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Mitochondrial DNA depletion syndrome 1 (MNGIE type)(MTDPS1)

MedGen UID:
167876
Concept ID:
C0872218
Disease or Syndrome
Synonyms: Mitochondrial DNA Depletion Syndrome, MNGIE Form; Mitochondrial neurogastrointestinal encephalomyopathy syndrome; Mitochondrial Neurogastrointestinal Encephalopathy Disease; Mitochondrial neurogastrointestinal encephalopathy syndrome; MITOCHONDRIAL NEUROGASTROINTESTINAL ENCEPHALOPATHY SYNDROME, TYMP-RELATED; MNGIE syndrome; MNGIE, TYMP-RELATED; MTDPS1; Myoneurogastrointestinal encephalopathy syndrome; Oculogastrointestinal muscular dystrophy; POLG-Related Disorders; POLIP SYNDROME; POLYNEUROPATHY, OPHTHALMOPLEGIA, LEUKOENCEPHALOPATHY, AND INTESTINAL PSEUDOOBSTRUCTION; Thymidine phosphorylase deficiency
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Sources: HPO, OMIM, Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in homozygotes. In the context of medical genetics, autosomal recessive disorders manifest in homozygotes (with two copies of the mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
Autosomal recessive inheritance (HPO, OMIM, Orphanet)
SNOMED CT: Oculogastrointestinal muscular dystrophy (722060007); Visceral myopathy with familial external ophthalmoplegia syndrome (722060007)
 
Genes (locations): POLG (15q26.1); TYMP (22q13.33)
OMIM®: 603041

Disease characteristics

Mitochondrial neurogastrointestinal encephalopathy (MNGIE) disease is characterized by progressive gastrointestinal dysmotility (manifesting as early satiety, nausea, dysphagia, gastroesophageal reflux, postprandial emesis, episodic abdominal pain and/or distention, and diarrhea); cachexia; ptosis/ophthalmoplegia or ophthalmoparesis; leukoencephalopathy; and demyelinating peripheral neuropathy (manifesting as paresthesias (tingling, numbness, and pain) and symmetric and distal weakness more prominently affecting the lower extremities). The order in which manifestations appear is unpredictable. Onset is usually between the first and fifth decades; in about 60% of individuals, symptoms begin before age 20 years. [from GeneReviews]
Authors:
Michio Hirano   view full author information

Additional descriptions

From OMIM
Mitochondrial DNA depletion syndrome-1 (MTDPS1) is an autosomal recessive progressive multisystem disorder clinically characterized by onset between the second and fifth decades of life of ptosis, progressive external ophthalmoplegia (PEO), gastrointestinal dysmotility (often pseudoobstruction), cachexia, diffuse leukoencephalopathy, peripheral neuropathy, and mitochondrial dysfunction. Mitochondrial DNA abnormalities can include depletion, deletion, and point mutations (Taanman et al., 2009). Genetic Heterogeneity of Autosomal Recessive Mitochondrial DNA Depletion Syndromes Autosomal recessive mitochondrial DNA depletion syndromes are clinically and genetically heterogeneous. See also MTDPS2 (609560), caused by mutation in the TK2 gene (188250); MTDPS3 (251880), caused by mutation in the DGUOK gene (601465); MTDPS4A (203700) and MTDPS4B (613662), both caused by mutation in the POLG gene (174763); MTDPS5 (612073), caused by mutation in the SUCLA2 gene (603921); MTDPS6 (256810), caused by mutation in the MPV17 gene (137960); MTDPS7 (271245), caused by mutation in the C10ORF2 gene (606075); MTDPS8A (612075) and MTDPS8B (see 612075), both caused by mutation in the RRM2B gene (604712); MTDPS9 (245400), caused by mutation in the SUCLG1 gene (611224); MTDPS10 (212350), caused by mutation in the AGK gene (610345); MTDPS11 (615084), caused by mutation in the MGME1 gene (615076); MTDPS12A (617184) and MTDPS12B (615418), both caused by mutation in the SLC25A4 gene (103220); MTDPS13 (615471), caused by mutation in the FBXL4 gene (605654); MTDPS14 (616896), caused by mutation in the OPA1 gene (605290); and MTDPS15 (617156), caused by mutation in the TFAM gene (600438).  http://www.omim.org/entry/603041
From GHR
Mitochondrial neurogastrointestinal encephalopathy (MNGIE) disease is a condition that affects several parts of the body, particularly the digestive system and nervous system. The major features of MNGIE disease can appear anytime from infancy to adulthood, but signs and symptoms most often begin by age 20. The medical problems associated with this disorder worsen with time.Abnormalities of the digestive system are among the most common and severe features of MNGIE disease. Almost all affected people have a condition known as gastrointestinal dysmotility, in which the muscles and nerves of the digestive system do not move food through the digestive tract efficiently. The resulting digestive problems include feelings of fullness (satiety) after eating only a small amount, trouble swallowing (dysphagia), nausea and vomiting after eating, episodes of abdominal pain, diarrhea, and intestinal blockage. These gastrointestinal problems lead to extreme weight loss and reduced muscle mass (cachexia).MNGIE disease is also characterized by abnormalities of the nervous system, although these tend to be milder than the gastrointestinal problems. Affected individuals experience tingling, numbness, and weakness in their limbs (peripheral neuropathy), particularly in the hands and feet. Additional neurological signs and symptoms can include droopy eyelids (ptosis), weakness of the muscles that control eye movement (ophthalmoplegia), and hearing loss. Leukoencephalopathy, which is the deterioration of a type of brain tissue known as white matter, is a hallmark of MNGIE disease. These changes in the brain can be seen with magnetic resonance imaging (MRI), though they usually do not cause symptoms in people with this disorder.  https://ghr.nlm.nih.gov/condition/mitochondrial-neurogastrointestinal-encephalopathy-disease

Clinical features

Abdominal pain
MedGen UID:
7803
Concept ID:
C0000737
Sign or Symptom
Your abdomen extends from below your chest to your groin. Some people call it the stomach, but your abdomen contains many other important organs. Pain in the abdomen can come from any one of them. The pain may start somewhere else, such as your chest. Severe pain doesn't always mean a serious problem. Nor does mild pain mean a problem is not serious. . Call your healthcare provider if mild pain lasts a week or more or if you have pain with other symptoms. Get medical help immediately if. - You have abdominal pain that is sudden and sharp. -You also have pain in your chest, neck or shoulder . - You're vomiting blood or have blood in your stool . - Your abdomen is stiff, hard and tender to touch . -You can't move your bowels, especially if you're also vomiting .
Ptosis
MedGen UID:
2287
Concept ID:
C0005745
Disease or Syndrome
The upper eyelid margin is positioned 3 mm or more lower than usual and covers the superior portion of the iris (objective); or, the upper lid margin obscures at least part of the pupil (subjective).
Progressive external ophthalmoplegia
MedGen UID:
102439
Concept ID:
C0162674
Disease or Syndrome
Progressive external ophthalmoplegia is a condition characterized by weakness of the eye muscles. The condition typically appears in adults between ages 18 and 40 and slowly worsens over time. The first sign of progressive external ophthalmoplegia is typically drooping eyelids (ptosis), which can affect one or both eyelids. As ptosis worsens, affected individuals may use the forehead muscles to try to lift the eyelids, or they may lift up their chin in order to see. Another characteristic feature of progressive external ophthalmoplegia is weakness or paralysis of the muscles that move the eye (ophthalmoplegia). Affected individuals have to turn their head to see in different directions, especially as the ophthalmoplegia worsens. People with progressive external ophthalmoplegia may also have general weakness of the muscles used for movement (myopathy), particularly those in the neck, arms, or legs. The weakness may be especially noticeable during exercise (exercise intolerance). Muscle weakness may also cause difficulty swallowing (dysphagia).When the muscle cells of affected individuals are stained and viewed under a microscope, these cells usually appear abnormal. These abnormal muscle cells contain an excess of cell structures called mitochondria and are known as ragged-red fibers.Although muscle weakness is the primary symptom of progressive external ophthalmoplegia, this condition can be accompanied by other signs and symptoms. In these instances, the condition is referred to as progressive external ophthalmoplegia plus (PEO+). Additional signs and symptoms can include hearing loss caused by nerve damage in the inner ear (sensorineural hearing loss), weakness and loss of sensation in the limbs due to nerve damage (neuropathy), impaired muscle coordination (ataxia), a pattern of movement abnormalities known as parkinsonism, and depression.Progressive external ophthalmoplegia is part of a spectrum of disorders with overlapping signs and symptoms. Similar disorders include ataxia neuropathy spectrum and Kearns-Sayre syndrome. Like progressive external ophthalmoplegia, the other conditions in this spectrum can involve weakness of the eye muscles. However, these conditions have many additional features not shared by most people with progressive external ophthalmoplegia.
Cachexia
MedGen UID:
2773
Concept ID:
C0006625
Sign or Symptom
Severe weight loss, wasting of muscle, loss of appetite, and general debility related to a chronic disease.
Abdominal pain
MedGen UID:
7803
Concept ID:
C0000737
Sign or Symptom
Your abdomen extends from below your chest to your groin. Some people call it the stomach, but your abdomen contains many other important organs. Pain in the abdomen can come from any one of them. The pain may start somewhere else, such as your chest. Severe pain doesn't always mean a serious problem. Nor does mild pain mean a problem is not serious. . Call your healthcare provider if mild pain lasts a week or more or if you have pain with other symptoms. Get medical help immediately if. - You have abdominal pain that is sudden and sharp. -You also have pain in your chest, neck or shoulder . - You're vomiting blood or have blood in your stool . - Your abdomen is stiff, hard and tender to touch . -You can't move your bowels, especially if you're also vomiting .
Constipation
MedGen UID:
1101
Concept ID:
C0009806
Sign or Symptom
Constipation means that a person has three or fewer bowel movements in a week. The stool can be hard and dry. Sometimes it is painful to pass. At one time or another, almost everyone gets constipated. In most cases, it lasts a short time and is not serious. . There are many things you can do to prevent constipation. They include - Eating more fruits, vegetables and grains, which are high in fiber. - Drinking plenty of water and other liquids. - Getting enough exercise. - Taking time to have a bowel movement when you need to. - Using laxatives only if your doctor says you should. - Asking your doctor if medicines you take may cause constipation. . It's not important that you have a bowel movement every day. If your bowel habits change, however, check with your doctor. . NIH: National Institute of Diabetes and Digestive and Kidney Diseases.
Vomiting
MedGen UID:
12124
Concept ID:
C0042963
Sign or Symptom
Forceful ejection of the contents of the stomach through the mouth by means of a series of involuntary spasmic contractions.
Gastroparesis
MedGen UID:
101809
Concept ID:
C0152020
Disease or Syndrome
Decreased strength of the Muscle layer of stomach, which leads to a decreased ability to empty the contents of the stomach despite the absence of obstruction.
Malnutrition
MedGen UID:
56429
Concept ID:
C0162429
Disease or Syndrome
Food provides the energy and nutrients you need to be healthy. If you don't get enough nutrients -- including proteins, carbohydrates, fats, vitamins, and minerals - you may suffer from malnutrition. Causes of malnutrition include:. -Lack of specific nutrients in your diet. Even the lack of one vitamin can lead to malnutrition. -An unbalanced diet. -Certain medical problems, such as malabsorption syndromes and cancers. Symptoms may include fatigue, dizziness, and weight loss. Or, you may have no symptoms. To diagnose the cause of the problem, your doctor may do blood tests and a nutritional assessment. Treatment may include replacing the missing nutrients and treating the underlying cause.
Intermittent diarrhea
MedGen UID:
66782
Concept ID:
C0239181
Sign or Symptom
Gastrointestinal dysmotility
MedGen UID:
324638
Concept ID:
C1836923
Finding
Abnormal intestinal contractions, such as spasms and intestinal paralysis, related to the loss of the ability of the gut to coordinate muscular activity because of endogenous or exogenous causes.
Malabsorption
MedGen UID:
811453
Concept ID:
C3714745
Finding
Impaired ability to absorb one or more nutrients from the intestine.
Sensorineural hearing loss
MedGen UID:
9164
Concept ID:
C0018784
Disease or Syndrome
Hearing loss resulting from damage to the COCHLEA and the sensorineural elements which lie internally beyond the oval and round windows. These elements include the AUDITORY NERVE and its connections in the BRAINSTEM.
Abdominal pain
MedGen UID:
7803
Concept ID:
C0000737
Sign or Symptom
Your abdomen extends from below your chest to your groin. Some people call it the stomach, but your abdomen contains many other important organs. Pain in the abdomen can come from any one of them. The pain may start somewhere else, such as your chest. Severe pain doesn't always mean a serious problem. Nor does mild pain mean a problem is not serious. . Call your healthcare provider if mild pain lasts a week or more or if you have pain with other symptoms. Get medical help immediately if. - You have abdominal pain that is sudden and sharp. -You also have pain in your chest, neck or shoulder . - You're vomiting blood or have blood in your stool . - Your abdomen is stiff, hard and tender to touch . -You can't move your bowels, especially if you're also vomiting .
Areflexia
MedGen UID:
115943
Concept ID:
C0234146
Finding
Absence of neurologic reflexes such as the knee-jerk reaction.
Leukoencephalopathy
MedGen UID:
78722
Concept ID:
C0270612
Disease or Syndrome
Any of various diseases affecting the white matter of the central nervous system.
Distal sensory impairment
MedGen UID:
335722
Concept ID:
C1847584
Finding
An abnormal reduction in sensation in the distal portions of the extremities.
Hypointensity of cerebral white matter on MRI
MedGen UID:
866563
Concept ID:
C4020908
Finding
A darker than expected signal on magnetic resonance imaging emanating from the cerebral white matter.
Gastroparesis
MedGen UID:
101809
Concept ID:
C0152020
Disease or Syndrome
Decreased strength of the Muscle layer of stomach, which leads to a decreased ability to empty the contents of the stomach despite the absence of obstruction.
Mitochondrial myopathy
MedGen UID:
56484
Concept ID:
C0162670
Disease or Syndrome
Mitochondrial diseases are a clinically heterogeneous group of disorders that arise as a result of dysfunction of the mitochondrial respiratory chain. They can be caused by mutation of genes encoded by either nuclear DNA or mitochondrial DNA (mtDNA). While some mitochondrial disorders only affect a single organ (e.g., the eye in Leber hereditary optic neuropathy [LHON]), many involve multiple organ systems and often present with prominent neurologic and myopathic features. Mitochondrial disorders may present at any age. Many individuals with a mutation of mtDNA display a cluster of clinical features that fall into a discrete clinical syndrome, such as the Kearns-Sayre syndrome (KSS), chronic progressive external ophthalmoplegia (CPEO), mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), myoclonic epilepsy with ragged-red fibers (MERRF), neurogenic weakness with ataxia and retinitis pigmentosa (NARP), or Leigh syndrome (LS). However, considerable clinical variability exists and many individuals do not fit neatly into one particular category, which is well-illustrated by the overlapping spectrum of disease phenotypes (including mitochondrial recessive ataxia syndrome (MIRAS) resulting from mutation of the nuclear gene POLG, which has emerged as a major cause of mitochondrial disease. Common clinical features of mitochondrial disease – whether involving a mitochondrial or nuclear gene – include ptosis, external ophthalmoplegia, proximal myopathy and exercise intolerance, cardiomyopathy, sensorineural deafness, optic atrophy, pigmentary retinopathy, and diabetes mellitus. Common central nervous system findings are fluctuating encephalopathy, seizures, dementia, migraine, stroke-like episodes, ataxia, and spasticity. A high incidence of mid- and late pregnancy loss is a common occurrence that often goes unrecognized.
Distal amyotrophy
MedGen UID:
338530
Concept ID:
C1848736
Disease or Syndrome
Muscular atrophy affecting muscles in the distal portions of the extremities.
Distal muscle weakness
MedGen UID:
355271
Concept ID:
C1864696
Finding
Reduced strength of the musculature of the distal extremities.
Ragged-red muscle fibers
MedGen UID:
477048
Concept ID:
C3275417
Finding
An abnormal appearance of muscle fibers observed on muscle biopsy. Ragged red fibers can be visualized with Gomori trichrome staining as irregular and intensely red subsarcolemmal zones, whereas the normal myofibrils are green. The margins of affect fibers appear red and ragged. The ragged-red is due to the accumulation of abnormal mitochondria below the plasma membrane of the muscle fiber, leading to the appearance of a red rim and speckled sarcoplasm.
Multiple mitochondrial DNA deletions
MedGen UID:
479006
Concept ID:
C3277376
Finding
The presence of multiple deletions of mitochondrial DNA (mtDNA).
Decreased activity of cytochrome C oxidase in muscle tissue
MedGen UID:
867360
Concept ID:
C4021724
Finding
An abnormally reduced activity of the enzyme cytochrome C oxidase in muscle tissue.
Subsarcolemmal accumulations of abnormally shaped mitochondria
MedGen UID:
505556
Concept ID:
CN003202
Finding
An abnormally increased number of mitochondria in the cytoplasma adjacent to the sarcolemma (muscle cell membrane), whereby the mitochondria also possess an abnormal morphology.
Lactic acidosis
MedGen UID:
1717
Concept ID:
C0001125
Disease or Syndrome
Acidosis caused by accumulation of lactic acid more rapidly than it can be metabolized. It may occur spontaneously or in association with diseases such as DIABETES MELLITUS; LEUKEMIA; or LIVER FAILURE.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVMitochondrial DNA depletion syndrome 1 (MNGIE type)

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