1. 13 线粒体疾病 mitochondrial diseases

2. Mutations (changes) in the mitochondrial chromosome are responsible for a number of disorders.

3. 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.  

4. The incidence about 1:3000-4000 individuals in the US
The incidence about 1: individuals in the US.   This is similar to the incidence of cystic fibrosis of caucasian births in the U.S.

5. There are many forms of mitochondrial disease
There are many forms of mitochondrial disease. Mitochondrial disease presents very differently from individual to individual.

6. 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.

7. 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

8. (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

9. (2) Substrate utilization
  Pyruvate disorders   β-oxidation defects (Fatty acid)   Ketone synthesis     HMG-CoA lyase     HMG-CoA synthase

10. (3) Citric acid (TCA) cycle
  Aconitase deficiency   Lipoamide dehydrogenase   Fumarase deficiency

11. (4) Oxidation-Phosphorylation coupling  
ATP Synthase   Luft's disease

12. (5) Respiratory chain  
mtDNA mutations   Intergenomic communication     Multiple mtDNA deletions     mtDNA depletion
Nuclear gene defects     Tissue-specific     Generalized   Succinic dehydrogenase

13. (6) Lipid membrane defect
Barth

14. (7) Nuclear gene defects

15. 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.

16. 3. LHON
LHON = Leber's; Hereditary; Optic; Neuropathy

17. 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

18. 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

19. 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

20.                                                                                            
Bilateral, noncongruous central scotoma breaking through to upper periphery Associated with LHON

22. MRI: Optic nerve may enhance on T2 weighted images
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

23. 4. MERRF
MERRF=Myoclonic Epilepsy; Ragged Red Fibers

24. 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

25. Onset
Late adolescence - Early adult

26. Clinical syndrome: CNS Polyneuropathy (20%) Hearing loss (40%)
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%)

28. Lactic acidosis: Variable Pathology of muscle
Laboratory
Lactic acidosis: Variable
Pathology of muscle
Ragged red fibers: COX -

29. 5. MELAS
MELAS=Mitochondrial Encephalomyopathy; Lactic Acidosis; Stroke

30. 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

31. Heteroplasmic: Mutant mtDNA proportion ~ 56% to 95% Genes
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

32. Encephalopathy: Often episodic Systemic features Myopathy
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

33. Scattered "ragged red" muscle fibers: Gomori trichrome
Scattered abnormal, vacuolated fibers with clear rim: H & E

34. Ragged red muscle fibers: Gomori trichrome

35. 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

36. 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)

37. 6. Kearns-Sayre Syndrome
Family history
Sporadic: Most patients
Familial cases: Rare; Mother to offspring

38. 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; to 13761, or 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

39. 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

42. Laboratory Muscle pathology Lactic acidosis (80%)
Ragged red fibers (98%): COX + and COX -
Variation in muscle fiber size
Lactic acidosis (80%)
Head CT: Basal ganglia calcifications (5%)
CSF Protein: High

43. 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.

44. 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.

45. 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.

46. 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.