Levodopa responsive Parkinsonism in adults with Angelman Syndrome

doi:10.1054/jocn.2000.0753

Journal of Clinical Neuroscience

Volume 8, Issue 5, September 2001, Pages 421-422

https://doi.org/10.1054/jocn.2000.0753 Get rights and content

Abstract

Two intellectually disabled adults with Angelman Syndrome are reported who developed intermittent episodes of a severe resting tremor, cogwheel rigidity and bradykinesia in their late teens. The Parkinsonism was not due to medications and there was a dramatic improvement with levodopa therapy. The association between Angelman Syndrome and Parkinsonism has not previously been described.

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Cited by (33)

Myoclonus in Angelman syndrome
2018, Epilepsy and Behavior
Citation Excerpt :
The natural history of aberrant movement is largely unknown, but the tremor in AS has been reported to increase in severity with age [9]. In addition to the typical tremor and ataxia, Harbord described two adults with AS who developed Parkinsonian symptoms, including cogwheel rigidity and bradykinesia; these symptoms subsequently responded to dopaminergic treatment [10]. The primary seizure semiologies in AS include atypical absence, generalized tonic–clonic, atonic, and myoclonic seizures [11].
Angelman syndrome (AS) is a neurogenetic imprinting disorder caused by loss of the maternally inherited Ube3a gene and is characterized by generalized epilepsy, limited expressive speech, sleep dysfunction, and movement disorders. Myoclonic seizures are often the first seizure type to appear, and myoclonic status, associated with developmental regression, may occur in the first few years of life. Additionally, there have been rare reports of prolonged episodes of myoclonus without electrographic correlate in adults with AS.
The medical records of 200 individuals seen in the Angelman Syndrome Clinic at the Massachusetts General Hospital and the Lurie Center for Autism were retrospectively reviewed to identify and characterize myoclonic seizures and episodes of nonepileptic myoclonus. Myoclonic seizures were reported in 14% of individuals with age of onset occurring before 8 years. These are brief events, unless the individual was experiencing myoclonic status, and electroencephalographs show interictal generalized spike and wave activity. Nonepileptic myoclonus occurred in 40% of individuals over 10 years of age, and prevalence appears to increase with age. The episodes of nonepileptic myoclonus arise during puberty or later, with age of onset ranging from 10 to 26 years. These events were captured on 5 video electroencephalographs and had no electrographic correlate. They can last from seconds to hours, always occurring in the hands and spreading to the face and all extremities in some individuals. Episodes of nonepileptic myoclonus have a discrete beginning and end, lacks a postictal period, and are not associated with significant alteration of consciousness or developmental regression. These episodes can be difficult to treat and are often refractory to medication; however, levetiracetam, clobazam, and clonazepam appear to be effective for some individuals. Myoclonic seizures are common in AS, typically occurring in young children and associated with epileptiform changes on electroencephalographs. Prolonged episodes are associated with developmental regression. In contrast, nonepileptic myoclonus typically begins in adolescence or early adulthood and has no electroencephalogram (EEG) correlate, alteration in consciousness, or regression but can significantly impact quality of life.
Selective multifaceted E3 ubiquitin ligases barricade extreme defense: Potential therapeutic targets for neurodegeneration and ageing
2015, Ageing Research Reviews
Efficient and regular performance of Ubiquitin Proteasome System and Autophagy continuously eliminate deleterious accumulation of nonnative protiens. In cellular quality control system, E3 ubiquitin ligases are significant employees for defense mechanism against abnormal toxic proteins. Few findings indicate that lack of functions of E3 ubiquitin ligases can be a causative factor of neurodevelopmental disorders, neurodegeneration, cancer and ageing. However, the detailed molecular pathomechanism implying E3 ubiquitin ligases in cellular functions in multifactorial disease conditions are not well understood. This article systematically represents the unique characteristics, molecular nature, and recent developments in the knowledge of neurobiological functions of few crucial E3 ubiquitin ligases. Here, we review recent literature on the roles of E6-AP, HRD1 and ITCH E3 ubiquitin ligases in the neuro-pathobiological mechanisms, with precise focus on the processes of neurodegeneration, and thereby propose new lines of potential targets for therapeutic interventions.
Paroxysmal tonic upward gaze complicating Angelman syndrome
2015, Pediatric Neurology
Paroxysmal tonic upward gaze is a childhood oculomotor syndrome characterized by episodes of conjugate upward deviation of the eyes. Its pathogenesis is unknown, and the etiology is heterogeneous.
We describe a 2-year-old girl with Angelman syndrome who developed paroxysmal tonic upward gaze at 9 months of age. She presented with developmental delay, blond hair, jerky movements, ataxia, and epilepsy. Genetic testing revealed a maternal deletion of 15q11-13, confirming Angelman syndrome.
This is the first report of Angelman syndrome complicated by paroxysmal tonic upward gaze. Both transient paroxysmal tonic upward gaze and Angelman syndrome have been associated with dopaminergic neurons. We speculate that the dopaminergic abnormalities present in Angelman syndrome may cause paroxysmal tonic upward gaze.
E6-AP association promotes SOD1 aggresomes degradation and suppresses toxicity
2013, Neurobiology of Aging
Citation Excerpt :
E6-AP promotes ubiquitination and degradation of expanded polyglutamine proteins and suppressed polyglutamine protein aggregation (Mishra et al., 2008). The patients with Angelman syndrome also develop Parkinson's-like symptoms in later age (Harbord, 2001). These results all elicit a clue that a loss of E6-AP function might elevate intracellular concentration of certain substrates or damaged proteins (Mulherkar et al., 2009).
Protein aggregation and ordered fibrillar amyloid deposition inside and outside of the central nervous system cells is the common pathologic hallmark of most aging-related neurodegenerative disorders. Dominant mutations in the gene encoding superoxide dismutase 1 (SOD1) protein are linked to familial amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by progressive degeneration of motor neurons, leading to muscle paralysis and death. The major histochemical hallmark in the remaining motor neurons of ALS is the intracellular accumulation of ubiquitinated inclusions consisting of insoluble aberrant protein aggregates. However, the molecular pathomechanisms underlying the process have been elusive. Here for the first time, we report that E6-AP, a homologous to E6-AP C terminus-type E3 ubiquitin ligase depleted in ALS mouse models before neurodegeneration. E6-AP coimmunoprecipitates with the SOD1 protein and is predominantly mislocalized in mutant SOD1-containing inclusion bodies. Overexpression of E6-AP increases the ubiquitination and facilitates degradation of SOD1 proteins. Finally, we show that the overexpression of E6-AP suppresses the aggregation and cell death mediated by mutated SOD1 proteins and cellular protective effect is more prominent when E6-AP is overexpressed along with Hsp70. These data suggest that enhancing the activity of E6-AP ubiquitin ligase might be a viable therapeutic strategy to eliminate mutant SOD1-mediated toxicity in ALS.
Ca<sup>2+</sup>/calmodulin-dependent protein kinase IIα (αCaMKII) controls the activity of the dopamine transporter: Implications for angelman syndrome
2012, Journal of Biological Chemistry
Citation Excerpt :
Consistent with a role of DAT in Angelman syndrome, Ube3Ap+/m− mice become hypodopaminergic and develop motor deficits that are equivalent to human Parkinson disease (39). In fact, frank (levodopa responsive) Parkinson disease has also been observed in young adults with Angelman syndrome (40). Hence, our data on DAT-mediated efflux in striata prepared from Angelman syndrome mice establishes an association between defective Ube3A and DAT and indicates that a defective αCaMKII is most likely the link between these two proteins.
The dopamine transporter (DAT) is a crucial regulator of dopaminergic neurotransmission, controlling the length and brevity of dopaminergic signaling. DAT is also the primary target of psychostimulant drugs such as cocaine and amphetamines. Conversely, methylphenidate and amphetamine are both used clinically in the treatment of attention-deficit hyperactivity disorder and narcolepsy. The action of amphetamines, which induce transport reversal, relies primarily on the ionic composition of the intra- and extracellular milieus. Recent findings suggest that DAT interacting proteins may also play a significant role in the modulation of reverse dopamine transport. The pharmacological inhibition of the serine/threonine kinase αCaMKII attenuates amphetamine-triggered DAT-mediated 1-methyl-4-phenylpyridinium (MPP⁺) efflux. More importantly, αCaMKII has also been shown to bind DAT in vitro and is therefore believed to be an important player within the DAT interactome. Herein, we show that αCaMKII co-immunoprecipitates with DAT in mouse striatal synaptosomes. Mice, which lack αCaMKII or which express a permanently self-inhibited αCaMKII (αCaMKII^T305D), exhibit significantly reduced amphetamine-triggered DAT-mediated MPP⁺ efflux. Additionally, we investigated mice that mimic a neurogenetic disease known as Angelman syndrome. These mice possess reduced αCaMKII activity. Angelman syndrome mice demonstrated an impaired DAT efflux function, which was comparable with that of the αCaMKII mutant mice, indicating that DAT-mediated dopaminergic signaling is affected in Angelman syndrome.
Drosophila modeling of heritable neurodevelopmental disorders
2011, Current Opinion in Neurobiology
Citation Excerpt :
This study therefore suggests that altered dopaminergic function may contribute to AS etiology, and may shed light on symptoms associated with UBE3A copy number variants linked to ASD [11,12]. Clinically, two AS patients presenting with Parkinsonism responded positively to levodopa/carbidopa treatment [13], suggesting dopaminergic function involvement in AS. Further evidence for dopaminergic involvement in AS has been uncovered in a murine maternal loss of Ube3a model, in which loss of tyrosine hydroxylase-reactive neurons in the substantia nigra was linked to motor deficits [14].
Heritable neurodevelopmental disorders are multifaceted disease conditions encompassing a wide range of symptoms including intellectual disability, cognitive dysfunction, autism and myriad other behavioral impairments. In cases where single, causative genetic defects have been identified, such as Angelman syndrome, Rett syndrome, Neurofibromatosis Type 1 and Fragile X syndrome, the classical Drosophila genetic system has provided fruitful disease models. Recent Drosophila studies have advanced our understanding of UBE3A, MECP2, NF1 and FMR1 function, respectively, in genetic, biochemical, anatomical, physiological and behavioral contexts. Investigations in Drosophila continue to provide the essential mechanistic understanding required to facilitate the conception of rational therapeutic treatments.

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^☆: Correspondence to: Dr M. Harbord, Department of Paediatrics and Child Health, Flinders Medical Centre, Bedford Park, SA 5042, Australia. Tel.: +61 8 8204 4459; Fax: +61 8 8204 3945.

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Clinical StudiesLevodopa responsive Parkinsonism in adults with Angelman Syndrome☆

Abstract

Am J Hum Genet

'Puppet' children. A report on three cases

Dev Med Child Neurol

Angelman's (Happy Puppet) Syndrome

Am J Dis Child

Angelman Syndrome: three molecular classes identified with chromosome 15q11–13 specific DNA markers

Am J Hum Genet

Angelman Syndrome in adulthood

Am J Med Genet

Clinical Studies
Levodopa responsive Parkinsonism in adults with Angelman Syndrome☆