Biology of Disease

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It would appear that several different approaches to treating and managing
mitochondrial disorders will be necessary. Most current treatments of
mitochondrial disorders are unsatisfactory and concentrate merely on
relieving symptoms. For example, administration of hydrogen carbonate and
dialysis may be used to relieve lactate acidosis. Exercise may decrease the
proportion of mutant mtDNA in muscle. Treatment with standard vitamins
and ubiquinone supplements has been tried but any benefits have yet to be
established.


Gene therapy using allotopic expression may offer a permanent cure in the
future. The strategy behind this technique is to insert a mitochondrial gene
into the nucleus where it is transcribed. The resulting messenger RNA is trans-
lated in the cytosol and the protein product is then imported into the mito-
chondria where it alleviates the effects of the mtDNA mutation.


Families affected by mitochondrial disorders should be offered counseling
on prognosis, risk of recurrence and prevention but even this is complex,
because the degree of mutant mtDNA can change dramatically during each
transmission of mitochondria from a mother to a child. The advice to affected
families on potential reproductive options may therefore be unsatisfactory.
Consequently, the clinical management of patients with mitochondrial
disorders is largely supportive.


16.5 Peroxisomal Disorders


Peroxisomes (Figure 16.10) are organelles surrounded by a single membrane,
that carry out certain oxidation reactions, particularly those involved in the
partial degradation of long chain fatty acids. Unlike mitochondria, these
oxidations are not coupled to the formation of ATP. Peroxisomal proteins
are synthesized in the cytosol and imported into the organelles by a com-
plex process that relies upon the relevant protein possessing a peroxisomal
targeting signal (PTS). The major signal (PTS1) consists of the carboxyl ter-
minal three amino acid residues being the consensus sequence –Ser-Lys-
Leu-COO–.


Defects in peroxisomes produce a variety of lethal human diseases. The most
common of these are adrenoleukodystrophy (ALD), Zellweger syndrome
and Refsum’s disease. These diseases are caused by defects in individual
peroxisomal enzymes or faults in the transport system necessary to convey
proteins from their site of synthesis in the cytosol to the peroxisome. All are
rare, occurring in approximately one in 50 000 live births.


Adrenoleukodystrophy is an X-linked disease (Chapter 15) caused by muta-
tions in a gene encoding an integral peroxisome membrane protein that acts
as an active carrier across the peroxisomal membrane. The disease is charac-
terized by increased concentrations of very long chain fatty acids (VLCFAs)
in the plasma and general tissues and progressive adrenal cortex dysfunc-
tion. Several types of ALD occur, the most severe affecting males of four to
eight years of age. The major symptoms are learning disabilities, seizures,
deafness, dysarthria, dysphagia, poor muscular coordination, vomiting,
increased pigmentation of the skin, progressive dementia and poor behav-
ior, such as aggression and hyperactivity. The adult form normally presents
at 20 to 36 years. Symptoms include stiffness and a progressive paraparesis
or weakness of the legs and ataxia, an inability to control muscular move-
ments. Progress of the adult form is slower than childhood ALD, but may
also result in loss of brain function and may be confused with multiple scle-
rosis. Occasionally, women carriers can show mild symptoms of ALD.


Zellweger syndrome is caused by defects in the general ability to import pro-
teins into peroxisomes. The peroxisomal enzymes remain in the cytosol and


PEROXISOMAL DISORDERS

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0.4 μm

P
P

P

P

Figure 16.10 Electron micrograph of liver
peroxisomes (P) identified by catalase activity.
Note the intensity of staining varies between
individual organelles. Courtesy of Drs M. Espeel
and F. Roels, Department of Anatomy, Embryology
and Histology, University of Ghent, Belgium.
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