upper limb in ambulant duchenne muscular dystrophy boys.

PLoS Curr 2014 Oct 7;6. Epub 2014 Oct 7.

Centro Clinico Nemo, Milan, Italy.

The Performance of Upper Limb (PUL) test was specifically developed for the assessment of upper limbs in Duchenne muscular dystrophy (DMD). The first published data have shown that early signs of involvement can also be found in ambulant DMD boys. The aim of this longitudinal Italian multicentric study was to evaluate the correlation between the 6 Minute Walk Test (6MWT) and the PUL in ambulant DMD boys. Both 6MWT and PUL were administered to 164 ambulant DMD boys of age between 5.0 and 16.17 years (mean 8.82). The 6 minute walk distance (6MWD) ranged between 118 and 557 (mean: 376.38, SD: 90.59). The PUL total scores ranged between 52 and 74 (mean: 70.74, SD: 4.66). The correlation between the two measures was 0.499. The scores on the PUL largely reflect the overall impairment observed on the 6MWT but the correlation was not linear. The use of the PUL appeared to be less relevant in the very strong patients with 6MWD above 400 meters, who, with few exceptions had near full scores. In patients with lower 6MWD the severity of upper limb involvement was more variable and could not always be predicted by the 6MWD value or by the use of steroids. Our results confirm that upper limb involvement can already be found in DMD boys even in the ambulant phase.
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http://dx.doi.org/10.1371/currents.md.a93d9904d57dcb08936f2ea89bca6fe6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4208936PMC
October 2014

Reliability of the Performance of Upper Limb assessment in Duchenne muscular dystrophy.

Neuromuscul Disord 2014 Mar 5;24(3):201-6. Epub 2013 Dec 5.

Unit of Neuromuscular and Neurodegenerative Diseases, Department of Neurosciences, Bambino Gesù Childrens Hospital, Rome, Italy.

The Performance of Upper Limb was specifically designed to assess upper limb function in Duchenne muscular dystrophy. The aim of this study was to assess (1) a cohort of typically developing children from the age of 3years onwards in order to identify the age when the activities assessed in the individual items are consistently achieved, and (2) a cohort of 322 Duchenne children and young adults to establish the range of findings at different ages. We collected normative data for the scale validation on 277 typically developing subjects from 3 to 25years old. A full score was consistently achieved by the age of 5years. In the Duchenne cohort there was early involvement of the proximal muscles and a proximal to distal progressive involvement. The scale was capable of measuring small distal movements, related to activities of daily living, even in the oldest and weakest patients. Our data suggest that the assessment can be reliably used in both ambulant and non ambulant Duchenne patients in a multicentric setting and could therefore be considered as an outcome measure for future trials.
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http://dx.doi.org/10.1016/j.nmd.2013.11.014DOI Listing
March 2014

CINRG pilot trial of coenzyme Q10 in steroid-treated Duchenne muscular dystrophy.

Muscle Nerve 2011 Aug 22;44(2):174-8. Epub 2011 Jun 22.

Children's National Medical Center, George Washington University, Washington, DC, USA.

Introduction: Corticosteroid treatment slows disease progression and is the standard of care for Duchenne muscular dystrophy (DMD). Coenzyme Q10 (CoQ10) is a potent antioxidant that may improve function in dystrophin-deficient muscle.

Methods: We performed an open-label, "add-on" pilot study of CoQ10 in thirteen 5-10-year-old DMD patients on steroids. The primary outcome measure was the total quantitative muscle testing (QMT) score.

Results: Twelve of 16 children (mean age 8.03 ± 1.64 years) completed the trial. Target serum levels of CoQ10 (≥2.5 μg/ml) were shown to be subject- and administration-dependent. Nine of 12 subjects showed an increase in total QMT score. Overall, CoQ10 treatment resulted in an 8.5% increase in muscle strength (P = 0.03).

Conclusions: Addition of CoQ10 to prednisone therapy in DMD patients resulted in an increase in muscle strength. These results warrant a larger, controlled trial of CoQ10 in DMD.
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http://dx.doi.org/10.1002/mus.22047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3136634PMC
August 2011

Existential well-being and spirituality of individuals with amyotrophic lateral sclerosis is related to psychological well-being of their caregivers.

Amyotroph Lateral Scler 2011 Mar 26;12(2):105-8. Epub 2010 Jul 26.

Department of Psychology, Catholic University of Milan, Italy.

Existential well-being (EWB) and spirituality issues are important factors in determining quality of life (QoL) in amyotrophic lateral sclerosis (ALS) patients. No conclusive data among the relation between patient's EWB, their spirituality and caregivers' QoL are available. In the mainframe of a longitudinal study, we performed a cross-sectional analysis aimed to investigate EWB and spirituality issues in sporadic ALS (SALS) patients and the relations with caregivers' psychological features. Thirty-seven SALS patients, together with their caregivers, consecutively recruited at NEuroMuscular Omnicentre, in Milan, were included in this study. EWB and spirituality questions were administrated to patients and caregivers. Caregivers also completed questionnaires about quality of life (MQoL-SI), care burden (ZBI), depression (BDI) and anxiety (STAI). Both EWBs and questions about spirituality of SALS patients showed a positive correlation with MQoL-SI and EWBs in their caregivers. Conversely, SALS patients' EWB and spirituality were negatively correlated with caregivers' STAI, BDI and ZBI scores. In conclusion, existential well-being, as well as spirituality issues, perceived by SALS patients seems to be directly related with quality of life, severity of mood disturbance and burden experienced by their caregivers.
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http://dx.doi.org/10.3109/17482968.2010.502941DOI Listing
March 2011

Bilateral putaminal necrosis associated with the mitochondrial DNA A8344G myoclonus epilepsy with ragged red fibers (MERRF) mutation: an infantile case.

J Child Neurol 2006 Jan;21(1):79-82

Department of Child Neurology and Psychiatry, Regional Referral Center for Neuromuscular Disorders in Childhood IRCCS C. Mondino Foundation, University of Pavia, Italy.

Myoclonus epilepsy with ragged red fibers (MERRF) is one of the major mitochondrial encephalomyopathies. Its main clinical features are myoclonus epilepsy, ataxia, and myopathy with ragged red fibers. Whereas there is a close correlation between MERRF syndrome and the A8344G mutation of mitochondrial DNA, the reverse is not true. In fact, this mutation is also responsible for various other syndromes, such as Leigh syndrome, spinocerebellar degeneration, atypical Charcot-Marie-Tooth disease, and multiple truncal lipomas. We describe a child with the A8344G mutation of mitochondrial DNA and an unusual clinical, neuroradiologic, and biochemical phenotype, characterized by early-onset, nonprogressive cerebellar ataxia, and subclinical myoclonias in association with bilateral putaminal necrosis on magnetic resonance imaging and a reduction in complex V activity. Our case confirms the existence of a relationship between alteration in adenosine triphosphatase activity and basal ganglia involvement. We recommend that the possibility of a mitochondrial pathology should always be taken into consideration in the presence of bilateral symmetric lesions of the basal ganglia, even when the typical clinical picture is lacking. (J Child Neurol 2006;21:79-82).
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http://dx.doi.org/10.1177/08830738060210010901DOI Listing
January 2006

CINRG randomized controlled trial of creatine and glutamine in Duchenne muscular dystrophy.

Ann Neurol 2005 Jul;58(1):151-5

Children's National Medical Center, George Washington University, Washington, DC, USA.

We tested the efficacy and safety of glutamine (0.6 gm/kg/day) and creatine (5 gm/day) in 50 ambulant boys with Duchenne muscular dystrophy in a 6-month, double-blind, placebo-controlled clinical trial. Drug efficacy was tested by measuring muscle strength manually (34 muscle groups) and quantitatively (10 muscle groups). Timed functional tests, functional parameters, and pulmonary function tests were secondary outcome measures. Although there was no statistically significant effect of either therapy based on manual and quantitative measurements of muscle strength, a disease-modifying effect of creatine in older Duchenne muscular dystrophy and creatine and glutamine in younger Duchenne muscular dystrophy cannot be excluded. Creatine and glutamine were well tolerated.
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http://dx.doi.org/10.1002/ana.20523DOI Listing
July 2005

Quantitative MR evaluation of body composition in patients with Duchenne muscular dystrophy.

Eur Radiol 2002 Nov 8;12(11):2704-9. Epub 2002 May 8.

Department of Neuroradiology, Istituto Neurologico Fondazione C. Mondino I.R.C.C.S, Via Palestro, 3, 27100 Pavia, Italy.

The aim of this study was to propose a quantitative MR protocol with very short acquisition time and good reliability in volume construction, for the evaluation of body composition in patients affected by Duchenne muscular dystrophy (DMD). This MR protocol was compared with common anthropometric evaluations of the same patients. Nine boys affected by DMD, ranging in age from 6 to 12 years, were selected to undergo MR examination. Transversal T1-weighted spin-echo sequences (0.5T; TR 300 ms, TE 10 ms, slice thickness 10 mm, slice gap 1 mm) were used for all acquisitions, each consisting of 8 slices and lasting just 54 s. Whole-body examination needed an average of nine acquisitions. Afterwards, images were downloaded to an independent workstation and, through their electronic segmentation with a reference filter, total volume and adipose tissue volumes were calculated manually. This process took up to 2 h for each patient. The MR data were compared with anthropometric evaluations. Affected children have a marked increase in adipose tissue and a decrease in lean tissue compared with reference healthy controls. Mean fat mass calculated by MR is significantly higher than mean fat mass obtained using anthropometric measurements ( p<0.001). Our MR study proved to be accurate and easy to apply, although it was time-consuming. We recommend it in monitoring the progression of the disease and planning DMD patients' diet.
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http://dx.doi.org/10.1007/s00330-002-1392-4DOI Listing
November 2002

Collaborative translational research leading to multicenter clinical trials in Duchenne muscular dystrophy: the Cooperative International Neuromuscular Research Group (CINRG).

Neuromuscul Disord 2002 Oct;12 Suppl 1:S147-154

Research Center for Genetic Medicine (CRI III), Children's National Medical Center, George Washington University, 111 Michigan Avenue, NW, Washington, DC 20010, USA.

Progress in the development of rationally based therapies for Duchenne muscular dystrophy has been accelerated by encouraging multidisciplinary, multi-institutional collaboration between basic science and clinical investigators in the Cooperative International Research Group. We combined existing research efforts in pathophysiology by a gene expression profiling laboratory with the efforts of animal facilities capable of conducting high-throughput drug screening and toxicity testing to identify safe and effective drug compounds that target different parts of the pathophysiologic cascade in a genome-wide drug discovery approach. Simultaneously, we developed a clinical trial coordinating center and an international network of collaborating physicians and clinics where those drugs could be tested in large-scale clinical trials. We hope that by bringing together investigators at these facilities and providing the infrastructure to support their research, we can rapidly move new bench discoveries through animal model screening and into therapeutic testing in humans in a safe, timely and cost-effective setting.
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http://dx.doi.org/10.1016/s0960-8966(02)00094-9DOI Listing
October 2002
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