Leigh syndrome
Other names Juvenile subacute necrotizing
encephalomyelopathy.
Leigh syndrome (also called
Leigh disease and subacute necrotizing encephalomyelopathy) is an inherited
neurometabolic disorder that affects the central nervous system. It is named
after Archibald Denis Leigh, a British neuropsychiatrist who first described
the condition in 1951. Normal levels of thiamine, thiamine monophosphate, and
thiamine diphosphate are commonly found but there is a reduced or absent level of
thiamine triphosphate. This is thought to be caused by a blockage in the enzyme
thiamine-diphosphate kinase, and therefore treatment in some patients would be
to take thiamine triphosphate daily.
Leigh syndrome is
classically described as beginning in infancy and leading to death within a
span of several years. However, as more
cases are recognized, it is apparent that symptoms can emerge at any
age—including adolescence or adulthood—and patients can survive for many years
following diagnosis. Symptoms are often first seen after a triggering event
that taxes the body's energy production, such as an infection or surgery. The
general course of Leigh syndrome is one of episodic developmental regression
during times of metabolic stress. Some patients have progressively long periods
without disease progression while others develop progressive decline.
Infants with the syndrome
have symptoms that include diarrhea, vomiting, and dysphagia (trouble
swallowing or sucking), leading to a failure to thrive. Children with early Leigh disease also may
appear irritable and cry much more than healthy babies. Seizures are often
seen. Excess lactate may be seen in the urine, cerebrospinal fluid, and blood
of a child with Leigh syndrome.
As the disease progresses,
the muscular system is debilitated throughout the body, as the brain cannot
control the contraction of muscles. Hypotonia (low muscle tone and strength),
dystonia (involuntary, sustained muscle contraction), and ataxia (lack of
control over movement) are often seen in people with Leigh disease. The eyes
are particularly affected; the muscles that control the eyes become weak,
paralyzed, or uncontrollable in conditions called ophthalmoparesis (weakness or
paralysis) and nystagmus (involuntary eye movements). The heart and lungs can
also fail as are a result of Leigh disease. Hypertrophic cardiomyopathy
(thickening of part of the heart muscle) is also sometimes found and can cause
death. Asymmetric septal hypertrophy has
also been associated with Leigh syndrome. In children with Leigh syndrome
associated ventricular septal defects, caused by pyruvate dehydrogenase
deficiency, high forehead and large ears are seen; facial abnormalities are not
typical of Leigh syndrome.
However, respiratory failure
is the most common cause of death in people with Leigh syndrome. Other
neurological symptoms include peripheral neuropathy, loss of sensation in
extremities caused by damage to the peripheral nervous system.
Hypertrichosis is seen in
Leigh syndrome caused by mutations in the nuclear gene SURF1.
Genomics
Two healthy mitochondria
from mammalian lung tissue as shown by electron microscope. Mutations in mitochondrial DNA (mtDNA) and
over 30 genes in nuclear DNA (gene SURF1 and some COX assembly factors) have
been implicated in Leigh disease.
Mitochondria are essential
organelles in eukaryotic cells. Their function is to convert the potential
energy of glucose, amino acids, and fatty acids into adenosine triphosphate
(ATP) in a process called oxidative phosphorylation. Mitochondria carry their
own DNA, called mitochondrial DNA (mtDNA). The information stored in the mtDNA
is used to produce several of the enzymes essential to the production of ATP.
Disorders of oxidative
phosphorylation, the process by which cells produce their main energy source of
adenosine triphosphate (ATP), may be caused by mutations in either mtDNA or in
nuclear encoded genes. The latter account for the majority of Leigh disease,
although it is not always possible to identify the specific mutation
responsible for the condition in a particular individual. Four out of the five
protein complexes involved in oxidative phosphorylation are most commonly disrupted
in Leigh syndrome, either because of malformed protein or because of an error
in the assembly of these complexes. Regardless of the genetic basis, it results
in an inability of the complexes affected by the mutation to perform their role
in oxidative phosphorylation. In the case of Leigh disease, crucial cells in
the brain stem and basal ganglia are affected. This causes a chronic lack of
energy in the cells, which leads to cell death and in turn, affects the central
nervous system and inhibits motor functions. The heart and other muscles also
require a lot of energy and are affected by cell death caused by chronic energy
deficiencies in Leigh syndrome.
Between 20 and 25 percent of
Leigh syndrome cases are caused by mutations in mitochondrial DNA. The most
common of these mutations is found in 10 to 20 percent of Leigh syndrome and
occurs in MT-ATP6, a gene that codes for a protein in the last complex of the
oxidative phosphorylation chain, ATP synthase, an enzyme that directly
generates ATP. Without ATP synthase, the electron transport chain will not
produce any ATP.[1] The most common MT-ATP6 mutation found with Leigh syndrome
is a point mutation at nucleotide 8993 that changes a thymine to a guanine.
This and other point mutations associated with Leigh syndrome destabilize or
malform the protein complex and keep energy production down in affected cells.
Several mitochondrial genes involved in creating the first complex of the
oxidative phosphorylation chain can be implicated in a case of Leigh syndrome, including
genes MT-ND2, MT-ND3, MT-ND5, MT-ND6 and MT-CO1.
Mitochondrial DNA is passed
down matrilineally in a pattern called maternal inheritance — a mother can
transmit the genes for Leigh syndrome to both male and female children, but
fathers cannot pass down mitochondrial genes.
Nuclear DNA mutations
The autosomal recessive
pattern of inheritance seen in some cases of Leigh syndrome
Nuclear DNA comprises most
of the genome of an organism and in sexually reproducing organisms is inherited
from both parents, in contrast to mitochondrial DNA's maternal pattern of
inheritance. Leigh syndrome caused by nuclear DNA mutations is inherited in an
autosomal recessive pattern. This means that two copies of the mutated gene are
required to cause the disease, so two unaffected parents, each of whom carries
one mutant allele, can have an affected child if that child inherits the mutant
allele from both parents.
75 to 80 percent of Leigh
syndrome is caused by mutations in nuclear DNA; mutations affecting the
function or assembly of the fourth complex involved in oxidative
phosphorylation, cytochrome c oxidase (COX), cause most cases of Leigh disease.
Mutations in a gene called SURF1 (surfeit1) are the most common cause of this
subtype of Leigh syndrome. The protein that SURF1 codes for is terminated early
and therefore cannot perform its function, shepherding the subunits of COX
together into a functional protein complex. This results in a deficit of COX
protein, reducing the amount of energy produced by mitochondria.[1] SURF1 is
located on the long arm of chromosome 9 Another nuclear DNA mutation that
causes Leigh syndrome affects another protein complex in the mitochondria,
pyruvate dehydrogenase, which is an enzyme in the Link reaction pathway.[1]
Some types of SURF1 mutations cause a subtype of Leigh syndrome that has a
particularly late onset but similarly variable clinical course.
Other nuclear genes
associated with Leigh syndrome are located on chromosome 2 (BCS1L and NDUFA10);
chromosome 5 (SDHA, NDUFS4, NDUFAF2, and NDUFA2); chromosome 8 (NDUFAF6),
chromosome 10 (COX15); chromosome 11 (NDUFS3, NDUFS8, and FOXRED1); chromosome
12 (NDUFA9 and NDUFA12); and chromosome 19 (NDUFS7). Many of these genes affect
the first oxidative phosphorylation complex.
X-linked Leigh syndrome
The X-linked recessive
pattern of inheritance seen occasionally in cases of Leigh syndrome.
Leigh syndrome can also be
caused by deficiency of the pyruvate dehydrogenase complex (PDHC), most
commonly involving a PDHC subunit which is encoded by an X-linked gene (OMIM
308930). The neurological features of Leigh syndrome caused by PDHC deficiency
are indistinguishable from other forms. However, non-neurological features
(other than lactic acidosis) are not seen in PDHC deficiency.
X-linked recessive Leigh
syndrome affects male children far more often than female children because they
only have one copy of the X chromosome. Female children would need two copies
of the faulty gene to be affected by X-linked Leigh syndrome.
French Canadian Leigh
syndrome
The type of Leigh syndrome
found at a much higher rate in the Saguenay-Lac-Saint-Jean region of Quebec is
caused by a mutation in the LRPPRC gene, located on the small ('p') arm of chromosome
2. Both compound heterozygosity and
homozygous mutations have been observed in French Canadian Leigh syndrome. This
subtype of the disease was first described in 1993 in 34 children from the
region, all of whom had a severe deficiency in cytochrome c oxidase (COX), the
fourth complex in the mitochondrial electron transport chain. Though the
subunits of the protein found in affected cells were functional, they were not
properly assembled. The deficiency was found to be almost complete in brain and
liver tissues and substantial (approximately 50% of normal enzyme activity) in
fibroblasts (connective tissue cells) and skeletal muscle. Kidney and heart
tissues were found to not have a COX deficiency.
French Canadian Leigh
syndrome has similar symptoms to other types of Leigh syndrome. The age of
onset is, on average, 5 months and the median age of death is 1 year and 7
months. Children with the disease are developmentally delayed, have mildly
dysmorphic facial features, including hypoplasia of the midface and wide nasal
bridge, chronic metabolic acidosis, and hypotonia (decreased muscular
strength). Other symptoms include tachypnea (unusually quick breathing rate),
poor sucking ability, hypoglycemia (low blood sugar), and tremors. Severe,
sudden metabolic acidosis is a common cause of mortality.
Estimates of the rate of
genetic carriers in the Saguenay-Lac-Saint-Jean region range from 1 in 23 to 1
in 28; the number of children born with the disease has been estimated at 1 in
2063 to 1 in 2473 live births. Genealogical studies suggest that the
responsible mutation was introduced to the region by early European settlers.
Pathophysiology
The characteristic symptoms
of Leigh syndrome are at least partially caused by bilateral, focal lesions in
the brainstem, basal ganglia, cerebellum, and other regions of the brain. The
lesions take on different forms, including areas of demyelination, spongiosis,
gliosis, necrosis, and capillary proliferation. Demyelination is the loss of
the myelin sheath around the axons of neurons, inhibiting their ability to
communicate with other neurons. The brain stem is involved in maintaining basic
life functions such as breathing, swallowing, and circulation; the basal
ganglia and cerebellum control movement and balance. Damage to these areas
therefore results in the major symptoms of Leigh syndrome—loss of control over
functions controlled by these areas.
The lactic acidosis
sometimes associated with Leigh syndrome is caused by the buildup of pyruvate,
which is unable to be processed in individuals with certain types of oxidative
phosphorylation deficiencies. The pyruvate is either converted into alanine via
alanine aminotransferase or converted into lactic acid by lactate
dehydrogenase; both of these substances can then build up in the body.
Diagnosis
Leigh syndrome is suggested
by clinical findings and confirmed with laboratory and genetic testing.
Clinical findings
Dystonia, nystagmus, and
problems with the autonomic nervous system suggest damage to the basal ganglia
and brain stem potentially caused by Leigh syndrome. Other symptoms are also
indicative of brain damage, such as hypertrichosis and neurologically caused
deafness. Laboratory findings of lactic acidosis or acidemia and
hyperalaninemia (elevated levels of alanine in the blood) can also suggest
Leigh syndrome. Assessing the level of organic acids in urine can also indicate
a dysfunction in the metabolic pathway.
Differential
diagnosis
Other diseases can have a
similar clinical presentation to Leigh syndrome; excluding other causes of
similar clinical symptoms is often a first step to diagnosing Leigh syndrome.
Conditions that can appear similar to Leigh disease include perinatal asphyxia,
kernicterus, carbon monoxide poisoning, methanol toxicity, thiamine deficiency,
Wilson's disease, biotin-responsive basal ganglia disease, and some forms of
encephalitis. Perinatal asphyxia can cause bilateral ganglial lesions and
damage to the thalamus, which are similar to the signs seen with Leigh
syndrome. When hyperbilirubinemia is not treated with phototherapy, the
bilirubin can accumulate in the basal ganglia and cause lesions similar to
those seen in Leigh syndrome. This is not common since the advent of
phototherapy.
Treatment
Succinic acid has been
studied, and shown effective for both Leigh syndrome, and MELAS syndrome. A
low-carbohydrate diet may be followed if a gene on the X chromosome is
implicated in an individual's Leigh syndrome. Thiamine (vitamin B1) may be
given if pyruvate dehydrogenase deficiency is known or suspected. The symptoms
of lactic acidosis are treated by supplementing the diet with sodium
bicarbonate (baking soda) or sodium citrate, but these substances do not treat
the cause of Leigh syndrome. Dichloroacetate may also be effective in treating
Leigh syndrome-associated lactic acidosis; research is ongoing on this
substance. Coenzyme Q10 supplements have
been seen to improve symptoms in some cases.
Clinical trials of the drug
EPI-743 for Leigh syndrome are ongoing.
In 2016, John Zhang and his
team at New Hope Fertility Center in New York, USA, performed a spindle
transfer mitochondrial donation technique on a mother in Mexico who was at risk
of producing a baby with Leigh disease. A healthy boy was born on 6 April 2016.
However, it is not yet certain if the technique is completely reliable and
safe.
Prognosis
Different genetic causes and
types of Leigh syndrome have different prognoses, though all are poor. The most
severe forms of the disease, caused by a full deficiency in one of the affected
proteins, cause death at a few years of age. If the deficiency is not complete,
the prognosis is somewhat better and an affected child is expected to survive
6–7 years, and in rare cases, to their teenage years.
Epidemiology
Leigh syndrome occurs in at
least 1 of 40,000 live births, though certain populations have much higher
rates. In the Saguenay-Lac-Saint-Jean region of central Quebec, Leigh syndrome
occurs at a rate of 1 in 2000 newborns.
History
Leigh syndrome was first
described by Denis Leigh in 1951 and distinguished from similar Wernicke's
encephalopathy in 1954. In 1968, the
disease's link with mitochondrial activity was first ascertained, though the
mutations in cytochrome c oxidase and other electron transport chain proteins
were not discovered until 1977.
Jan Ricks Jennings, MHA,
LFACHE
Senior Consultant
Senior Management Resources, LLC
JanJenningsBlog.Blogspot.com
412.913.0636 Cell
724.733.0509 Office
December 3, 2021
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