MITOCHONDRIAL

ENCEPHALOMYOPATHIES
(MEM)
 Mitochondria are under the control of two genomes: their
own mtDNA and that of the nucleus nDNA. Therefore,
mitochondrial diseases, that is, genetic diseases resulting in
mitochondrial dysfunction, can be due to mutations in either
genome.

 We will consider diseases caused by mutations in mtDNA

and also a group of disorders (defects of intergenomic
signalling) characterized by mutations in nDNA that in turn
alter mtDNA integrity or replication.
 Principles of Mitochondrial Genetics

 Human mtDNA is a small circle of double-stranded

DNA, comprising only 37 genes. Of these, 13
encode polypeptides (subunits of the respiratory
chain): seven subunits of complex I,
one subunit of complex III,
three subunits of complex IV (COX), and
two subunits of complex V.
 The other 24 genes encode 22 transfer ribonucleic acids
(tRNAs) and two ribosomal RNAs (rRNAs) that are
required for translation of messenger RNAs on
mitochondrial ribosomes.

 The subunits of complex II and two small electron

carriers, coenzyme Q10 and cytochrome c, are encoded
exclusively by nDNA.
Mendelian versus Mitochondrial Genetics
 The following main principles distinguish mitochondrial
genetics from mendelian genetics and help explain many of the
clinical peculiarities of mtDNA-related disorders.

 Polyplasmy. Most cells contain multiple mitochondria, and

each mitochondrion contains multiple copies of mtDNA, so that
there are hundreds or thousands of mitochondrial genomes in
each cell.
 Heteroplasmy. When an mtDNA mutation affects
some but not all genomes, a cell, a tissue, indeed a
whole individual will harbour two populations of
mtDNA, normal (or wild-type) and mutant, a condition
known as heteroplasmy. Most (but not all) pathogenic
mtDNA mutations are heteroplasmic.
 Threshold effect. Functional impairment associated
with a pathogenic mtDNA mutation is largely
determined by the degree of heteroplasmy, and a
minimum critical number of mutant genomes must be
present before tissue dysfunction becomes evident.
Tissues with high metabolic demands, such as brain,
heart, and muscle, tend to have lower tolerance for
mtDNA mutations than metabolically less active tissues.
 Mitotic segregation. Both organellar division and mtDNA
replication are apparently stochastic events unrelated to cell
division; thus, the number of mitochondria (and mtDNA)
can vary not just in space (i.e., among cells and tissues) but
also in time (i.e., during development or aging). Moreover,
at cell division, the proportion of mutant mtDNAs in
daughter cells may drift, allowing relatively rapid changes
in genotype that can translate into changes in phenotype,
including the clinical picture, if and when the threshold is
crossed.
 Maternal inheritance. At fertilization, all
mitochondria (and all mtDNA) are contributed to the
zygote by the oocyte. Therefore, a mother carrying an
mtDNA mutation will pass it on to all of her children,
males and females, but only her daughters will transmit
it to their progeny in a “vertical,' matrilinear line.
 When maternal inheritance is evident in a clinical
setting, it provides conclusive evidence that an
mtDNA mutation must underlie the disease in
question. However, the other features of
mitochondrial genetics (e.g., heteroplasmy and the
threshold effect) often mask maternal inheritance by
causing striking intra-familial clinical heterogeneity.
 Thus, when an mtDNA-related disorder is suspected,
it is crucial to collect the family history meticulously,
with special attention to “soft' signs (e.g., short
stature, hearing loss, migrainous headache) in
potentially oligo-symptomatic maternal relatives.
 Clinical Manifestations
 Although specific syndromes can be identified by particular
combinations of symptoms and signs, several clinical
manifestations seem to be prevalent among different syndromes,
especially short stature, neurosensory hearing loss,
peripheral neuropathy, and diabetes mellitus.
 Lactic acidosis, often detected in blood and cerebrospinal fluid
(CSF), is the most common laboratory sign.
 As a result of impaired respiration, mitochondria in muscle
proliferate and enlarge, which is the basis for finding RRF.
Neuropathologic and neuroradiologic changes fall into
four main patterns:

1)Microcephaly and ventricular dilatation, sometimes

associated with agenesis of the corpus callosum, are
seen in infants with severe congenital lactic acidosis.
2)Bilateral, symmetric lesions of basal ganglia,
thalamus, brainstem, and cerebellar roof nuclei are
the signature of Leigh syndrome.
3) Multifocal encephalomalacia, usually involving the
cortex of the posterior cerebral hemispheres,
corresponds to the “strokes' of the MELAS syndrome.

4) Spongy encephalopathy, predominantly in white

matter, is characteristic of KSS.

 Calcification of the basal ganglia can be seen in all of

these disorders, but in a minority of patients with any
syndrome.
Diagnosis of a mitochondrial disease is based on:

(1) recognition of an appropriate clinical syndrome,

(2) presence of lactic acidosis in blood or CSF,

(3) demonstration of RRF in muscle biopsy,

(4) documentation of impaired respiration in biochemical assays

of muscle extracts or isolated mitochondria, or

(5) identification of a pathogenic mutation in mtDNA.

Not all of these criteria are necessarily present in an individual

syndrome.
 PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA
(PEO)
 Progressive limitation of eye movements usually
accompanied by eyelid droop (ptosis). There may be
weakness of muscles of the face, oropharynx, neck, or
limbs.

 This condition is clearly heterogeneous, but several

distinct syndromes can be recognized, some related to
primary abnormalities of mtDNA (with sporadic single
deletions or maternally inherited point mutations), others
related to autosomal genes directly affecting mtDNA
(defects of intergenomic signalling with multiple deletions
of mtDNA).
 Sporadic PEO with Single mtDNA Deletions

A) PEO with or without Limb Weakness

 This is a relatively benign condition, often compatible with a

normal life span. Symptoms usually begin in childhood but may
be delayed to adolescence or adult years. Ptosis is often the first
symptom, followed by ophthalmoparesis. The disorder is bilateral
and symmetric, so diplopia is exceptional. Some patients also
have pharyngeal and limb weakness.
B) Kearns-Sayre Syndrome

 This syndrome is identified by an invariant triad: onset before age

20 years, PEO, and pigmentary retinopathy.
 In addition, there must be one of the following: heart block
(usually needing a pacemaker), cerebellar syndrome, or CSF
protein content of 100 mg/dL or more.
 DM and hypoparathyroidism are among several endocrine
disorders sometimes associated with KSS.
 The course is relentlessly downhill, and patients rarely survive
past the second decade.
Molecular Genetics
 In both sporadic PEO and KSS, patients harbor a single
deletion in their mtDNA that is identical in all tissues in
any patient, although the number of deleted genomes
varies from tissue to tissue (heteroplasmy).
 The single mtDNA deletions arise spontaneously early in
oogenesis or embryogenesis.
 Although the molecular defect is the same in both
conditions, intermediate cases are surprisingly few.
 LABORATORY ABNORMALITIES

 In both conditions, muscle biopsy shows RRFs that are devoid of

histochemically demonstrable COX activity and blood usually
shows raised levels of lactate and pyruvate.
 Increased lactate in the CSF is seen only in KSS.
 At postmortem examination, typical cases of KSS show spongy
degeneration of the brain.
 CT or MRI shows evidence of leukoencephalopathy, and there
may be calcification of basal ganglia.
 TREATMENT

 In KSS, pacemaker can prevent sudden death as a result of the

cardiac conduction disorder.
 Episodic coma may result from the combination of diabetes
mellitus and encephalopathy.
 The cerebellar syndrome can be severe enough to be disabling.
 Treatment with coenzyme Q10 may reverse some EEG
abnormalities but has not reversed heart block, ophthalmoplegia,
or the neurologic syndrome.
 MATERNALLY INHERITED PEO WITH
POINT MUTATIONS OF MTDNA

 A substantial number of patients with mitochondrial PEO (i.e.,

PEO and RRF in the muscle biopsy) show maternal inheritance of
their syndrome.

 PEO predominates in this syndrome but is often associated with

various combinations of other symptoms, including hearing loss,
endocrinopathy, heart block, cerebellar ataxia, or pigmentary
retinopathy.
 The most common mutation in these patients is the typical
A3243G MELAS mutation, but other mutations have also been
described, including the A8344G mutation typically seen in
MERRF syndrome. The reason for the appearance of PEO in
patients with the MELAS mutation is not known, but it may be
related to a selective accumulation of mutant mtDNA in
muscle.

 There is usually lactic acidosis, and muscle biopsies show RRF.

 AUTOSOMAL PEO WITH MULTIPLE
DELETIONS OF MTDNA

 PEO has been described in numerous families with autosomal-

dominant (adPEO) or autosomal-recessive (arPEO) inheritance.

 Generally, adPEO syndromes are dominated by myopathic

symptoms, while arPEO syndromes tend to be multisystemic.
 AUTOSOMAL-DOMINANT PEO

 The clinical syndrome is characterized by ophthalmoplegia,

although hearing loss, tremor, cataracts, and psychiatric
disorders are variably present and suggest multisystemic
involvement.

 Onset is usually in adult age, and there may be weakness of

facial, pharyngeal, and respiratory muscles in addition to slowly
progressive proximal limb weakness.
AUTOSOMAL-RECESSIVE PEO WITH
CARDIOMYOPATHY

 Severe hypertrophic cardiomyopathy, proximal

weakness, and PEO are the clinical hallmarks.

 Onset is in childhood, and cardiac transplantation is

needed to prevent early death.
 MITOCHONDRIAL NEURO-GASTRO-
INTESTINAL ENCEPHALOMYOPATHY (MNGIE)

 It starts in childhood or adolescence with chronic intractable

diarrhoea, loud borborygmi, and recurrent intestinal pseudo-
obstruction, causing severe emaciation.

 There is also PEO, both proximal and distal limb weakness, and
sensory neuropathy. MRI shows diffuse leukodystrophy, although
patients are rarely frankly demented. Death usually occurs in the
fourth or fifth decade.
 LABORATORY ABNORMALITIES

 In all these conditions, muscle biopsy shows RRF and COX-

negative fibres; these are more abundant in arPEO than in adPEO
syndromes.
 Lactic acidosis is usually present but may not be very marked.
 In MNGIE, nerve conduction studies and nerve biopsies have
shown features of both axonal and demyelinating neuropathy.
 MOLECULAR GENETICS

 Southern blot analyses of muscle mtDNA in these conditions

show multiple bands representing species of mtDNA molecules
harboring deletions of different sizes (more abundantly in arPEO
than in adPEO patients).
 The autosomal nature of these disorders suggests that defects of
nuclear genes either facilitate an intrinsic propensity of mtDNA
to undergo rearrangements or cause a failure to eliminate
spontaneously occurring rearrangements.
 OTHER FORMS OF MITOCHONDRIAL
PEO
 Ophthalmoplegia is often seen in patients with the congenital or
the infantile myopathic variants of mtDNA depletion, which are
transmitted as autosomal-recessive traits.
 Ptosis, PEO, or both can also accompany the late-onset
mitochondrial myopathies, often associated with multiple
mtDNA deletions that have been described in sporadic elderly
individuals and have been interpreted as an exaggerated
manifestation of the normal aging process.
MULTISYSTEM NEUROLOGIC DISEASES
WITHOUT OPHTHALMOPLEGIA
 MELAS SYNDROME

 The distinguishing features of this syndrome are the stroke-like

attacks with hemiparesis, hemianopia, or cortical blindness that
almost invariably occur before age 40 years, and often in
childhood.
 Common additional features are focal or generalized seizures,
recurrent migraine-like headaches and vomiting, and dementia.
 The course is one of gradual deterioration.
 Laboratory abnormalities include elevated blood and
CSF lactate and MRI evidence of encephalomalacic foci,
usually involving the occipital cortex and not
conforming to the distribution of major vessels.

 Muscle biopsy shows RRF, which are

uncharacteristically COX-positive, rather than COX-
negative as in most other mtDNA-related diseases.
 In about 80% of patients, the molecular defect is a point
mutation (A3243G) in the tRNA Leu(UUR) gene of mtDNA. In the
remaining patients, a handful of mutations have been described.

 A3243G is the most frequent pathogenic mtDNA mutation, and

it has been associated not only with MELAS and maternally
inherited PEO but also with diabetes mellitus alone or with
deafness.
 MERRF SYNDROME

 Typical clinical features include myoclonus, generalized seizures,

cerebellar ataxia, myopathy, and, in some families, multiple
symmetric lipomas.
 Onset may occur in childhood or in adult life, and the course may
be slowly progressive or rapidly downhill.
 As the acronym denotes, muscle biopsy shows RRF, which are
COX-negative.
 Most patients with MERRF have a mutation (A8344G) in the
tRNALys gene of mtDNA.
NEUROPATHY, ATAXIA, AND
RETINITIS PIGMENTOSA (NARP)

 The combination of neuropathy, ataxia, and retinitis

pigmentosa (NARP) is a maternally transmitted
multisystem disorder of young adult life, comprising, in
various combinations, sensory neuropathy, ataxia,
seizures, dementia, and retinitis pigmentosa.
 Lactic acid in blood may be normal or slightly elevated,
and muscle biopsy does not show RRF.
 The molecular defect is a point mutation (T8993G) in the gene
that encodes ATPase 6.
 When this mutation approaches homoplasmic levels, onset is in
infancy, and the clinical and neuropathologic features are those
of Leigh syndrome (maternally inherited Leigh syndrome
[MILS]).
 A different mutation at the very same nucleotide (T8993C)
causes a phenotype similar to MILS but generally milder. A few
other mutations in the ATPase 6 gene have been associated with
Leigh-like syndromes or with familial bilateral striatal necrosis.
LEBER HEREDITARY OPTIC NEUROPATHY
(LHON)

 A maternally inherited disorder characterized by loss of

central vision and occurring more often in males.
 CLINICAL MANIFESTATIONS

 Onset usually occurs in adolescence or early-adult years but may

occur from ages 5 to 80 years. Cloudiness of central vision
progresses painlessly over weeks, usually first in one eye, to a
larger, denser centrocecal scotoma. Both eyes are usually affected
within weeks or months, sometimes simultaneously; it is only
rarely unilateral. Color vision is affected, and acuity drops to
20/200 or finger counting. Residual visual loss may be severe and
generally remains stationary. Sometimes, there is later
improvement, infrequently striking and occasionally sudden.
 The fundus may appear normal until optic atrophy supervenes,
but at onset, the disc often appears blurred and suggestive of
edema, as in papillitis. This subsides after a few weeks or
months. Optic atrophy follows, starting in the temporal portion
of the disc, and then usually generalized.
 Neurologic examination, however, may reveal subtle neurologic
abnormalities, including postural tremor, dystonia, motor tics,
parkinsonism with dystonia, or peripheral neuropathy. Several
patients (mostly women) with LHON have had multiple
sclerosis–like manifestations.
 At least three Leber-plus syndromes have been reported:
optic neuropathy and dystonia, optic neuropathy and
spastic dystonia, and the Queensland variant with optic
neuropathy, athetosis, tremor, corticospinal tract signs,
posterior column dysfunction, psychiatric disturbances,
and acute encephalopathy.
PATHOLOGY:

 autopsy studies of LHON patients revealed atrophy of

the retinal ganglion cells and nerve fiber layers and optic
nerve.
MOLECULAR GENETICS

 There are mtDNA primary mutations that are thought to

be pathogenic. Secondary mutations may be
synergistically pathogenic in combination with each
other or with primary mutations. About 85% of patients
with LHON harbor primary mutations that are usually
homoplasmic, in contrast to the mitochondrial
encephalomyopathies, which typically show
heteroplasmic.
 The penetrance rates of the LHON mutations are
uncertain; however, some reports estimate that
symptoms appear in 20% to 83% of men and 4% to 32%
of women at risk. Sixty percent to 90% of LHON
patients are men. The molecular basis for male
predominance is not known. An unknown X-linked
factor may interact with a LHON mtDNA mutation, but
linkage studies have failed to identify such a locus.
 DIFFERENTIAL DIAGNOSIS
 The diagnosis of LHON is usually made when the typical course
of visual loss occurs with a family history or with observation of
the typical acute fundus appearance in a patient or compatible
fundus changes in close maternal relatives. Now, it can be
diagnosed, by genetic analysis of a blood sample.

 Other forms of bilateral optic neuropathies with centrocecal

scotomas include demyelinating, toxic-nutritional optic
neuropathy (including tobacco—alcohol amblyopia), other types
of hereditary optic atrophy, occasionally glaucoma or ischemic
optic neuropathy, and only rarely compressive lesions.
 The dominant hereditary optic atrophy is also
characterized by centrocecal scotomas, dyschromatopsia,
and temporal pallor but is generally milder, usually
beginning insidiously between ages 4 and 8 years and
slowly progressing with visual acuity from 20/30 to no
worse than 20/200.
 Other forms of hereditary optic atrophy may occur as part of
complex neurologic disorders, including the lipidoses,
spinocerebellar ataxias, and polyneuropathies, including
Charcot-Marie-Tooth polyneuropathies. Autosomal-recessive
Behr complicated optic atrophy may be a transitional form
between the ataxias and isolated hereditary optic atrophy.
Other autosomal-recessive forms of optic atrophy include the
rare but severe simple optic atrophy beginning in early infancy
and that associated with diabetes insipidus, diabetes mellitus,
and hearing defect (DIDMOAD or Wolfram syndrome).
 A source of confusion in nomenclature is the severe
congenital visual loss known as Leber congenital
amaurosis. This is autosomal-recessive degeneration of
the retina rather than of the optic nerve and is usually
characterized by retinal arteriolar narrowing and retinal
pigmentary degeneration. Occasionally, the fundus
appears normal at first. The electroretinogram is
extinguished, whereas it is normal with optic
neuropathy.
 TREATMENT
 No treatment is of proven value, including corticosteroids, optic nerve
sheath fenestration, or craniotomy with lysis of optic nerve chiasm–
arachnoidal adhesions. Given the usual sequential involvement of the two
eyes, however, it may be possible to prevent loss of vision in the second
eye.
 Products that might enhance mitochondrial respiratory enzymes
(coenzyme Q10, idebenone, and thiamine) have been used but are not of
proven value. Antioxidants have also been used to reduce possible damage
from free radicals generated by the impaired oxidative metabolism.
According to consensus, tobacco and alcohol should be avoided in family
members at risk.
DEPLETION OF MTDNA

 Depletion of mtDNA is the other major defect of

intergenomic signalling, together with multiple mtDNA
deletions described above.
 As the name implies, this is a quantitative rather than
qualitative mtDNA abnormality, consisting of markedly
decreased levels of mtDNA in one or more tissues.

 Three syndromes stand out, all inherited as autosomal-

recessive traits: congenital myopathy, infantile
myopathy, and hepatopathy.
CONGENITAL MYOPATHY

 At or soon after birth, there is generalized weakness

(sometimes including PEO) with lactic acidosis and
markedly elevated serum creatine kinase. Some children also
have renal involvement with Fanconi syndrome.

 Muscle biopsy shows abundant RRF that are COX-negative.

Due to intractable respiratory failure, these children do not
live more than a few months. Southern blot analysis shows a
profound defect of mtDNA in muscle (less than 10% of
normal).
INFANTILE MYOPATHY
 In some children, weakness starts a little later but is usually
evident by age 1 year and may cause PEO.
 Progression is rapid, leading to flaccid paralysis, respiratory
insufficiency, and death within 1 or 2 more years.
 There is only partial mtDNA depletion in muscle (about 30% of
normal), with some fibers virtually devoid of mtDNA while
others look normal.
 Recognizing this entity is especially difficult because the
clinical presentation is nonspecific, lactic acidosis initially may
not be present and is generally mild, and early biopsies may
show nonspecific myopathic features rather than mitochondrial
proliferation with RRF (which do appear in later biopsies).
HEPATOPATHY

 Infants with severe mtDNA depletion in liver experience

intractable liver failure soon after birth and die within months.
Liver biopsy shows mitochondrial proliferation in hepatocytes,
and biochemical analysis shows very low activities of all
respiratory chain complexes containing mtDNA-encoded
subunits.

 It is likely that the genetic errors underlying the different

variants of mtDNA depletion all involve one or more nDNA-
encoded factors involved in the control of mtDNA replication.
These factors, however, are unknown.
ACQUIRED MTDNA DEPLETION

 An iatrogenic form of mtDNA depletion has been

recognized in patients with acquired immunodeficiency
syndrome in whom a mitochondrial myopathy developed
during treatment with zidovudine (Retrovir). The
myopathy is reversible upon discontinuation of the drug.
 MITOCHONDRIAL DISEASES WITH
MUTATIONS OF NDNA
 The vast majority of polypeptides in mitochondria are encoded in
nDNA therefore; nDNA mutations are likely to be the cause of
many mitochondrial diseases.
 Most of these disorders are autosomal-recessive and lack ragged-
red fibers (RRF) or other structural abnormalities of mitochondria
with some Exceptions.
 As a rule, symptoms begin in infancy or childhood, when the
metabolic demands of growth and development are the greatest.
 Clinical manifestations may be tissue-specific or generalized.
Diagnosis depends on the clinical syndrome plus biochemical and
DNA analyses.
 DISORDERS OF SUBSTRATE
TRANSPORT AND UTILIZATION
 Abnormalities of fatty acid oxidation provide examples of both
substrate transport defects and substrate utilization defects.
 It leads to periods of metabolic decompensation during fasting.
Liver, myocardium, and limb muscle are particularly vulnerable;
the brain is affected secondarily, a result of non-ketotic
hypoglycemia and increased fatty acid levels in serum.
 In infants, the disorder may mimic Reye syndrome and may cause
sudden infant death. The most common clinical disorders are a
Reye-like syndrome and DiMauro syndrome, manifested by
recurrent myoglobinuria.
 Deficiencies of the pyruvate dehydrogenase (PDH)
complex account for most cases of congenital lactic
acidosis. The disorder may be symptomatic in the
newborn period with hypotonia, convulsions, episodic
apnea, weak sucking, dysmorphic features, low
birthweight, failure to thrive, and coma. The distinctive
neuropathology includes cystic degeneration of
subcortical white matter, basal ganglia, and brainstem.
 Less common features include agenesis of the corpus
callosum, ectopic olivary nuclei, hydrocephalus, optic
atrophy, spongy degeneration, and other nonspecific
abnormalities. A similar phenotype may become
symptomatic later in life. In addition, girls and women
may manifest as carriers with mental retardation and
ataxia. In these milder forms, lactic acidosis may be
minimal.
DISORDERS OF THE CITRIC ACID CYCLE
 Congenital lactic acidosis can be due to one of several
enzymes of the Krebs cycle. Symptoms begin at birth or
early infancy with failure to thrive, hypotonia, seizures,
microcephaly, and optic atrophy. Diagnosis can be made
by analysis of urinary organic acids, with patterns
distinctive for each condition.
 DISORDERS OF THE RESPIRATORY CHAIN
 These conditions are another cause of congenital lactic acidosis.
In contrast to the previously cited autosomal or X-linked
conditions, respiratory enzyme disorders can result from
mutations of either nDNA or mtDNA.

 Pathogenic mutations in two nDNA-encoded subunits of complex

I have been identified. Coenzyme Q10 deficiency leads to an
encephalomyopathy with recurrent myoglobinuria and RRF that
responds to replacement therapy. Cytochrome-c oxidase (COX)
deficiency, as mentioned previously, may be associated with a
fatal infantile myopathy or a relatively benign condition.
 LEIGH SYNDROME
 The most common form of complex IV deficiency (COX) is
subacute necrotizing encephalomyelopathy (Leigh syndrome). The
condition was first described in a 7-month-old infant who showed
necrotizing lesions in the brainstem that resembled those of
Wernicke encephalopathy.
 The lesions are found in the periaqueductal region of the midbrain
and pons and in the medulla adjacent to the fourth ventricle. Other
parts of the central nervous system and peripheral nerves may also
be affected. The lesions are a combination of cell necrosis,
demyelination, and a vascular proliferation.

 The topology and vascular lesions are distinctive.

 Pathologically, the condition differs from Wernicke disease
because the hypothalamus and mammillary bodies are spared in
Leigh syndrome.
 The condition may be inherited in an autosomal-recessive, X-
linked, or maternal pattern. In adults, it is usually sporadic.
 Infants may develop normally for months; others may show signs
of encephalopathy in early infancy. Poor feeding, feeble crying,
and respiratory difficulty may be early symptoms. This is
followed by impaired vision and hearing, ataxia, limb weakness,
intellectual deterioration, and seizures. Nystagmus is common.
 In patients with later onset, there may be PEO, dystonia, or
ataxia. Once affected, the child may die in infancy or childhood;
some live until the third decade.
LABORATORY ABNORMALITIES
 CSF protein content is mildly elevated in 25% of patients.
 Lactate and pyruvate levels are almost always increased in
CSF and, to a lesser degree, in blood and urine.
 These findings and the histopathology lead to a search for an
abnormality of pyruvate metabolism.
 EEG changes and abnormal evoked responses are nonspecific.

 CT may show symmetric lucencies in basal ganglia and the

thalamus; the ventricles may be enlarged.
 MRI demonstrates the distinctive topography in detail.
 PATHOGENESIS
 The biochemical lesions are diverse but impair cerebral oxidative
metabolism. Affected enzymes include PDH, biotinidase, or
complex I, II, or IV (COX) of the respiratory chain.
 In most autosomally inherited cases, the mutations are in nDNA-
encoded subunits of the enzymes; however, in COX-deficient
Leigh syndrome, the first pathogenic mutations were identified in
SURF1, a putative assembly or maintenance factor for COX.
Point mutations of mtDNA in ATPase 6, have been associated
with maternally inherited Leigh syndrome.
 There are no RRF in any of these conditions. Leigh syndrome is
usually fatal before age 1 year when associated with the
neuropathy, ataxia, and retinitis pigmentosa (NARP) mutation or
PDH complex deficiency.
IMPAIRED MITOCHONDRIAL TRANSPORT

 In methylmalonic aciduria, a point mutation within the

mitochondrial targeting sequence of methylmalonyl-CoA
mutase led to failure of protein importation into mitochondria.
In hyperoxaluria type I, the enzyme is misdirected to the
mitochondrial matrix rather than its normal location, the
peroxisome.
Thank you