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: 3.25). 06/2008; 8(5-6):396-413. DOI: 10.1016/j.mito.2008.05.003
Source: PubMed


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.


Available from: Russell P Saneto
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    • "The current strategy for diagnosis and classification of mitochondrial disorders includes a comprehensive and meticulous analysis of family history, clinical findings, biochemical and histopathological analyses, magnetic resonance imaging findings and molecular diagnostic testing (Graham, 2012). Among these, magnetic resonance imaging (MRI) is one of the easily accessible initial tools available to the clinician for interrogating the presence and pattern of central nervous system changes in patients with mitochondrial disorders (Bricout et al., 2014; Saneto et al., 2008). Apart from the structural imaging, the advanced imaging techniques also help to define the anatomical lesions, metabolism and hemodynamics in these patients (Haas & Dietrich, 2004; Finsterer, 2009a). "
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    ABSTRACT: Large studies analyzing magnetic resonance imaging correlates in different genotypes of mitochondrial disorders are far and few. This study sought to analyze the pattern of magnetic resonance imaging findings in a cohort of genetically characterized patients with mitochondrial disorders. The study cohort included 33 patients (age range 18months-50years, M:F - 0.9:1) with definite mitochondrial disorders seen over a period of 8yrs. (2006-2013). Their MR imaging findings were analyzed retrospectively. The patients were classified into three groups according to the genotype, Mitochondrial point mutations and deletions (n=21), SURF1 mutations (n=7) and POLG1 (n=5). The major findings included cerebellar atrophy (51.4%), cerebral atrophy (24.2%), signal changes in basal ganglia (45.7%), brainstem (34.2%) & white matter (18.1%) and stroke like lesions (25.7%). Spinal cord imaging showed signal changes in 4/6 patients. Analysis of the special sequences revealed, basal ganglia mineralization (7/22), lactate peak on magnetic resonance spectrometry (10/15), and diffusion restriction (6/22). Follow-up images in six patients showed that the findings are dynamic. Comparison of the magnetic resonance imaging findings in the three groups showed that cerebral atrophy and cerebellar atrophy, cortical signal changes and basal ganglia mineralization were seen mostly in patients with mitochondrial mutation. Brainstem signal changes with or without striatal lesions were characteristically noted in SURF1 group. There was no consistent imaging pattern in POLG1 group. Magnetic resonance imaging findings in mitochondrial disorders are heterogeneous. Definite differences were noted in the frequency of anatomical involvement in the three groups. Familiarity with the imaging findings in different genotypes of mitochondrial disorders along with careful analysis of the family history, clinical presentation, biochemical findings, histochemical and structural analysis will help the physician for targeted metabolic and genetic testing. Copyright © 2015. Published by Elsevier B.V.
    Mitochondrion 09/2015; 25. DOI:10.1016/j.mito.2015.08.002 · 3.25 Impact Factor
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    • "Since then, the diagnosis of Leigh syndrome has been based on symmetrical lesions in one or more areas of the central nervous system, including the basal ganglia, diencephalon, brainstem, cerebellum and spinal cord, on either post mortem examination or on neuroimaging [3,4]. Typically, the affected areas appear hypodense on computed tomography (CT) and show hyperintense signal on T2-weighted and hypointense signal on T1-weighted magnetic resonance imaging (MRI) [5,6]. "
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    ABSTRACT: Leigh syndrome is a progressive neurodegenerative disorder, associated with primary or secondary dysfunction of the mitochondrial oxidative phosphorylation. Despite the fact that Leigh syndrome is the most common phenotype of mitochondrial disorders in children, longitudinal natural history data is missing. This study was undertaken to assess the phenotypic and genotypic spectrum of patients with Leigh syndrome, characterise the clinical course and identify predictors of survival in a large cohort of patients. This is a retrospective study of patients with Leigh syndrome that have been followed at eight centers specialising in mitochondrial diseases in Europe; Gothenburg, Rotterdam, Helsinki, Copenhagen, Stockholm, Brussels, Bergen and Oulu. A total of 130 patients were included (78 males; 52 females), of whom 77 patients had identified pathogenic mutations. The median age of disease onset was 7 months, with 80.8% of patients presenting by the age of 2 years. The most common clinical features were abnormal motor findings, followed by abnormal ocular findings. Epileptic seizures were reported in 40% of patients. Approximately 44% of patients experienced acute exacerbations requiring hospitalisation during the previous year, mainly due to infections. The presence of pathological signs at birth and a history of epileptic seizures were associated with higher occurrence of acute exacerbations and/or relapses. Increased lactate in the cerebrospinal fluid was significantly correlated to a more severe disease course, characterised by early onset before 6 months of age, acute exacerbations and/or relapses, as well as brainstem involvement. 39% of patients had died by the age of 21 years, at a median age of 2.4 years. Disease onset before 6 months of age, failure to thrive, brainstem lesions on neuroimaging and intensive care treatment were significantly associated with poorer survival. This is a multicenter study performed in a large cohort of patients with Leigh syndrome. Our data help define the natural history of Leigh syndrome and identify novel predictors of disease severity and long-term prognosis.
    Orphanet Journal of Rare Diseases 04/2014; 9(1):52. DOI:10.1186/1750-1172-9-52 · 3.36 Impact Factor
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    • "With the exception of inferior olivary lesions, however, brainstem lesions are rare in POLG associated encephalopathy. The combination of brainstem and thalamic lesions may occur in Leigh disease, but here the brainstem changes affect primarily gray matter structures such as the substantia nigra, subthalamic and red nuclei and not white matter tracts [32]. "
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    ABSTRACT: Background Correct diagnosis is pivotal to understand and treat neurological disease. Herein, we report the diagnostic work-up utilizing exome sequencing and the characterization of clinical features and brain MRI in two siblings with a complex, adult-onset phenotype; including peripheral neuropathy, epilepsy, relapsing encephalopathy, bilateral thalamic lesions, type 2 diabetes mellitus, cataract, pigmentary retinopathy and tremor. Methods We applied clinical and genealogical investigations, homozygosity mapping and exome sequencing to establish the diagnosis and MRI to characterize the cerebral lesions. Results A recessive genetic defect was suspected in two siblings of healthy, but consanguineous parents. Homozygosity mapping revealed three shared homozygous regions and exome sequencing, revealed a novel homozygous c.367 G>A [p.Asp123Asn] mutation in the α-methylacyl-coA racemase (AMACR) gene in both patients. The genetic diagnosis of α-methylacyl-coA racemase deficiency was confirmed by demonstrating markedly increased pristanic acid levels in blood (169 μmol/L, normal <1.5 μmol/L). MRI studies showed characteristic degeneration of cerebellar afferents and efferents, including the dentatothalamic tract and thalamic lesions in both patients. Conclusions Metabolic diseases presenting late are diagnostically challenging. We show that appropriately applied, homozygosity mapping and exome sequencing can be decisive for establishing diagnoses such as late onset α-methylacyl-coA racemase deficiency, an autosomal recessive peroxisomal disorder with accumulation of pristanic acid. Our study also highlights radiological features that may assist in diagnosis. Early diagnosis is important as patients with this disorder may benefit from restricted dietary phytanic and pristanic acid intake.
    Orphanet Journal of Rare Diseases 01/2013; 8(1):1. DOI:10.1186/1750-1172-8-1 · 3.36 Impact Factor
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