alpha-synuclein and DiGeorge-Syndrome

Juvenile parkinsonism is arbitrarily defined as parkinsonian symptoms and signs presenting prior to 21 years of age. Levodopa-responsive juvenile parkinsonism that is consistent with diagnostic criteria for Parkinson's disease is most often caused by mutations in the PARK-Parkin, PARK-PINK1, or PARK-DJ1 genes. However, many other genetic and acquired parkinsonian disorders presenting in childhood or young adulthood are being reported, often with atypical features, such as presence of other movement disorders, cognitive decline, and psychiatric symptoms. The genetic landscape of juvenile parkinsonism is rapidly changing with the discovery of new genes. Although the mainstay of treatment remains levodopa, other symptomatic therapies such as botulinum toxin for focal dystonia, supportive medical therapies, and deep brain stimulation in select cases, may also be used to provide the most optimal long-term outcomes. Since the topic has not been reviewed recently, we aim to provide an update on genetics, differential diagnosis, evaluation, and treatment of juvenile parkinsonism.

Topics: Adolescent; alpha-Synuclein; Antiparkinson Agents; Child; Child, Preschool; Deep Brain Stimulation; Diagnosis, Differential; DiGeorge Syndrome; Dystonic Disorders; Genetic Diseases, X-Linked; Hepatolenticular Degeneration; Humans; Huntington Disease; Levodopa; Parkinsonian Disorders; Protein Deglycase DJ-1; Protein Kinases; Spinocerebellar Ataxias; Ubiquitin-Protein Ligases; Young Adult

Clinical case reports of parkinsonism co-occurring with hemizygous 22q11.2 deletions and the associated multisystem syndrome, 22q11.2 deletion syndrome (22q11.2DS), suggest that 22q11.2 deletions may lead to increased risk of early-onset Parkinson disease (PD). The frequency of PD and its neuropathological presentation remain unknown in this common genetic condition.. To evaluate a possible association between 22q11.2 deletions and PD.. An observational study of the occurrence of PD in the world's largest cohort of well-characterized adults with a molecularly confirmed diagnosis of 22q11.2DS (n = 159 [6 with postmortem tissue]; age range, 18.1-68.6 years) was conducted in Toronto, Ontario, Canada. Rare postmortem brain tissue from individuals with 22q11.2DS and a clinical history of PD was investigated for neurodegenerative changes and compared with that from individuals with no history of a movement disorder.. A clinical diagnosis of PD made by a neurologist and neuropathological features of PD. RESULTS Adults with 22q11.2DS had a significantly elevated occurrence of PD compared with standard population estimates (standardized morbidity ratio = 69.7; 95% CI, 19.0-178.5). All cases showed early onset and typical PD symptom pattern, treatment response, and course. All were negative for family history of PD and known pathogenic PD-related mutations. The common use of antipsychotics in patients with 22q11.2DS to manage associated psychiatric symptoms delayed diagnosis of PD by up to 10 years. Postmortem brain tissue revealed classic loss of midbrain dopaminergic neurons in all 3 postmortem 22q11.2DS-PD cases. Typical α-synuclein-positive Lewy bodies were present in the expected distribution in 2 cases but absent in another.. These findings suggest that 22q11.2 deletions represent a novel genetic risk factor for early-onset PD with variable neuropathological presentation reminiscent of LRRK2-associated PD neuropathology. Individuals with early-onset PD and classic features of 22q11.2DS should be considered for genetic testing, and those with a known 22q11.2 deletion should be monitored for the development of parkinsonian symptoms. Molecular studies of the implicated genes, including DGCR8, may help shed light on the underlying pathophysiology of PD in 22q11.2DS and idiopathic PD.

Topics: Adult; Age of Onset; Aged; alpha-Synuclein; Brain; Calcium-Binding Proteins; Canada; Chromosome Deletion; DiGeorge Syndrome; DNA-Binding Proteins; Female; Genetic Testing; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Male; Microfilament Proteins; Middle Aged; Mutation; Neurologic Examination; Observational Studies as Topic; Parkinson Disease; Protein Serine-Threonine Kinases; Severity of Illness Index; Tyrosine 3-Monooxygenase; Young Adult