Neuroimaging in mitochondrial disorders

2018 ◽  
Vol 62 (3) ◽  
pp. 409-421 ◽  
Author(s):  
Mario Mascalchi ◽  
Martino Montomoli ◽  
Renzo Guerrini
Keyword(s):  
Mitochondrial Disease ◽  
Brain Mri ◽  
Cerebellar Atrophy ◽  
Mitochondrial Diseases ◽  
Resonance Spectroscopy ◽  
Normal Brain ◽  
Subcortical Structures ◽  
Mri Findings ◽  
Metabolic Derangement ◽  
Signal Changes

MRI and 1H magnetic resonance spectroscopy (1HMRS) are the main neuroimaging methods to study mitochondrial diseases. MRI can demonstrate seven ‘elementary’ central nervous system (CNS) abnormalities in these disorders, including diffuse cerebellar atrophy, cerebral atrophy, symmetric signal changes in subcortical structures (basal ganglia, brainstem, cerebellum), asymmetric signal changes in the cerebral cortex and subcortical white matter, leukoencephalopathy, and symmetric signal changes in the optic nerve and the spinal cord. These elementary MRI abnormalities can be variably combined in the single patient, often beyond what can be expected based on the classically known clinical-pathological patterns. However, a normal brain MRI is also possible. 1HMRS has a diagnostic role in patients with suspected mitochondrial encephalopathy, especially in the acute phase, as it can detect within the lesions, but also in normal appearing nervous tissue or in the ventricular cerebrospinal fluid (CSF), an abnormally prominent lactate peak, reflecting failure of the respiratory chain with a shift from the Krebs cycle to anaerobic glycolysis. So far, studies correlating MRI findings with genotype in mitochondrial disease have been possible only in small samples and would greatly benefit from data pooling. MRI and 1HMRS have provided important information on the pathophysiology of CNS damage in mitochondrial diseases by enabling in vivo non-invasive assessment of tissue abnormalities, the associated changes of blood perfusion and cellular metabolic derangement. MRI and 1HMRS are expected to serve as surrogate biomarkers in trials investigating therapeutic options in mitochondrial disease.

scholarly journals Case Report: SATB2-Associated Syndrome Overlapping With Clinical Mitochondrial Disease Presentation: Report of Two Cases

2021 ◽  
Vol 12 ◽  
Author(s):  
Yuri A. Zarate ◽  
Hilary J. Vernon ◽  
Katherine A. Bosanko ◽  
Praveen K. Ramani ◽  
Murat Gokden ◽  
...  
Keyword(s):  
Magnetic Resonance ◽  
Mitochondrial Disease ◽  
Relative Proportion ◽  
Mitochondrial Disorder ◽  
Mitochondrial Diseases ◽  
Evaluation Process ◽  
Global Developmental Delay ◽  
Resonance Spectroscopy ◽  
Extensive Evaluation ◽  
Complex I Activity

SATB2-associated syndrome (SAS) is an autosomal dominant neurogenetic multisystemic disorder. We describe two individuals with global developmental delay and hypotonia who underwent an extensive evaluation to rule out an underlying mitochondrial disorder before their eventual diagnosis of SAS. Although the strict application of the clinical mitochondrial disease score only led to the designation of “possible” mitochondrial disorder for these two individuals, other documented abnormalities included nonspecific neuroimaging findings on magnetic resonance imaging and magnetic resonance spectroscopy, decreased complex I activity on muscle biopsy for patient 2, and variation in the size and relative proportion of types of muscle fibers in the muscle biopsies that were aligned with mitochondrial diseases. SAS should be in the differential diagnoses of mitochondrial disorders, and broad-spectrum diagnostic tests such as exome sequencing need to be considered early in the evaluation process of undiagnosed neurodevelopmental disorders.

Diagnostic brain MRI findings in primary progressive multiple sclerosis

2000 ◽  
Vol 6 (2) ◽  
pp. 81-85 ◽  
Author(s):  
M Kremenchutzky ◽  
D Lee ◽  
G P A Rice ◽  
G C Ebers
Keyword(s):  
Multiple Sclerosis ◽  
Age Of Onset ◽  
Brain Mri ◽  
Diagnostic Value ◽  
Progressive Multiple Sclerosis ◽  
Normal Brain ◽  
Primary Progressive Multiple Sclerosis ◽  
Mri Findings ◽  
Primary Progressive ◽  
Mri Scans

The clinical course of multiple sclerosis can be classified as relapsing from onset (relapsing-remitting), or progressive from onset (primary progressive -PPMS). These clinical phenotypes have been based on historical and clinical observations. It has been reported that PPMS patients tend to have quantitatively less MRI activity and disease burden. We evaluated the sensitivity and diagnostic value of conventional brain MRI scan in 143 PPMS patients. Brain MRIs were blindly evaluated to determine if they satisfied Paty and/or Fazekas diagnostic criteria. Patient were divided into those with typical atypical or normal scans. They satisfied brain MRI criteria in 92% cases. Findings included: 131 typical four atypical, and eight normal scans. All 12 non-typical scans' subject had spinal onset; spinal MRI scans were positive in four of seven cases. Sex, age of onset, site and number of symptoms involved at onset among those groups were not significantly different but accumulation of disability had a tendency to be slower in these few individuals with normal or atypical head MRI's. Although there may be quantitative differences in lesion activity/burden, MRI scanning in PPMS unexpectedly has diagnostic sensitivity very similar to that seen in RRMS. A normal brain MRI is unusual in PPMS patients.

scholarly journals Relationship Between Changes in Brain MRI and 1H-MRS, Severity of Chronic Liver Damage, and Recovery After Liver Transplantation

2009 ◽  
Vol 234 (9) ◽  
pp. 1075-1085 ◽  
Author(s):  
Li-Ling Long ◽  
Xiang-Rong Li ◽  
Zhong-Kui Huang ◽  
Yue-Ming Jiang ◽  
Sherleen X. Fu ◽  
...  
Keyword(s):  
Liver Transplantation ◽  
Magnetic Resonance ◽  
Liver Transplant ◽  
Globus Pallidus ◽  
Liver Damage ◽  
Brain Mri ◽  
Chronic Liver ◽  
Resonance Spectroscopy ◽  
Brain Metabolites ◽  
Normal Brain

Magnetic resonance imaging (MRI) and 1H magnetic resonance spectroscopy (1H-MRS) have been used in clinics for diagnosis of chronic liver diseases. This study was designed to investigate the relationship between MRI/MRS outcomes and the severity of liver damage. Of 50 patients examined, the MRI signal intensity in the globus pallidus as determined by pallidus index (PI) increased as the disease severity (scored by Child Pugh ranking) worsened ( r = 0.353, P < 0.05). The changes in PI values were also linearly associated with Mn concentrations in whole blood (MnB) ( r = 0.814, P < 0.01). MRS analysis of four major brain metabolites (i.e., Cho, mI, Glx, and NAA) revealed that the ratios of Cho/Cr and mI/Cr in cirrhosis and CHE patients were significantly decreased in comparison to controls ( P < 0.05), whereas the ratio of Glx/Cr was significantly increased ( P < 0.05). The Child Pugh scores significantly correlated with mI/Cr (−0.484, P < 0.01) and Glx (0.369, P < 0.05), as well as MnB (0.368, P < 0.05), but not with other brain metabolites. Three patients who received a liver transplant experienced normalization of brain metabolites within 3 months of post-transplantation; the MR imaging of Mn in the globus pallidus completely disappeared 5 months after the surgery. Taken together, this clinical study, which combined MRI/MRS analysis, autopsy exam and liver transplant, clearly demonstrates that liver injury-induced brain Mn accumulation can reversibly alter the homeostasis of brain metabolites Cho, mI and Glx. Our data further suggest that liver transplantation can restore normal brain Mn levels.

scholarly journals VPS41 recessive mutation causes ataxia and dystonia with retinal dystrophy and mental retardation by inhibiting HOPS function and mTORC1 signaling

2019 ◽  
Author(s):  
R.E.N. van der Welle ◽  
R. Jobling ◽  
C. Burns ◽  
P. Sanza ◽  
C. ten Brink ◽  
...  
Keyword(s):  
Neuroprotective Effect ◽  
Protein Sorting ◽  
Brain Mri ◽  
Retinal Dystrophy ◽  
Cerebellar Atrophy ◽  
Recessive Mutation ◽  
Compound Heterozygous ◽  
Mri Findings ◽  
Mtorc1 Signaling ◽  
Vacuolar Protein

AbstractThe vacuolar protein sorting protein 41 (VPS41) is a neuroprotective protein in models of Parkinson’s disease (PD). As part of the HOPS (Homotypic fusion and Protein Sorting) complex, VPS41 regulates fusion of lysosomes with late endosomes and autophagosomes. Independent of HOPS, VPS41 regulates transport of newly synthesized lysosomal membrane proteins and secretory proteins. Here we report two brothers with compound heterozygous mutations in VPS41 (VPS41R662* and VPS41S285P), born to healthy and non-consanguineous parents. Both patients displayed transient retinal dystrophy, ataxia and dystonia, with brain MRI findings of cerebellar atrophy and a thin saber-shape corpus callosum. Patient-derived fibroblasts contained enzymatically active lysosomes that were poorly reached by endocytic cargo and failed to attract the mTORC1 complex. Consequently, transcription factor TFE3, a driver of autophagy and lysosomal genes, showed continuous nuclear localization which resulted in elevated LC3-II levels and an impaired response to nutrient starvation. CRISPR/CAS VPS41 HeLa knockout cells showed a similar phenotype that could be rescued by wildtype VPS41 but not by VPS41S285P or VPS41R662*. mTORC1 inhibition was also seen after knockout of HOPS subunits VPS11 or VPS18. Regulated neuropeptide secretion in PC12 VPS41 knockout cells was rescued by VPS41S285P expression, indicating that this HOPS-independent function was preserved. Co-expression of the VPS41S285P and VPS41R662* variants in a C. elegans model of PD abolished the protective effect of VPS41 against α-synuclein-induced neurodegeneration. We conclude that both disease-associated VPS41 variants specifically abrogate HOPS function, which leads to a delay in endocytic cargo delivery to lysosomes, mTORC1 inhibition and irresponsiveness to autophagic clues. Our studies signify a link between HOPS function and mTORC1 signaling and imply that HOPS function is required for the neuroprotective effect of VPS41 in PD.

scholarly journals Choline transporter-like 1 deficiency causes a new type of childhood-onset neurodegeneration

Brain ◽  
2019 ◽  
Vol 143 (1) ◽  
pp. 94-111 ◽  
Author(s):  
Christina R Fagerberg ◽  
Adrian Taylor ◽  
Felix Distelmaier ◽  
Henrik D Schrøder ◽  
Maria Kibæk ◽  
...  
Keyword(s):  
Signal Intensity ◽  
Membrane Lipids ◽  
Brain Mri ◽  
Cerebellar Atrophy ◽  
Ultrastructural Changes ◽  
Normal Brain ◽  
Childhood Onset ◽  
Choline Transport ◽  
Choline Transporter ◽  
Transporter Deficiency

Abstract Cerebral choline metabolism is crucial for normal brain function, and its homoeostasis depends on carrier-mediated transport. Here, we report on four individuals from three families with neurodegenerative disease and homozygous frameshift mutations (Asp517Metfs*19, Ser126Metfs*8, and Lys90Metfs*18) in the SLC44A1 gene encoding choline transporter-like protein 1. Clinical features included progressive ataxia, tremor, cognitive decline, dysphagia, optic atrophy, dysarthria, as well as urinary and bowel incontinence. Brain MRI demonstrated cerebellar atrophy and leukoencephalopathy. Moreover, low signal intensity in globus pallidus with hyperintensive streaking and low signal intensity in substantia nigra were seen in two individuals. The Asp517Metfs*19 and Ser126Metfs*8 fibroblasts were structurally and functionally indistinguishable. The most prominent ultrastructural changes of the mutant fibroblasts were reduced presence of free ribosomes, the appearance of elongated endoplasmic reticulum and strikingly increased number of mitochondria and small vesicles. When chronically treated with choline, those characteristics disappeared and mutant ultrastructure resembled healthy control cells. Functional analysis revealed diminished choline transport yet the membrane phosphatidylcholine content remained unchanged. As part of the mechanism to preserve choline and phosphatidylcholine, choline transporter deficiency was implicated in impaired membrane homeostasis of other phospholipids. Choline treatments could restore the membrane lipids, repair cellular organelles and protect mutant cells from acute iron overload. In conclusion, we describe a novel childhood-onset neurometabolic disease caused by choline transporter deficiency with autosomal recessive inheritance.

Heterogeneity of PNPT1 neuroimaging: mitochondriopathy, interferonopathy or both?

2020 ◽  
pp. jmedgenet-2020-107367
Author(s):  
Alessandra Pennisi ◽  
Agnès Rötig ◽  
Charles-Joris Roux ◽  
Raphaël Lévy ◽  
Marco Henneke ◽  
...  
Keyword(s):  
Type I Interferon ◽  
Brain Mri ◽  
Mitochondrial Protein ◽  
Mitochondrial Diseases ◽  
Leigh Syndrome ◽  
Interferon Response ◽  
Normal Brain ◽  
Type I ◽  
Congenital Cmv Infection ◽  
Neuroimaging Data

BackgroundBiallelic variants in PNPT1 cause a mitochondrial disease of variable severity. PNPT1 (polynucleotide phosphorylase) is a mitochondrial protein involved in RNA processing where it has a dual role in the import of small RNAs into mitochondria and in preventing the formation and release of mitochondrial double-stranded RNA into the cytoplasm. This, in turn, prevents the activation of type I interferon response. Detailed neuroimaging findings in PNPT1-related disease are lacking with only a few patients reported with basal ganglia lesions (Leigh syndrome) or non-specific signs.Objective and methodsTo document neuroimaging data in six patients with PNPT1 highlighting novel findings.ResultsTwo patients exhibited striatal lesions compatible with Leigh syndrome; one patient exhibited leukoencephalopathy and one patient had a normal brain MRI. Interestingly, two unrelated patients exhibited cystic leukoencephalopathy resembling RNASET2-deficient patients, patients with Aicardi-Goutières syndrome (AGS) or congenital CMV infection.ConclusionWe suggest that similar to RNASET2, PNPT1 be searched for in the setting of cystic leukoencephalopathy. These findings are in line with activation of type I interferon response observed in AGS, PNPT1 and RNASET2 deficiencies, suggesting a common pathophysiological pathway and linking mitochondrial diseases, interferonopathies and immune dysregulations.

scholarly journals Predictors exploration of abnormal brain magnetic resonance versus normal brain computed tomography imaging in acute carbon monoxide poisoning

2021 ◽  
Keyword(s):  
Computed Tomography ◽  
Carbon Monoxide ◽  
Magnetic Resonance ◽  
Brain Mri ◽  
Brain Lesions ◽  
Normal Brain ◽  
Co Poisoning ◽  
Mri Findings ◽  
Brain Computed Tomography ◽  
Abnormal Brain

Acute brain lesions observed on magnetic resonance imaging (MRI) performed during acute-phase carbon monoxide (CO) poisoning were associated with patient prognosis. However, it may be difficult in critically ill patients because of the long examination time and for patients who have economical limitations due to the high price. The purpose of this study was to identify predictive factors for abnormal brain lesions on MRI in cases of normal brain findings on brain computed tomography (CT) in acute CO poisoning patients. This study was retrospectively analyzed at the tertiary emergency medical center located in Gyeonggi-do, Korea by prospectively collecting CO poisoning registry. From August 2016 to August 2019, 287 patients visited the hospital due to CO poisoning. Exclusion criteria included age under 18 years, being discharged against medical advice, no initial MRI data, no initial CT data, and having abnormal lesions on brain CT. Of the 103 patients included in the final study, the median age was 39 years old; 35 (34.0%) were male and 74 (71.8%) were intentionally exposed to CO. 27 (26.2%) patients had abnormal MRI findings. Based on multivariable analysis, elevated blood urea nitrogen (BUN) concentration (odds ratio, 1.165; 95% confidence interval, 1.037–1.308; p = 0.01) showed a significant association with abnormal MRI findings. The area under the curve was 0.753 (95% confidence interval, 0.636–0.869) in the receiver operating characteristic curve of BUN concentration for abnormal brain MRI presentations. Brain injury may be detected on brain MRI in acute CO poisoning patients even there was a normal brain CT scan. Our study revealed that elevated BUN concentration may be significantly correlated with abnormal MRI findings.

MRI FINDINGS OF MITOCHONDRIAL DISEASES IN INFANTS AND CHILDREN

2006 ◽  
Vol 37 (S 1) ◽  
Author(s):  
CS Chi ◽  
HF Lee ◽  
CR Tsai ◽  
CH Chen ◽  
LH Chen
Keyword(s):  
Mitochondrial Diseases ◽  
Infants And Children ◽  
Mri Findings ◽  
In Infants And Children

Brain MRI-findings in Ph - negative myeloproliferative disorders

2019 ◽  
Vol 91 (7) ◽  
pp. 29-34 ◽  
Author(s):  
M M Tanashyan ◽  
A L Melikyan ◽  
P I Kuznetsova ◽  
A A Raskurazhev ◽  
A A Shabalina ◽  
...  
Keyword(s):  
Cerebrovascular Disease ◽  
Sinus Thrombosis ◽  
Cerebral Arteries ◽  
Brain Mri ◽  
Myeloproliferative Disorders ◽  
Cerebral Venous Sinus Thrombosis ◽  
Mri Findings ◽  
Cerebral Lesions ◽  
Cerebrovascular Pathology ◽  
Underlying Mechanisms

Myeloproliferative disorders (MPD) are accompanied by a high proportion of thrombotic complications, which may lead to cerebrovascular disease (CVD). Aim. To describe MRI-findings in patients with Ph - negative MPD and evaluate any cerebrovascular disease. Materials and methods. We included 104 patients with Ph - negative MPD (age varied between 20 and 58) with clinical correlates of cerebrovascular pathology. Results. Brain MRI showed post - stroke lesions in 20% of patients (7 hemispheric infarcts due to thrombotic occlusion of one of the large cerebral arteries, 14 - cortical infarcts). 37 patients (36%) had vascular cerebral lesions. Cerebral venous sinus thrombosis occurred in 5 patients - in 7% (n=3) of patients with polycythemia vera and 5% (n=2) - in patients with essential thrombocythemia. The incidence of vascular cerebral lesions was associated with higher levels of the following: erythrocyte, platelet count, fibrinogen, and with the decrease in fibrinolytic activity, as well. Conclusion. The pioneering results of the study include the description and analysis of brain MRI-findings in patients with Ph - negative MPD. The underlying mechanisms of cerebrovascular pathology in these patients are associated with certain blood alterations (particularly, hemorheology) which present a major risk factor.

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