Will genotype drive treatment options?

Brüggemann, Norbert; Klein, Christine

doi:10.1002/mds.27699

Cited by 14 publications

(15 citation statements)

References 29 publications

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“…In the context of monogenic PD, the function of the encoded proteins provides a potential starting point for gene-specific therapies [141]. Finally, new treatment options might result from the currently discovered mechanistic relationship between (monogenic) PD and inflammation [107].…”

Section: Implications For Genetic Testingmentioning

confidence: 99%

Mitochondria and Parkinson’s Disease: Clinical, Molecular, and Translational Aspects

Borsche

Pereira

Klein

et al. 2021

JPD

Self Cite

155

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Mitochondrial dysfunction represents a well-established player in the pathogenesis of both monogenic and idiopathic Parkinson’s disease (PD). Initially originating from the observation that mitochondrial toxins cause PD, findings from genetic PD supported a contribution of mitochondrial dysfunction to the disease. Here, proteins encoded by the autosomal recessively inherited PD genes Parkin, PTEN-induced kinase 1 (PINK1), and DJ-1 are involved in mitochondrial pathways. Additional evidence for mitochondrial dysfunction stems from models of autosomal-dominant PD due to mutations in alpha-synuclein (SNCA) and leucine-rich repeat kinase 2 (LRRK2). Moreover, patients harboring alterations in mitochondrial polymerase gamma (POLG) often exhibit signs of parkinsonism. While some molecular studies suggest that mitochondrial dysfunction is a primary event in PD, others speculate that it is the result of impaired mitochondrial clearance. Most recent research even implicated damage-associated molecular patterns released from non-degraded mitochondria in neuroinflammatory processes in PD. Here, we summarize the manifold literature dealing with mitochondria in the context of PD. Moreover, in light of recent advances in the field of personalized medicine, patient stratification according to the degree of mitochondrial impairment followed by mitochondrial enhancement therapy may hold potential for at least a subset of genetic and idiopathic PD cases. Thus, in the second part of this review, we discuss therapeutic approaches targeting mitochondrial dysfunction with the aim to prevent or delay neurodegeneration in PD.

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Section: Implications For Genetic Testingmentioning

confidence: 99%

Mitochondria and Parkinson’s Disease: Clinical, Molecular, and Translational Aspects

Borsche

Pereira

Klein

et al. 2021

JPD

Self Cite

155

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“…Among the neurogenetic diseases, glucose transporter type-1 deficiency, X-linked adrenoleukodystrophy, and dopa-responsive dystonia are considered successful models of these patient-tailored therapies [20,21]. The number of neurogenetic diseases is increasing with the development of new therapeutic modalities [22,23]. In our study cohort, these patient-tailored therapies have remarkably changed the clinical course in 4 patients (1.1%) among the 376 children with neurodevelopmental symptoms that were evaluated using WES.…”

Section: Discussionmentioning

confidence: 90%

Clinical Application of Whole Exome Sequencing to Identify Rare but Remediable Neurologic Disorders

Kim

Yum

Seo

et al. 2020

JCM

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Background: The aim of this study was to describe the application of whole exome sequencing (WES) in the accurate genetic diagnosis and personalized treatment of extremely rare neurogenetic disorders. Methods: From 2017 to 2019, children with neurodevelopmental symptoms were evaluated using WES in the pediatric neurology clinic and medical genetics center. The clinical presentation, laboratory findings including the genetic results from WES, and diagnosis-based treatment and outcomes of the four patients are discussed. Results: A total of 376 children with neurodevelopmental symptom were evaluated by WES, and four patients (1.1%) were diagnosed with treatable neurologic disorders. Patient 1 (Pt 1) showed global muscle hypotonia, dysmorphic facial features, and multiple anomalies beginning in the perinatal period. Pt 1 was diagnosed with congenital myasthenic syndrome 22 of PREPL deficiency. Pt 2 presented with hypotonia and developmental arrest and was diagnosed with autosomal recessive dopa-responsive dystonia due to TH deficiency. Pt 3, who suffered from intractable epilepsy and progressive cognitive decline, was diagnosed with epileptic encephalopathy 47 with a heterozygous FGF12 mutation. Pt 4 presented with motor delay and episodic ataxia and was diagnosed with episodic ataxia type II (heterozygous CACNA1A mutation). The patients’ major neurologic symptoms were remarkably relieved with pyridostigmine (Pt 1), levodopa (Pt 2), sodium channel blocker (Pt 3), and acetazolamide (Pt 4), and most patients regained developmental milestones in the follow-up period (0.4 to 3 years). Conclusions: The early application of WES helps in the identification of extremely rare genetic diseases, for which effective treatment modalities exist. Ultimately, WES resulted in optimal clinical outcomes of affected patients.

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“…Aufgrund dieser und weiterer Laborbefunde ist es inzwischen gelungen, Medikamente zu entwickeln, die die Kinase-Aktivität von LRRK2 hemmen und wichtige Sicherheitsaspekte in klinischen Phase-I-Studien erfüllen [50]. Aktuell werden erste klinische Studien bei betroffenen G2019 S-Mutationsträgern im LRRK2-Gen geplant, was die Umsetzung eines präzisionsmedizinischen, auf genetischer Stratifizierung basierenden Ansatzes impliziert [51]. Zwar wurde die G2019 S-Mutation nicht bei anderen Ethnien gefunden, aber in der indischen Bevölkerung wurde eine andere Mutation entdeckt, welche ebenfalls die Kinase-Aktivität von LRRK2 erhöht, sodass ein erfolgreich entwickelter Kinase-Inhibitor möglicherweise auch weiteren Patienten zugutekommen kann [52].…”

Section: Lrrk2unclassified

Ansätze zur Etablierung von Präzisionsmedizin bei der Parkinson-Krankheit mit dem Schwerpunkt Genetik

Stute

Krüger

2020

Fortschr Neurol Psychiatr

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ZusammenfassungWährend Parkinson mit seiner vielfältigen und sehr individuellen Kombination aus motorischen und nichtmotorischen Symptomen zunehmend genauer charakterisiert ist, nicht zuletzt durch die Untersuchung von großen Patientenkohorten mit Deep-Phenotyping-Approach, folgt die Therapie weiterhin einem einheitlichen Schema. Durch bessere Stratifikation bieten Präzisionsmedizin-Ansätze die Möglichkeit, die Behandlung und patientenzentrierte Versorgung zu verbessern. Spezifische Therapien für den Einsatz bei monogenetischen Parkinson-Formen, die aktuell untersucht werden, könnten helfen, Krankheitsmechanismen zu verstehen und dadurch auch zum Verständnis des idiopathischen Parkinson-Syndroms beitragen, sowie neue Behandlungsziele aufzeigen. Wir zeigen Daten zur Vorhersage von Wirksamkeit und Langzeit-Vorteil von aktuellen medikamentösen Behandlungen sowie von Tiefer Hirnstimulation (THS) im Kontext von wachsendem pharmakogenetischen Wissen. Konfrontiert mit asymptomatischen Trägern genetischer Mutationen (monogenetische Erkrankung) von variabler Penetranz und prodromalen Stadien wie REM-Schlaf-Verhaltensstörungen, zeichnen sich erste präventive Therapiestrategien ab. Ihr Einfluss auf die Krankheitsprogression und Aussichten für die klinische Praxis müssen adressiert werden.

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Will genotype drive treatment options?

Cited by 14 publications

References 29 publications

Mitochondria and Parkinson’s Disease: Clinical, Molecular, and Translational Aspects

Mitochondria and Parkinson’s Disease: Clinical, Molecular, and Translational Aspects

Clinical Application of Whole Exome Sequencing to Identify Rare but Remediable Neurologic Disorders

Ansätze zur Etablierung von Präzisionsmedizin bei der Parkinson-Krankheit mit dem Schwerpunkt Genetik

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