Clinical Trial of Levodopa/Carbidopa ( Sinemet) Therapy in Angel Man Syndrome
Condition: Angelman Syndrome
MeSH terms: Angelman Syndrome; Syndrome
Study type: Interventional

Summary: 
      The purpose of this study is to evaluate the safety and effectiveness (how well a drug works)
      of Carbidopa/levodopa (Sinemet) in individuals with Angelman syndrome. Sinemet is a
      medication that helps to raise dopamine levels (a chemical that signals nerve cells) in the
      brain and central nervous system. There is evidence that dopamine concentrations may be
      abnormal in patients with Angelman syndrome. This study is investigating whether Sinemet
      helps motor control, intellectual function and the achievement of developmental milestones in
      people with Angelman syndrome
    

Detailed description: 
      Angelman syndrome (AS) is a well-recognized cause of disability in children who present with
      movement or balance disorder, usually ataxia and/or tremulous movement of the limbs, severe
      speech and cognitive delay behavior disorders and was initially described by Harry Angelman
      as the " happy puppet syndrome" due to their disposition. Seizures, abnormal sleep-wake
      cycles and distinctive facial features have been also commonly seen. This disorder is almost
      exclusively diagnosed in childhood but adults have been reported. Angelman syndrome affects
      an estimated 1 in 12,000 to 20,000 people. Many of the characteristic features are caused by
      the loss of function of maternally inherited UBE3A allele on chromosome 15q11-q13 locus.
      Several different genetic mechanisms can cause loss of function of maternally inherited UBE3A
      gene. Majority of AS is caused by deletion of chromosome 15q11.2-q13 (approximately 70%), 11%
      is caused by a mutation in maternal copy of UBE3A. Paternal uniparental disomy (pat UPD)
      occurs in 7%. Rarely, a defect in imprinting region and chromosome rearrangement can also
      lead to AS.

      Ubiquitin-protein ligase E3A (UBE3A) is involved in protein degradation through the ubiquitin
      proteasome pathway and displays predominantly in human fetal brain and adult frontal cortex.
      UBE3a is essential in the regulation of GTP cyclohydrolase I, an essential enzyme in dopamine
      biosynthesis. Knockout mouse studies have evaluated dopamine dependent behaviors as well as
      dopamine synthesis, content and release in the mesolimbic and nigrostriatal pathway of AS
      model mice. Impairment of UBE3A results in the accumulation of protein substrate and is also
      associated with a loss of dopaminergic neuronal function which plays a role in the clinical
      symptomatology. AS ( knockout) mice were reported to have maternal deficiency of Ube3a with
      reduced dopamine cell number in the substantia nigra pars compacta ((basal ganglia) . They
      demonstrated motoric and cognitive deficits. There are several mouse models that have
      demonstrated both the disorder and the beneficial effect of L dopa in the knockout mouse
      providing a basis for clinical human trials.

      To date the primary treatment of children with Angelman syndrome has been only supportive and
      symptomatic such as physical, occupation and speech therapies, melatonin and Benadryl for
      insomnia and the treatment of seizure disorders. Little attention or success has been
      directed to the primary gait disturbance, namely ataxia and the cognitive impairment
      including processing, attention and speech delays which are cardinal features of the
      disorder.

      In 2001, Harbord has reported two adults with Angelman syndrome and Parkinson's disease who
      had a positive response to L Dopa constituting the first report of the use of levodopa in
      Angelman syndrome.

      Pediatric neurotransmitter disorders have previously been recognized involving the dopamine
      pathway. In the past investigators have reported on the distinct developmental and behavioral
      profile, cognitive deficits, motor and language skills utilizing standardized testing in the
      NIH Rare Disease Clinical Research Network, Angelman Rett collaborative.

      This study will look at the effects of L Dopa on motor control including ataxia, cognitive
      function and developmental milestones in subjects with Angelman syndrome.
    

Intervention name(s): Levodopa
Intervention type(s): Drug
Intervention description(s): The target dose of Sinemet is 2-10 mg per kilogram per day of levodopa. The initial dose will be determined by your weight and age and will start at a low dosage level, 1 mg per kilogram per day. The dose will be re-evaluated after the first 2 weeks and may be adjusted at each visit depending on your response to the drug.
Other intervention name(s): Sinemet
Intervention MeSH terms: Levodopa
Intervention model: Single Group Assignment
Intervention model description: This is an open label study to assess the motor and cognitive and developmental effects of carbidopa/levodopa when administered orally in doses of 1 -10mg per kg per day. This study will recruit and monitor patients over a 2 year period.
Masking: None (Open Label)
Primary purpose: Treatment