Neuromelanin MRI in a family with mitochondrial parkinsonism harboring a Y955C mutation in POLG1
ABSTRACT BACKGROUND: Progressive external ophthalmoplegia (PEO) and parkinsonism can be caused by genetic mutations that affect mitochondrial DNA (mtDNA) maintenance. We characterized parkinsonism in a family with dominantly inherited PEO. METHODS: We conducted clinical, histological and genetic analyses on two affected members suffering from PEO and parkinsonism, and reviewed the cases in the literature. To clarify parkinsonism related to multiple mtDNA deletions, we used 3-T neuromelanin magnetic resonance imaging (MRI) to assess signal changes in the substantia nigra (SN) and locus ceruleus (LC) in our patients, and compared the results to those observed in idiopathic Parkinson's disease (iPD) (n = 35). RESULTS: We report the first case of a Japanese family harboring a heterozygous p.Y955C mutation in POLG1. The clinical features of parkinsonism related to the Y955C mutation in a total of 16 patients, including our two cases, are indistinguishable from iPD. However, neuromelanin MRI showed a distinct pattern in our cases compared to iPD. The neuromelanin imaging results were consistent with the neuropathological findings reported in cases of POLG1 mutations, in which neurons of the SN were profoundly affected while those in the LC were preserved. CONCLUSIONS: Our results suggest that 3-T neuromelanin MRI may be useful for differentiating POLG1 mutation-associated parkinsonism from iPD, and that POLG1 mutations may cause selective neuronal loss in the SN via a mechanism different from that of iPD.
- Neural Regeneration Research 04/2014; 9(7):759-60. DOI:10.4103/1673-5374.131583 · 0.23 Impact Factor
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ABSTRACT: Quantitative MRI of neuromelanin (NM) containing structures (referred to as NM-MRI) in the brainstem, namely the locus coeruleus (LC) and substantia nigra (SN), may assist with the early detection of Parkinson's disease (PD) and Alzheimer's disease (AD) as well as differential diagnosis in the early disease stages. In this study, two gradient echo (GRE) sequences with magnetization transfer contrast (MTC) preparation pulses were developed to simultaneously image the LC and SN. This has been a challenge with NM-MRI techniques used in previous studies due to the relatively high specific absorption rate (SAR) induced by these techniques. In addition, a semi-automated quantitative analysis scheme was applied to estimate volumes and contrast-to-noise ratios (CNR) of the LC and SN based on segmentation of both structures. Compared to a T1-weighted turbo spin echo (TSE) sequence typically used for simultaneous imaging of the LC and SN, the two GRE-MTC sequences exhibited improved performance in terms of higher sensitivity (in CNR) in imaging the SN and lower SAR during the scans. A multiple-measurement protocol was adopted as well, so that motion degraded measurements could be removed and artifacts associated with motion corrected. The presented approach has demonstrated advantages in imaging acquisition (lower SAR and higher sensitivity), imaging pre-processing (with motion correction) and quantitative image analysis (segmentation-based estimation of volume and CNR) as compared with existing NM-MRI approaches. This approach has potential for detection and monitoring of neurodegeneration in LC and SN in disease states including AD and PD.Magnetic Resonance Imaging 07/2014; 32(10). DOI:10.1016/j.mri.2014.07.003 · 2.02 Impact Factor
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ABSTRACT: Background: Progressive external ophthalmoplegia (PEO) is an eye movement disorder characterised by paresis of the extra ocular muscles and muscle restricted multiple mitochondrial DNA (mtDNA) deletions. Classification of patients is particularly difficult due to overlapping phenotypes and a poor genotype-phenotype relationship. Despite the identification of several nuclear encoded genes causing PEO, over half of patients with clinically confirmed PEO do not have a genetic diagnosis. Objective: To systematically review genotypic and phenotypic correlates of published cases of adult-onset PEO. Methods: Patients were identified from interrogation of articles from Scopus, Medline via PubMed, and Genetic Abstracts databases using electronic searches (1st January 1970 to 8th November 2013). Reference lists and UniProt entries were also manually checked for additional articles. Results: Twelve nuclear encoded genes were identified (TYMP, SLC25A4, POLG, C10ORF2, OPA1, POLG2, RRM2B, TK2, DGUOK, MPV17, MGME1, and DNA2) systematically from 583 patients. At the time of writing, mutations in SPG7 and AFG3L2 genes were reported to be associated with ophthalmoparesis and multiple mtDNA deletions in fourteen additional adult-onset PEO patients, bringing the total number of known genes to fourteen. Conclusions: Diagnostic yield is still critically dependent on the meticulous clinical and biochemical characterisation of patients. Understanding the intimate relationship between genotype and phenotype remains a fundamental challenge. The results of this systematic review provide guidance to both patients and clinician about future prognosis, and will serve, in future, to assess methods of disease prevention and evaluation of targeted therapeutic strategies.