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Mitochondrial DNA depletion syndrome 1(MTDPS1)

MedGen UID:
1631838
Concept ID:
C4551995
Disease or Syndrome
Synonyms: Mitochondrial DNA depletion syndrome 1 (MNGIE type); Mitochondrial DNA Depletion Syndrome, MNGIE Form; Mitochondrial neurogastrointestinal encephalomyopathy syndrome; Mitochondrial Neurogastrointestinal Encephalopathy Disease; MITOCHONDRIAL NEUROGASTROINTESTINAL ENCEPHALOPATHY SYNDROME, TYMP-RELATED; MNGIE, TYMP-RELATED; POLIP SYNDROME; POLYNEUROPATHY, OPHTHALMOPLEGIA, LEUKOENCEPHALOPATHY, AND INTESTINAL PSEUDOOBSTRUCTION
 
Genes (locations): POLG (15q26.1); TYMP (22q13.33)
 
Monarch Initiative: MONDO:0011283
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 Mitochondrial DNA Depletion Syndromes Mitochondrial DNA depletion syndromes are clinically and genetically heterogeneous, and most are autosomal recessive disorders. 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); MTDPS15 (617156), caused by mutation in the TFAM gene (600438); MTDPS16 (618528), caused by mutation in the POLG2 gene (604983); MTDPS17 (618567), caused by mutation in the MRM2 gene (606906); MTDPS18 (618811), caused by mutation in the SLC25A21 gene (607571); MTDPS19 (618972), caused by mutation in the SLC25A10 gene (606794); and MTDPS20 (619780), caused by mutation in the LIG3 gene (600940).  http://www.omim.org/entry/603041
From MedlinePlus Genetics
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 over time.

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.

Almost all people with MNGIE disease 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).  https://medlineplus.gov/genetics/condition/mitochondrial-neurogastrointestinal-encephalopathy-disease

Clinical features

From HPO
Abdominal cramps
MedGen UID:
7801
Concept ID:
C0000729
Sign or Symptom
A type of abdominal pain characterized by a feeling of contractions and typically fluctuating in intensity.
Abdominal pain
MedGen UID:
7803
Concept ID:
C0000737
Sign or Symptom
An unpleasant sensation characterized by physical discomfort (such as pricking, throbbing, or aching) and perceived to originate in the abdomen.
Allodynia
MedGen UID:
105350
Concept ID:
C0458247
Finding
Pain due to a stimulus that does not normally provoke pain.
Areflexia of lower limbs
MedGen UID:
347285
Concept ID:
C1856694
Finding
Inability to elicit tendon reflexes in the lower limbs.
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.
Weight loss
MedGen UID:
853198
Concept ID:
C1262477
Finding
Reduction of total body weight.
Slender build
MedGen UID:
376828
Concept ID:
C1850573
Finding
Asthenic habitus refers to a slender build with long limbs, an angular profile, and prominent muscles or bones.
Constipation
MedGen UID:
1101
Concept ID:
C0009806
Sign or Symptom
Infrequent or difficult evacuation of feces.
Dysphagia
MedGen UID:
41440
Concept ID:
C0011168
Disease or Syndrome
Difficulty in swallowing.
Diarrhea
MedGen UID:
8360
Concept ID:
C0011991
Sign or Symptom
Abnormally increased frequency (usually defined as three or more) loose or watery bowel movements a day.
Colonic diverticula
MedGen UID:
3878
Concept ID:
C0012819
Disease or Syndrome
The presence of multiple diverticula of the colon.
Intestinal perforation
MedGen UID:
9525
Concept ID:
C0021845
Disease or Syndrome
A hole (perforation) in the wall of the intestine.
Intestinal pseudo-obstruction
MedGen UID:
5864
Concept ID:
C0021847
Disease or Syndrome
A functional rather than mechanical obstruction of the intestines, associated with manifestations that resemble those caused by an intestinal obstruction, including distension, abdominal pain, nausea, vomiting, constipation or diarrhea, in an individual in whom a mechanical blockage has been excluded.
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
A deficiency in the intake of energy and nutrients.
Hyperactive bowel sounds
MedGen UID:
534742
Concept ID:
C0232694
Finding
Abnormally increased gurgling/rumbling sounds made by the movement of fluid and gas in the intestines.
Intermittent diarrhea
MedGen UID:
66782
Concept ID:
C0239181
Sign or Symptom
Repeated episodes of diarrhea separated by periods without diarrhea.
Early satiety
MedGen UID:
536892
Concept ID:
C0239233
Sign or Symptom
The condition of being unable to eat a full meal because of a feeling of fullness (satiety), or or feeling very full after eating only a small amount of food.
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 disorder
MedGen UID:
9164
Concept ID:
C0018784
Disease or Syndrome
A type of hearing impairment in one or both ears related to an abnormal functionality of the cochlear nerve.
Hypoesthesia
MedGen UID:
6974
Concept ID:
C0020580
Finding
Decreased ability to perceive touch.
Peripheral neuropathy
MedGen UID:
18386
Concept ID:
C0031117
Disease or Syndrome
Peripheral neuropathy is a general term for any disorder of the peripheral nervous system. The main clinical features used to classify peripheral neuropathy are distribution, type (mainly demyelinating versus mainly axonal), duration, and course.
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
This term describes abnormality of the white matter of the cerebrum resulting from damage to the myelin sheaths of nerve cells.
Dementia
MedGen UID:
99229
Concept ID:
C0497327
Mental or Behavioral Dysfunction
A loss of global cognitive ability of sufficient amount to interfere with normal social or occupational function. Dementia represents a loss of previously present cognitive abilities, generally in adults, and can affect memory, thinking, language, judgment, and behavior.
Sensorimotor neuropathy
MedGen UID:
207266
Concept ID:
C1112256
Disease or Syndrome
Distal sensory impairment
MedGen UID:
335722
Concept ID:
C1847584
Finding
An abnormal reduction in sensation in the distal portions of the extremities.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
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.
Inborn mitochondrial myopathy
MedGen UID:
56484
Concept ID:
C0162670
Disease or Syndrome
A type of myopathy associated with mitochondrial disease and characterized by findings on biopsy such as ragged red muscle fibers.
Distal muscle weakness
MedGen UID:
140883
Concept ID:
C0427065
Finding
Reduced strength of the musculature of the distal extremities.
Distal amyotrophy
MedGen UID:
338530
Concept ID:
C1848736
Disease or Syndrome
Muscular atrophy affecting muscles in the distal portions of the 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).
Cytochrome C oxidase-negative muscle fibers
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:
871128
Concept ID:
C4025597
Anatomical Abnormality
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
An abnormal buildup of lactic acid in the body, leading to acidification of the blood and other bodily fluids.
Elevated circulating thymidine concentration
MedGen UID:
351077
Concept ID:
C1864226
Finding
Concentration of thymidine in the blood circulation above the normal range.
Elevated circulating deoxyuridine concentration
MedGen UID:
1814408
Concept ID:
C5676844
Finding
Concentration of 2-deoxyuridine in the blood circulation is above the normal range.
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).
Diplopia
MedGen UID:
41600
Concept ID:
C0012569
Disease or Syndrome
Diplopia is a condition in which a single object is perceived as two images, it is also known as double vision.
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).\n\nProgressive 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.\n\nWhen 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.\n\nAlthough 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.
Ophthalmoparesis
MedGen UID:
155551
Concept ID:
C0751401
Sign or Symptom
Ophthalmoplegia is a paralysis or weakness of one or more of the muscles that control eye movement.

Professional guidelines

PubMed

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