Transcript The modified Walker criteria

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Our body ’s nucleated cells
contain 500 - 2000
mitochondria
In the cone cell
photoreceptors of the eye,
mitochondria make up 80%
of the intracellular volume
In extraocular muscles like
the lateral rectus :60%
In heart muscle :40%
In the liver, mitochondria are
specialized to detoxify
ammonia in the urea cycle
Mitochondria are also
required, for neurotransmitter
metabolism,
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The first mitochondrial disorder was
recognized in 1962; since then,
mitochondrial disorders have emerged
as major clinical entities
Organs such as the brain, heart, and
skeletal muscle are highly energy
dependent and vulnerable to defects in
energy metabolism
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Mitochondrial encephalomyopathies
are a genetically, biochemically, and
clinically heterogeneous group of
disorders associated with abnormalities
of oxidative phosphorylation
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The final diagnosis relied on clinical and
molecular criteria
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There is no absolute gold standard to
establish a diagnosis of mitochondrial
encephalomyopathy
Lethal infantile mitochondrial disease :
 Fulminant neonatal onset (death within 6 months of life)
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Classic Mitochondrial syndrome
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(mtDNA deletion/duplication and point mutation):
MELAS – A3243G and T3271C
MERRF _ A8344G and T8356C
NARP _ T8993G and T8993C
Cardiomyopathy _ G8363A
LHON _ G11778A, G3460A, T1448C , G14459A
Kern Sayre Syndrome
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MNGIE
 Severe gastrointestinal dysmotility
( Vomiting and pseudo-obstruction)
 Cachexia
 Ptosis
 External ophtalmoplegia
 Peripheral neuropathy
 Leukoencephalopathy
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Cardiomyopathy and myopathy :
clinical subtype dominated by cardiac and myopathic
symptoms (within this group) :
- Sengers syndrome :
congenital cataracts, hypertrophic cardiomyopathy,
mitochondrial myopathy, and lactic acidosis
-Barth syndrome diagnosed with : left ventricular
noncompaction (LVNC), skeletal myopathy, 3methylglutaconic aciduria, and short stature
The group of nonspecific encephalomyopathy
included all patients who would not fit into any of the
other subtypes
Developmental delay
 Abnormality of tone
 Movement disorder
 Seizure
 Cardiomyopathy
 Arrythmia
 Ophthalmologic disease
 Hearing loss
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Lactic acidosis
 Neuroimaging
 Histopathologic finding
 Enzyme histochemistry
 Ultrastructural abnormalities of
mitochondria
 Quantitative biochemical analysis (RC
defects)
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Diagnostic criteria for pediatric
mitochondrial disorders have
been modified from an adult
classification system
 The modified Walker criteria
 Because the natural history of this
heterogeneous group of
disorders remains largely
unknown, the modified Walker
criteria is useful to assess the
frequency of major clinical
manifestations in a population of
infants and children with definite
diagnosis of mitochondrial
disease
 By using the modified Walker
criteria,
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we are able to gather a large
group of pediatric patients with a
definite diagnosis of a
mitochondrial disorder and study
their clinical histories
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Modified Walker Criteria Applied to Children of Mitochondrial Disease
2 major criteria or 1 major plus 2 minor = Mitochondrial D.
Major Criteria
Clinically complete Respiratory chain
encephalomyopathy or a mitochondrial
cytopathy defined as fulfilling all 3 of the
following
Minor Criteria
Symptoms compatible with a
Respiratory Chain defect
Histology
>2% ragged red fibers in skeletal muscle
Smaller numbers of RRF, Sub sarcolemal
Accumulation of Mitochondria or
widespread electron microscopy
abnormalities of mitochondria
Enzymology
Cytochrome c oxidase negative fibers or
residual activity of a RC complex <20% in a
tissue; <30% in a cell line, or <30% in 2 or
more tissues
Antibody-based demonstration of an RC
defect or residual activity of an RC
complex 20%–30% in a tissue, 30%–40%
in a cell line, or 30%–40% in 2 or more
tissues
Functional
Fibroblast ATP synthesis rates >3 SD below
mean
Fibroblast ATP synthesis rates 2–3 SD
below mean, or fibroblasts unable to
grow in galactose media
Molecular
Nuclear or mtDNA mutation of undisputed
pathogenicity
Nuclear or mtDNA mutation of probable
pathogenicity
Clinical
Metabolic
One or more metabolic indicators of
impaired metabolic function
1-Unexplained combination of
multisystemic symptoms that is essentially
pathogonomic for RC defects
 2-Progressive clinical course with
episodes of exacerbations or a family
history strongly indicative of mtDNA
mutation
 3-Other possible neurometabolic
disorders have been excluded
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RC defect ,Pediatric features :
 Stillbirth associated with a paucity of
intrauterine movement, neonatal death,
movement disorder, severe FTT, neonatal
hypotonia, neonatal hypertonia are
minor criteria
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Conditions with Nuclear DNA Defects
Substrate Transport defect
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carnitine transporter
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carnitine palmitoyltransferase I
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the carnitine–acylcarnitine translocase
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carnitine palmitoyltransferase II
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Defects of Substrate Utilization
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Pyruvate carboxylase deficiency,
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pyruvate dehydrogenase complex deficiency
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defects of beta oxidation
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Defects of Oxidation–Phosphorylation
Coupling
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Defects of the Krebs Cycle
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Defects of the Respiratory Chain
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Defects of Protein Importation
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Defects of Intergenomic Signaling
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Defects of the Lipid of the Inner
Mitochondrial Membrane
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Defects of Mitochondrial Motility, Fusion,
and Fission
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Inherited Conditions Associated with
Mitochondrial DNA Defects
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Sporadic Large-Scale Rearrangements
Point Mutations Deffects
Protein-Coding Genes
Point Mutations Affecting Synthetic Genes
Acquired Conditions Associated with
Mitochondrial Dysfunction
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Muscle weakness (proximal > distal and upper > lower
extremities)
Hypotonia
Peripheral neuropathy
Ataxia
Ptosis
Ophthalmoplegia
Bulbar signs
Spasticity Stroke-like episodes
Migraine
Headaches
Tremor, chorea, ballismus
Dystonia
Seizures
Myoclonus
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CPEO :Chronic progressive external
ophthalmoplegia
LHON :Leber hereditary optic neuropathy
MELAS :Mitochondrial encephalopathy,
lactic acidosis, and stroke
MERRF :Myoclonic epilepsy with ragged red
fibers
MNGIE :Mitochondrial myopathy,
peripheral neuropathy, and gastrointestinal
encephalopathy
NARP :Neuropathy, ataxia, and retinitis
pigmentosa
KSS :Kearns-Sayre syndrome
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With congenital anomalies :
Are premature,24-48 hours of life
:severe hypoglycemia,hypotonia,
hepatomegaly, metabolic acidosis,
sweaty feet odor
Abnormal feature , high forehead, low
set ear, hypertelorism, hypoplastic mid
facial and anomaly of kidney
Most of them die in first weeks of life
Without congenital anomalies,
hypotonia, tachypnea, metabolic
acidosis, hepatomegaly,
hypoglycemia, and a peculiar odor
reminiscent of isovaleric acidemia
Adult phenotype or late onset :
Vomiting, hypoglycemia,
hepatomegaly, and limb weakness
Milder form of multiple acyl coenzyme
A dehydrogenase deficiency respond
to riboflavin
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Extremely different in age and
presentation
Asymptomatic during childhood
Presented in juvenile and adult
life with episodic vomiting,
hypoglycemia, hepatomegaly or
proximal weakness
Some patients have had
progressive lipid storage
myopathy with carnitine
deficiency
Caused by mutation in ETF
dehydrogenase gene and can
be treated with coQ10 and
Riboflavin
These patients present with
exercise intolerance, fatigue,
proximal myopathy and high
serum CPK
Due to defect of the electron transfer
flavoprotein (ETF) or ETF ubiquinone
oxidoreductase which are nuclear
encoded proteins through which
electrons from flavoprotein acyl-coA
dehydrogenase enter the respiratory
chain
 High dose Riboflavin
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Described by Denis Leigh, British physician, in 1951
One of the more deadly mitochondrial D.
Bilaterally symmetrical MRI abnormalities in the brain stem,
cerebellum, and basal ganglia,
Accompanied by elevated lactic acid in the blood and
cerebrospinal fluid and Urine
Belongs to a group of neurodevelopmental
disorders known as ASD and is characterized by
impaired social interactions, deficits in language
and communication, repetitive as well as
restricted behaviors
 usually observed in the first three years of life
 males are affected 4 times more than females
 Symptoms include hyperactivity, inattention,
irritability (including severe tantrums, aggression,
and self-injurious behavior), intellectual
impairment, sleep disturbances, sensory
hypersensitivity, and seizures
 Exact cause of autism remain unknown but it
considered to be a result of various genetic,
environmental, and immunological factors along
with increased vulnerability to oxidative stress.
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No biomarkers exist to diagnose therefore
diagnosis is based on observed behaviors
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No known cures exist for autism
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Significantly lower levels of:
complexes III and V in the
cerebellum
complex I in the frontal
cortex
complexes II, III, and V in the
temporal cortex
No defects in the parietal
and occipital cortices have
been observed as of yet
This can lead to abnormal
energy metabolism