Medical Genetics
13 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,
Medical Genetics
The incidence about 1:3000-4000
individuals in the US,This is similar
to the incidence of cystic fibrosis of
caucasian births in the U.S,
Medical Genetics
There are many forms of
mitochondrial disease,Mitochondrial
disease presents very differently
from individual to individual,
Medical Genetics
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
1,Biochemical & Genetic abnormalities
of mitochondrial function
(1) Mitochondrial substrate transport
(2) Substrate utilization
(3) Citric acid (TCA) cycle
(4) Oxidation-Phosphorylation coupling
(5) Respiratory chain
(6) Lipid membrane defect,
(7) Nuclear gene defects
Medical Genetics
(1) Mitochondrial substrate transport
ATP/ADP translocator deficiency
ATPase deficiency
Carnitine-acylcarnitine translocase deficiency
Carnitine deficiency
Primary deficiency
Secondary deficiency
Carnitine palmitoyl transferase
Protein import defects
Solute carriers
Medical Genetics
(2) Substrate utilization
Pyruvate disorders
β-oxidation defects (Fatty acid)
Ketone synthesis
HMG-CoA lyase
HMG-CoA synthase
Medical Genetics
(3) Citric acid (TCA) cycle
Aconitase deficiency
Lipoamide dehydrogenase
Fumarase deficiency
Medical Genetics
(4) Oxidation-Phosphorylation
coupling
ATP Synthase
Luft's disease
Medical Genetics
(5) Respiratory chain
mtDNA mutations
Intergenomic communication
Multiple mtDNA deletions
mtDNA depletion
Nuclear gene defects
Tissue-specific
Generalized
Succinic dehydrogenase
Medical Genetics
(6) Lipid membrane defect
Barth
Medical Genetics
(7) Nuclear gene defects
Medical Genetics
2,The Symptoms of Mitochondrial Disease
? Loss of muscle coordination,muscle weakness
? Neurological problems,seizures
? Visual and/or hearing problems
? Developmental delays,learning disabilities
? Heart,liver or kidney disease
? Gastrointestinal disorders,severe constipation
? Diabetes
? Increased risk of infection
? Thyroid and/or adrenal dysfunction
? Autonomic dysfunction
? Neuropsychological changes characterized by
confusion,disorientation and memory loss,
Medical Genetics
3,LHON
LHON = Leber's; Hereditary; Optic;
Neuropathy
Medical Genetics
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
Medical Genetics
Mutations (General)
–3 Mutations account for 96% of cases
? All in Complex I genes
? Mutations,G11778A (69%),G3460A (13%),
T14484C (14%)
–Mutation pattern
? Most patient's mutations are homoplasmic
? Some patients in each family may be
heteroplasmic
Medical Genetics
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
? 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
Medical Genetics
Bilateral,noncongruous
central scotoma
breaking through to upper
periphery
Associated with
LHON
Medical Genetics
Medical Genetics
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
Medical Genetics
4,MERRF
MERRF=Myoclonic Epilepsy; Ragged
Red Fibers
Medical Genetics
mtDNA point mutations,Heteroplasmic
? tRNA Lys, A8344G (Frequent); T8356C;
G8363A; G8361A
– Syndromes,MERRF or MERRF/MELAS overlap
? tRNA Ser
– Syndromes,MERRF/MELAS overlap; Epilepsia
Partialis Continua; HAM
? tRNA Leu
Medical Genetics
Onset
Late adolescence - Early adult
Medical Genetics
Clinical syndrome,
? CNS
– Myoclonus (60%)
– Epilepsy (45%)
– Cerebellar dysfunction,Ataxia
– Dementia
– Optic atrophy (20%)
? Polyneuropathy (20%)
– Distal sensory loss (large fiber modalities)
? Hearing loss (40%)
? Myopathy
? Short stature (10%)
? Lipomata (10%)
Medical Genetics
Medical Genetics
Laboratory
? Lactic acidosis,Variable
? Pathology of muscle
–Ragged red fibers,COX -
Medical Genetics
5,MELAS
MELAS=Mitochondrial
Encephalomyopathy; Lactic Acidosis;
Stroke
Medical Genetics
Inheritance
? Maternal
? Occasional sporadic & non-inherited
mutation (tRNA Leu)
? Clinical heterogeneity
– Rare to find more than 1 fully expressed
MELAS in same family
– Maternal relatives often oligo- or
asymptomatic
Medical Genetics
mtDNA point mutations
? Heteroplasmic,Mutant mtDNA
proportion ~ 56% to 95%
? Genes
–tRNA Leu (common)
? A3243G mutation,80% of MELAS
syndromes
? Other MELAS mutation loci,T3271C has
later age of onset; 3291
Medical Genetics
Clinical Syndrome
? Onset
– 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
Medical Genetics
Scattered abnormal,
vacuolated fibers with clear
rim,H & E
Scattered "ragged
red" muscle fibers,
Gomori trichrome
Medical Genetics
Ragged red muscle fibers,Gomori trichrome
Medical Genetics
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
Medical Genetics
Laboratory
? 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)
Medical Genetics
6,Kearns-Sayre Syndrome
Family history
? Sporadic,Most patients
? Familial cases,Rare; Mother to
offspring
Medical Genetics
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
Medical Genetics
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
Medical Genetics
Medical Genetics
Medical Genetics
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
Medical Genetics
6.Mitochondrial Disease Diagnosis
? There is no reliable and consistent
means of diagnosis,
? Diagnosis can be made by one of the
few physicians that specializes in
mitochondrial disease,
? Diagnosis can be made by blood DNA
testing and/or muscle biopsy but
neither of these tests are completely
reliable,
Medical Genetics
7.Mitochondrial Disease Treatment
? Treatment consists of vitamin therapy and
conserving energy,
? The goal is to improve symptoms and slow
progression of the disease,
? Conserve energy,
? Pace activities,
? Maintain an ambient environmental
temperature,
? Avoid exposure to illness,
? Ensure adequate nutrition and hydration,
Medical Genetics
8,The Prognosis
? The prognosis is variable,Some
people live a normal life and are
minimally affected,others can be
severely compromised with the
disease,
? It is completely individualized
? The prognosis is unpredictable,
Medical Genetics
9,Future Goals
? To develop a better understanding of the
biology of mitochondria,
? To learn more about mitochondrial disease
in human beings,
? To refine diagnostic methods,
? To improve and expand treatment options,
? To educate the general public and medical
arena,
? To improve the day to day life of
individuals living with mitochondrial
disease,
13 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,
Medical Genetics
The incidence about 1:3000-4000
individuals in the US,This is similar
to the incidence of cystic fibrosis of
caucasian births in the U.S,
Medical Genetics
There are many forms of
mitochondrial disease,Mitochondrial
disease presents very differently
from individual to individual,
Medical Genetics
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
1,Biochemical & Genetic abnormalities
of mitochondrial function
(1) Mitochondrial substrate transport
(2) Substrate utilization
(3) Citric acid (TCA) cycle
(4) Oxidation-Phosphorylation coupling
(5) Respiratory chain
(6) Lipid membrane defect,
(7) Nuclear gene defects
Medical Genetics
(1) Mitochondrial substrate transport
ATP/ADP translocator deficiency
ATPase deficiency
Carnitine-acylcarnitine translocase deficiency
Carnitine deficiency
Primary deficiency
Secondary deficiency
Carnitine palmitoyl transferase
Protein import defects
Solute carriers
Medical Genetics
(2) Substrate utilization
Pyruvate disorders
β-oxidation defects (Fatty acid)
Ketone synthesis
HMG-CoA lyase
HMG-CoA synthase
Medical Genetics
(3) Citric acid (TCA) cycle
Aconitase deficiency
Lipoamide dehydrogenase
Fumarase deficiency
Medical Genetics
(4) Oxidation-Phosphorylation
coupling
ATP Synthase
Luft's disease
Medical Genetics
(5) Respiratory chain
mtDNA mutations
Intergenomic communication
Multiple mtDNA deletions
mtDNA depletion
Nuclear gene defects
Tissue-specific
Generalized
Succinic dehydrogenase
Medical Genetics
(6) Lipid membrane defect
Barth
Medical Genetics
(7) Nuclear gene defects
Medical Genetics
2,The Symptoms of Mitochondrial Disease
? Loss of muscle coordination,muscle weakness
? Neurological problems,seizures
? Visual and/or hearing problems
? Developmental delays,learning disabilities
? Heart,liver or kidney disease
? Gastrointestinal disorders,severe constipation
? Diabetes
? Increased risk of infection
? Thyroid and/or adrenal dysfunction
? Autonomic dysfunction
? Neuropsychological changes characterized by
confusion,disorientation and memory loss,
Medical Genetics
3,LHON
LHON = Leber's; Hereditary; Optic;
Neuropathy
Medical Genetics
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
Medical Genetics
Mutations (General)
–3 Mutations account for 96% of cases
? All in Complex I genes
? Mutations,G11778A (69%),G3460A (13%),
T14484C (14%)
–Mutation pattern
? Most patient's mutations are homoplasmic
? Some patients in each family may be
heteroplasmic
Medical Genetics
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
? 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
Medical Genetics
Bilateral,noncongruous
central scotoma
breaking through to upper
periphery
Associated with
LHON
Medical Genetics
Medical Genetics
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
Medical Genetics
4,MERRF
MERRF=Myoclonic Epilepsy; Ragged
Red Fibers
Medical Genetics
mtDNA point mutations,Heteroplasmic
? tRNA Lys, A8344G (Frequent); T8356C;
G8363A; G8361A
– Syndromes,MERRF or MERRF/MELAS overlap
? tRNA Ser
– Syndromes,MERRF/MELAS overlap; Epilepsia
Partialis Continua; HAM
? tRNA Leu
Medical Genetics
Onset
Late adolescence - Early adult
Medical Genetics
Clinical syndrome,
? CNS
– Myoclonus (60%)
– Epilepsy (45%)
– Cerebellar dysfunction,Ataxia
– Dementia
– Optic atrophy (20%)
? Polyneuropathy (20%)
– Distal sensory loss (large fiber modalities)
? Hearing loss (40%)
? Myopathy
? Short stature (10%)
? Lipomata (10%)
Medical Genetics
Medical Genetics
Laboratory
? Lactic acidosis,Variable
? Pathology of muscle
–Ragged red fibers,COX -
Medical Genetics
5,MELAS
MELAS=Mitochondrial
Encephalomyopathy; Lactic Acidosis;
Stroke
Medical Genetics
Inheritance
? Maternal
? Occasional sporadic & non-inherited
mutation (tRNA Leu)
? Clinical heterogeneity
– Rare to find more than 1 fully expressed
MELAS in same family
– Maternal relatives often oligo- or
asymptomatic
Medical Genetics
mtDNA point mutations
? Heteroplasmic,Mutant mtDNA
proportion ~ 56% to 95%
? Genes
–tRNA Leu (common)
? A3243G mutation,80% of MELAS
syndromes
? Other MELAS mutation loci,T3271C has
later age of onset; 3291
Medical Genetics
Clinical Syndrome
? Onset
– 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
Medical Genetics
Scattered abnormal,
vacuolated fibers with clear
rim,H & E
Scattered "ragged
red" muscle fibers,
Gomori trichrome
Medical Genetics
Ragged red muscle fibers,Gomori trichrome
Medical Genetics
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
Medical Genetics
Laboratory
? 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)
Medical Genetics
6,Kearns-Sayre Syndrome
Family history
? Sporadic,Most patients
? Familial cases,Rare; Mother to
offspring
Medical Genetics
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
Medical Genetics
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
Medical Genetics
Medical Genetics
Medical Genetics
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
Medical Genetics
6.Mitochondrial Disease Diagnosis
? There is no reliable and consistent
means of diagnosis,
? Diagnosis can be made by one of the
few physicians that specializes in
mitochondrial disease,
? Diagnosis can be made by blood DNA
testing and/or muscle biopsy but
neither of these tests are completely
reliable,
Medical Genetics
7.Mitochondrial Disease Treatment
? Treatment consists of vitamin therapy and
conserving energy,
? The goal is to improve symptoms and slow
progression of the disease,
? Conserve energy,
? Pace activities,
? Maintain an ambient environmental
temperature,
? Avoid exposure to illness,
? Ensure adequate nutrition and hydration,
Medical Genetics
8,The Prognosis
? The prognosis is variable,Some
people live a normal life and are
minimally affected,others can be
severely compromised with the
disease,
? It is completely individualized
? The prognosis is unpredictable,
Medical Genetics
9,Future Goals
? To develop a better understanding of the
biology of mitochondria,
? To learn more about mitochondrial disease
in human beings,
? To refine diagnostic methods,
? To improve and expand treatment options,
? To educate the general public and medical
arena,
? To improve the day to day life of
individuals living with mitochondrial
disease,
