NORD gratefully acknowledges Sumit Parikh, MD, Neurometabolic and Neurogenetics Staff Clinician, Cleveland Clinic, for assistance in the preparation of this report.
Maternally inherited Leigh syndrome (MILS) and neuropathy, ataxia and retinitis pigmentosa (NARP) syndrome are rare genetic multisystem disorders that are part of a spectrum or continuum of disease caused by abnormalities affecting mitochondrial energy production. NARP is characterized by nerve disease affecting the nerves outside of the central nervous system (peripheral neuropathy), an impaired ability to coordinate voluntary movements (ataxia), an eye condition known as retinitis pigmentosa (RP), and a variety of additional abnormalities. MILS is generally a more severe mitochondrial disorder that often becomes apparent during infancy or childhood and is characterized by brain disease (encephalopathy), elevated levels of lactic acid in the body (lactic acidosis), seizures, heart disease (cardiomyopathy), breathing (respiratory) abnormalities, and developmental delays. The specific symptoms and severity of these disorders in each individual can vary greatly from one person to another and even among members of the same family.
MILS and NARP syndrome are maternally inherited mitochondrial disorders. They are caused by specific mutations affecting the mitochondrial gene known as the ATPase 6 gene. When individuals have more than 90 percent of mutated mitochondrial DNA (mtDNA) in their cells, they are classified as having MILS and not NARP syndrome. Most individuals with NARP syndrome have 70-80 percent of mutated mtDNA. In some families, one individual may have NARP syndrome while another individual is diagnosed with MILS. (For more information on mtDNA see the Causes section below.)Introduction
Mitochondrial disorders are characterized by mutations affecting the parts of the cell that release energy (mitochondria). Mitochondrial diseases often hamper the ability of affected cells to break down food and oxygen and produce energy. In most mitochondrial disorders, abnormally high numbers of defective mitochondria are present in the cells of the body. Mitochondrial diseases often affect more than one organ system of the body. NARP syndrome was first identified in the medical literature in 1990. Leigh syndrome was first reported in the medical literature in 1951.The term “Leigh Syndrome” represents a clinical constellation of symptoms and characteristic MRI pattern and can occur due to many metabolic and genetic causes of which mitochondrial disorders are the most common. MILS is one of many causes of Leigh syndrome.
The symptoms of this spectrum of disease can vary dramatically from one person to another. Some individuals may have no apparent symptoms (asymptomatic) or only mild symptoms; other individuals may have severe, life-threatening complications, even during infancy in some cases of MILS. The severity of symptoms often correlates to the amount of mutated mtDNA in cells. Generally, the more mutated mtDNA, the worse the symptoms.
It is important to note that affected individuals may not have all of the symptoms discussed below. Affected individual and/or their families should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.
NEUROPATHY, ATAXIA & RETINITIS PIGMENTOSA (NARP) SYNDROME
Individuals with NARP syndrome will display some combination of the following symptoms. The onset of symptoms is often during early childhood. Individuals with NARP syndrome may remain stable for years. However, they often experience episodes of deterioration usually associated with a viral illness.
Common symptoms associated with NARP syndrome include an impaired ability to coordinate voluntary movements (ataxia), migraines, seizures, learning disabilities, and delays in attaining development milestones such as sitting up, crawling, or walking (developmental delays).
Individuals with NARP syndrome also have disease affecting the nerves that results in loss of sensation (sensory neuropathy). 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. The first ocular symptom is usually salt-and-pepper retinopathy, a condition where colored spots form on the membrane lining the eyes (retina) giving it a “salt and pepper” appearance. Affected individuals eventually develop retinitis pigmentosa (RP). RP is a general term for a group of vision disorders that cause progressive degeneration of the retina resulting in visual impairment. RP usually begins with difficulty seeing at night, eventually leading to night blindness. Additional ocular symptoms include rapid, involuntary eye movements (nystagmus) and sluggish pupils.
Additional symptoms have been reported in individuals with NARP syndrome including hearing loss, progressive paralysis of certain eye muscles (progressive external ophthalmoplegia), cardiac conduction defects such as heart block, and a mild anxiety disorder. Affected individuals may eventually develop dementia. Short stature has also been reported.
The abnormal accumulation of lactic acid in the blood (lactic acidosis), which is a common finding in mitochondrial disorders, rarely occurs in NARP syndrome.
MATERNALLY INHERITED LEIGH SYNDROME (MILS)
MILS is often apparent during the first three months to one year of life. However, onset can occur at any time from birth through adulthood. Later onset is often associated with a slower progression of symptoms. Many cases of MILS first become apparent following a viral infection.
The specific symptoms and severity of MILS can vary greatly from individual to the next. Generally, Leigh syndrome, which is also known as infantile necrotizing encephalopathy, is a progressive neurodegenerative disorder. If the onset is during infancy, the initial signs may be poor sucking ability and loss of head control. Additional early symptoms can include a profound loss of appetite, recurrent vomiting, irritability, continuous crying and possible seizure activity. Delays in reaching developmental milestones may also occur.
Affected individuals may experience decompensation, which is the inability of an organ system to compensate for illness or deficiency. In MILS, decompensation occurs during an illness and is typically associated with the progressive loss of abilities requiring the coordination of mental and muscular activity (psychomotor regression).
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. As mentioned above, affected children may also lose previously acquired intellectual skills and intellectual disability can occur. Progressive neurological deterioration associated with MILS may be characterized by additional symptoms including generalized muscle weakness, lack of muscle tone (hypotonia), tremors, movement disorders such as chorea (rapid, involuntary, jerky movements), seizures, infantile spasms, and spasticity, a condition characterized by involuntary muscle spasms that result in slow, stiff movements of the legs. Dystonia may also occur. Dystonia is a group of neurological disorders characterized by involuntary muscle contractions that force the body into abnormal, sometimes painful, movements and positions.
Individuals with MILS may develop a variety of respiratory abnormalities including the temporary cessation of spontaneous breathing (apnea), difficulty breathing (dyspnea), abnormally rapid breathing (hyperventilation), and/or abnormal breathing patterns. Some infants may also experience difficulty swallowing (dysphagia). Visual problems may include abnormally rapid eye movements (nystagmus), sluggish pupils, crossed eyes (strabismus), paralysis of certain eye muscles (ophthalmoplegia), deterioration of the nerves of the eyes (optic atrophy), and/or visual impairment leading to blindness.
MILS may also affect the heart. Some children with this disorder may have abnormal enlargement of the heart (hypertrophic cardiomyopathy) and overgrowth of the fibrous membrane that divides the various chambers of the heart (asymmetric septal hypertrophy). Disease affecting the nerves outside of the central nervous system (peripheral neuropathy) may eventually occur, causing progressive weakness of the arms and legs.
Episodes of lactic acidosis may occur and are characterized by abnormally high levels of lactic acid in the blood, brain and other tissues of the body.
In some cases, life-threatening complications, often secondary to heart or breathing abnormalities, can develop. In some cases of MILS, such complications can develop by three years of age.
MILS and NARP syndrome are associated with changes (mutations) in the genetic material found in the DNA of mitochondria (mtDNA). Mitochondria, which are found by the hundreds in the cells of the body, particularly in muscle and nerve tissue, carry the blueprints for regulating energy production. As opposed to the genetic instructions of cellular chromosomes (autosomal DNA), which are found within the nucleus of each cell, mitochondrial genetic instructions are found outside of the nucleus of the cell. The mutation associated with NARP syndrome affects the mitochondrial gene known as the ATPase 6 gene. Several mitochondrial genes including the ATPase 6 gene can cause MILS. Leigh syndrome is one of the most common pediatric presentations of mitochondrial disease and can also occur due to other changes (mutations) in the mitochondrial or nuclear DNA – changes that do not lead to NARP.
Genetic information is contained in two types of DNA: nuclear DNA (nDNA) is contained in the nucleus of a cell and is inherited from both biological parents. Mitochondrial DNA (mtDNA) is contained in the mitochondria of cells and is inherited exclusively from a child’s mother. Genetic diseases due to nDNA mutations (change in genetic material), are determined by two genes, one received from the father and one from the mother. mtDNA that is found in sperm cells typically break off during fertilization. As a result, all human mtDNA comes from the mother. An affected mother will pass the mutation(s) on to all her children, but only her daughters will pass the mutation(s) on to their children.
The genetic mutations that are present in the mtDNA may outnumber the normal copies of the genes. Generally, symptoms may not occur until mutations are present in a significant percentage of the mitochondria. The uneven distribution of normal and mutated mtDNA in different tissues can affect different organ systems in members of the same family. Thus, affected family members may exhibit a variety of different symptoms and varying degrees of severity. When individuals have more than 90 percent of mutated mitochondrial DNA (mtDNA) in their cells, they are classified as having MILS and not NARP syndrome. Most individuals with NARP syndrome have 70-80 percent of mutated mtDNA.
As stated above, the percentage of mutated mtDNA generally corresponds to the overall severity of these disorders. However, affected individuals have been reported who have a high percentage of mutated mtDNA (<90%), but only develop mild symptoms. This suggests that other factors may play a role in the overall severity of MILS and NARP syndrome.
NARP syndrome and MILS affects males and females in equal numbers. Symptoms often become apparent in young adults. The exact incidence of NARP syndrome, MILS, and mitochondrial disorders in the general population is unknown. NARP syndrome is estimated to occur in 1 in 12,000 births. Leigh disease, in general, is estimated to affect 1 in 36,000-40,000 live births. Some researchers estimate that as many as 30% of Leigh disease patients are MILS.
Mitochondrial disorders are estimated to occur in 1 in 4,000 births in the United States. Because these disorders often go unrecognized they are believed to be under-diagnosed, making it difficult to determine their true frequency in the general population.
The diagnosis of a mitochondrial disorder such as MILS or NARP syndrome is difficult. However, physicians, especially those experienced with these types of disorders, can make a diagnosis based upon the identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests.
A diagnosis of some cases of MILS or NARP syndrome can be confirmed through molecular genetic testing. Molecular genetic testing can detect mutations in specific genes known to cause MILS and NARP syndrome, and is available on a clinical basis. The mtDNA mutations associated with these disorders can be detected in white blood cells (leukocytes), but other tissue samples may also be necessary such as skin, skeletal muscle, hair follicles or urinary sediment.
Clinical Testing and Workup
A wide variety of tests may be necessary to rule out other conditions and to help obtain a diagnosis of a mitochondrial disorder. Such tests include metabolic screening tests including a complete blood count, urine analysis and cerebrospinal fluid (CSF) analysis. These tests measure for certain substances including lactate and pyruvate levels in the blood or CSF, creatinine kinase, ammonia, plasma amino acids, plasma carnitine, urinary organic acids, and plasma acetyl-carnitine profile.
Imaging techniques including computerized tomography (CT) scanning and magnetic resonance imaging (MRI) may reveal abnormal areas in certain parts of the brain. For example, in NARP syndrome, degeneration (atrophy) of the cerebellum and cerebrum may be noted on MRI. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues.
An electrocardiogram may be used to diagnose heart rhythm abnormalities and an echocardiogram may be used to diagnosis cardiomyopathy.
Surgical removal and microscopic study (biopsy) of certain tissue such as muscle or skin tissue may also be performed, although such test results are usually unremarkable. Additional biochemical and genetic studies can be performed in muscle as well. Due to advances in genetic testing, muscle biopsies are not needed as frequently in the evaluation of mitochondrial disorders.
A test that assesses the health of muscles and the nerves that control muscles (electromyography) may be recommended. During this exam, a needle electrode is inserted through the skin into an affected muscle. The electrode records the electrical activity of the muscle. This record shows how well a muscle responds to the nerves and can determine whether muscle weakness is caused by the muscles themselves or nerves that control the muscles. A nerve conduction study, in which motor and sensory nerves are electrically stimulated to assess a nerve’s ability and speed in conducting nerve impulses, may also be performed. Electromyography and nerve conduction studies can demonstrate peripheral neuropathy.
Individuals diagnosed with or suspected of having MILS or NARP syndrome should undergo a complete ophthalmological exam.
There are no proven therapies for MILS or NARP syndrome. Treatment recommendations are based primarily upon open label studies, case reports, and personal observations. Treatment is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, cardiologists, neurologists, eye specialists (ophthalmologists), and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Genetic counseling is recommended for individuals and families of affected individuals with this disorder.
Individuals with MILS may be treated with the administration of thiamine (vitamin B1) or thiamine derivatives. Some people with the disorder may experience a temporary symptomatic improvement and slight slowing of the progression of the disease.
Additional treatment for these disorders is symptomatic and supportive. For example, sodium bicarbonate or sodium citrate may be used to treat acidosis, antiseizure medications (anticonvulsants) may be used to treat seizures, and anticongestive therapy may be necessary to treat heart abnormalities. Dystonia may be treated with baclofen, benzhexol, tetrabenezine and gabapentin alone or in combination. Injections of botulinum toxin may also be used to treat dystonia.
Services that benefit people who are visually impaired may also be helpful for some affected individuals. Monitoring daily caloric intake and adequacy of diet is recommended. Psychosocial support for the entire family is essential as well.
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