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Medical Genetics
线粒体疾病
mitochondrial diseases
Medical Genetics
Mutations (changes) in the
mitochondrial chromosome are
responsible for a number of
disorders.
Medical Genetics
Mitochondrial disease is a chronic,
genetic disorder that occurs when
the mitochondria of the cell fails to
produce enough energy for cell or
organ function.
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The incidence about 1:3000-4000
individuals in the US.
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Characteristics
Unlike nuclear genes, which are
inherited from both parents,
mitochondrial genes are inherited
only from the mother.
In mammals, 99.99% of
mitochondrial DNA (mtDNA)
is inherited from the
mother.
This is because the sperm
carries its mitochondria
around a portion of its tail
and has only about 100
mitochondria compared to
100,000 in the oocyte.
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Threshold effect
• % of mutant mtDNAs must be above a
threshold to produce clinical
manifestations
• % of mutant mtDNAs needed to cause cell
dysfunction varies according to tissue
oxidative requirements
• Disease signs especially manifest in
– Tissues with a high energy expenditure:
Dependent on oxidative metabolism
– Specific tissues: Brain, Heart & Muscle
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Mitotic segregation
– % of mutant mtDNAs in daughter cells
can shift at cell division
– Produces rapid changes of genotype
that may lead to crossing of threshold
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There are many forms of
mitochondrial disease. Mitochondrial
disease presents very differently
from individual to individual.
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Mitochondrial disease is inherited
in a number of different ways.
There may be one individual in a
family or many individuals affected
over a number of generations.
Medical Genetics
If there is a mutation in a
mitochondrial gene, it is passed from
a mother to all of her children; sons
will not pass it on, but daughters will
pass it on to all of their children, and
so on.
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3. LHON
LHON = Leber's; Hereditary; Optic;
Neuropathy
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Genetic-Clinical correlations:
Maternal Inheritance
• Recurrence risks: Brother 30%; Sister 8%;
Nephew 46%; Niece 10%; Male cousin
31%; Female cousin 6%
• 40% of patients with commonest mutation
(G11778A) have negative family history
• Large families with maternal inheritance:
G11778 & T14484C mutations
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Mutations (General)
– 3 Mutations account for 96% of cases
• All in Complex I genes
• Mutations: G11778A (69%), G3460A (13%),
T14484C (14%)
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Clinical features (General)
Male predominance:No relation to any X-linked genes
Onset :Midlife: Mean 30 years; Range 1 to 70
Visual loss
– Clinical features
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Painless
Visual loss pattern
Severity: May deteriorate to 20/200 or less
Progression: Mean 4 months;
Interval between eyes affected: ~ 2 months
Tendency to recover depends on mutation
Pupillary reactions: May be relatively spared for degree of
visual loss
– Ocular pathology
Other features: Some families
Cardiac conduction defects; Spastic dystonia; Spastic
paraparesis; Dystonia
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Laboratory
• Muscle pathology
– No ragged red fibers
– EOM mitochondria: Diffuse increase in
number and size; Disorganized cristae
– Preservation of myofibrils
• MRI: Optic nerve may enhance on T2
weighted images
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4. MERRF
MERRF=Myoclonic Epilepsy; Ragged
Red Fibers
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mtDNA point mutations:
• tRNA Lys : A8344G (Frequent);
T8356C; G8363A; G8361A
– Syndromes: MERRF or MERRF/MELAS
overlap
• tRNA Ser
– Syndromes: MERRF/MELAS overlap;
Epilepsia Partialis Continua;
• tRNA Leu
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Onset
Late adolescence - Early adult
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Clinical syndrome:
• CNS
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Myoclonus (60%)
Epilepsy (45%)
Cerebellar dysfunction: Ataxia
Dementia
Optic atrophy (20%)
• Polyneuropathy (20%)
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– Distal sensory loss (large fiber modalities)
Hearing loss (40%)
Myopathy
Short stature (10%)
Lipomata (10%)
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Laboratory
• Lactic acidosis: Variable
• Pathology of muscle
– Ragged red fibers
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5. MELAS
MELAS=Mitochondrial
Encephalomyopathy; Lactic Acidosis;
Stroke
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mtDNA point mutations
– tRNA Leu (common)
• A3243G mutation: 80% of MELAS
syndromes
• Other MELAS mutation loci: T3271C has
later age of onset; 3291
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Clinical Syndrome
• Onset
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– Mean = 10 years; Range = 2 to 40
Encephalopathy: Often episodic
Systemic features
Myopathy
Polyneuropathy
More common in patients with myopathy
Mean life span with full clinical syndrome
~ 2 to 4 decades
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Scattered abnormal,
vacuolated fibers with clear
rim: H & E
Scattered "ragged
red" muscle fibers:
Gomori trichrome
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Ragged red muscle fibers: Gomori trichrome
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Genetic counseling: A3423G mutation
• % of affected offspring: Increased with higher
mutant load in maternal blood
• Mutant load 1% to 19%: 20% chance of affected
offspring
• Mutant load > 20%: 50% chance of affected
offspring
• Full expression of phenotype in multiple family
members: Rare
• Partial expression in multiple family members:
Common
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Laboratory
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Lactic acidosis: Blood & CSF
EMG: Mormal or Myopathic
Serum CK: Normal to 2x high (32%)
MRI: Strokes
Biochemistry
– Respiratory chain dysfunction
– Reduced activity of Complexes I & IV
• Pathology (A3243G mutation)
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6. Kearns-Sayre Syndrome
Family history
• Sporadic: Most patients
• Familial cases: Rare; Mother to
offspring
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mtDNA mutation types
• Single large mtDNA deletion (2 to 8 kb)
– Most common mutation type (80%)
– Common deletions
• Most common: 4977 base pairs from 8488 to 13460; 13
base pair repeat at mutation break point
• Thai patients: 3558 bp deletion; 10204 to 13761, or 10208
to 13765
– Most deletions preserve
• Promoters of transcription of heavy & light strands
• 12S & 16S ribosomal RNA genes
• Origin of heavy strand replication
– Change in number of deletions over time
• Increased in muscle
• Reduced in rapidly turning over cells (hematopoetic)
• Large scale tandem duplication
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Clinical features
• General
– Characteristic signs: PEO; Pigmentary degeneration of retina;
Heart block; Mitochondrial myopathy
• Onset: < 20 years; Later onset patients may have only PEO
• Ocular
– External Ophthalmoplegia
• Dysphagia: 50% of adults symptomatic
• Myopathy
– Weakness (90%): Proximal > Distal; Symmetric
– Occasional fatigue or pain on exertion
• CNS
– Hearing loss (95%)
– Ataxia (90%)
• Systemic features
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Laboratory
• Muscle pathology
– Ragged red fibers (98%): COX + and COX – Variation in muscle fiber size
• Lactic acidosis (80%)
• Head CT: Basal ganglia calcifications (5%)
• CSF Protein: High