Background and purpose
AIFM1 (apoptosis-inducing factor, mitochondrion-associated-1) in mitochondria has captured a great attention due to its well-described function in apoptosis. Mutations in AIFM1 have resulted in multiple clinical phenotypes, including CMTX4. These syndromes usually involve multiple locations within the nervous system and/or multiple organs. This study describes a novel missense mutation in AIFM1 and its associated peripheral nerve disease.
Methods
Patients with AIFM1 mutation were characterized clinically, electrophysiologically, genetically and by MRI imaging. The fibroblasts were isolated from the patients to study mitochondrial OXPHOS complexes.
Results
We identified a family with a novel missense mutation (Phe210Leu) in AIFM1 that developed an isolated late-onset axonal polyneuropathy in which the central nervous system and other organs were spared. Interestingly, this Phe210Leu mutation resulted in abnormal assembly of mitochondrial complex-I (CI) and III (CIII) and failed to disrupt AIFM1 binding with MIA40 in the patients’ cells. Deficiency of either AIFM1 or MIA40 is known to impair the assembly of mitochondrial complex-1 and IV. Yet, levels of both AIFM1 and MIA40 were unchanged.
Conclusions
Phe210Leu mutation in AIFM1 induces an axonal polyneuropathy that might be contributed by the misassembly of mitochondrial CI and CIII. This misassembly appears to be independent of the traditional mechanism via AIFM1/MIA40 deficiency.
ObjectiveThe SCN11A gene encodes the NaV1.9 sodium channel found exclusively in peripheral nociceptive neurons.MethodsAll enrolled participants were evaluated clinically by electrophysiologic studies, DNA sequencing, and punch skin biopsies.ResultsAll affected family members are afflicted by episodes of pain. Pain was predominantly nociceptive, but not neuropathic in nature, which led a diagnosis of fibromyalgia in some patients. All patients had normal findings in nerve conduction studies for detecting large nerve fiber neuropathies and skin biopsies for detecting small nerve fiber pathology.ConclusionsUnlike those patients with missense mutations in SCN11A, small fiber sensory neuropathy, and neuropathic pain, the Arg225Cys SCN11A in the present study causes predominantly nociceptive pain with minimal features of neuropathic pain and undetectable pathophysiologic changes of peripheral neuropathy. This finding is consistent with dysfunction of nociceptive neurons. In addition, since nociceptive pain in patients has led to the diagnosis of fibromyalgia, this justifies a future search of mutations of SCN11A in patients with additional pain phenotypes such as fibromyalgia to expand the clinical spectrum beyond painful small fiber sensory neuropathy.
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