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Leigh's Disease

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Leigh's disease is an inherited, rapidly progressing metabolic syndrome that primarily affects the central nervous system. It is caused by mutations in the mitochondrial and nuclear DNA, leading to impaired energy utilization and metabolism. Clinical presentation includes the progressive loss of motor skills and other neurological deficits as well cardiac, respiratory, and other organ-related symptoms. This syndrome is universally fatal, usually within the first several years of life.


Presentation

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
  • 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]
  • A 21-year-old man with a longstanding history of impaired visual acuity, strabismus, broad-based gait, and below-average intellectual capacity developed respiratory difficulties and intermittent generalized weakness at age 19.[ncbi.nlm.nih.gov]
  • He had growth retardation, feeding difficulty and general weakness. Brain sonography and computed tomography demonstrated symmetrical lesions in the caudate, lenticular nuclei, thalamus and hypothalamus, suggesting bilateral necrosis.[ncbi.nlm.nih.gov]
  • Affected individuals may develop weak muscle tone (hypotonia), involuntary muscle contractions (dystonia), and problems with movement and balance (ataxia).[ghr.nlm.nih.gov]
Fever
  • SYMPTOMS : Neurological symptoms generally start unexpectedly or in a subacute mode, and,sometimes, are increased by fever,surgical treatment or aspecific infections.[flipper.diff.org]
  • 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]
  • Cognitive deterioration may appear insidious or may be rapid, usually after a bout of fever or onset of seizures. Nutritional troubles resulting from the decreased ability to feed may precede or exacerbate the underlying encephalopathy.[dovepress.com]
  • 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]
  • Occasional findings include epilepsy; learning problems; cognitive decline; and reduced consciousness, neurologic deterioration, and fever following minor head trauma. Many affected individuals become wheelchair dependent in their teens or twenties.[umdf.org]
Progressive Dementia
  • Death may come as a result of general body wasting due to progressive dementia and muscle weakness, or complications from other affected organs such as heart or kidneys.[umdf.org]
Constitutional Symptom
  • Additionally, loss of appetite, vomiting, seizures, diabetes, and other constitutional symptoms may appear, eventually leading to an impaired respiratory and renal function.[symptoma.com]
Sighing
  • 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]
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 two-and-a-half-year-old male child presented with recurrent attacks of intractable vomiting, psychomotor retardation since 14 months of age. He had also lower cranial nerve palsy and corticospinal involvement.[ncbi.nlm.nih.gov]
  • A 7-month-old boy presented clinically with vomiting, lethargy, respiratory difficulty, deteriorated consciousness, and hypotonia.[ncbi.nlm.nih.gov]
  • The person can experience vomiting, a loss of appetite, irritability, as well as seizures.[disabled-world.com]
  • 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]
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]
  • 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]
  • 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]
  • These symptoms may be accompanied by loss of appetite, vomiting, irritability, continuous crying, and seizures.[medicinenet.com]
Failure to Thrive
  • The most common symptoms are generalized weakness, failure to thrive, psychomotor retardation, anorexia, muscle atrophy, absence of reflexes, and sometimes seizures.[symptoma.com]
  • These problems often result in an inability to grow and gain weight at the expected rate (failure to thrive).[disabled-world.com]
  • She presented at age 12 months with failure to thrive, neurodevelopmental regression, and frequent vomiting. Physical examination showed facial dysmorphism, hirsutism, and generalized muscle hypotonia.[ajnr.org]
  • . • Symptoms may include failure to thrive, weakness/hypertonia, ataxia, oculomotor palsy, seizures, and episodes of lactic acidosis, among other features. • The course of Leigh syndrome is usually relapsing, often in response to physiologic stress (ie[medlink.com]
  • Clinical presentation is variable; patients often exhibit psychomotor retardation, vomiting, failure to thrive, and signs of brain stem and basal ganglia dysfunction. 4 Ophthalmologic signs and symptoms are common and include nystagmus, ophthalmoplegia[healio.com]
Nausea
  • Granisetron (1 mg) was administered pre-emptively to prevent postoperative nausea and vomiting. The procedure lasted 3.5 hours and the total fluid administration included 500 mL of normal saline.[saudija.org]
Numbness of the Tongue
  • A previously-well 32-year-old woman presented with episodes of severe headache, neck pain, numbness of the tongue and facial sweating.[ncbi.nlm.nih.gov]
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]
  • ) abnormal, quick eye movements crossed eyes impaired vision hypertrophy of the heart muscle weakness in the arms and legs There are various subdivisions of Leigh syndrome and sometimes, the symptoms may vary slightly.[medic8.com]
  • Affected children may experience delayed development, muscle weakness, problems with movement, or difficulty breathing. MT-ATP6 gene mutations associated with Leigh syndrome change one DNA building block (nucleotide) in the MT-ATP6 gene.[ghr.nlm.nih.gov]
  • Affected children may experience delayed development, muscle weakness, problems with movement, or difficulty breathing. Approximately 10 to 15 percent of people with Leigh syndrome have a mutation in the SURF1 gene.[ghr.nlm.nih.gov]
  • In contrast, respiratory dysfunction and muscle weakness (33%) were more frequent among patients younger than 4 years old, mostly observed in the first year of age.[medicalexpress.net.br]
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]
  • Physical examination showed facial dysmorphism, hirsutism, and generalized muscle hypotonia. Venous blood lactate was elevated at rest (32 mg/dL; normal, 8–22 mg/dL).[ajnr.org]
  • 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]
  • We report a 16-month-old boy with psychomotor regression, muscle hypotonia, peripheral neuropathy, and lactic acidosis.[scinapse.io]
Psychomotor Retardation
  • A two-and-a-half-year-old male child presented with recurrent attacks of intractable vomiting, psychomotor retardation since 14 months of age. He had also lower cranial nerve palsy and corticospinal involvement.[ncbi.nlm.nih.gov]
  • 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]
  • 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]
  • Medline NLM definition: A disease of pyruvate metabolism manifesting in infancy with psychomotor retardation, dysphagia, hypotonia, ataxia, weakness, external ophthalmoplegia, vision loss, hearing loss, and convulsions.[ucl.ac.uk]
Seizure
  • 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]
  • Symptoms usually begin between ages of three months and two years and include loss of appetite, vomiting, irritability and seizure activity.[wikidata.org]
  • Seizures (five of ten cases) were also frequent. In most patients, the diagnosis of LS was established postmortemly by the presence of symmetrical spongiform lesions affecting several brain centers at autopsy.[ncbi.nlm.nih.gov]
  • Neurological symptoms include cognitive impairment, hypotonia, ataxia, tremor, polyneuropathy, hyporeflexia, seizures, as well as generalized weakness.[symptoma.com]
  • It’s also supported by the findings on his EEG – that shows that he is having seizures one third to one half of the time. The seizures cause more cells to die.[lifeethics.org]
Ataxia
  • The second attack was noted one month later, to be associated with hypotonia and truncal ataxia.[ncbi.nlm.nih.gov]
  • He had suffered epileptic fits, bilateral internuclear ophthalmoplegia, bulbar and pontine paralysis, tetraparesia, ataxia and dystonia. A CT brain scan showed low density lesions of the striatum bilaterally.[ncbi.nlm.nih.gov]
  • PDHb phosphatase activity did not differ significantly among normal control cells, Leigh's lines, spinocerebellar ataxias, or other neurologic disorders. The results do not support the idea that PDHb phosphatase is deficient in Leigh's disease.[ncbi.nlm.nih.gov]
  • 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]
  • Syndromes such as beriberi, Wernicke’s disease, Leigh’s disease, African Seasonal Ataxia, and various inherited ataxias, have all benefited from improved scientific approaches.[books.google.com]
Irritability
  • Symptoms usually begin between ages of three months and two years and include loss of appetite, vomiting, irritability and seizure activity.[wikidata.org]
  • 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]
  • 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]
  • These symptoms may be accompanied by loss of appetite, vomiting, irritability, continuous crying, and seizures.[medicinenet.com]
Peripheral Neuropathy
  • 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]
  • Pyramidal and extrapyramidal signs, nystagmus, breathing disorders, ophthalmoplegia and peripheral neuropathy are often noted later. Epilepsy is relatively uncommon.[orpha.net]
  • Neurologic features include hypotonia, spasticity, movement disorders (including chorea), cerebellar ataxia, and peripheral neuropathy. Extraneurologic manifestations may include hypertrophic cardiomyopathy.[ncbi.nlm.nih.gov]
  • […] syndrome and peripheral neuropathy.[scinapse.io]
  • 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.[ghr.nlm.nih.gov]
Lethargy
  • A 7-month-old boy presented clinically with vomiting, lethargy, respiratory difficulty, deteriorated consciousness, and hypotonia.[ncbi.nlm.nih.gov]
  • Symptoms: Seizures, apnea, bradycardia, vomiting, lethargy, coma, enlarged liver, limb weakness, myoglobin in the urine, Reye-like symptoms triggered by fasting. Cause: Autosomal recessive.[umdf.org]

Workup

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.

Left Ventricular Hypertrophy
  • Other cases of Leigh's disease with hypertension or left ventricular hypertrophy have shown similar brain stem lesions.[ncbi.nlm.nih.gov]

Treatment

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].

Prognosis

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.

Etiology

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.

Epidemiology

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.

Sex distribution
Age distribution

Pathophysiology

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.

Prevention

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

Summary

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.

Patient Information

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.

References

Article

  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.
  7. Shrikhande DY, Kalakoti P, Syed MM, et al. A rare mitochondrial disorder: Leigh syndrome–a case report. Ital J Pediatr. 2010;36:62.
  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;

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Last updated: 2019-07-11 21:57