Melas

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  • 09/22/10
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  • For many patients, mitochondrial disease is an inherited condition that runs in families (genetic). An uncertain percentage of patients acquire symptoms due to other factors, including mitochondrial toxins. The types of mitochondrial disease inheritance include
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  • Lactic Acidosis (as mentioned earlier) causes the pH of the blood and other body fluids to lower due to an increase in lactic acid. This is bad because it changes the buffering capacity of all these fluids is altered. The large clumps of abnormal mitochondria in the brain are what causes the strokes and myopathy
  • Most mitochondrial diseases are maternally inherited. Very few are paternally passed on. This is because when the sperm and egg join, the zygote gets almost all of its mitochondria from the egg. Mitochondria are not synthesized, rather they must divide from existing mitochondria. Thus, there are more maternal mitochondria that can divide and make replicas.
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  • There are no cures for mitochondrial diseases, but treatment can help reduce symptoms, or delay or prevent the progression of the disease.
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  • Melas

    1. 1. MELAS and ITS SISTERS Prof. Dr. Saad S Al Ani Senior Pediatric Consultant Head of Pediatric Department Khorfakkan Hospital Sharjah ,UAE [email_address]
    2. 2. Case presentation:1 <ul><li>Kara, 10 year old , is the eldest of 3 children, and was born into pretty boring family histories of good health . </li></ul>
    3. 3. Cont. <ul><li>Kara’s “uniqueness” became obvious when she started school in 2005 . Her slowness to complete work, her poor balance and ever poorer sporting skills made Kara simply seem “hard work” ! </li></ul>
    4. 4. Cont. <ul><li>The excess body hair </li></ul><ul><li>early loss of teeth </li></ul><ul><li>her slowness in all tasks </li></ul><ul><li>repeated spontaneous vomits </li></ul><ul><li>plummeting percentile bands </li></ul>
    5. 5. Cont. <ul><li>an awkward running style </li></ul><ul><li>stiff muscles, “stick legs” </li></ul><ul><li>stress incontinence </li></ul><ul><li>jerky eye movements </li></ul><ul><li>poor concentration, </li></ul><ul><li>a “failed” OT ( occupational therapy ) assessment, </li></ul>
    6. 6. Cont. <ul><li>Straight after turning 8, found her one morning semiconscious and vomiting in bed . </li></ul><ul><li>With a brain scan that looks “moth eaten” </li></ul>
    7. 7. Cont. <ul><li>School is now a social drop in place, as simple tiredness has triggered her last 3 attacks . </li></ul><ul><li>Her motivation to learn is a fading light </li></ul><ul><li>Early dementia has now set in </li></ul>
    8. 8. Cont. <ul><li>She has become increasingly unsteady, even slower in all daily tasks </li></ul><ul><li>Her hearing now requires aids </li></ul><ul><li>Her eyesight is slowly disappearing </li></ul><ul><li>Her personality is regressing along with her social graces . </li></ul>
    9. 9. WHAT IS THE DIAGNOSIS ?
    10. 10. Case presentation:2 <ul><li>12 year old girl with rapid cycling bipolar disease. </li></ul><ul><li>HPI: Mood difficulties began at the age of 8 years with diagnosis of bipolar disease made at 9 years of age. </li></ul><ul><li>Seizure started at 10 years of age. </li></ul>
    11. 11. Cont. <ul><li>Academic achievement has been very good but her work toward these goals was often obsessive. </li></ul><ul><li>She has shown some decline in academics over the last 2 years. </li></ul><ul><li>Her motivation to be socially accepted has deteriorated. </li></ul>
    12. 12. Cont. <ul><li>HPI: She has shown decline in coordinated motor movements with increased clumsiness. </li></ul><ul><li>PMHx: Chronic constipation (multiple episodes of fecal impaction), hypothyroidism, and seizures. </li></ul><ul><li>Family Hx: Lives with mother and two siblings. </li></ul><ul><ul><li>Mother has neuropathy of unclear etiology. </li></ul></ul><ul><ul><li>Brother has been diagnosed with ETC complex III dysfunction and myopathy. (brother has a different father) </li></ul></ul><ul><ul><li>Sister has just been diagnosed with bipolar disorder. </li></ul></ul>
    13. 13. Cont. <ul><li>PE: </li></ul><ul><ul><li>CN II-XII intact </li></ul></ul><ul><ul><li>Motor: Axial hypotonia </li></ul></ul><ul><ul><li>DTRs: Trace in all tendons tested </li></ul></ul><ul><ul><li>Cerebellar: Normal </li></ul></ul><ul><li>Neuroimaging </li></ul><ul><ul><li>Normal MRI </li></ul></ul>
    14. 14. Cont. <ul><li>Labs </li></ul><ul><ul><li>Elevated lactate > 2 blood draws. </li></ul></ul><ul><ul><li>Elevated alanine. </li></ul></ul><ul><ul><li>Reduced level of free carnitine. </li></ul></ul><ul><ul><li>Presence of ethylmalonic acid in urine organic acid profile. </li></ul></ul>
    15. 15. Cont. <ul><li>Muscle biopsy </li></ul><ul><ul><li>Decreased activity of complex III of the electron transport chain. </li></ul></ul><ul><ul><li>Normal mtDNA </li></ul></ul><ul><ul><li>Normal histology on light microscopy examination. </li></ul></ul>
    16. 16. WHAT IS THE DIAGNOSIS ?
    17. 17. A mitochondrial cytopathy
    18. 18. What are mitochondria? <ul><li>An intracellular organelle. </li></ul><ul><li>There are 100 to 1000s of </li></ul><ul><li>mitochondria/cell. </li></ul><ul><li>All mitochondria come from </li></ul><ul><li>the mother. </li></ul><ul><li>Mitochondria have their own </li></ul><ul><li>DNA. </li></ul>
    19. 19. (cont.) <ul><li>Found in all cell types, except the </li></ul><ul><li>RBC. </li></ul><ul><li>Major functions of mitochondria: </li></ul><ul><ul><li>-Makes energy in the form of ATP. </li></ul></ul><ul><ul><li>-Programmed cell death (apoptosis). </li></ul></ul>
    20. 20. (cont.) <ul><li>The mitochondria use electrons and protons from metabolism and molecular oxygen to reduce water and generate proton-motive force to produce ATP from ADP: oxidative phosphorylation . </li></ul>
    21. 21. <ul><li>Role of ATP (energy) </li></ul><ul><ul><li>1.Mechanical Work </li></ul></ul><ul><ul><ul><li>Muscle contraction </li></ul></ul></ul><ul><ul><li>2.Chemical Work </li></ul></ul><ul><ul><ul><li>Na + /K + Ion Pump </li></ul></ul></ul><ul><ul><li>3.Synthetic Work [Anabolism] </li></ul></ul><ul><ul><ul><li>Macromolecules </li></ul></ul></ul><ul><ul><ul><ul><li>- Nucleic Acids </li></ul></ul></ul></ul><ul><ul><ul><ul><li>- Proteins </li></ul></ul></ul></ul><ul><ul><ul><ul><li>- Lipids </li></ul></ul></ul></ul><ul><ul><ul><ul><li>- Complex carbohydrates </li></ul></ul></ul></ul>Why is energy so important?
    22. 22. Intermediary Energy Metabolism ATP Pool Glucose Fats Proteins Glycolysis TCA Cycle ETC b-oxidation TCA Cycle ETC Deamination TCA Cycle ETC
    23. 23. Chemical Energy Cars Gasoline Cells ATP
    24. 24. When this process is dysfunctional , then disease can occur.
    25. 25. Mitochondrial cytopathies are diseases of energy production .
    26. 26. Epidemiology Are these diseases common?
    27. 27. Frequency <ul><li>Prevalence of more than 10.2 per 100,000 for the m.3243A -> G mutation in the adult Finnish population. </li></ul><ul><li>In Northern England , the prevalence of this mutation in the adult population has been determined to be approximately 1 per 13,000 . </li></ul>
    28. 28. Epidemiology <ul><li>Three large studies looking at the prevalence of mitochondrial disorders have shown: </li></ul><ul><ul><li>The majority of adults with mitochondrial disease have an underlying mtDNA mutation . </li></ul></ul><ul><ul><li>The majority of children with mitochondrial disease have an underlying nuclear DNA mutation. </li></ul></ul>
    29. 29. Causes of mitochondrial disease <ul><li>DNA (DNA contained in the nucleus of the cell) inheritance </li></ul><ul><li>mtDNA (DNA contained in the mitochondria) inheritance </li></ul><ul><li>Combination of mtDNA and nDNA defects </li></ul><ul><li>Random occurrences </li></ul>
    30. 30. Mitochondrial Inheritance
    31. 31. <ul><li>Over 1000 proteins localized to mitochondria </li></ul><ul><ul><li>13 are mitochondrial-encoded </li></ul></ul><ul><ul><li>Remainder are nuclear-encoded </li></ul></ul>
    32. 32. <ul><li>16.6 kb (vs. 3 billion in the nuclear genome) </li></ul><ul><li>37 genes </li></ul><ul><ul><li>-22 tRNAs </li></ul></ul><ul><ul><li>-2 rRNAs </li></ul></ul><ul><ul><li>-13 proteins </li></ul></ul><ul><ul><ul><li>All subunits of ETC </li></ul></ul></ul><ul><li>mtDNA is entirely devoted toward energy metabolism </li></ul>Mitochondrial DNA (mtDNA)
    33. 33. <ul><li>Over 180 point mutations and almost as many deletions associated with human disease </li></ul><ul><li>‘ Maternally inherited ’ </li></ul><ul><li>mtDNA come only from the ovum </li></ul>Inheritance of mtDNA Mutations
    34. 34. <ul><li>Sporadic </li></ul><ul><li>Autosomal </li></ul><ul><li>Nuclear-encoded regulatory proteins interact with mtDNA (intragenomic communication) and can result in secondary mtDNA mutations </li></ul>Inheritance of mtDNA Mutations (cont.)
    35. 35. Mitochondrial Inheritance Multiple organ disease
    36. 36. Mitochondrial vs. Nuclear Genome <ul><li>Mitochondrial genome has </li></ul><ul><ul><li>1.Smaller number of genes </li></ul></ul><ul><ul><li>2.Higher copy number </li></ul></ul><ul><ul><li>3.Less effective repair mechanisms </li></ul></ul><ul><ul><ul><li>4.Higher mutation rate </li></ul></ul></ul>
    37. 37. mtDNA vs. Nuclear DNA Mutations <ul><li>Nuclear: severe disease of infantile onset </li></ul><ul><li>Mito : milder disease of later onset </li></ul><ul><li>nuclear mutations predominate in small children </li></ul><ul><li>mtDNA mutations predominate in those with adult-onset symptoms </li></ul><ul><li>Could be mutations in either genome at any age </li></ul>
    38. 38. Maternal Inheritance <ul><li>mtDNA from mother to child(ren ) </li></ul><ul><ul><li>Child has identical sequence as matrilineal relatives mother—sibs (through mom), maternal aunts/uncles, maternal grandmother </li></ul></ul><ul><li>High recurrence risk in future sibs of an affected child (with a point mutation), approaching 100% </li></ul><ul><li>Marked inter- and intra- familial variation of symptoms, age of onset and severity </li></ul>
    39. 39. Maternal genetic transmission An affected woman transmits the trait to all her children . Affected men (represented by squares do not pass the trait to any of their offspring
    40. 40. Clinical Manifestation of Mitochondrial Dysfunction Multiple organ disease
    41. 41. Mitochondrial Cytopathies: Clinical Features <ul><li>CNS </li></ul><ul><ul><li>1.Myoclonus </li></ul></ul><ul><ul><li>2.Generalized Seizures </li></ul></ul><ul><ul><li>3.Stroke </li></ul></ul><ul><ul><li>4.Migraine Headache </li></ul></ul><ul><ul><li>5.Ataxia </li></ul></ul><ul><ul><li>6.Mental Retardation </li></ul></ul><ul><ul><li>7.Psychiatric Disease (?) </li></ul></ul>
    42. 42. Clinical Manifestation of Mitochondrial Dysfunction <ul><li>Skeletal Muscle </li></ul><ul><ul><li>1.Myopathy (hypotonia) </li></ul></ul><ul><ul><li>2.CPEO( Chronic Progressive External Ophthalmoplegia ) </li></ul></ul><ul><ul><li>3.Recurrent Myogloburia </li></ul></ul><ul><ul><li>4.Weakness/Fatigue </li></ul></ul>
    43. 43. Clinical Manifestation of Mitochondrial Dysfunction <ul><li>Bone Marrow </li></ul><ul><ul><li>1.Siderblastic Anemia </li></ul></ul><ul><ul><li>2.Pancytopenia </li></ul></ul><ul><li>Renal Function </li></ul><ul><ul><li>Fanconi Syndrome </li></ul></ul>
    44. 44. Clinical Manifestation of Mitochondrial Dysfunction <ul><li>Systemic Symptoms </li></ul><ul><ul><li>1.Lactic Acidosis </li></ul></ul><ul><ul><li>2.Short Stature </li></ul></ul><ul><ul><li>3.Fatigue </li></ul></ul><ul><ul><li>4.Failure to Gain Weight </li></ul></ul><ul><ul><li>5.Asthma </li></ul></ul><ul><ul><li>6.Intermittent Air Hunger </li></ul></ul>
    45. 45. Clinical Manifestation of Mitochondrial Dysfunction <ul><li>Endocrine </li></ul><ul><ul><li>1.Diabetes Mellitus </li></ul></ul><ul><ul><li>2.Hypoparathyroidism </li></ul></ul><ul><ul><li>3.Exocrine Pancreatic Failure </li></ul></ul><ul><ul><li>4.Thyroid Disease </li></ul></ul><ul><li>Heart </li></ul><ul><ul><li>1.Cardiomyopathy </li></ul></ul><ul><ul><li>2.Conduction Defects </li></ul></ul>
    46. 46. Clinical Manifestation of Mitochondrial Dysfunction <ul><li>Vision </li></ul><ul><ul><li>1.Optic Neuropathy </li></ul></ul><ul><ul><li>2.Retinitis Pigmentosa </li></ul></ul><ul><li>Hearing </li></ul><ul><ul><li>1.High-frequency Hearing Loss </li></ul></ul><ul><ul><li>2.Aminoglycoside-induced Deafness </li></ul></ul>
    47. 47. Clinical Manifestation of Mitochondrial Dysfunction <ul><li>Gastrointestinal </li></ul><ul><ul><li>1.Pseudo-obstruction </li></ul></ul><ul><ul><li>2.Constipation </li></ul></ul><ul><ul><li>3.Vomiting </li></ul></ul><ul><li>Liver </li></ul><ul><ul><li>1.Hypoglycemia </li></ul></ul><ul><ul><li>2.Gluconeogenic Defects </li></ul></ul><ul><ul><li>3.Liver Failure and Cirrhosis </li></ul></ul>
    48. 48. mtDNA-related Syndromes 1.M itochondrial e ncephalopathy, l actic a cidosis and s troke-like episodes ( MELAS ) 2 .Aminoglycoside-induced deafness 3 .Cyclic vomiting syndrome
    49. 49. mtDNA-related Syndromes (cont.) 4 .Kearns-Sayre syndrome ( KSS ) 5 .Pearson syndrome 6 .Leigh disease 7.N europathy , a taxia and r etinitis p igmentosa (NARP)
    50. 50. mtDNA-related Syndromes (cont.) 8.M itochondrial n euro g astro i ntestinal e ncephalopathy ( MNGIE) 8.M yoclonic e pilepsy and r agged- r ed f iber disease ( MERRF ) 9.L eber’s h ereditary o ptic n europathy ( LHON )
    51. 51. Mitochondrial Encephalomyopathy with Lactic Acidosis and Stroke-like Episodes (MELAS)
    52. 52. <ul><li>M itochondrial e ncephalopathy, l actic a cidosis and s troke-like episodes ( MELAS ) </li></ul><ul><ul><li>Stroke-like episodes , onset infancy to adulthood </li></ul></ul><ul><ul><li>Maternally inherited diabetes , deafness , cognitive impairment , short stature , migraine </li></ul></ul><ul><ul><li>Most common cause is heteroplasmy for A3243G mutation ( point mutation in tRNA gene for leucine ) </li></ul></ul><ul><ul><li>Other causes include T3271C and other point mutations , large rearrangements and presumed nuclear defects </li></ul></ul>MELAS
    53. 53. Mitochondrial encephalopathy, lactic acidosis and cerebrovascular accident syndrome ( MELAS ) Mitochondrial encephalopathy, lactic acidosis and cerebrovascular accident syndrome (MELAS) in PICU
    54. 54. Mitochondrial encephalopathy, lactic acidosis and cerebrovascular accident syndrome ( MELAS ) Mitochondrial encephalopathy, lactic acidosis and cerebrovascular accident syndrome (MELAS) in PICU
    55. 55. More Characteristics <ul><li>MELAS affects no specific race or gender more so than others </li></ul><ul><li>Presentation of the disease occurs with the first stroke-like episode (usually 14-15 yrs of age) </li></ul><ul><li>This is a progressive disorder with a high mortality rate </li></ul>
    56. 56. How does MELAS work? <ul><li>Abnormal mitochondria do not metabolize pyruvate </li></ul><ul><li>Excess pyruvate is reduced to lactic acid which accumulates in blood and other fluids </li></ul><ul><li>Large clumps of abnormal mitochondria form in the walls of small arteries and capillaries in the brain and muscles </li></ul>
    57. 57. Characteristics <ul><li>It is the most common maternally inherited mitochondrial disease </li></ul><ul><li>Clinical Features: Strokes , myopathy , muscle twitching , dementia , and deafness </li></ul><ul><li>To a lesser extent: vomiting , migraine-like headaches , diabetes , droopy eyelids , muscle weakness , and short stature </li></ul>
    58. 58. MELAS : Mitochondrial staining of intramuscular vessels Succinic dehydrogenase (SDH) stain Increased SDH staining of a medium sized perimysial vessel in a MELAS patient. Normal : Mild SDH staining of a medium sized perimysial vessel.
    59. 59. Brain pathology in MELAS <ul><li>MRI during episode of hemiparesis </li></ul><ul><li>Cortical lesion (Right side, posterior): Spares white matter </li></ul><ul><li>Lesion location </li></ul><ul><ul><li>Not confined to territory of single vessel </li></ul></ul><ul><ul><li>Involves only part of territory of several vessels </li></ul></ul><ul><li>Swelling </li></ul>
    60. 60. MRI during episode of hemiparesis FLAIR image T2 weighted image                                                            T2 weighted image FLAIR image
    61. 61. CT during episode of homonymous hemianopia Medial occipital lesion (Arrow) Enlarged ventricles
    62. 62. MELAS : Muscle fiber pathology Scattered abnormal, vacuolated fibers with clear rim : H & E Scattered &quot;ragged red&quot; muscle fibers : Gomori trichrome
    63. 63. Late in disease course MRI: Severe involvement   of occipital cortex Severly abnormal temporal gray matter. Temporal horn of ventricles is enlarged.
    64. 64. Diagnosis of Mitochondrial Cytopathies 1.Clinical Exam and History 2.Lab Results 3.CNS Imaging 4.Biopsy Data
    65. 65. Prenatal Diagnosis for mtDNA <ul><li>Can be done, as chorionic villus and amniocyte mutant loads in certain situations </li></ul>
    66. 66. Treatment <ul><li>Certain vitamin and enzyme therapies </li></ul><ul><li>Diet therapy </li></ul><ul><li>Antioxidant treatments </li></ul>
    67. 67. Important Points <ul><li>Mitochondrial Cytopathies </li></ul><ul><ul><li>Suspect when: </li></ul></ul><ul><ul><li>> 2 unrelated organ systems are involved. </li></ul></ul><ul><ul><li>inheritance seems maternal . </li></ul></ul><ul><ul><li>the neurological exam seems paradoxical . </li></ul></ul><ul><ul><li>the usual presentation of a syndrome is not “usual ” and history is suspect for a bioenergetic disorder. </li></ul></ul>
    68. 68. References <ul><li>Scaglia, Fernando, MD. MELAS Syndrome. http://www.emedicine.com/ped/topic1406.htm . October 26, 2004 </li></ul><ul><li>http://herkules.oulu.fi/isbn9514255674/html/graphic33.gif </li></ul><ul><li>Dahl H-HM, Thorburn DR (2001) Mitochodrial Diseases, Am J Medical Genetics 106:1-115 </li></ul>
    69. 69. Thank you

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