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Mitochondrial DNA-depletion syndrome 3, hepatocerebral(MTDPS3)

MedGen UID:
462863
Concept ID:
C3151513
Disease or Syndrome
Synonyms: DGUOK-Related Mitochondrial DNA Depletion Syndrome, Hepatocerebral Form; Infantile-Onset Spinocerebellar Ataxia; MTDPS3
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)
 
Gene (location): DGUOK (2p13.1)
OMIM®: 251880
Orphanet: ORPHA279934

Disease characteristics

Excerpted from the GeneReview: Deoxyguanosine Kinase Deficiency
The two forms of deoxyguanosine kinase (DGUOK) deficiency are a neonatal multisystem disorder and an isolated hepatic disorder that presents later in infancy or childhood. The majority of affected individuals have the multisystem illness with hepatic disease (jaundice, cholestasis, hepatomegaly, and elevated transaminases) and neurologic manifestations (hypotonia, nystagmus, and psychomotor retardation) evident within weeks of birth. Those with isolated liver disease may also have renal involvement and some later develop mild hypotonia. Progressive hepatic disease is the most common cause of death in both forms. [from GeneReviews]
Authors:
Ayman W El-Hattab  |  Fernando Scaglia  |  Lee-Jun Wong   view full author information

Additional descriptions

From OMIM
Mitochondrial DNA depletion syndrome-3 is a severe autosomal recessive disorder characterized by onset in infancy of progressive liver failure and neurologic abnormalities, hypoglycemia, and increased lactate in body fluids. Affected tissues show both decreased activity of the mtDNA-encoded respiratory chain complexes (I, III, IV, and V) and mtDNA depletion (Mandel et al., 2001). For a discussion of genetic heterogeneity of autosomal recessive mtDNA depletion syndromes, see MTDPS1 (603041).  http://www.omim.org/entry/251880
From GHR
Deoxyguanosine kinase deficiency is an inherited disorder that can cause liver disease and neurological problems. Researchers have described two forms of this disorder. The majority of affected individuals have the more severe form, which is called hepatocerebral because of the serious problems it causes in the liver and brain.Newborns with the hepatocerebral form of deoxyguanosine kinase deficiency may have a buildup of lactic acid in the body (lactic acidosis) within the first few days after birth. They may also have weakness, behavior changes such as poor feeding and decreased activity, and vomiting. Affected newborns sometimes have low blood sugar (hypoglycemia) as a result of liver dysfunction. During the first few weeks of life they begin showing other signs of liver disease which may result in liver failure. They also develop progressive neurological problems including very weak muscle tone (severe hypotonia), abnormal eye movements (nystagmus) and the loss of skills they had previously acquired (developmental regression). Children with this form of the disorder usually do not survive past the age of 2 years.Some individuals with deoxyguanosine kinase deficiency have a milder form of the disorder without severe neurological problems. Liver disease is the primary symptom of this form of the disorder, generally becoming evident during infancy or childhood. Occasionally it first appears after an illness such as a viral infection. Affected individuals may also develop kidney problems. Mild hypotonia is the only neurological effect associated with this form of the disorder.  https://ghr.nlm.nih.gov/condition/deoxyguanosine-kinase-deficiency

Clinical features

Nystagmus
MedGen UID:
45166
Concept ID:
C0028738
Disease or Syndrome
Rhythmic, involuntary oscillations of one or both eyes related to abnormality in fixation, conjugate gaze, or vestibular mechanisms.
Abnormal conjugate eye movement
MedGen UID:
337198
Concept ID:
C1845274
Finding
Any deviation from the normal motor coordination of the eyes that allows for bilateral fixation on a single object.
Generalized aminoaciduria
MedGen UID:
339863
Concept ID:
C1847868
Finding
An increased concentration of all types of amino acid in the urine.
Portal hypertension
MedGen UID:
9375
Concept ID:
C0020541
Disease or Syndrome
Abnormal increase of resistance to blood flow within the hepatic PORTAL SYSTEM, frequently seen in LIVER CIRRHOSIS and conditions with obstruction of the PORTAL VEIN.
Failure to thrive
MedGen UID:
115900
Concept ID:
C0231246
Finding
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
Growth delay
MedGen UID:
765377
Concept ID:
C3552463
Sign or Symptom
A deficiency or slowing down of growth pre- and postnatally.
Ascites
MedGen UID:
416
Concept ID:
C0003962
Finding
Accumulation of fluid in the peritoneal cavity.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Enlargement of the liver.
Portal hypertension
MedGen UID:
9375
Concept ID:
C0020541
Disease or Syndrome
Abnormal increase of resistance to blood flow within the hepatic PORTAL SYSTEM, frequently seen in LIVER CIRRHOSIS and conditions with obstruction of the PORTAL VEIN.
Jaundice
MedGen UID:
43987
Concept ID:
C0022346
Sign or Symptom
Jaundice causes your skin and the whites of your eyes to turn yellow. Too much bilirubin causes jaundice. Bilirubin is a yellow chemical in hemoglobin, the substance that carries oxygen in your red blood cells. As red blood cells break down, your body builds new cells to replace them. The old ones are processed by the liver. If the liver cannot handle the blood cells as they break down, bilirubin builds up in the body and your skin may look yellow. . Many healthy babies have some jaundice during the first week of life. It usually goes away. However, jaundice can happen at any age and may be a sign of a problem. Jaundice can happen for many reasons, such as. - Blood diseases. - Genetic syndromes. - Liver diseases, such as hepatitis or cirrhosis. - Blockage of bile ducts . - Infections . - Medicines .
Splenomegaly
MedGen UID:
52469
Concept ID:
C0038002
Finding
Enlargement of the spleen.
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.
Hepatic failure
MedGen UID:
88444
Concept ID:
C0085605
Disease or Syndrome
severe inability of the liver to function normally, as evidenced by severe jaundice and abnormal levels of ammonia, bilirubin, alkaline phosphatase, glutamic oxaloacetic transaminase, lactic dehydrogenase, and reversal of the albumin/globulin ratio.
Micronodular cirrhosis
MedGen UID:
75640
Concept ID:
C0267812
Disease or Syndrome
A type of cirrhosis characterized by the presence of small regenerative nodules.
Elevated hepatic transaminases
MedGen UID:
338525
Concept ID:
C1848701
Finding
Elevations of the levels of SGOT and SGPT in the serum. SGOT (serum glutamic oxaloacetic transaminase) and SGPT (serum glutamic pyruvic transaminase) are transaminases primarily found in the liver and heart and are released into the bloodstream as the result of liver or heart damage. SGOT and SGPT are used clinically mainly as markers of liver damage.
Periportal fibrosis
MedGen UID:
337906
Concept ID:
C1849766
Finding
The presence of fibrosis affecting the interlobular stroma of liver.
Hepatocellular necrosis
MedGen UID:
343247
Concept ID:
C1855038
Disease or Syndrome
Feeding difficulties in infancy
MedGen UID:
436211
Concept ID:
C2674608
Finding
Impaired feeding performance of an infant as manifested by difficulties such as weak and ineffective sucking, brief bursts of sucking, and falling asleep during sucking. There may be difficulties with chewing or maintaining attention.
Hepatic steatosis
MedGen UID:
398225
Concept ID:
C2711227
Disease or Syndrome
The presence of steatosis in the liver.
Depletion of mitochondrial DNA in liver
MedGen UID:
870570
Concept ID:
C4025018
Finding
An abnormal reduction in the number of mitochondria in hepatocytes.
Seizure Disorders
MedGen UID:
4506
Concept ID:
C0014544
Disease or Syndrome
Epilepsy is a brain disorder that causes people to have recurring seizures. The seizures happen when clusters of nerve cells, or neurons, in the brain send out the wrong signals. People may have strange sensations and emotions or behave strangely. They may have violent muscle spasms or lose consciousness. Epilepsy has many possible causes, including illness, brain injury, and abnormal brain development. In many cases, the cause is unknown. Doctors use brain scans and other tests to diagnose epilepsy. It is important to start treatment right away. There is no cure for epilepsy, but medicines can control seizures for most people. When medicines are not working well, surgery or implanted devices such as vagus nerve stimulators may help. Special diets can help some children with epilepsy. NIH: National Institute of Neurological Disorders and Stroke.
Peripheral neuropathy
MedGen UID:
18386
Concept ID:
C0031117
Disease or Syndrome
Your peripheral nerves are the ones outside your brain and spinal cord. Like static on a telephone line, peripheral nerve disorders distort or interrupt the messages between the brain and the rest of the body. . There are more than 100 kinds of peripheral nerve disorders. They can affect one nerve or many nerves. Some are the result of other diseases, like diabetic nerve problems. Others, like Guillain-Barre syndrome, happen after a virus infection. Still others are from nerve compression, like carpal tunnel syndrome or thoracic outlet syndrome. In some cases, like complex regional pain syndrome and brachial plexus injuries, the problem begins after an injury. Some people are born with peripheral nerve disorders. Symptoms often start gradually, and then get worse. They include . - Numbness. - Pain. - Burning or tingling. - Muscle weakness. - Sensitivity to touch. Treatment aims to treat any underlying problem, reduce pain and control symptoms. NIH: National Institute of Neurological Disorders and Stroke.
Unspecified encephalopathy
MedGen UID:
39314
Concept ID:
C0085584
Disease or Syndrome
Encephalopathy is a term that means brain disease, damage, or malfunction. In general, encephalopathy is manifested by an altered mental state.
Hyperreflexia
MedGen UID:
57738
Concept ID:
C0151889
Finding
Hyperreflexia is the presence of hyperactive stretch reflexes of the muscles.
Cerebral degeneration
MedGen UID:
56343
Concept ID:
C0154671
Disease or Syndrome
Partial or complete wasting (loss) of brain tissue that was once present.
Microcephaly
MedGen UID:
473122
Concept ID:
C0424688
Finding
Occipito-frontal (head) circumference (OFC) less than -3 standard deviations compared to appropriate, age matched, normal standards (Ross JJ, Frias JL 1977, PMID:9683597). Alternatively, decreased size of the cranium.
Thrombocytopenia
MedGen UID:
52737
Concept ID:
C0040034
Disease or Syndrome
A reduction in the number of circulating thrombocytes.
Generalized aminoaciduria
MedGen UID:
339863
Concept ID:
C1847868
Finding
An increased concentration of all types of amino acid in the urine.
Muscular hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Muscular hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle), often involving reduced muscle strength. Hypotonia is characterized by a diminished resistance to passive stretching.
Splenomegaly
MedGen UID:
52469
Concept ID:
C0038002
Finding
Enlargement of the spleen.
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.
Hypoglycemia
MedGen UID:
6979
Concept ID:
C0020615
Disease or Syndrome
Hypoglycemia means low blood glucose, or blood sugar. Your body needs glucose to have enough energy. After you eat, your blood absorbs glucose. If you eat more sugar than your body needs, your muscles, and liver store the extra. When your blood sugar begins to fall, a hormone tells your liver to release glucose. In most people, this raises blood sugar. If it doesn't, you have hypoglycemia, and your blood sugar can be dangerously low. Signs include . -Hunger. -Shakiness. -Dizziness. -Confusion. -Difficulty speaking. -Feeling anxious or weak. In people with diabetes, hypoglycemia is often a side effect of diabetes medicines. Eating or drinking something with carbohydrates can help. If it happens often, your health care provider may need to change your treatment plan. You can also have low blood sugar without having diabetes. Causes include certain medicines or diseases, hormone or enzyme deficiencies, and tumors. Laboratory tests can help find the cause. The kind of treatment depends on why you have low blood sugar. NIH: National Institute of Diabetes and Digestive and Kidney Diseases.
Hypothermia
MedGen UID:
5720
Concept ID:
C0020672
Finding
Reduced body temperature due to failed thermoregulation.
Hypoalbuminemia
MedGen UID:
68694
Concept ID:
C0239981
Finding
Reduced serum albumin concentration
Hyperbilirubinemia
MedGen UID:
86321
Concept ID:
C0311468
Finding
An increased amount of bilirubin in the blood.
Decreased activity of mitochondrial respiratory chain
MedGen UID:
324408
Concept ID:
C1835995
Finding
Decreased activity of the mitochondrial respiratory chain.
Generalized aminoaciduria
MedGen UID:
339863
Concept ID:
C1847868
Finding
An increased concentration of all types of amino acid in the urine.
Microcephaly
MedGen UID:
473122
Concept ID:
C0424688
Finding
Occipito-frontal (head) circumference (OFC) less than -3 standard deviations compared to appropriate, age matched, normal standards (Ross JJ, Frias JL 1977, PMID:9683597). Alternatively, decreased size of the cranium.
Microcephaly
MedGen UID:
473122
Concept ID:
C0424688
Finding
Occipito-frontal (head) circumference (OFC) less than -3 standard deviations compared to appropriate, age matched, normal standards (Ross JJ, Frias JL 1977, PMID:9683597). Alternatively, decreased size of the cranium.
Jaundice
MedGen UID:
43987
Concept ID:
C0022346
Sign or Symptom
Jaundice causes your skin and the whites of your eyes to turn yellow. Too much bilirubin causes jaundice. Bilirubin is a yellow chemical in hemoglobin, the substance that carries oxygen in your red blood cells. As red blood cells break down, your body builds new cells to replace them. The old ones are processed by the liver. If the liver cannot handle the blood cells as they break down, bilirubin builds up in the body and your skin may look yellow. . Many healthy babies have some jaundice during the first week of life. It usually goes away. However, jaundice can happen at any age and may be a sign of a problem. Jaundice can happen for many reasons, such as. - Blood diseases. - Genetic syndromes. - Liver diseases, such as hepatitis or cirrhosis. - Blockage of bile ducts . - Infections . - Medicines .

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
Follow this link to review classifications for Mitochondrial DNA-depletion syndrome 3, hepatocerebral in Orphanet.

Recent clinical studies

Etiology

Sezer T, Ozçay F, Balci O, Alehan F
J Child Neurol 2015 Jan;30(1):124-8. Epub 2014 Jan 14 doi: 10.1177/0883073813517000. PMID: 24423689
Navarro-Sastre A, Tort F, Garcia-Villoria J, Pons MR, Nascimento A, Colomer J, Campistol J, Yoldi ME, López-Gallardo E, Montoya J, Unceta M, Martinez MJ, Briones P, Ribes A
Mol Genet Metab 2012 Nov;107(3):409-15. Epub 2012 Aug 31 doi: 10.1016/j.ymgme.2012.08.018. PMID: 22980518
El-Hattab AW, Li FY, Schmitt E, Zhang S, Craigen WJ, Wong LJ
Mol Genet Metab 2010 Mar;99(3):300-8. Epub 2009 Oct 13 doi: 10.1016/j.ymgme.2009.10.003. PMID: 20074988
Brahimi N, Jambou M, Sarzi E, Serre V, Boddaert N, Romano S, de Lonlay P, Slama A, Munnich A, Rötig A, Bonnefont JP, Lebre AS
Mol Genet Metab 2009 Jul;97(3):221-6. Epub 2009 Mar 27 doi: 10.1016/j.ymgme.2009.03.007. PMID: 19394258
Tadiboyina VT, Rupar A, Atkison P, Feigenbaum A, Kronick J, Wang J, Hegele RA
Am J Med Genet A 2005 Jun 15;135(3):289-91. doi: 10.1002/ajmg.a.30748. PMID: 15887277

Diagnosis

Vilarinho S, Choi M, Jain D, Malhotra A, Kulkarni S, Pashankar D, Phatak U, Patel M, Bale A, Mane S, Lifton RP, Mistry PK
J Hepatol 2014 Nov;61(5):1056-63. Epub 2014 Jul 10 doi: 10.1016/j.jhep.2014.06.038. PMID: 25016221Free PMC Article
Navarro-Sastre A, Tort F, Garcia-Villoria J, Pons MR, Nascimento A, Colomer J, Campistol J, Yoldi ME, López-Gallardo E, Montoya J, Unceta M, Martinez MJ, Briones P, Ribes A
Mol Genet Metab 2012 Nov;107(3):409-15. Epub 2012 Aug 31 doi: 10.1016/j.ymgme.2012.08.018. PMID: 22980518
Al-Jasmi F, Penefsky HS, Souid AK
Mol Genet Metab 2011 Dec;104(4):529-36. Epub 2011 Sep 23 doi: 10.1016/j.ymgme.2011.09.023. PMID: 21996136

Therapy

Parini R, Furlan F, Notarangelo L, Spinazzola A, Uziel G, Strisciuglio P, Concolino D, Corbetta C, Nebbia G, Menni F, Rossi G, Maggioni M, Zeviani M
J Hepatol 2009 Jan;50(1):215-21. Epub 2008 Oct 31 doi: 10.1016/j.jhep.2008.08.019. PMID: 19012992

Prognosis

Al-Hussaini A, Faqeih E, El-Hattab AW, Alfadhel M, Asery A, Alsaleem B, Bakhsh E, Ali A, Alasmari A, Lone K, Nahari A, Eyaid W, Al Balwi M, Craig K, Butterworth A, He L, Taylor RW
J Pediatr 2014 Mar;164(3):553-9.e1-2. Epub 2013 Dec 8 doi: 10.1016/j.jpeds.2013.10.082. PMID: 24321534
Prasad C, Melançon SB, Rupar CA, Prasad AN, Nunez LD, Rosenblatt DS, Majewski J
Mol Genet Metab 2013 Mar;108(3):190-4. Epub 2012 Dec 31 doi: 10.1016/j.ymgme.2012.12.007. PMID: 23375728
El-Hattab AW, Li FY, Schmitt E, Zhang S, Craigen WJ, Wong LJ
Mol Genet Metab 2010 Mar;99(3):300-8. Epub 2009 Oct 13 doi: 10.1016/j.ymgme.2009.10.003. PMID: 20074988
Brahimi N, Jambou M, Sarzi E, Serre V, Boddaert N, Romano S, de Lonlay P, Slama A, Munnich A, Rötig A, Bonnefont JP, Lebre AS
Mol Genet Metab 2009 Jul;97(3):221-6. Epub 2009 Mar 27 doi: 10.1016/j.ymgme.2009.03.007. PMID: 19394258
Spinazzola A, Santer R, Akman OH, Tsiakas K, Schaefer H, Ding X, Karadimas CL, Shanske S, Ganesh J, Di Mauro S, Zeviani M
Arch Neurol 2008 Aug;65(8):1108-13. doi: 10.1001/archneur.65.8.1108. PMID: 18695062

Clinical prediction guides

Chanprasert S, Wang J, Weng SW, Enns GM, Boué DR, Wong BL, Mendell JR, Perry DA, Sahenk Z, Craigen WJ, Alcala FJ, Pascual JM, Melancon S, Zhang VW, Scaglia F, Wong LJ
Mol Genet Metab 2013 Sep-Oct;110(1-2):153-61. Epub 2013 Jul 17 doi: 10.1016/j.ymgme.2013.07.009. PMID: 23932787
El-Hattab AW, Li FY, Schmitt E, Zhang S, Craigen WJ, Wong LJ
Mol Genet Metab 2010 Mar;99(3):300-8. Epub 2009 Oct 13 doi: 10.1016/j.ymgme.2009.10.003. PMID: 20074988
Brahimi N, Jambou M, Sarzi E, Serre V, Boddaert N, Romano S, de Lonlay P, Slama A, Munnich A, Rötig A, Bonnefont JP, Lebre AS
Mol Genet Metab 2009 Jul;97(3):221-6. Epub 2009 Mar 27 doi: 10.1016/j.ymgme.2009.03.007. PMID: 19394258

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