Leigh Syndrome
1
Republic of the Philippines
CARAGA STATE UNIVERSITY
SENIOR HIGHSCHOOL
P.O. Box 165, Ampayon, 8600 Butuan City, Philippines
Tel. No. (085) 342 6251
www.carsu.edu.ph
Leigh Syndrome
General Biology 2 - Galilei
Mr. Florence Jhun F. Almadin
Gillie Mae C. Dadios
January 29, 2018
2
Leigh Syndrome
INTRODUCTION
The incidence of genetic brain disorders has intensely increased over the past years.
Although the cases of genetic brain diseases are now more frequent than during the first half of
the century and rising modern techniques are now applied, some genetic brain diseases are still
difficult to diagnose clinically. (DiMauro S. et al. 2013).
Numerous studies indicate that genetic brain disorders affect the development and function
of the brain. Leigh syndrome, a rare inherited neurometabolic disorder affects the central nervous
system of the brain. Denis Leigh, a British neuropathologist, first described Leigh syndrome in
1951on a postmortem pathologic evaluation of a 7-month-old infant who presented with severe
encephalopathy and respiratory difficulties. According on his evaluation, the syndrome is caused
by mutations in mitochondrial DNA, nuclear DNA or by deficiencies of an enzyme called pyruvate
dehydrogenase. As of 2013, Leigh syndrome can be caused by mutations in more than 35 different
genes of both nuclear and mitochondria origin, involving all five respiratory chain complexes
(Ruhoy and Saneto, 2014).
On this study, the researcher would discuss the specific symptoms of Leigh’s syndrome,
how it affects the functions of the brain, its frequency, genetic changes, inheritance pattern, the
diagnosis and treatments on how to treat Leigh syndrome.
PATHOPHYSIOLOGY
Leigh syndrome is a severe, progressive, multisystem, neurodegenerative disorder. The
progressive disorder begins in infants between the ages of 3 months and 2 years old. The
syndrome is acquired by mutations in one of more than 75 different genes. In humans, most genes
are found in DNA specifically in the cell's nucleus, called nuclear DNA. However, some genes are
10/6/2021
3
Leigh Syndrome
found in DNA on specialized structures in the cell called mitochondria which type of DNA is
known as mitochondrial DNA (mtDNA). Most people with Leigh syndrome have a mutation in
nuclear DNA, but about 20 percent is also accounted to have a mutation in mtDNA (Genetic
Testing Registry, n.d).
Ahya et al. (2010) explained that in Leigh disease, genetic mutations in mitochondrial DNA
interfere with the energy production process that run the cells in an area of the brain that plays a
role in motor movements. Mitochondria uses oxygen to convert the energy from food which in
turn is used through a process called oxidative phosphorylation. In the process, five protein
complexes, made up of several proteins each are involved named complex I, II, III, IV, and V.
Many of the gene mutations associated with Leigh syndrome affects proteins in these complexes
which disrupt their assembly. These mutations reduce or eliminate the activity of one or more of
these complexes which can lead in the development of the syndrome that results from a chronic
lack of energy in these cells, which consequently affects the central nervous system and causes
progressive degeneration of motor functions (Ahya et al. 2010).
The most common cause of Leigh syndrome is the disruption of complex I, also called
NADH:ubiquinone oxidoreductase, accounting for nearly one third of cases of the condition. At
least 25 genes involved in the formation of complex I are found in either nuclear or mitochondrial
DNA have been associated with the syndrome (Ahya et al. 2010).
Complex II is the smallest complex of the respiratory chain. Mutations in complex II are
relatively rare, as are documented causes of mitochondrial disorders in general. It functions to
oxidize FADH2, transferring electrons to ubiquinone in the electron transport chain. These
reactions are based on the functions of catalytic subunits A and B. More than ten different
autosomal recessive pathogenic mutations in A have been described that cause mitochondrial
10/6/2021
4
Leigh Syndrome
disorders. Some patients described with complex II deficiency had the clinical phenotype and
cerebral MRI findings consistent with Leigh syndrome (Cameron et al. 2013).
Disruption of complex IV, also called cytochrome c oxidase or COX, is also a common
cause of Leigh syndrome, underlying approximately 15 percent of cases. One of the most
frequently mutated genes in Leigh syndrome is SURF1 which is found in nuclear DNA that
provides instructions for making a protein that helps assemble the COX protein complex (complex
IV). The complex, which is involved in the last step of electron transfer in oxidative
phosphorylation, provides the energy that will be used in the next step of the process to generate
ATP. Mutations in the SURF1gene typically lead to an abnormally short SURF1 protein that is
broken down in cells, resulting in the absence of functional SURF1 protein. The loss of SURF1
protein reduces the formation of normal COX complexes, which impairs mitochondrial energy
production (Ahya et al. 2010).
Ahya et al. (2010) added that the most common mtDNA mutation in Leigh
syndrome affects the MT-ATP6 gene, which provides instructions for making a piece of complex
V, also known as the ATP synthase protein complex. Using the energy provided by the other
protein complexes, the ATP synthase complex generates ATP. MT-ATP6 gene mutations, found
in approximately 10 percent of people with Leigh syndrome, block the generation of ATP. Other
mtDNA mutations associated with Leigh syndrome decrease the activity of other oxidative
phosphorylation protein complexes or lead to reduced formation of mitochondrial proteins, all of
which mutilates energy production (Ahya et al. 2010).
Ahya et al. (2010) also pointed out that impaired oxidative phosphorylation can lead to cell
death because of decreased energy available in the cell. Certain tissues that require large amounts
of energy, such as the brain, muscles, and heart is sensitive to declines in cellular energy. Cell
10/6/2021
5
Leigh Syndrome
death in the brain likely can cause the characteristic lesions seen in Leigh syndrome, which
contribute to the signs and symptoms of the condition. Cell death in other sensitive tissues may
also contribute to the features of Leigh syndrome (Ahya et al. 2010).
CLINICAL MANIFESTATION
The etiology of Leigh syndrome is caused by nuclear DNA mutations that are inherited in
a Mendelian fashion, with autosomal recessive and X-linked inheritance (Bannwarth et al. 2013).
Lopez et al. (2006) also reported that mutations in other genes involved in mitochondrial function,
the tricarboxylic acid (TCA) cycle, and coenzyme Q10 may also induce the syndrome.
The signs and symptoms of the syndrome are instigated in part by patches of damaged
tissue (lesions) that develop in the brains of people with their espoused condition. A medical
procedure called magnetic resonance imaging (MRI) reveals characteristic lesions in
certain regions of the brain. The regions include the basal ganglia, which help control movement;
the cerebellum, which controls the ability to balance and coordinates movement; and the
brainstem, which connects the brain to the spinal cord and controls functions such as swallowing
and breathing. The brain lesions are often accompanied by loss of the myelin coating around
nerves (demyelination), which reduces the ability of the nerves to activate muscles used for
movement or relay sensory information from the rest of the body back to the brain (Genetic Testing
Registry, n.d)
Sofou et al. (2014) stated people who suffers from Leigh disease usually experienced the
symptoms from the neonatal period through adulthood but is typically between age three and 12
months, often following a viral infection. The earliest signs are characterized by progressive loss
of mental and movement abilities (psychomotor regression) and poor sucking ability. These
10/6/2021
6
Leigh Syndrome
symptoms may be accompanied by loss of appetite, difficulty swallowing (dysphagia) vomiting,
irritability, continuous crying, and seizures. As the disorder progresses, symptoms may also
include generalized weakness, lack of muscle tone, and episodes of lactic acidosis, which can lead
to impairment of respiratory and kidney function and typically results in death within two to three
years (Sofou et al. 2014).
Severe muscle and movement problems are also common in Leigh syndrome. Affected
individuals may develop weak muscle tone (hypotonia), involuntary muscle contractions
(dystonia) and problems with movement and balance (ataxia). Loss of sensation and weakness in
the limbs (peripheral neuropathy), common in people with Leigh syndrome, may also make
movement difficult (Genetic Testing Registry, n.d).
On the ophthalmologic findings of Santorelli et al. (1993) on their study, symptoms also
include optic atrophy or degeneration of the nerves that carry information from the eyes to
the brain, involuntary eye movements (nystagmus) and paralysis of the muscles that move the eyes
(ophthalmoparesis). Moreover, pigmentary retinopathy occurs in up to 40% of individuals with a
mtDNA 8993 pathogenic variant (Santorelli et al. 1993).
Severe breathing problems are common too, and can worsen until they cause acute
respiratory failure. Some affected individuals develop hypertrophic cardiomyopathy, which is the
thickening of a heart muscle that forces the heart to work harder to pump blood, hepatomegaly or
liver failure and renal tubulopathy or diffuse glomerulocystic kidney damage manifestations
(Wang et al. 2008). Leigh syndrome as a whole is the most phenotypically heterogeneous
mitochondrial disease, with more than 200 associated phenotypes (Rahman et al. 2017).
10/6/2021
7
Leigh Syndrome
In view of the inconsistent nature of the disease and the notable absence of a specific
biochemical or molecular defect, definitive diagnoses has relied on demonstration of the typical
pattern of brain lesions on MRI, autopsy and clinical findings (Blok et al. 1996). Furthermore,
neurologic, ophthalmologic, and cardiologic evaluations at regular intervals of the patients are
conducted to monitor progression and appearance of new symptoms (Rahman et al. 2017).
MEDICAL MANAGEMENT
On understanding the molecular mechanisms underlying mitochondrial disease, there is no
specific treatment for Leigh syndrome. However, available therapeutic approaches are extremely
limited (Catteruccia et al. 2012).
The aim of symptomatic treatment is to manage symptoms and to improve the energy state
by increasing and optimizing ATP production and lowering lactate levels. In Leigh syndrome, the
treatment is accomplished by the elimination of noxious metabolics and the supply of oxygen
radical scavengers (Catteruccia et al. 2012).
With regards to this, Rahman J., Rahman S. and Thorburn (2017) suggested supportive
treatments which include use of sodium bicarbonate or sodium citrate for acute exacerbations of
acidosis and antiepileptic drugs for seizures. Dystonia is treated with benzhexol, baclofen,
tetrabenazine, and gabapentin alone or in combination, or by injections of botulinum toxin.
Anticongestive therapy may be required for cardiomyopathy. Regular nutritional assessment of
daily caloric intake and adequacy of diet and psychological support for the affected individual and
family are essential. Physiotherapy and pharmacotherapy for neuromuscular concerns, appropriate
feeding methods to prevent malnutrition and aspiration, and aggressive treatment of fever and
10/6/2021
8
Leigh Syndrome
infections are further important treatment parameters to hopefully improve quality of life and
decrease stress on both the patient and the family (Rahman J., Rahman S. and Thorburn 2017).
CONCLUSION
In summary, Leigh syndrome is an inherited mitochondrial disease that significantly alter
the brain’s function and utility, bringing forth anticipated demise to the patients who were
diagnosed from the syndrome. It can be fully grasp that the aftermath of the disease is unfavorably
severe and cannot be cured completely for prenatal diagnosis and efforts for prevention are still in
the nascent stage. With appropriate investigations, accurate diagnosis and prompt institution of
adequate supportive therapy, symptomatic amelioration can be achieved, which thereby will add
life to the limited years of survival of the children who suffers from the syndrome. Further research
aimed at prenatal identification of the responsible mutations and prevention of the disease is
necessary and imperative.
10/6/2021
9
Leigh Syndrome
REFERENCES
Ahya K., Kalakoti P., Shrikhande D., Singh G & Syed M. (2010). A rare mitochondrial disorder:
Leigh syndrome – a case report. Ital J Pediatr. Retrieved from https://doi.org/.
Bannwarth S., Lebre A. and Procaccio V. et al. (2013). Prevalence of rare mitochondrial DNA mu
tations in mitochondrial disorders. J Med Genet.
Cameron J., Jain-Ghai S., Maawali A. et al. (2013). Complex II deficiency – a case report and re
view of the literature. Am J Med Genet A.
Catteruccia M., Martinelli D. and Piemonte F. et al. (2012). EPI-743 reverses the progression of
the pediatric mitochondrial disease--genetically defined Leigh Syndrome. Mol Genet Metab.
DiMauro S., Schon E., Carelli V., Hirano M. (2013). The clinical maze of mitochondria neurology.
Nat Rev Neurol.
Genetic Testing Registry (n.d). Leigh Syndrome (mtDNA mutation). Retrieved from https://www.
ncbi.nlm.nih.gov/gtr/conditions/CN230159/.
López L., Schuelke M., Quinzii C. et al. (2006). Leigh syndrome with nephropathy and CoQ10
deficiency due to decaprenyl diphosphate synthase subunit 2 (PDSS2) mutations. Am J Hum
Genet.
Rahman J., Rahman S. and Thorburn D. (2017). Mitochondrial DNA-Associated Leigh Syndrome.
Retrieved from https://www.ncbi.nlm.nih.gov/books/NBK1173/.
Rahman S., Blok R. and Dahl H. et al. (1996). Leigh syndrome: clinical features and DNA abnor
malities. Ann Neurol.
Ruhoy, I., & Saneto S. (2014, November 13). The genetics of Leigh syndrome and its implications
for clinical practice and risk management. Retrieved from 10.2147/TACG.S46176.
Santorelli F., DeVivo D., DiMauro S., Macaya A. and Shanske S. (1993). The mutation at nt 8993
of mitochondrial DNA is a common cause of Leigh’s syndrome. Ann Neurol.
Sofou K, De Coo I., Isohanni P. et al. (2014). A multicenter study on Leigh syndrome: disease cour
se and predictors of survival. Orphanet J Rare Dis.
Wang J., Craigen W., El-Hattab A. Lee I., , Li F., Weng S. and Wong L. (2012). SURF1-associated
leigh syndrome: a case series and novel mutations. Hum Mutat.
10/6/2021
10
Leigh Syndrome
Title: Mitochondrial DNA-Associated Leigh Syndrome
Author: David R Thorburn, PhD, FHGSA, FFSc(RCPA), Joyeeta Rahman, BSc, and Shamima
Rahman, PhD, FRCP, FRCPCH.
Abstract:
Mitochondrial DNA (mtDNA)-associated Leigh syndrome is a part of a continuum of progressive
neurodegenerative disorders caused by abnormalities of mitochondrial energy generation. Leigh
syndrome (or subacute necrotizing encephalomyelopathy) is characterized by onset of symptoms
typically between ages three and 12 months, often following a viral infection. Decompensation
(often with elevated lactate levels in blood and/or CSF) during an intercurrent illness is typically
associated with psychomotor retardation or regression. Neurologic features include hypotonia,
spasticity, movement disorders (including chorea), cerebellar ataxia, and peripheral neuropathy.
Extraneurologic manifestations may include hypertrophic cardiomyopathy. About 50%
of affected individuals die by age three years, most often as a result of respiratory or cardiac
failure.
Keywords: cerebellar ataxia; hypertrophic cardiomyopathy; mitochondrial energy; psychomotor
retardation; respiratory failure.
Leigh Syndrome (mtDNA mutation)
Author: Genetic Testing Registry
Abstract:
Leigh syndrome is a severe neurological disorder that usually becomes apparent in the first year
of life. This condition is characterized by progressive loss of mental and movement abilities
(psychomotor regression) and typically results in death within two to three years, usually due to
respiratory failure. A small number of individuals do not develop symptoms until adulthood or
have symptoms that worsen more slowly. The first signs of Leigh syndrome seen in infancy are
usually vomiting, diarrhea, and difficulty swallowing (dysphagia), which disrupts eating. These
problems often result in an inability to grow and gain weight at the expected rate (failure to thrive).
Severe muscle and movement problems are common in Leigh syndrome. Affected individuals may
develop weak muscle tone (hypotonia), involuntary muscle contractions (dystonia), and problems
with movement and balance (ataxia). Loss of sensation and weakness in the limbs (peripheral
neuropathy), common in people with Leigh syndrome, may also make movement difficult. Several
other features may occur in people with Leigh syndrome. Many individuals with this condition
develop weakness or paralysis of the muscles that move the eyes (ophthalmoparesis); rapid,
involuntary eye movements (nystagmus); or degeneration of the nerves that carry information from
the eyes to the brain (optic atrophy). Severe breathing problems are common, and these problems
can worsen until they cause acute respiratory failure. Some affected individuals develop
hypertrophic cardiomyopathy, which is a thickening of the heart muscle that forces the heart to
work harder to pump blood. In addition, a substance called lactate can build up in the body, and
excessive amounts are often found in the blood, urine, or the fluid that surrounds and protects the
brain and spinal cord (cerebrospinal fluid) of people with Leigh syndrome. The signs and
symptoms of Leigh syndrome are caused in part by patches of damaged tissue (lesions) that
develop in the brains of people with this condition. A medical procedure called magnetic resonance
imaging (MRI) reveals characteristic lesions in certain regions of the brain. These regions include
10/6/2021
11
Leigh Syndrome
the basal ganglia, which help control movement; the cerebellum, which controls the ability to
balance and coordinates movement; and the brainstem, which connects the brain to the spinal cord
and controls functions such as swallowing and breathing. The brain lesions are often accompanied
by loss of the myelin coating around nerves (demyelination), which reduces the ability of the
nerves to activate muscles used for movement or relay sensory information from the rest of the
body back to the brain.
Keywords: demyelination; infancy; lesions; magnetic resonance imaging; neurological disorder
paralysis
Title: The genetics of Leigh syndrome and its implications for clinical practice and risk
management
Author: Ilene S. Ruhoy and Russell P. Saneto
Abstract:
Leigh syndrome is an extremely genetically heterogeneous mitochondrial disorder. Newly
identified nuclear genetic causes are increasing, largely as a result of the use of next-generation
and whole-exome sequencing.14–16 Nuclear DNA mutations are inherited in a Mendelian
fashion, with autosomal recessive and X-linked inheritance seen as the etiology of Leigh
syndrome. Identification of causative mutations can be a cumbersome task, as the investigator is
confronted by two separate genomes, both nuclear and mitochondrial.17 The identification of
pathological mutations in the mtDNA can be unclear due to mitochondrial genetics and
physiology. As a result of multiple mtDNA molecules in individual mitochondrion, mutations can
be heteroplasmic, meaning that mutated mtDNA and normal mtDNA coexist within individual
mitochondrion. Identical DNA genomes, either normal or mutated, within the mitochondrion are
called homoplasmic. Both situations can give rise to Leigh syndrome.18 However, the precise
genetic cause of multiple cases of Leigh syndrome remains unknown.19
As of 2013, Leigh syndrome can be caused by mutations in more than 35 different genes (Table
2) of both nuclear and mitochondria origin, involving all five respiratory chain
complexes.20 There are 13 mtDNA-encoded structural proteins of complex I, III, IV, and V,
whereas the other approximately 77 structural subunits are nuclear-encoded proteins. The electron
donors of coenzyme Q10 and cytochrome c are also nuclear-encoded proteins. Mutations in any
of these structural components of the respiratory chain can induce Leigh syndrome. Mutations in
other genes involved in mitochondrial function, the tricarboxylic acid (TCA) cycle, and coenzyme
Q10 have also been found as an etiology of Leigh syndrome.3,21–23Depending on the mutated
genome, Leigh syndrome can be inherited as a maternally inherited mitochondrial trait (mtD-NAencoded), as an autosomal recessive trait resulting from mutations in nuclear genes encoding
mitochondrial respiratory chain complex subunits, complex assembly proteins, coenzyme Q10,
mitochondrial targeted tRNA synthetases and X-linked genes involved in PDHA1 and complex I
assembly factor NDUFA1 (nuclear-encoded). Although most patients with Leigh syndrome have
a mutation in nuclear DNA, about 25% have a mutation in mtDNA.
Keywords: coenzyme Q10; heterogeneous; heteroplasmic; nuclear-encoded proteins; respiratory
chain; X-linked genes.
10/6/2021
12
Leigh Syndrome
Title: Unusual Clinical Presentations in Four Cases of Leigh Disease, Cytochrome C Oxidase
Deficiency, and SURF1 Gene Mutations
Author: Stacey K.H. Tay, MD, Sabrina Sacconi, MD, H. Ohran Akman, PhD
Abstract:
Mutations in the SURF1 gene are the most frequent causes of Leigh disease with cytochrome c
oxidase deficiency. We describe four children with novel SURF1 mutations and unusual features:
three had prominent renal symptoms and one had ragged red fibers in the muscle biopsy. We
identified five pathogenic mutations in SURF1: two mutations were novel, an in-frame nonsense
mutation (834G→A) and an out-of-frame duplication (820-824dupTACAT). Although renal
manifestations have not been described in association with SURF1 mutations, they can be part of
the clinical presentation. Likewise, mitochondrial proliferation in muscle (with ragged red fibers)
is most unusual in Leigh disease but might be part of an emerging phenotype.
Keywords: cytochrome c oxidase deficiency; in-frame nonsense mutation; out-of-frame
duplication; pathogenic mutations; SURF1 gene.
Title: A rare mitochondrial disorder: Leigh Syndrome- a case report
Author: Dhananjay Y Shrikhande, MM Aarif Syed, Kunal Ahya and Gurmeet Singh
Abstract:
Leigh syndrome is a rare progressive neurodegenerative, mitochondrial disorder of childhood with
only a few cases documented from India. The clinical presentation of Leigh syndrome is highly
variable. However, in most cases it presents as a progressive neurological disease with motor and
intellectual developmental delay and signs and symptoms of brain stem and/or basal ganglia
involvement. Raised lactate levels in blood and/or cerebrospinal fluid is noted. It is the
neuroimaging, mainly the Magnetic Resonance Imaging showing characteristic symmetrical
necrotic lesions in the basal ganglia and/or brain stem that leads to the diagnosis. Here, we report
a case of 7 months old female child presenting to us with status epilepticus, delayed developmental
milestones and regression of the achieved milestones suspected to be a case of neurodegenerative
disorder, which on MRI was diagnosed as Leigh syndrome.
Keywords: cerebrospinal fluid; developmental delay; neuroimaging; status epilepticus.
10/6/2021