TY - JOUR
T1 - Mitochondrial disorders in children
T2 - Toward development of small-molecule treatment strategies
AU - Koopman, Werner J.H.
AU - Beyrath, Julien
AU - Fung, Cheuk Wing
AU - Koene, Saskia
AU - Rodenburg, Richard J.
AU - Willems, Peter H.G.M.
AU - Smeitink, Jan A.M.
PY - 2016/4/1
Y1 - 2016/4/1
N2 - This review presents our current understanding of the pathophysiology and potential treatment strategies with respect to mitochondrial disease in children. We focus on pathologies due to mutations in nuclear DNA-encoded structural and assembly factors of the mitochondrial oxidative phosphorylation (OXPHOS) system, with a particular emphasis on isolated mitochondrial complex I deficiency. Following a brief introduction into mitochondrial disease and OXPHOS function, an overview is provided of the diagnostic process in children with mitochondrial disorders. This includes the impact of whole-exome sequencing and relevance of cellular complementation studies. Next, we briefly present how OXPHOS mutations can affect cellular parameters, primarily based on studies in patient-derived fibroblasts, and how this information can be used for the rational design of small-molecule treatment strategies. Finally, we discuss clinical trial design and provide an overview of small molecules that are currently being developed for treatment of mitochondrial disease.
AB - This review presents our current understanding of the pathophysiology and potential treatment strategies with respect to mitochondrial disease in children. We focus on pathologies due to mutations in nuclear DNA-encoded structural and assembly factors of the mitochondrial oxidative phosphorylation (OXPHOS) system, with a particular emphasis on isolated mitochondrial complex I deficiency. Following a brief introduction into mitochondrial disease and OXPHOS function, an overview is provided of the diagnostic process in children with mitochondrial disorders. This includes the impact of whole-exome sequencing and relevance of cellular complementation studies. Next, we briefly present how OXPHOS mutations can affect cellular parameters, primarily based on studies in patient-derived fibroblasts, and how this information can be used for the rational design of small-molecule treatment strategies. Finally, we discuss clinical trial design and provide an overview of small molecules that are currently being developed for treatment of mitochondrial disease.
KW - Children
KW - Clinical trial
KW - Drug development
KW - Mitochondria
KW - Outcome measures
U2 - 10.15252/emmm.201506131
DO - 10.15252/emmm.201506131
M3 - Article
C2 - 26951622
AN - SCOPUS:84959907620
SN - 1757-4676
VL - 8
SP - 311
EP - 327
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
IS - 4
ER -