2. Dr E.Rahimian Neuroradiologist Haghighat Imaging center

3. MRI Findings in Mitochondrial Disorders Definitions  Genetically based disorders of mitochondrial function resulting in progressive or intermittent brain injury.  Characteristically due to deficiencies/defects of enzymes affecting the respiratory (electron- transport) chain, Krebs cycle, and/or other components of energy production by mitochondria

4. MRI Findings in Mitochondrial Disorders Mitochondrial diseases are a heterogeneous group of disorders caused by defects in intracellular energy production. Clinical symptoms originating from all organ systems have been described, but tissues with high-energy requirements, such as muscle and brain,are particularly vulnerable.

5. MRI Findings in Mitochondrial Disorders Several distinct syndromes have been recognized among the variable clinical phenotypes :

6. Mitochondrial encephalomyelopathies (MEMs)  Subacute necrotizing encephalomyelopathy or Leigh syndrome (LS)  Pyruvate dehydrogenase complex defects ·  Cytochrome oxidase (COX, complex IV)deficiency  Adenosine triphosphatase (ATPase) 6 gene mutations (complex V)  Other electron transport chain (ETC) enzymedeficiencies (complex I, II, III)  Pantothenate kinase-associated neurodegeneration (PKAN), or Hallervorden-Spatz syndrome  Glutaric acid urias, type I (GAl) and type 2 (GA2)  Myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS)

7. MRI Findings in Mitochondrial Disorders  Myoclonic epilepsy with ragged-red fibers (MERRF) Seen primarily in adults  Kearns-Sayre syndrome (KSS),progressive external ophthalmoplegia  Menkes disease (trichopoliodystrophy), Alpers disease, Friedreich ataxia  Fatal infantile myopathy, benign infantile Myopathy  familial mitochondrial encephalopathy with macrocephaly, cardiomyopathy, and complex I deficiency

8. MRI Findings in Mitochondrial Disorders Best diagnostic clue MEMs have a broad range of imaging appearances, characterized by regions of brain destruction, Volume loss, and/or mineralization. They typically affect both gray and white matter most disorders of mitochondrial function will cause lesions in the basal ganglia 

9. Leigh Syndrome Best diagnostic clue Bilateral, symmetric, T2/FLAIR putamina and periaqueductal Gray matter (PAG) · Location Common : Basal ganglia (BG): Corpora striata (putamina> caudate heads) > globi pallidi (GP) · Brain stem (BS):PAG, substantia nigra/ subthalamic nuclei, pons, medulla · Thalami, dentate nuclei Infrequent: White matter (WM) (cerebral> cerebellar, may be cavitary), spine, cortical gray. matter Size 

10. Size  BS: Small, discrete foci « 1 cm) · Involvement of central WM tracts typical  BG: Involvement of posterior putamina classic but variable; may affect entire lentiform nuclei  Thalami: Focal involvement of dorsomedial nuclei  Except WM, lesions are bilaterally symmetric

11. Leigh Syndrome  Edema, expansion characteristic of early disease; volume loss characteristic of late disease PAGedema may cause hydrocephalus  Involvement of lower BS(pons, medulla) and lack of BG involvement characteristic of LS secondary to SURFl mutation  Uncommon appearance · Predominant WM disease (simulates leukodystrophy

12. Leigh Syndrome

13. Axial FLAIR MR shows swelling and abnormal hyper intensity in the caudate heads and putamin, Foci of hyper intensity are also present in the medial thalami, a typical location of involvement in Leigh syndrome

14. Single voxel MR spectroscopy (TE = 26 msec) of the same patient shows a large lactate doublet = at 1.3 ppm. The identification of a lactate peak supports the diagnosis of mitochondrial disease

15. Leigh Syndrome

40. Image Interpretation Pearls - Putaminal involvement classic but variable Thalamic and PAGinvolvement simulates Wernicke encephalopathy; however, mamillary bodies spared in - Leigh syndrome Only brain stem involvement in SURFl mutations

41. MELAS Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS)

42. MELAS Imaging Stroke-like cortical lesions crossing vascular territories, Posterior location most common "Shifting spread" (appearance, disappearance, reappearance elsewhere) is classic Lactate (Lac) "doublet" at 1.3 ppm in 60-65% MRS Basal ganglia (BG) lesions and calcifications

43. MRI Findings in Mitochondrial Disorders Image Interpretation Pearls Think of MEMs when encountering an atypical presentation of stroke, severe encephalitis, or seizure. Don't forget to consider MEMs when an infant presents with sub-durals, Can also have retinal hemorrhages!

44. MELAS

59. MELAS is a mitochondrial neuronopathy and involves the entire brain. Therefore, DW- MR spectroscopy can find some useful intracellular pathophysiologic information that conventional MR imaging cannot display. In conclusion, it is a very useful noninvasive technique for brain diseases apart from cerebral infarction.

60. Succinic Semialdehyde Dehydrogenase Deficiency MRI reveals T 2 hyperintensities in multiple regions, involving the globus pallidi (43%), cerebellar dentate nucleus (17%), subcortical white matter (7%), and brain stem (7%), as well as other abnormalities.

61. Succinic Semialdehyde Dehydrogenase Deficiency  MRS revealed a prominent singlet at 2.40 ppm in cerebral and cerebellar white matter originating from accumulated succinate in affected white matter. Biochemical investigations demonstrated isolated deficiency of complex II in muscle and fibroblasts of these patien

62. Succinic Semialdehyde Dehydrogenase Deficiency Deficiency of complex II (succinate dehydrogenase, SDH) represents a rare cause of mitochondrial disease and is associated with a wide range of clinical symptoms. Recently, mutations of SDHAF1, the gene encoding for the SDH assembly factor 1, were reported in SDH- defective infantile leukoencephalopathy.

63. Succinic Semialdehyde Dehydrogenase Deficiency

68. Persistent Diffusion Abnormalities in the Brain Stem of Three Children with Mitochondrial Diseases AJNR Am J Neuroradiol October 2006 27: 1924-1926 In conclusion, we found that DWI demonstrated the symmetric hyperintense lesions in the pontine and mesencephalic tegmenta of 3 children with KSS, PS, or LS. The hyperintense lesions on DWI persisted for longer than 1 year, whereas the ADC values of the affected areas remained lower than those of the surrounding areas during the observation periods. Spongiform degeneration or reversible cytotoxic edema may contribute to the formation of the common lesions observed in the brain stem of thesemitochondrial diseases.

69. Selected T2-weighted images, DWI, and ADC maps