Biology of Disease

reported in patients. In the UK, it is estimated that mitochondrial disorders

occur with a frequency of about seven in 100 000.

Diagnosis and Treatment of Mitochondrial Disorders

Considerable advances have been made in our understanding of the pathol-

ogy of mitochondrial disorders. However, the diagnosis and detection of

mtDNA mutations is problematic because of the varied etiology and clinical

features of these diseases (Table 16.3). Similarly, predictors of disease progres-

sion are also highly unsatisfactory. The concentrations of lactate in plasma,

cerebrospinal fluid and urine may, individually or collectively, be increased

relative to normal, although these changes are also seen in numerous other

clinical conditions. However, a plasma lactate : pyruvate ratio of greater than

40 is usually considered a significant indicator of mitochondrial dysfunc-

tion in adults. Other indicators may be the presence of organic acids and

myoglobin in the urine, ketoacidosis (Chapter 7), and impaired renal, liver

and glandular functions.

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Disease Mutation General features

Chronic progressive external

ophthalmoplegia (CPEO)

deletion with loss of several

genes

paralysis of eye muscle,

myopathy

Kearns-Sayre syndrome (KSS) deletion with loss of several

genes

CPEO and retinal deterioration,

ataxia, heart disease, loss of

hearing, kidney failure and

diabetes

Leber hereditary optic

neuropathy (LHON)

mutations in genes for subunits

of NADH dehydrogenase

damage to optic nerve leading

to blindness

Leigh syndrome mutations in genes for subunits

of ATP synthase and inner

membrane oxidation complexes

loss of verbal and motor skills

following degeneration of basal

ganglia

Mitochondrial

encephalomyopathy, lactic

acidosis and stroke-like

episodes (MELAS)

mutations in genes for tRNALeu,

tRNAGluand NADH

dehydrogenase

myopathy, dementia, seizures,

lactic acidosis

Myoneurogastrointestinal

encephalopathy

(MNGIE)

multiple mtDNA deletions progressive external

ophthalmoplegia,

gastrointestinal

dysmotility (often pseudo

obstruction), diffuse

leukoencephalopathy,

myopathy

Myoclonic epilepsy and

ragged-red fiber (MERRF)

mutations in genes for tRNALys,

tRNALeu

myoclonic seizures, ataxia,

lactic acidosis, ‘ragged-red

fibers’ – an abnormality of the

tissue when seen in a

microscope

Neurogenic muscle weakness,

ataxia and retinitis

pigmentosa (NARP)

mutations in genes for

subunits of ATP synthase

muscle wasting, ataxia,

blindness

Pearson syndrome deletion with loss of several

genes

childhood bone marrow

dysfunction, multiple blood

disorders and pancreatic failure

Table 16.3Examples of mitochondrial diseases

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