Neuroimaging of mitochondrial disease.

Division of Pediatric Neurology, Children's Hospital and Regional Medical Center/University of Washington, 4800 Sand Point Way NE, Seattle, WA 98105, USA.
Mitochondrion (Impact Factor: 3.52). 06/2008; 8(5-6):396-413. DOI: 10.1016/j.mito.2008.05.003
Source: PubMed

ABSTRACT Mitochondrial disease represents a heterogeneous group of genetic disorders that require a variety of diagnostic tests for proper determination. Neuroimaging may play a significant role in diagnosis. The various modalities of nuclear magnetic resonance imaging (MRI) allow for multiple independent detection procedures that can give important anatomical and metabolic clues for diagnosis. The non-invasive nature of neuroimaging also allows for longitudinal studies. To date, no pathonmonic correlation between specific genetic defect and neuroimaging findings have been described. However, certain neuroimaging results can give important clues that a patient may have a mitochondrial disease. Conventional MRI may show deep gray structural abnormalities or stroke-like lesions that do not respect vascular territories. Chemical techniques such as proton magnetic resonance spectroscopy (MRS) may demonstrate high levels of lactate or succinate. When found, these results are suggestive of a mitochondrial disease. MRI and MRS studies may also show non-specific findings such as delayed myelination or non-specific leukodystrophy picture. However, in the context of other biochemical, structural, and clinical findings, even non-specific findings may support further diagnostic testing for potential mitochondrial disease. Once a diagnosis has been established, these non-invasive tools can also aid in following disease progression and evaluate the effects of therapeutic interventions.

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    ABSTRACT: Background Kearns-Sayre syndrome (KSS) is a mitochondrial DNA deletion syndrome that presents with profound cerebral folate deficiency and other features. Preliminary data support the notion that folinic acid therapy might be useful in the treatment of KSS patients. Our aim was to assess the clinical and neuroimaging outcomes of KSS patients receiving folinic acid therapy.Methods Patients: We recruited eight patients with diagnoses of KSS. Four cases were treated at 12 de Octubre Hospital, and the other two cases were treated at Sant Joan de Déu Hospital. Two patients refused to participate in the treatment protocol. Methods: Clinical, biochemical and neuroimaging data (magnetic resonance imaging or computed tomography scan) were collected in baseline conditions and at different time points after the initiation of therapy. Cerebrospinal fluid 5-methyltetrahydrofolate levels were analysed with HPLC and fluorescence detection. Large-scale mitochondrial DNA deletions were analysed by Southern blot. Treatment protocol: The follow-up periods ranged from one to eight years. Cases 1¿4 received oral folinic acid at a dose of 1 mg/kg/day, and cases 6 and 8 received 3 mg/kg/day.ResultsNo adverse effects of folinic acid treatment were observed. Cerebral 5-methyltetrahydrofolate deficiencies were observed in all cases in the baseline conditions. Moreover, all three patients who accepted lumbar puncture after folinic acid therapy exhibited complete recoveries of their decreased basal cerebrospinal fluid 5-methyltetrahydrofolate levels to normal values. Two cases neurologically improved after folinic therapy. Disease worsened in the other patients.Post-treatment neuroimaging was performed for the 6 cases that received folinic acid therapy. One patient exhibited improvements in white matter abnormalities. The remaining patients displayed progressions in subcortical cerebral white matter, the cerebellum and cerebral atrophy.Conclusions Four patients exhibited clinical and radiological progression of the disease following folinic acid treatment. Only one patient who was treated in an early stage of the disease exhibited both neurological and radiological improvements following elevated doses of folinic acid, and an additional patient experienced neurological improvement. Early treatment with high-dose folinic acid therapy seems to be advisable for the treatment of KSS.Trial registrationEudracT2007-00-6748-23.
    Orphanet Journal of Rare Diseases 12/2014; 9(1):3. DOI:10.1186/s13023-014-0217-2 · 3.96 Impact Factor
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    ABSTRACT: Dyslexia is a very common disorder among school children, with a prevalence ranging from 5% to12% in Western countries based on the various evaluation standards used for diagnosis and phenotype assessment. There is strong evidence from familial and twin studies indicating that the disorder has a genetic component. Although linkage analysis and association studies have identified potential risk loci located on chromosomes 1, 2, 3, 4, 6, 11, 12, 13, 15, 17, 18, and X, the lod scores are only marginally significant and the susceptible regions are broad and flat. To date, only DCDC2, KIAA0319, ROBO1, DYX1C1 PCNT, DIP2A, S100B, PRMT2, MRPL19 and C20RF3 have been reported as susceptibly involved genes; however, some of these results are controversial and despite intensive studies, gene prediction is extremely challenging. In silico cloning provides an efficient alternative for the discovery of possible candidate genes. Here, we explore the possibility of predicting the genes that might contribute to dyslexia using in silico cloning. We use the dyslexia candidate region on 2p11 as an example, where forty-two out of sixty genes have known functions assigned by the Ensembl Genome Browser. Three genes, namely, SUCLG1, IMM T and RM35_HUMAN are correlated with mitochondrial function and it is suggested, based on aspects of the physiology of dyslexia, that mutations in these genes may be important; specific information on these genes is described.
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    ABSTRACT: Leigh syndrome, also referred to as subacute necrotizing encephalomyelopathy, is a severe, early-onset neurodegenerative disorder that is relentlessly progressive and devastating to both the patient and the patient's family. Attributed to the ultimate failure of the mitochondrial respiratory chain, once it starts, the disease often results in the regression of both mental and motor skills, leading to disability and rapid progression to death. It is a mitochondrial disorder with both phenotypic and genetic heterogeneity. The cause of death is most often respiratory failure, but there are a whole host of complications, including refractory seizures, that may further complicate morbidity and mortality. The symptoms may develop slowly or with rapid progression, usually associated with age of onset. Although the disease is usually diagnosed within the first year of life, it is important to note that recent studies reveal phenotypic heterogeneity, with some patients having evidence of in utero presentation and others having adult-onset symptoms.
    The Application of Clinical Genetics 01/2014; 7:221-234. DOI:10.2147/TACG.S46176


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May 21, 2014