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Musculoskeletal manifestations of Prader-Willi syndrome

Discussion in 'Pediatrics' started by NewsBot, May 27, 2010.

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    The musculoskeletal manifestations of prader-willi syndrome.
    Shim JS, Lee SH, Seo SW, Koo KH, Jin DK.
    J Pediatr Orthop. 2010 Jun;30(4):390-5.
     
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    Prader–Willi syndrome

    Prader–Willi syndrome (PWS) is a rare genetic disorder caused by a loss of function of specific genes on chromosome 15.[2] In newborns, symptoms include weak muscles, poor feeding, and slow development.[2] Beginning in childhood, those affected become constantly hungry, which often leads to obesity and type 2 diabetes.[2] Mild to moderate intellectual impairment and behavioral problems are also typical of the disorder.[2] Often, affected individuals have a narrow forehead, small hands and feet, short height, and light skin and hair. Most are unable to have children.[2]

    About 74% of cases occur when part of the father's chromosome 15 is deleted.[2] In another 25% of cases, the affected person has two copies of the maternal chromosome 15 from the mother and lacks the paternal copy.[2] As parts of the chromosome from the mother are turned off through imprinting, they end up with no working copies of certain genes.[2] PWS is not generally inherited, but rather the genetic changes happen during the formation of the egg, sperm, or in early development.[2] No risk factors are known for the disorder.[4] Those who have one child with PWS have less than a 1% chance of the next child being affected.[4] A similar mechanism occurs in Angelman syndrome, except the defective chromosome 15 is from the mother, or two copies are from the father.[5][6]

    Prader–Willi syndrome has no cure.[7] Treatment may improve outcomes, especially if carried out early.[7] In newborns, feeding difficulties may be supported with feeding tubes.[3] Strict food supervision is typically required, starting around the age of three, in combination with an exercise program.[3] Growth hormone therapy also improves outcomes.[3] Counseling and medications may help with some behavioral problems.[3] Group homes are often necessary in adulthood.[3]

    PWS affects between 1 in 10,000 to 30,000 people worldwide.[2] The condition is named after Swiss physicians Andrea Prader and Heinrich Willi who, together with Alexis Labhart, described it in detail in 1956.[1] An earlier description was made in 1887 by British physician John Langdon Down.[8][9]

    1. ^ a b "Prader-Labhardt-Willi syndrome". Whonamedit. Archived from the original on August 21, 2016. Retrieved August 20, 2016.
    2. ^ a b c d e f g h i j k l m n "Prader-Willi syndrome". Genetics Home Reference. June 2014. Archived from the original on August 27, 2016. Retrieved August 19, 2016.
    3. ^ a b c d e f g "What are the treatments for Prader-Willi syndrome (PWS)?". NICHD. January 14, 2014. Archived from the original on August 10, 2016. Retrieved August 20, 2016.
    4. ^ a b "How many people are affected/at risk for Prader-Willi syndrome (PWS)?". NICHD. January 14, 2014. Archived from the original on August 27, 2016. Retrieved August 20, 2016.
    5. ^ "Prader-Willi Syndrome (PWS): Other FAQs". NICHD. January 14, 2014. Archived from the original on July 27, 2016. Retrieved August 19, 2016.
    6. ^ "Angelman syndrome". Genetic Home Reference. May 2015. Archived from the original on August 27, 2016. Retrieved August 20, 2016.
    7. ^ a b "Is there a cure for Prader-Willi syndrome (PWS)?". NICHD. January 14, 2014. Archived from the original on August 27, 2016. Retrieved August 20, 2016.
    8. ^ Mia, Md Mohan (2016). Classical and Molecular Genetics. American Academic Press. p. 195. ISBN 978-1-63181-776-2. Archived from the original on September 11, 2017.
    9. ^ Jorde, Lynn B.; Carey, John C.; Bamshad, Michael J. (2015). Medical Genetics (5 ed.). Elsevier Health Sciences. p. 120. ISBN 978-0-323-18837-1.
     
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    Press Release:
    A new way of looking at Prader-Willi Syndrome
     
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    Change in Prevalence of Congenital Defects in Children With Prader-Willi Syndrome
    M. Torrado, et al
    Pediatrics (published online)
     
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    Press Release:
    Symptoms of Prader-Willi syndrome associated with interference in circadian, metabolic genes
     
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    Press Release:
    Sequencing studies help pinpoint gene in Prader-Willi syndrome
     
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    Osteopathic Manipulative Treatment improves gait pattern and posture in adult patients with Prader-Willi syndrome
    Luca Vismara, Veronica Cimolin, Manuela Galli, Graziano Grugni, Andrea Ancillao, Paolo Capodaglio
    International Journal of Osteopathic Medicine; Article in Press
     
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    News Release:
    Weight Loss Surgery Offers New Hope to Children and Adolescents with Prader-Willi Syndrome
    Laparoscopic Sleeve Gastrectomy Is a Viable and Safe Solution for Obese Pediatric PWS Patients, Reports New Study in Surgery for Obesity and Related Diseases
     
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    PUBLIC RELEASE: 26-DEC-2016
    Experimental therapy for Prader-Willi syndrome shows promise in mice
    NIH-funded study describes strategy that activates silenced genes
     
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    Gait initiation and termination strategies in patients with Prader-Willi syndrome.
    Cimolin V et al
    J Neuroeng Rehabil. 2017 May 23;14(1):44. doi: 10.1186/s12984-017-0257-7.
     
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    Dynamic balance assessment during gait in children with Down and Prader-Willi syndromes using inertial sensors
    V.BelluscioaE.BergaminiaG.SalatinoaT.MarrobP.GentilibM.IosabD.MorellibG.Vannozzia
    Human Movement Science Volume 63, February 2019, Pages 53-61
     
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    Physiotherapists perceived developing positive rapport facilitates participation in exercise among people with Prader-Willi Syndrome: a qualitative study.
    Shields N et al
    Disabil Rehabil. 2019 Apr 11:1-6
     
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    Plantar Flexor Function in Adults with and without Prader-Willi Syndrome
    Pamukoff, Derek N et al
    Medicine & Science in Sports & Exercise: April 17, 2020 - Volume Publish Ahead of Print -
     
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    Press Release:
    Levo Therapeutics Announces Top-line Results from Phase 3 CARE-PWS Study of LV-101 (Intranasal Carbetocin) for the Treatment of Prader-Willi Syndrome
    August 06, 2020 08:06
    CHICAGO--(BUSINESS WIRE)--Levo Therapeutics, Inc., a biotechnology company dedicated to using genetic insights to advance treatments for Prader-Willi syndrome (PWS) and related disorders, announced today top-line results from the Phase 3 CARE-PWS clinical study evaluating LV-101 (intranasal carbetocin) for the treatment of PWS. This syndrome is a complex, neurodevelopmental disorder that occurs in approximately 1 in 16,000 birthsi and is characterized by a false state of starvation and associated hyperphagia (unrelenting hunger), to which a deficiency in oxytocin is believed to be contributoryii. LV-101 is a selective oxytocin-receptor agonist. CARE-PWS tested two doses of LV-101 versus placebo with an even randomization (1:1:1), specifying the 9.6 mg dose as the primary endpoint and the 3.2 mg dose as the first secondary endpoint. After consultation with the U.S. Food and Drug Administration (FDA), enrollment was closed early due to COVID-19 with 119 evaluable patients in the Primary Analysis Setiii.

    Levo Therapeutics Announces Top-line Results from Phase 3 CARE-PWS Study of LV-101 (Intranasal Carbetocin) for the Treatment of Prader-Willi Syndrome

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    While the study did not meet its primary outcome measurements evaluating the 9.6 mg dose of LV-101 (intranasal carbetocin), statistical significance was achieved with the 3.2 mg dose as evaluated by the Hyperphagia Questionnaire for Clinical Trials (HQ-CT) score (p=0.016) as the first secondary endpoint. When pooling the two dose arms of LV-101, per a pre-specified analysis, the change in HQ-CT score from baseline to week 8 resulted in a p-value of 0.055. Consistency in benefit/response was observed in the 3.2 mg dose arm across other key secondary endpoints, including clinical global impression of change (CGI-C; p=0.027) and anxiety and distress behaviors, as evaluated by the PWS Anxiety and Distress Behaviors Questionnaire (PADQ; p=0.027). Neither dose demonstrated a statistically significant effect on the Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS). LV-101 was generally well-tolerated in the study.

    “This is a long-awaited step towards addressing the substantial needs of individuals living with PWS,” said Sara Cotter, CEO of Levo Therapeutics. “We are excited by these important results that were achieved after decades of interest in addressing the oxytocin deficiency in PWS. We are also pleased that our efforts to develop new tools for clinical evaluation of this rare, neurodevelopmental disorder have enhanced our understanding of the real-world impact LV-101 has on anxiety and distress behaviors.”

    “With no approved therapies to address their most challenging symptoms, patients with PWS continue to suffer from insatiable hunger and anxiety, which are debilitating and can be life-threatening if left untreated,” said Jennifer L. Miller, M.D., Pediatric Endocrinologist, University of Florida. “These positive results of the Phase 3 CARE-PWS study strengthen the belief that intranasal carbetocin appears to be an effective treatment for patients living with PWS.”

    Upon completion of the placebo-controlled period (i.e., after week 8), all patients were transitioned into the long-term follow-up period and received intranasal carbetocin. Greater than 98% of patients enrolled in CARE-PWS elected to enter the long-term follow-up period. Of note, further improvements in scores were observed and subsequently maintained after week 8 in both dose arms.

    Safety data show that LV-101 (intranasal carbetocin) was generally well-tolerated. Treatment emergent adverse events (TEAEs) occurring in 5% or more of participants during the placebo-controlled period (TEAEs ≥ 5%) at the 3.2 mg dose include headache (16.3% vs. 7.0% for placebo), flushing (14.0% vs. 0.0% for placebo), diarrhea (9.3% vs. 2.3% for placebo), nasal discomfort (7.0% vs. 2.3% for placebo), pyrexia (7.0% vs. 0.0% for placebo), and upper respiratory tract infection (7.0% vs. 4.7% for placebo), all of which were considered mild or moderate. TEAEs ≥ 5% at the 9.6 mg dose include flushing (20.5% vs. 0.0% for placebo), epistaxis (13.6% vs. 2.3% for placebo), and headache (9.1% vs. 7.0% for placebo), all of which were also mild to moderate in severity.

    “The results from the CARE-PWS study have brought hope to the PWS community as together we pursue effective therapies for these patients in need,” said Theresa V. Strong, Ph.D., founding member of the Foundation for Prader-Willi Research. “We look forward to continuing to partner with Levo Therapeutics to help bring LV-101 expeditiously to the PWS community.”

    “The impact that PWS has on parents and caregivers is incredibly burdensome, beginning with diagnosis in infancy and continuing as individual symptoms worsen over time. The unfortunate reality is that there is currently no treatment for the most life-limiting symptoms of PWS,” said Elizabeth Roof, M.A., Vanderbilt University. “As clinical researchers, we are thrilled to see the results from CARE-PWS and that treatment with LV-101 showed meaningful improvements in hyperphagia and anxiety in patients with PWS, two hallmark symptoms of this rare and unique syndrome.”

    With these results in hand, all patients actively participating in CARE-PWS will be transitioned to receive the 3.2 mg dose of LV-101 for the remainder of their long-term follow-up and extension periods.

    “We would like to thank the CARE-PWS participants, their families, our partners, and the entire PWS community for their support and ongoing contributions to this research,” added Sara Cotter. “We look forward to working closely with regulatory authorities in the United States and abroad to bring this promising therapeutic to patients as quickly as possible.”

    CARE-PWS Phase 3 Study Design

    CARE-PWS (CARbetocin Efficacy and Safety Study in PWS; study NCT03649477) is a multi-center, randomized, double-blind, 8-week placebo-controlled study designed to test the effectiveness, safety, and tolerability of LV-101 (intranasal carbetocin) in participants age 7-18 with PWS. Effectiveness is measured using both caregiver-reported and clinician-reported measures of hyperphagia (extreme hunger), obsessive and compulsive behaviors, and anxiety. Safety and tolerability are measured by adverse events, laboratory tests, and physical exams.

    All participants received active treatment with LV-101 after the 8-week placebo-controlled period, during a long-term follow-up period of 56 weeks. At week 8, participants who were randomized to placebo in the placebo-controlled period were transitioned to one of the two LV-101 doses, while the participants in the active treatment arms remained on their originally assigned dose.

    The two primary efficacy measures of the study are the changes from baseline to week 8 in either HQ-CT scores or CY-BOCS scores (9.6 mg versus placebo). Secondary efficacy measures include changes in HQ-CT or CY-BOCS scores from baseline to week 8 for patients receiving the 3.2 mg dose versus placebo, changes in PADQ scores from baseline to week 8, and CGI-C scores through week 8.

    Extension Study

    CARE-PWS includes an optional extension period, where subjects participating in the long-term follow-up period have an opportunity to continue receiving intranasal carbetocin. Of the patients who have completed CARE-PWS’s 56-week long-term follow up period, 100% have elected to participate in the extension program.

    About LV-101 (Intranasal Carbetocin)

    Carbetocin is an analog of the naturally-occurring neuroendocrine hormone oxytocin. Carbetocin was designed to have an improved receptor binding profile compared to oxytocin, with greater affinity for the oxytocin receptor and lower affinity for related vasopressin receptors. Through our licensor, Ferring Pharmaceuticals, carbetocin is approved in over 90 countries outside the United States for the prevention of uterine atony and excessive bleeding during cesarean section delivery, as well as newly approved in the EU following vaginal birth, with an estimated cumulative exposure of over 10 million patients. LV-101 is an investigational intranasal form of carbetocin, intended to be administered to patients with PWS three times each day before meals. For additional background information, the results of the Phase 2 study of intranasal carbetocin (LV-101) in patients with genetically confirmed PWS can be found online at JCI Insight. LV-101 has been granted orphan drug and Fast Track designations from the U.S. Food and Drug Administration (FDA).

    About Prader-Willi Syndrome (PWS)

    Prader-Willi syndrome (PWS) is a complex, multisystem neurodevelopmental disorder that occurs in approximately 1 in 16,000 births i. The underlying cause of PWS is the lack of expression of paternally-inherited imprinted genes on chromosome 15q11-q13. These genetic anomalies lead to a distinctive phenotype that includes mild to moderate levels of intellectual disability, compulsivity, growth hormone deficiency, life-threatening hyperphagia, and anxiety.
     
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    Lower extremity coordination and joint kinetic distribution during gait in adults with and without Prader-Willi Syndrome
    Derek N Pamukoff et al
    J Biomech. 2022 Jun 30
     
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