MELAS and ITS SISTERS

Prof. Dr. Saad S Al Ani

Senior Pediatric Consultant

Head of Pediatric Department

Khorfakkan Hospital

Sharjah ,UAE

saadsalani@yahoo.com

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Case presentation:1

• Kara, 10 year old , is the eldest of 3 children, and was born into pretty boring family histories of good health.

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Cont.

• 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”!

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Cont.

• The excess body hair• early loss of teeth• her slowness in all tasks• repeated spontaneous vomits• plummeting percentile bands

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Cont.

• an awkward running style• stiff muscles, “stick legs”• stress incontinence • jerky eye movements• poor concentration,• a “failed” OT (occupational

therapy) assessment,

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Cont.

• Straight after turning 8, found her one morning semiconscious and vomiting in bed.

• With a brain scan that looks “moth eaten”

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Cont.

• School is now a social drop in place, as simple tiredness has triggered her last 3 attacks.

• Her motivation to learn is a fading light

• Early dementia has now set in

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Cont.

• She has become increasingly unsteady, even slower in all daily tasks

• Her hearing now requires aids• Her eyesight is slowly disappearing• Her personality is regressing along

with her social graces.

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Case presentation:2

• 12 year old girl with rapid cycling bipolar disease.

• HPI: Mood difficulties began at the age of 8 years with diagnosis of bipolar disease made at 9 years of age.

• Seizure started at 10 years of age.

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Cont.

• Academic achievement has been

very good but her work toward these goals was often obsessive.

• She has shown some decline in academics over the last 2 years.

• Her motivation to be socially accepted has deteriorated.

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Cont.

• HPI: She has shown decline in coordinated motor movements with increased clumsiness.

• PMHx: Chronic constipation (multiple episodes of fecal impaction), hypothyroidism, and seizures.

• Family Hx: Lives with mother and two siblings.– Mother has neuropathy of unclear etiology.– Brother has been diagnosed with ETC complex III

dysfunction and myopathy. (brother has a different father)

– Sister has just been diagnosed with bipolar disorder.

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Cont.

• PE: – CN II-XII intact– Motor: Axial hypotonia– DTRs: Trace in all tendons

tested– Cerebellar: Normal

• Neuroimaging– Normal MRI

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Cont.

• Labs– Elevated lactate > 2 blood draws.– Elevated alanine.– Reduced level of free carnitine.– Presence of ethylmalonic acid in

urine organic acid profile.

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Cont.

• Muscle biopsy– Decreased activity of complex III

of the electron transport chain.– Normal mtDNA– Normal histology on light

microscopy examination.

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• An intracellular organelle.• There are 100 to 1000s of mitochondria/cell.• All mitochondria come from the mother.• Mitochondria have their own DNA.

What are mitochondria?

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• Found in all cell types, except the RBC.• Major functions of mitochondria:

-Makes energy in the form of ATP. -Programmed cell death (apoptosis).

(cont.)

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• 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.

(cont.)

Role of ATP (energy)1.Mechanical Work

Muscle contraction

2.Chemical WorkNa+/K+ Ion Pump

3.Synthetic Work [Anabolism]Macromolecules

- Nucleic Acids

- Proteins

- Lipids

- Complex carbohydrates

Why is energy so important?

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Intermediary Energy Metabolism

Chemical Energy

Cars Gasoline

Cells ATP

When this process is dysfunctional, then disease

can occur.

Mitochondrial cytopathies are diseases of energy

production.

Epidemiology

Are these diseases common?

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Frequency

• Prevalence of more than 10.2 per 100,000 for the m.3243A → G mutation in the adult Finnish population.

• In Northern England, the prevalence of this mutation in the adult population has been determined to be approximately 1 per 13,000.

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Epidemiology

• Three large studies looking at the prevalence of mitochondrial disorders have shown:– The majority of adults with

mitochondrial disease have an underlying mtDNA mutation.

– The majority of children with mitochondrial disease have an underlying nuclear DNA mutation.

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Causes of mitochondrial disease

1. DNA (DNA contained in the nucleus of the cell) inheritance

2. mtDNA (DNA contained in the mitochondria) inheritance

3. Combination of mtDNA and nDNA defects

4. Random occurrences

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Mitochondrial Inheritance

Over 1000 proteins localized to mitochondria

13 are mitochondrial-encoded

Remainder are nuclear-encoded

•16.6 kb (vs. 3 billion in the nuclear genome)

•37 genes-22 tRNAs -2 rRNAs

-13 proteinsAll subunits of ETC

•mtDNA is entirely devoted toward energy metabolism

Mitochondrial DNA (mtDNA)

•Over 180 point mutations and almost as many deletions associated with human disease •‘Maternally inherited’•mtDNA come only from the ovum

Inheritance of mtDNA Mutations

Sporadic•Autosomal•Nuclear-encoded regulatory proteins interact with mtDNA (intragenomic communication) and can result in secondary mtDNA mutations

Inheritance of mtDNA Mutations (cont.)

Mitochondrial Inheritance

Multiple organ disease

Mitochondrial vs. Nuclear Genome

Mitochondrial genome has1.Smaller number of genes

2.Higher copy number

3.Less effective repair mechanisms

4.Higher mutation rate

mtDNA vs. Nuclear DNA Mutations

•Nuclear: severe disease of infantile onset•Mito: milder disease of later onset• nuclear mutations predominate

in small children • mtDNA mutations predominate

in those with adult-onset symptoms

•Could be mutations in either genome at any age

Maternal Inheritance

•mtDNA from mother to child(ren)Child has identical sequence as

matrilineal relatives mother—sibs (through mom), maternal

aunts/uncles, maternal grandmother

•High recurrence risk in future sibs of an affected child (with a point mutation), approaching 100% •Marked inter- and intra- familial variation of symptoms, age of onset and severity

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

Clinical Manifestation of Mitochondrial Dysfunction

Multiple organ disease

Mitochondrial Cytopathies: Clinical Features

CNS1.Myoclonus

2.Generalized Seizures

3.Stroke

4.Migraine Headache

5.Ataxia

6.Mental Retardation

7.Psychiatric Disease (?)

Clinical Manifestation of Mitochondrial Dysfunction

Skeletal Muscle1.Myopathy (hypotonia)

2.CPEO(Chronic Progressive External Ophthalmoplegia

)

3.Recurrent Myogloburia

4.Weakness/Fatigue

Clinical Manifestation of Mitochondrial Dysfunction

Bone Marrow1.Siderblastic Anemia

2.Pancytopenia

Renal FunctionFanconi Syndrome

Clinical Manifestation of Mitochondrial Dysfunction

Systemic Symptoms1.Lactic Acidosis

2.Short Stature

3.Fatigue

4.Failure to Gain Weight

5.Asthma

6.Intermittent Air Hunger

Clinical Manifestation of Mitochondrial Dysfunction

Endocrine1.Diabetes Mellitus

2.Hypoparathyroidism3.Exocrine Pancreatic

Failure4.Thyroid Disease

Heart1.Cardiomyopathy

2.Conduction Defects

Clinical Manifestation of Mitochondrial Dysfunction

Vision1.Optic Neuropathy

2.Retinitis Pigmentosa

Hearing1.High-frequency Hearing Loss

2.Aminoglycoside-induced Deafness

Clinical Manifestation of Mitochondrial Dysfunction

Gastrointestinal1.Pseudo-obstruction

2.Constipation3.Vomiting

Liver1.Hypoglycemia

2.Gluconeogenic Defects3.Liver Failure and

Cirrhosis

mtDNA-related Syndromes

1.Mitochondrial encephalopathy, lactic acidosis and stroke-like

episodes (MELAS)

2.Aminoglycoside-induced

deafness3.Cyclic vomiting syndrome

mtDNA-related Syndromes (cont.)

4.Kearns-Sayre syndrome (KSS)

5.Pearson syndrome

6.Leigh disease

7.Neuropathy, ataxia and retinitis pigmentosa (NARP)

mtDNA-related Syndromes (cont.)

8.Mitochondrial

neurogastrointestinal encephalopathy (MNGIE)

8.Myoclonic epilepsy and ragged-red fiber disease (MERRF)

9.Leber’s hereditary optic

neuropathy (LHON)

Mitochondrial Encephalomyopathy with Lactic Acidosis and Stroke-like Episodes

(MELAS)

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• Mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS)– Stroke-like episodes, onset infancy to

adulthood– Maternally inherited diabetes, deafness,

cognitive impairment, short stature, migraine

– Most common cause is heteroplasmy for A3243G mutation (point mutation in tRNA gene for leucine)

– Other causes include T3271C and other point mutations, large rearrangements and presumed nuclear defects

MELAS

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Mitochondrial encephalopathy, lactic acidosis and cerebrovascular accident syndrome (MELAS) Mitochondrial encephalopathy, lactic acidosis and cerebrovascular accident syndrome (MELAS) in PICU

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Mitochondrial encephalopathy, lactic acidosis and cerebrovascular accident syndrome (MELAS) Mitochondrial encephalopathy, lactic acidosis and cerebrovascular accident syndrome (MELAS) in PICU

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More Characteristics

• MELAS affects no specific race or gender more so than others

• Presentation of the disease occurs with the first stroke-like episode (usually 14-15 yrs of age)

• This is a progressive disorder with a high mortality rate

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How does MELAS work?

• Abnormal mitochondria do not metabolize pyruvate

• Excess pyruvate is reduced to lactic acid which accumulates in blood and other fluids

• Large clumps of abnormal mitochondria form in the walls of small arteries and capillaries in the brain and muscles

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Characteristics

• It is the most common maternally inherited mitochondrial disease

• Clinical Features: Strokes, myopathy, muscle twitching, dementia, and deafness

• To a lesser extent: vomiting, migraine-like headaches, diabetes, droopy eyelids, muscle weakness, and short stature

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MELAS: Mitochondrial staining of intramuscular vessels

Succinic dehydrogenase (SDH) stain

Increased SDH staining of amedium sized perimysial vesselin a MELAS patient.

Normal: Mild SDH staining of amedium sized perimysial vessel.

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Brain pathology in MELAS

• MRI during episode of hemiparesis

• Cortical lesion (Right side, posterior): Spares white matter

• Lesion location – Not confined to territory of single

vessel – Involves only part of territory of

several vessels

• Swelling

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MRI during episode of hemiparesis

FLAIR image

                                            

             T2 weighted image FLAIR image T2 weighted image

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CT during episode of homonymous hemianopia

Medial occipital lesion (Arrow) Enlarged ventricles

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MELAS: Muscle fiber pathology

Scattered abnormal, vacuolated fibers with clear rim: H & E

Scattered "ragged red" muscle fibers: Gomori trichrome

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Late in disease course

MRI: Severe involvement  of occipital cortex

Severly abnormal temporal gray matter.Temporal horn of ventricles is enlarged.

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Diagnosis of Mitochondrial Cytopathies

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Prenatal Diagnosis for mtDNA

Can be done, as chorionic villus and amniocyte mutant loads in certain situations

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Treatment

• Certain vitamin and enzyme therapies

• Diet therapy

• Antioxidant treatments

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Important Points

• Mitochondrial Cytopathies– Suspect when:– > 2 unrelated organ systems are involved.– inheritance seems maternal.– the neurological exam seems paradoxical.– the usual presentation of a syndrome is not “usual” and

history is suspect for a bioenergetic disorder.

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References

• Scaglia, Fernando, MD. MELAS Syndrome. http://www.emedicine.com/ped/topic1406.htm. October 26, 2004

• http://herkules.oulu.fi/isbn9514255674/html/graphic33.gif• Dahl H-HM, Thorburn DR (2001) Mitochodrial Diseases, Am

J Medical Genetics 106:1-115

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