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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; 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). [HPO:curators]
Autosomal recessive inheritance (HPO, OMIM, Orphanet)
 
Gene (location): DGUOK (2p13.1)
OMIM®: 251880
Orphanet: ORPHA279934

Definition

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]

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

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.
Ascites
MedGen UID:
416
Concept ID:
C0003962
Disease or Syndrome
Accumulation of fluid in the peritoneal cavity.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormal 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.
Hypoglycemia
MedGen UID:
6979
Concept ID:
C0020615
Disease or Syndrome
A decreased concentration of glucose in the blood.
Hypothermia
MedGen UID:
5720
Concept ID:
C0020672
Finding
Abnormally low body temperature.
Jaundice
MedGen UID:
43987
Concept ID:
C0022346
Sign or Symptom
A clinical manifestation of HYPERBILIRUBINEMIA, characterized by the yellowish staining of the SKIN; MUCOUS MEMBRANE; and SCLERA. Clinical jaundice usually is a sign of LIVER dysfunction.
Muscular hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
A condition of decreased tone of the skeletal muscles and diminished resistance to passive stretching.
Nystagmus
MedGen UID:
45166
Concept ID:
C0028738
Disease or Syndrome
Involuntary movements of the eye that are divided into two types, jerk and pendular. Jerk nystagmus has a slow phase in one direction followed by a corrective fast phase in the opposite direction, and is usually caused by central or peripheral vestibular dysfunction. Pendular nystagmus features oscillations that are of equal velocity in both directions and this condition is often associated with visual loss early in life. (Adams et al., Principles of Neurology, 6th ed, p272)
Seizures
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
Clinical or subclinical disturbances of cortical function due to a sudden, abnormal, excessive, and disorganized discharge of brain cells. Clinical manifestations include abnormal motor, sensory and psychic phenomena. Recurrent seizures are usually referred to as EPILEPSY or "seizure disorder."
Splenomegaly
MedGen UID:
52469
Concept ID:
C0038002
Finding
Abnormal enlargement of the spleen.
Thrombocytopenia
MedGen UID:
52737
Concept ID:
C0040034
Disease or Syndrome
A reduction in the number of circulating thrombocytes.
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
A disorder characterized by the inability of the liver to metabolize chemicals in the body. Causes include cirrhosis and drug-induced hepatotoxicity. Signs and symptoms include jaundice and encephalopathy. Laboratory test results reveal abnormal plasma levels of ammonia, bilirubin, lactic dehydrogenase, and alkaline phosphatase.
Hyperreflexia
MedGen UID:
57738
Concept ID:
C0151889
Finding
Autonomic nervous system overreaction to stimuli, most commonly after spinal cord injury at a T-5 level and above.
Polyneuropathy
MedGen UID:
57502
Concept ID:
C0152025
Disease or Syndrome
A disease or disorder affecting more than one nerve.
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.
Hypoalbuminemia
MedGen UID:
68694
Concept ID:
C0239981
Finding
A condition in which albumin level in blood (SERUM ALBUMIN) is below the normal range. Hypoalbuminemia may be due to decreased hepatic albumin synthesis, increased albumin catabolism, altered albumin distribution, or albumin loss through the urine (ALBUMINURIA).
Micronodular cirrhosis
MedGen UID:
75640
Concept ID:
C0267812
Disease or Syndrome
A type of cirrhosis characterized by the presence of small regenerative nodules.
Hyperbilirubinemia
MedGen UID:
86321
Concept ID:
C0311468
Finding
Abnormally high level of bilirubin in the blood. Excess bilirubin is associated with jaundice.
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.
Decreased activity of mitochondrial respiratory chain
MedGen UID:
324408
Concept ID:
C1835995
Finding
Decreased activity of the mitochondrial respiratory chain.
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.
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
Generalized hypotonia
MedGen UID:
346841
Concept ID:
C1858120
Finding
Generalized muscular hypotonia (abnormally low muscle tone).
Encephalopathy
MedGen UID:
368408
Concept ID:
C1963101
Finding
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
Inflammation of the liver related to lipid accumulation in fatty liver.
Growth delay
MedGen UID:
765377
Concept ID:
C3552463
Sign or Symptom
A deficiency or slowing down of growth pre- and postnatally.
Cerebral atrophy
MedGen UID:
892664
Concept ID:
C4020860
Disease or Syndrome
Depletion of mitochondrial DNA in liver
MedGen UID:
870570
Concept ID:
C4025018
Finding
An abnormal reduction in the number of mitochondria in hepatocytes.

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
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
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

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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