Clinical presentation of Leigh's disease (also called infantile necrotizing encephalopathy) is characterized by rapid deterioration of the central nervous system functions, beginning within months after birth. Neurological symptoms include cognitive impairment, hypotonia, ataxia, tremor, polyneuropathy, hyporeflexia, seizures, as well as generalized weakness. Ocular symptoms, including nystagmus, retinitis, optic atrophy and paresis may be encountered in these patients, which can eventually progress to blindness [8]. Constitutional symptoms, such as malaise, fatigue, anorexia and failure to thrive are present in many patients, while respiratory and gastrointestinal disturbances such as hypoxia and tachypnea, vomiting, and dysphagia are frequently encountered. Other accompanying illnesses may be present, such as hypertrophic cardiomyopathy, presence of ventricular septal defects, diabetes mellitus, nephrotic syndrome, as well as thyroid dysfunction [9].

If the onset of the symptoms is delayed, dysarthria and mental retardation may be observed.

• Weakness

  Affected individuals may develop weak muscle tone (hypotonia), involuntary muscle contractions (dystonia), and problems with movement and balance (ataxia). [malacards.org]

  An unusual presentation of Leigh's disease consisting of rapid progression of leg weakness in a young child is discussed. Magnetic resonance imaging revealed an intramedullary mass lesion of the conus medullaris. [ncbi.nlm.nih.gov]

  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. [ninds.nih.gov]

• Fever

  Leigh syndrome, named after a British neuropsychologist who first described it in 1951, involves metabolic strokes deep in the brain, with a loss of skills from stressors such as fever, illness and anesthesia. [chop.edu]

  Figure 1 Figure 1: Pedigree Chart The child was asymptomatic till 9 months of age when he developed fever and seizures and was administered symptomatic treatment. [ispub.com]

  Death often occurs during an episode of exacerbation and is often associated with fever. [docslide.us]

  After three days the onset of symptoms, she presented weakness of lower limbs, fever and drowsiness. At this time she was hospitalized and 24hs later, she became comatous and had respiratory failure. [scielo.br]

  As his body is attacked with viral infections, fever or even as he gets overheated, he is at risk for additional brain damage that ultimately will result in system failures. [cnn.com]

• Weight Loss

  However, he was seen by a health visitor because of poor feeding, weight loss, general lethargy and rapid breathing. At the local hospital hypotonia, absent reflexes and a tremor were observed. [rcni.com]

  After a short period of clinical improvement, he deteriorated rapidly, with feeding problems and weight loss. [ajnr.org]

  LEMS patients with or without cancer may also undergo significant weight loss. The tendon reflexes are diminished or absent on examination. [rarediseases.org]

  […] in the night Peripheral vision loss Central vision loss External ophthalmoplegia/ophthalmoperesis Paralysis/weakness of the muscles that open eyelids and move the eyes, resulting in restricted eye movement and droopy eyes Physical appearance: Short stature [lhsc.on.ca]

  In 45 out of the 52 cases reported, weight loss, weak- ness and some degree of psychomotor retardation were prominent features, either alone or in combination. Anorexia and vomiting were very frequent. [docslide.us]

• Hypothermia

  Patients 17, 18, and 19 showed autonomic nervous disorders, mainly hypothermia, fever or bradycardia. In addition, a few patients appeared lethargic or even comatose in the late stages of the disease (26, 30, 32, 43). [frontiersin.org]

  […] gastritis, megacolon, intestinal paralysis (11.5%); dysarthria (11.5%); hyperhidrosis/excessive sweating (9.2%); motor delay (9.2%); peripheral neuropathy (6.9%); scoliosis (6.9%); speech delay (6.1%); renal dysfunction (5.4%); sleep disturbances (2.3%); hypothermia [ojrd.biomedcentral.com]

• Progressive Dementia

  Symptoms: Myoclonus, epilepsy, progressive ataxia, muscle weakness and degeneration, deafness, and dementia. [umdf.org]

• Sighing

  Some patients had irregular breathing, deep sighing respiration, unexplained hyperventilation, or hiccups with lethargy and serious feeding problems lasting for a few days to several weeks. [ajnr.org]

  Even so, episodes of deep sighing respirations, hyperventilation, rapid irregular breathing and sobbing unassociated with crying were reported in 26 of the 86 cases. [docslide.us]

  Intermittent sighing respirations may be found secondary to brainstem dysfunction. Rarely can it present in the childhood (juvenile form). Respiratory failure is usually responsible for mortality. [ispub.com]

• Respiratory Distress

  Increasing respiratory distress, in spite of sup- plemental oxygen, led to the infant's transfer to St. Louis Children's Hospital. The infant was intubated immediately on arrival. Chest X-ray demonstrated severe hyaline membrane disease. [docslide.net]

  In this case series, the most common symptoms were respiratory problems (7/26, excluding patient 1 and 9), which were very prominent in LS: 2 patients showed bradypnea (28, 32), 5 patients showed apnea or dyspnea or respiratory distress (26, 31, 32, 42 [frontiersin.org]

• Vomiting

  Symptoms usually begin between ages of three months and two years and include loss of appetite, vomiting, irritability and seizure activity. [wikidata.org]

  A 7-month-old boy presented clinically with vomiting, lethargy, respiratory difficulty, deteriorated consciousness, and hypotonia. [ncbi.nlm.nih.gov]

  These symptoms may be accompanied by loss of appetite, vomiting, irritability, continuous crying, and seizures. [medicinenet.com]

  The person can experience vomiting, a loss of appetite, irritability, as well as seizures. [disabled-world.com]

  Early symptoms may include poor sucking ability; loss of head control and motor skills; loss of appetite; vomiting; and seizures. [malacards.org]

• Failure to Thrive

  These difficulties lead to decrease nutrition intake, which can exacerbate subsequent malnutrition or failure to thrive. In addition, Leigh syndrome is also associated with muscle and movement issues. [eyewiki.aao.org]

  The most common symptoms are generalized weakness, failure to thrive, psychomotor retardation, anorexia, muscle atrophy, absence of reflexes, and sometimes seizures. [symptoma.com]

  Early symptoms: Vomiting, diarrhoea, and problems with swallowing that leads to failure to thrive (inability/difficulty growing and gaining weight at the expected rate) in infancy Loss of head control and motor skills Seizures As the condition progresses [ideas.org.au]

  Usual presentation occurs in infancy, with diarrhoea, vomiting, failure to thrive, hypotonia, developmental regression, and death within a span of few years. [ajnr.org]

• Loss of Appetite

  Symptoms usually begin between ages of three months and two years and include loss of appetite, vomiting, irritability and seizure activity. [wikidata.org]

  The earliest signs may be poor sucking ability,and the loss of head control and motor skills.These symptoms may be accompanied by loss of appetite, vomiting, irritability, continuous crying, and seizures. [ninds.nih.gov]

  Following there is a loss of appetite, vomiting, prolonged crying, fits and irritability. The individual result in having poor muscle tone and is usually weak. There may be kidney and respiratory problems associated. [biochemist01.wordpress.com]

  Symptoms begin in infancy and include poor sucking ability, the loss of head control and motor skills, loss of appetite, vomiting, irritability, continuous crying, and seizures. [medicinenet.com]

• Nausea

  SLIDESHOW How to Get Rid of Nausea and Vomiting See Slideshow Support for Leigh's disease Epilepsy Foundation 8301 Professional Place Landover, MD 20785-7223 [email protected] http://www.epilepsyfoundation.org Tel: 301-459-3700 800-EFA-1000 (332-1000) [medicinenet.com]

  Symptoms The cancer cells in the covering of the brain can cause a range of symptoms, including: headaches changes to your sight such as double vision or loss of sight confusion weakness seizures (fits) feeling sick (nausea) vomiting hearing changes facial [cancerresearchuk.org]

  This increased pressure can cause vague but uncomfortable symptoms including headaches (often worse in the morning), nausea, vision changes, and difficulty walking. [jamanetwork.com]

  Clinical presentation is varied, but most commonly includes a headache, spine or radicular limb pain or sensory abnormalities, nausea and vomiting, and focal neurological deficits 3. Meningism is only present in a minority of patients (13% 3 ). [radiopaedia.org]

  Grades 3 and 4 Serious toxicity (one or more), which made in-patient treatment mandatory, was documented in six patients: nausea/vomiting/headaches/seizures and nerve palsy (n=1); nausea/vomiting/headaches/seizures (status epilepticus) and fatigue (n= [dovepress.com]

• Muscle Weakness

  NARP is characterized by proximal neurogenic muscle weakness with sensory neuropathy, ataxia, and pigmentary retinopathy. Onset of symptoms, particularly ataxia and learning difficulties, is often in early childhood. [ncbi.nlm.nih.gov]

  weakness hypotonia (loss of muscle tone) muscle spasms twitching stiffness in the muscles and joints delayed neurological progress respiratory problems, most notably apnoea, short rapid breaths and irregular breathing patterns dysphagia (difficulty swallowing [medic8.com]

  In the few reported cases with these mutations, affected children have had delayed development, problems with movement and coordination, weak muscle tone (hypotonia), and an unusually small head size (microcephaly). [ghr.nlm.nih.gov]

  Affected individuals may develop muscle weakness affecting the arms and legs, especially affecting the muscles of the upper arms and upper legs (proximal muscle weakness). Affected individuals also have eye (ocular) symptoms. [rarediseases.org]

  In addition, Leigh syndrome is also associated with muscle and movement issues. Patient often have hypotonia (weak muscle tone), dystonia (involuntary muscle contractions) and ataxia (trouble with balance). [eyewiki.aao.org]

• Muscle Hypotonia

  An 11-month-old boy with muscle hypotonia and neurologic deteriorations had lactic acidosis, pyruvic acidemia and alaninemia due to deficiency of the pyruvate dehydrogenase complex in his platelets and of pyruvate decarboxylase in his muscle. [ncbi.nlm.nih.gov]

  At 14 months, his developmental milestones slowed and muscle hypotonia appeared. At 16 months, he had neurodevelopmental regression, generalized symmetrical hypotonia, and absent deep tendon reflexes. [ajnr.org]

  We report a 16-month-old boy with psychomotor regression, muscle hypotonia, peripheral neuropathy, and lactic acidosis. [scinapse.io]

  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. [en.wikipedia.org]

• Psychomotor Retardation

  A 4 1/2-month-old girl suffered from psychomotor retardation, generalized hypotonia, poor feeding, hyperreflexia, nystagmus, optical atrophy and choreoathetosis from the age of 3 months. Her blood lactate level was elevated to 40 mg/dL. [ncbi.nlm.nih.gov]

  Clinical features depend on which areas of the central nervous system are involved and include subacute onset of psychomotor retardation, hypotonia, ataxia, weakness, vision loss, eye movement abnormalities, seizures, and dysphagia. [uniprot.org]

  A group of metabolic disorders primarily of infancy characterized by the subacute onset of psychomotor retardation, hypotonia, ataxia, weakness, vision loss, eye movement abnormalities, seizures, dysphagia, and lactic acidosis. [connects.catalyst.harvard.edu]

  The most common symptoms are generalized weakness, failure to thrive, psychomotor retardation, anorexia, muscle atrophy, absence of reflexes, and sometimes seizures. [symptoma.com]

• Seizure

  Symptoms usually begin between ages of three months and two years and include loss of appetite, vomiting, irritability and seizure activity. [wikidata.org]

  As for generalized seizure types, myoclonic seizure, tonic seizure, atonic seizure, and tonic-clinic seizure were observed with relatively even prevalence among patients. [frontiersin.org]

  Early symptoms may include poor sucking ability; loss of head control and motor skills; loss of appetite; vomiting; and seizures. [malacards.org]

  Neurological symptoms include cognitive impairment, hypotonia, ataxia, tremor, polyneuropathy, hyporeflexia, seizures, as well as generalized weakness. [symptoma.com]

  The importance of obtaining a blood or cerebrospinal fluid lactate in all infants with unexplained seizures, cortical blindness or apnoea is emphasized. [ncbi.nlm.nih.gov]

• Ataxia

  The second attack was noted one month later, to be associated with hypotonia and truncal ataxia. [ncbi.nlm.nih.gov]

  Affected individuals may develop weak muscle tone (hypotonia), involuntary muscle contractions (dystonia), and problems with movement and balance (ataxia). [malacards.org]

  When the onset of the disorder is later during childhood, ataxia or difficulty articulating words (dysarthria) may be the initial signs. Ataxia can cause affected children to appear clumsy or unsteady. [rarediseases.org]

• Irritability

  Symptoms usually begin between ages of three months and two years and include loss of appetite, vomiting, irritability and seizure activity. [wikidata.org]

  The earliest signs may be poor sucking ability,and the loss of head control and motor skills.These symptoms may be accompanied by loss of appetite, vomiting, irritability, continuous crying, and seizures. [ninds.nih.gov]

  Following there is a loss of appetite, vomiting, prolonged crying, fits and irritability. The individual result in having poor muscle tone and is usually weak. There may be kidney and respiratory problems associated. [biochemist01.wordpress.com]

  These symptoms may be accompanied by loss of appetite, vomiting, irritability, continuous crying, and seizures. [medicinenet.com]

• Nystagmus

  The authors present the case of a 9-year-old girl with dorsal midbrain syndrome causing convergence retraction nystagmus. [healio.com]

  Most frequently the central nervous system is affected, with psychomotor retardation, seizures, nystagmus, optic atrophy, ataxia, or respiratory failure. [malacards.org]

  Low VA was common and more than 1/3 of the children had optic atrophy, with or without a combination of photophobia and nystagmus. Many of the children were hyperopastigmatic. [iovs.arvojournals.org]

• Peripheral Neuropathy

  […] syndrome and peripheral neuropathy. [scinapse.io]

  Sural nerves were examined in 3 childhood cases of Leigh's disease (from 2 families), each with electrophysiological documentation of peripheral neuropathy. [ncbi.nlm.nih.gov]

  2016 26 The neuroimaging of Leigh syndrome: case series and review of the literature. 24 Bonfante E...Riascos RF 26739140 2016 27 Disturbed mitochondrial and peroxisomal dynamics due to loss of MFF causes Leigh-like encephalopathy, optic atrophy and peripheral [malacards.org]

  Neurological features include movement disorders (e.g. chorea, dystonia, ataxia), hypotonia, spasticity, peripheral neuropathy, ophthalmoplegia, and basal ganglia hyperintensities on magnetic resonance imaging brain scans. [n.neurology.org]

The diagnosis of Leigh's disease is achieved through a detailed workup involving biochemical tests and neuroimaging studies.

Biochemical findings, such as indirect markers of energy utilization, including lactate levels, should be investigated to identify the underlying defect, and levels of pyruvate may be evaluated in the cerebrospinal fluid (CSF) together with lactate, both usually having increased values. Liver and muscle enzymes should also be evaluated, including transaminases (AST and ALT), alkaline phosphatase (ALP), and lactate dehydrogenase (LDH).

Neuroimaging studies are performed to assess the severity of the lesions in the central nervous system. Magnetic resonance imaging (MRI) of endocranium typically reveals symmetric lesions of the brain stem and basal ganglia, including cerebral atrophy and leukodystrophy, while infarctions may be observed in severe cases.

• Cerebrospinal Fluid Abnormality

  Cerebrospinal fluid abnormalities in meningeosis neoplastica: a retrospective 12-year analysis. Fluids Barriers CNS. (2017) 14:7. doi: 10.1186/s12987-017-0057-2 PubMed Abstract | CrossRef Full Text | Google Scholar 35. [frontiersin.org]

• Hyperlactacidemia

  BBGD mainly presents with hyperlactacidemia, vomiting, seizures and encephalopathy. The CNS free-thiamine dosage is frequently in low quantities nearly to absence, which can enhance diagnosis suspicion [61]. [ojrd.biomedcentral.com]

Currently, the treatment of Leigh's disease comprises supportive management that improves levels of ATP and suppression of lactate levels, as well as other accompanying disorders. Thiamine (vitamin B1) has been used in a number of patients due to a reported slight improvement of the neurological status, while riboflavin (vitamin B2) is also administered, presumably because of its role of aiding in ATP production.

Ketogenic diets, and the use of intravenous soya bean oil has been shown to improve the metabolic status of patients, particularly in those with respiratory failure, while other strategies to manage lactic acidosis includes administration of oral sodium citrate and sodium bicarbonate. Dystonia frequently occurs in these patients, and the use of gabapentin and baclofen is indicated in such circumstances, and in severe cases, botulinum toxin is used, while antiepileptic drugs are also frequently given because of epilepsy [10].

The prognosis of patients with Leigh's disease is quite poor, and most patients die within the first few years of life. The severity of the disease depends on the type of the mutation, and which enzymes are affected. Individuals with PDH deficiency, as well as those lacking activity of the mitochondrial complex IV have the worst prognosis, while those with partial enzyme deficiencies may live up to 6 or 7 years [7]. Rarely have individuals lived until their teenage years, and this rapidly progressive disorder is universally fatal.

This disease occurs due to heterogenous genetic malformations both in mitochondrial and nuclear DNA, which makes this syndrome quite complex, because it can cause only one, or several mutations of enzymes in the metabolic pathway [3]. Hallmarks of this disease include mutations of the mitochondrial respiratory chain, cytochrome C oxidase [4], coenzyme Q, pyruvate dehydrogenase, as well as other enzymes and parts of the metabolism that are critical for energy utilization and ATP formation. The mutation that is most commonly encountered in Leigh's disease is the disruption of complex IV mitochondrial chain, or cytochrome C oxidase, which is involved in the last step of electron transfer during oxidative phosphorylation. Another commonly encountered mutation includes genes that are responsible for the production of complex V, also known as the ATP synthase complex, which is responsible for the generation of ATP at the end of the electron transport chain, and it is found in 10-20% of patients with Leigh's disease [5].

So far, autosomal recessive and X-linked patterns of inheritance have been observed since nuclear DNA contains genes from both parents, while mitochondrial DNA is transferred only from maternal genes. However, causes of this syndrome and the resulting mutations have not yet been identified.

This genetic disorder is considered rare. Although prevalence rates vary, it is estimated that it occurs in approximately 1 in 36,000 individuals. The majority of the patients develop symptoms within the first year of life and the disease rarely has a delayed onset. The diagnosis is almost always confirmed when patients are between three months and two years old. Predilection for gender or race is not established.

Mutations in this genetic disorder target enzymes and other parts of the metabolic pathway that are essential for the production of the energy that supplies the body. The production of adenosine triphosphate (ATP) is not possible without the activity of enzymes such as pyruvate dehydrogenase (PDH), coenzyme Q, or the mitochondrial respiratory chain. When mutations in the mitochondrial and nuclear DNA occur, which is the case in this disease, the electron transport chain, oxidative phosphorylation, as well as tricyclic acid cycle, are all unable to replenish ATP and cellular energy sources, leading to generalized energy deficiency [6]. As a result, cells are not able to perform their functions, and once their reserves are depleted, generalized cellular damage occurs, eventually leading to their death. These changes are most prominent in the central nervous system, where neurons need constant replenishment of ATP through aerobic glycolysis to sustain their metabolic needs.

Although specific mutations in this inherited genetic disorder have been identified, its cause remains unknown, and prevention is currently not possible.

Leigh's disease is a rare genetic disorder of energy metabolism primarily affecting the central nervous system. This disorder occurs as a result of mutations in mitochondrial and nuclear DNA, which leads to impaired energy metabolism. Deficiency of various enzymes including pyruvate dehydrogenase (PDH), coenzyme Q, or defects in the mitochondrial chain complex are documented, which are of essential value in the tricyclic acid cycle, oxidative phosphorylation and energy utilization. Both autosomal recessive and X-linked inheritance patterns can be observed in these patients [1], but its actual cause is still unknown. This rare disease is estimated to occur in 1 per 36,000 live births, and symptoms usually start before the age of 12 months, but they may appear later in childhood. The onset usually occurs between three months and two years of age.

Since this disease leads to inability to create sufficient energy through metabolism, rapid cellular deterioration occurs, particularly in the central nervous system, which results in symptoms such as psychomotor retardation, ataxia, dystonia, atrophy of the optic nerves, as well as symptoms of peripheral nervous system involvement, such as polyneuropathy [2]. Additionally, loss of appetite, vomiting, seizures, diabetes, and other constitutional symptoms may appear, eventually leading to an impaired respiratory and renal function. The diagnosis of Leigh's disease is made through biochemical blood findings and neuroimaging studies of the endocranium, which shows symmetric lesions of the basal ganglia and the brain stem. Apart from supportive therapy which includes thiamine, riboflavin, and management of complications (such as lactic acidosis, epilepsy, etc.) specific therapy for this disorder does not exist. The prognosis is very poor, and depends on the severity of disease, but the majority of patients live only for a few years.

Leigh's disease is a rare inherited disorder that affects primarily the central nervous system. This disorder occurs as a result of DNA mutations which impair the parts of the metabolism responsible for energy production. As a result, the majority of cells in the body are unable to perform their metabolic functions, consequently leading to progressive deterioration and death of cells throughout the body. This disorder is rapidly progressive, and it is most commonly observed in children between three months and two years of life. It carries a very poor prognosis, with only a few patients reaching adolescence, making this disorder a universally fatal disease.

Leigh's disease primarily causes damage to the brain, specifically the basal ganglia, which are involved in motor functions, as well as the brain stem, which performs numerous vital functions. The most common symptoms are generalized weakness, failure to thrive, psychomotor retardation, anorexia, muscle atrophy, absence of reflexes, and sometimes seizures. Patients may have accompanying diseases such as congenital heart defects, diabetes, kidney or thyroid problems. Breathing problems are common, and both kidney and lung functions are severely impaired in patients with Leigh's disease.

The diagnosis is made by obtaining levels of lactate and pyruvate in the cerebrospinal fluid through a lumbar puncture, while a magnetic resonance imaging SCAN (MRI) of the brain is performed to assess the damage of the central nervous system.

Treatment is mainly supportive, since there is no cure for this disorder. Thiamine (vitamin B1) is believed to provide some degree of improvement in terms of neurological complaints, while other treatment is aimed at correcting the accompanying issues, such as lactic acidosis, hypoxia, kidney failure, and seizures. In patients with a certain type of mutation, a high-fat and low-carbohydrate diet may be recommended, to prevent lactic acidosis.

1. Rahman S, Blok RB, Dahl HH, et al. Leigh syndrome: clinical features and biochemical and DNA abnormalities. Ann Neurol. 1996;39(3):343-351.
2. Finsterer J. Leigh and Leigh-like syndrome in children and adults. Pediatr Neurol. 2008;39(4):223-235.
3. Leigh D. Subacute necrotizing encephalomyelopathy in an infant. J Neurol Neurosurg. Psychiat. 1951;14:216-221.
4. Willems JL, Monnens LA, Trijbels JM, et al. Leigh's encephalomyelopathy in a patient with cytochrome c oxidase deficiency in muscle tissue. Pediatrics. 1977;60:850-857.
5. Shoffner JM, Fernhoff PM, Krawiecki NS, et al. Subacute necrotizing encephalopathy: oxidative phosphorylation defects and the ATPase 6 point mutation. Neurology. 1992;42:2168-2174.
6. Medina L, Chi TL, DeVivo DC, et al. MR findings in patients with subacute necrotizing encephalomyelopathy (Leigh syndrome): correlation with biochemical defect. AJR Am J Roentgenol. 1990;154(6):1269-74.
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8. Miranda AF, Ishii S, DiMauro S, et al. Cytochrome c oxidase deficiency in Leigh's syndrome: genetic evidence for a nuclear DNA-encoded mutation. Neurology. 1989;39:697-702.
9. Arii J, Tanabe Y. Leigh syndrome: serial MR imaging and clinical follow-up. AJNR Am J Neuroradiol. 2000;1(8):1502-9.
10. Thornburn DR, Rahman S. Mitochondrial DNA-Associated Leigh Syndrome and NARP. GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2003;