+++
Disorders Due
to Mtdna Mutations
++
Among the maternally inherited encephalomyopathies, four syndromes
are more common. The first is MELAS (mitochondrial encephalomyopathy,
lactic acidosis, and strokelike episodes), which usually presents
in children or young adults after normal early development. Symptoms
include recurrent vomiting; migrainelike headaches; and strokelike
episodes causing cortical blindness, hemiparesis, or hemianopia. MRI
of the brain shows “infarcts” that do not correspond
to the distribution of major vessels, raising the question of whether
the strokes are vascular or metabolic in nature. The most common
mtDNA mutation is A3243G in the tRNALeu(UUR) gene,
but about a dozen other mutations have been associated with MELAS.11
++
The second syndrome is MERRF (myoclonus epilepsy with ragged-red
fibers), characterized by myoclonus, seizures, mitochondrial myopathy,
and cerebellar ataxia. Less common signs include dementia, hearing
loss, peripheral neuropathy, and multiple lipomas. The typical mtDNA
mutation in MERRF is A8344G in the tRNALys gene,
but other mutations in the same gene have been reported.11
++
The third syndrome comes in two subtypes. The first is NARP (neuropathy,
ataxia, retinitis pigmentosa), which usually affects young adults
and causes retinitis pigmentosa, dementia, seizures, ataxia, proximal
weakness, and sensory neuropathy. The second is a maternally inherited
form of Leigh syndrome (MILS). NARP and MILS can affect maternal
relatives in the same family.
++
The fourth syndrome, Leber’s hereditary optic neuropathy
(LHON), is characterized by acute or subacute loss of vision in
young adults, more frequently males, due to bilateral optic atrophy.
Mutations in three genes of complex I (ND genes) have been associated with
LHON: G11778A in ND4, G3460A in ND1, and T14484C
in ND6.12
++
Three sporadic conditions are associated with mtDNA single deletions:
Kearns-Sayre syndrome (KSS), progressive external ophthalmoplegia
(PEO), and Pearson syndrome (PS). KSS is a multisystem disorder
with onset before age 20; symptoms include impaired eye movements
(PEO), pigmentary retinopathy, and heart block. Frequent additional
signs include ataxia, dementia, and endocrine problems (diabetes
mellitus, short stature, hypoparathyroidism). Lactic acidosis and
markedly elevated cerebrospinal fluid (CSF) protein (over 100 mg/dL)
are typical laboratory abnormalities.13
++
PEO is a relatively benign disorder characterized by ptosis,
PEO, and proximal myopathy. Sideroblastic anemia and exocrine pancreatic
dysfunction characterize Pearson syndrome, a usually fatal disorder
of infancy.
++
Two mtDNA genes encoding subunits of complex I (ND3 and ND5)
have to be considered when confronted with patients with Leigh syndrome
(LS) or MELAS, even if maternal inheritance is missing or not obvious,
if ragged-red fibers are not abundant, and if lactic acidosis is
not severe.14
++
It is often stated that any patient having multiple organ involvement
and evidence of maternal inheritance should be suspected of harboring
a pathogenic mtDNA mutation until proven otherwise. While this rule
of thumb has some practical value, it is also important to remember
that the reverse is not true—that is, patients with involvement
of a single tissue and no evidence of maternal inheritance can still
have pathogenic mutations of mtDNA. This is especially true for skeletal
muscle. We have mentioned previously how isolated myopathy with
PEO can be due to single large-scale mtDNA deletions. Isolated myopathy
without PEO has been associated with point mutations in several
tRNA genes.15 In addition, exercise intolerance,
myalgia, and myoglobinuria can be the sole presentation of respiratory
chain defects due to mutations in protein-coding genes.15
+++
Disorders Due
to Mutations in Ndna
++
“Direct hits” refer to mutations in genes encoding
subunits of the respiratory chain. Until very recently, only pathogenic
mutations in subunit A of complex II and in a handful of complex
I subunits have been associated with disease, usually LS and leukoencephalopathy (Fig. 158-2). A mutation in the ubiquitously expressed
COX6b1 subunit has now been associated with cystic leukoencephalopathy, the
first direct hit affecting complex IV.16
++
“Indirect hits” are mutations that alter proteins
that are not subunits of the respiratory chain (RC) but that are
indispensable for the correct assembly of RC complexes. These have
been described for all complexes except complex II (Fig.
158-2). They cause a variety of multisystemic syndromes, often characterized
by encephalopathy (Leigh syndrome [LS] or LS-like)
and the selective involvement of another organ or tissue, which
can offer a diagnostic clue (eg, the cardiopathy in patients with
SCO2 mutations). For practitioners, mutations in the SURF1 gene
are especially important, because they are the most common causes
of COX-deficient LS, which in turn is one of the most common forms
of LS. Neuroradiological LS-like lesions are also present in infants
with congenital lactic acidosis; renal tubulopathy; liver failure
with hepatosiderosis; and encephalopathy with psychomotor retardation,
a devastating syndrome labeled GRACILE (growth retardation, aminoaciduria,
cholestasis, iron overload, lactacidosis, and early death) due to
mutations in an assembly protein (BCS1L) for complex III (Fig. 158-2).
++
A recent addition to this group of disorders is coenzyme Q10
(CoQ10) deficiency, which can cause four major autosomal recessive syndromes.
The first is a predominantly myopathic form, with exercise intolerance
and recurrent myoglobinuria, as well as central nervous system involvement,
with seizures, ataxia, or mental retardation. The second is a predominantly
ataxic form, mimicking spinocerebellar ataxia, with prominent cerebellar
atrophy and a variety of inconsistently associated features, including
seizures, mental retardation, pyramidal signs, and peripheral neuropathy.
The third syndrome is a pure myopathy, with exercise intolerance
and proximal limb weakness. The fourth presentation is a mitochondrial
encephalomyopathy associated with nephrosis: This association is
an important clue to the correct diagnosis, because other RC disorders
are often associated with renal tubular dysfunction but rarely with glomerular
disease. As has long been suspected, mutations in several genes
directly or indirectly involved in CoQ10 biosynthesis have been
identified,17-19 and more will undoubtedly be discovered.
Diagnosing CoQ10 deficiency has practical importance, because many
patients respond, some dramatically, to CoQ10 supplementation.
+++
Disorders Due
to Defects in Intergenomic Signaling
++
In these disorders, mutations in nuclear genes cause qualitatively
(multiple deletions) or quantitatively (depletion) alterations of
mtDNA. Multiple deletions and depletion often coexist, because they
are commonly due to altered control of the intramitochondrial nucleotide
pool, which is essential for maintaining mtDNA.
++
The most common clinical feature of patients with multiple mtDNA
deletions in skeletal muscle is progressive external
ophthalmoplegia (PEO), which can be inherited as an autosomal dominant
or recessive trait (Table 158-2). Autosomal
dominant PEO has been associated with mutations in four genes that
encode proteins involved in mitochondrial nucleotide metabolism: ANT1,
encoding an isoform of the adenine nucleotide transporter; PEO1
(formerly known as Twinkle), encoding a helicase;
and POLG, encoding the mitochondrial g polymerase. Autosomal dominant
PEO with visual and hearing loss can also be due to mutations in OPA1,
which encodes a dynamin-related GTPase essential for mitochondrial
motility and is more often associated with dominant optic atrophy
(DOA), the Mendelian counterpart of the maternally inherited Leber
hereditary optic neuropathy (see above).
++
++
Mutations in POLG are especially interesting for many reasons.
First, they appear to be the most common causes of Mendelian PEO.
Second, they can cause both dominant and recessive forms of PEO.
Third, they have been associated with a striking variety of clinical
features, including sensory ataxic neuropathy, dysarthria, and opthalmoplegia
(SANDO), mitochondrial recessive ataxic syndrome (MIRAS), deafness,
hypogonadism, seizures, myoclonus, affective disorders, and gastrointestinal dysmotility.
Fourth, and crucially important for pediatricians, POLG mutations
are the most common causes of Alpers syndrome, a disorder of childhood
characterized by liver insufficiency and gray matter involvement (poliodystrophy)
and accompanied by mtDNA depletion (see below). This clinical heterogeneity
is largely explained by the complexity of the enzyme, which comprises
an exonuclease domain with proofreading function, and a polymerase
domain with mtDNA-replicating function, connected by a “linker” domain.20 A fifth
noteworthy feature of POLG mutations is that they can also affect
the gene (POLG2) encoding the accessory rather than the catalytic subunit
and can cause autosomal recessive PEO.21
++
A special autosomal recessive form of PEO that combines multiple
deletions and depletion of mtDNA in muscle is MNGIE (mitochondrial neurogastrointestinal
encephalomyopathy), a disorder of young adults characterized by
PEO, peripheral neuropathy, leukoencephalopathy, and severe gastrointestinal
dysmotility leading to cachexia and early death. The gene (TYMP) responsible
for MNGIE encodes the enzyme thymidine phosphorylase (TP): although
extramitochondrial, mutated TP alters the homeostasis of the intramitochondrial
nucleotide pool.22
++
Two main syndromes have been associated with mtDNA depletion,
one dominated by myopathy and the other by liver and brain dysfunction.9 Myopathic
mtDNA depletion can be fatal in infancy or later in childhood due
to respiratory failure, but it may also affect the CNS and mimic spinal
muscular atrophy.23 The hepatocerebral form of
mtDNA depletion usually manifests in infancy or early childhood
and has been attributed to mutations in POLG (see above), DGUOK (encoding
deoxyguanosine kinase), SUCLA2 (encoding the b subunit of succinyl-CoA-synthase [SCS-A]),
SUCLG1 (encoding the a subunit of SCS-A), or RRM2B (encoding a p53-controlled
ribonucleotide reductase subunit [p53R2]). Autosomal
recessive hepatocerebral syndrome was also attributed to mutations
in two genes that are not directly involved in nucleotide metabolism:
MPV17 (encoding an inner mitochondrial membrane protein)24 and
PEO125 (mutations in this gene can also cause autosomal dominant
PEO and multiple mtDNA deletions, as described above). A homozygous
mutation (R50Q) in MPV17 causes a distinctive severe disorder dominated
by peripheral neuropathy and liver failure in children of the Navajo
Nation (Navajo neurohepatopathy, NNH).26
++
Defects of mtDNA translation have been associated with mutations
in various nucleus-encoded factors needed for mitochondrial protein
synthesis, including mitoribosomal proteins (MRPS16; MRPS22, resulting
in multisystemic disease); mRNA-specific translation factors (LRPPRC,
resulting in Leigh syndrome, Canadian type); general translation factors
(EFG1, resulting in hepatocerebral syndrome; TSFM, resulting in
encephalomyopathy or cardiomyopathy); tRNA processing and base-modification
enzymes (PUS1, resulting in myopathy, lactic acidosis, and sideroblastic
anemia [MLASA]); and aminoacyl-tRNA synthetases (Arg-tRNA
synthetase, resulting in pontocerebellar hypoplasia; Asp-tRNA synthetase,
resulting in leukoencephalopathy; Gly-tRNA synthetase, resulting
in Charcot-Marie-Tooth type 2 [CMT2], or in spinal
muscular atrophy type V [SMA V]).27 As
rare as these disorders are—at least until now—they
should be considered in the differential diagnosis of more common
pediatric neurology disorders, such as LS, leukodystrophy, and hepatocerebral
syndrome.
+++
Defects of the
Lipid Milieu
++
The inner mitochondrial membrane (IMM) is essential for respiratory
chain (RC) function. Thus, alterations of the phospholipid composition
of the MIM may result in RC defects. This appears to be the case
of Barth syndrome, an X-linked disorder of childhood manifesting
as myopathy, cardiomyopathy, leucopenia, and growth retardation.
The gene responsible for Barth syndrome (initially dubbed G4.5 and now
called TAZ) encodes a family of proteins called tafazzins, which
share conserved regions with acyltransferases of diverse organisms.
It has been documented in Barth syndrome that mutant tafazzins lead
to impaired or altered synthesis of cardiolipin, the major phospholipids
component of the IMM, which may impair the function of multiple
respiratory chain complexes, including their ability to assemble
in “supercomplexes.”28
+++
Defects of Mitochondrial Dynamics
++
In most tissues, including the CNS, mitochondria are extremely
dynamic organelles, which move constantly, split by fission, and
fuse with one another: This gives mitochondria the ability to travel
very long distances (eg, from the soma of a spinal cord motor neuron
to the neuromuscular junction of a motor nerve in the toe), to spread
energy in different areas of the cell, and to regulate their survival
through mitophagy.29
++
Although the respiratory chain may be affected only indirectly,
disorders of mitochondrial dynamics are being described with increased frequency
and generally affect the optic nerve (dominant optic atrophy due
to mutations in OPA1), the peripheral nerve (CMT type 2 due to mutations
in MFN2), or the long tracts in the CNS (hereditary spastic paraplegia [HSP]). There
is also good evidence that defects of mitochondrial motility may
play a role in the pathogenesis of common neurodegenerative disorders,30 but
this is beyond the scope of this chapter.