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Navajo neurohepatopathy(MTDPS6)

MedGen UID:
338045
Concept ID:
C1850406
Disease or Syndrome
Synonyms: Mitochondrial DNA depletion syndrome 6 (hepatocerebral type); MPV17 - Related Hepatocerebral Mitochondrial DNA Depletion Syndrome; MPV17- Related Hepatocerebral Mitochondrial DNA Depletion Syndrome; MPV17- Related Mitochondrial DNA Depletion Syndrome, Hepatocerebral Form; MTDPS6; Navajo neuropathy
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Autosomal recessive inheritance refers to genetic conditions that occur only when mutations are present in both copies of a given gene (i.e., the person is homozygous for a mutation, or carries two different mutations of the same gene, a state referred to as compound heterozygosity).
 
Gene: MPV17
Cytogenetic location: 2p23.3
OMIM®: 256810
Orphanet: ORPHA255229

Disease characteristics

MPV17-related hepatocerebral mitochondrial DNA (mtDNA) depletion syndrome is characterized by infantile-onset liver dysfunction that typically progresses to liver failure; neurologic involvement (developmental delay, hypotonia, and muscle weakness in the majority; ataxia, seizures, and motor and sensory peripheral neuropathy in some); failure to thrive; and metabolic derangements including lactic acidosis and hypoglycemic crises. Less frequent manifestations include renal tubulopathy, hypoparathyroidism, gastrointestinal dysmotility, and corneal anesthesia. Progressive liver disease often leads to death in infancy or early childhood. Hepatocellular carcinoma has been reported. [from GeneReviews]
Full text of GeneReview (by section):
Summary  |  GeneReview Scope  |  Diagnosis  |  Clinical Description  |  Differential Diagnosis  |  Management  |  Genetic Counseling  |  Resources  |  Molecular Genetics  |  References  |  Chapter Notes
Authors:
Ayman W El-Hattab  |  Fernando Scaglia  |  William J Craigen, et. al.   view full author information

Additional descriptions

From OMIM
Mitochondrial DNA depletion syndrome-6 is an autosomal recessive disorder characterized by infantile onset of progressive liver failure, often leading to death in the first year of life. Those that survive develop progressive neurologic involvement, including ataxia, hypotonia, dystonia, and psychomotor regression (Spinazzola et al., 2008). For a discussion of genetic heterogeneity of autosomal recessive mtDNA depletion syndromes, see MTDPS1 (603041).  http://www.omim.org/entry/256810
From GHR
MPV17-related hepatocerebral mitochondrial DNA depletion syndrome is an inherited disorder that can cause liver disease and neurological problems. The signs and symptoms of this condition begin in infancy and typically include vomiting, diarrhea, and an inability to grow or gain weight at the expected rate (failure to thrive). Many affected infants have a buildup of a chemical called lactic acid in the body (lactic acidosis) and low blood sugar (hypoglycemia). Within the first weeks of life, infants develop liver disease that quickly progresses to liver failure. The liver is frequently enlarged (hepatomegaly) and liver cells often have a reduced ability to release a digestive fluid called bile (cholestasis). Rarely, affected children develop liver cancer. After the onset of liver disease, many affected infants develop neurological problems, which can include developmental delay, weak muscle tone (hypotonia), and reduced sensation in the limbs (peripheral neuropathy). Individuals with MPV17-related hepatocerebral mitochondrial DNA depletion syndrome typically survive only into infancy or early childhood. MPV17-related hepatocerebral mitochondrial DNA depletion syndrome is most frequently seen in the Navajo population of the southwestern United States. In this population, the condition is known as Navajo neurohepatopathy. People with Navajo neurohepatopathy tend to have a longer life expectancy than those with MPV17-related hepatocerebral mitochondrial DNA depletion syndrome. In addition to the signs and symptoms described above, people with Navajo neurohepatopathy may have problems with sensing pain that can lead to painless bone fractures and self-mutilation of the fingers or toes. Individuals with Navajo neurohepatopathy may lack feeling in the clear front covering of the eye (corneal anesthesia), which can lead to open sores and scarring on the cornea, resulting in impaired vision. The cause of these additional features is unknown.  http://ghr.nlm.nih.gov/condition/mpv17-related-hepatocerebral-mitochondrial-dna-depletion-syndrome

Clinical features

Short stature
MedGen UID:
87607
Concept ID:
C0349588
Finding
Failure to thrive
MedGen UID:
776583
Concept ID:
C2364119
Finding
Nystagmus
MedGen UID:
409575
Concept ID:
C1963184
Finding
Recurrent corneal erosions
MedGen UID:
504466
Concept ID:
CN000463
Finding
The presence of recurrent corneal epithelial erosions. Although most corneal epithelial defects heal quickly, some may show recurrent ulcerations.
Hyporeflexia
MedGen UID:
101804
Concept ID:
C0151888
Finding
Areflexia
MedGen UID:
115943
Concept ID:
C0234146
Finding
Ataxia
MedGen UID:
504767
Concept ID:
CN001146
Finding
Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- oder overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
Global developmental delay
MedGen UID:
504774
Concept ID:
CN001157
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Dystonia
MedGen UID:
504804
Concept ID:
CN001220
Finding
An abnormally increased muscular tone that causes fixed abnormal postures. There is a slow, intermittent twisting motion that leads to exaggerated turning and posture of the extremities and trunk.
Decreased number of peripheral myelinated nerve fibers
MedGen UID:
505527
Concept ID:
CN003050
Finding
A loss of myelinated nerve fibers in the peripheral nervous system (in general, this finding can be observed on nerve biopsy).
Pain insensitivity
MedGen UID:
429077
Concept ID:
CN006129
Finding
Inability to perceive painful stimuli.
Sensorimotor neuropathy
MedGen UID:
429082
Concept ID:
CN006238
Finding
Painless fractures due to injury
MedGen UID:
325208
Concept ID:
C1837602
Finding
osteomyelitis leading to amputation due to slow healing fractures
MedGen UID:
351263
Concept ID:
C1864975
Finding
Increased susceptibility to fractures
MedGen UID:
394128
Concept ID:
C2676783
Finding
Macrovesicular hepatic steatosis
MedGen UID:
373290
Concept ID:
C1837256
Finding
A morphologic finding indicating intracytoplasmic fat accumulation in the liver parenchyma. Unlike microvesicular steatosis, the fat accumulation displaces the nucleus of the hepatocytes, creating a characteristic signet-ring appearance.
Reye syndrome-like episodes
MedGen UID:
340530
Concept ID:
C1850413
Finding
Diarrhea
MedGen UID:
368098
Concept ID:
C1963091
Finding
Vomiting
MedGen UID:
776588
Concept ID:
C2712332
Finding
Cirrhosis
MedGen UID:
504826
Concept ID:
CN001275
Finding
A chronic disorder of the liver in which liver tissue becomes scarred and is partially replaced by regenerative nodules and fibrotic tissue resulting in loss of liver function.
Microvesicular hepatic steatosis
MedGen UID:
504837
Concept ID:
CN001295
Finding
A form of hepatic steatosis characterized by the presence of small, lipid-laden vesicles in the affected hepatocytes.
Hepatomegaly
MedGen UID:
505165
Concept ID:
CN002031
Finding
Abnormally increased size of the liver.
Elevated hepatic transaminases
MedGen UID:
505403
Concept ID:
CN002632
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.
Acute hepatic failure
MedGen UID:
505930
Concept ID:
CN005710
Finding
Hepatic failure refers to the inability of the liver to perform its normal synthetic and metabolic functions, which can result in coagulopathy and alteration in the mental status of a previously healthy individual. Hepatic failure is defined as acute if there is onset of encephalopathy within 8 weeks of the onset of symptoms in a patient with a previously healthy liver.
Prolonged neonatal jaundice
MedGen UID:
505938
Concept ID:
CN005732
Finding
Neonatal jaundice refers to a yellowing of the skin and other tissues of a newborn infant as a result of increased concentrations of bilirubin in the blood. Neonatal jaundice affects over half of all newborns to some extent in the first week of life. Prolonged neonatal jaundice is said to be present if the jaundice persists for longer than 14 days in term infants and 21 days in preterm infants.
Acral ulceration and osteomyelitis leading to autoamputation of digits
MedGen UID:
376785
Concept ID:
C1850417
Finding
Prolonged neonatal jaundice
MedGen UID:
505938
Concept ID:
CN005732
Finding
Neonatal jaundice refers to a yellowing of the skin and other tissues of a newborn infant as a result of increased concentrations of bilirubin in the blood. Neonatal jaundice affects over half of all newborns to some extent in the first week of life. Prolonged neonatal jaundice is said to be present if the jaundice persists for longer than 14 days in term infants and 21 days in preterm infants.
Lactic acidosis
MedGen UID:
344523
Concept ID:
C1855560
Finding
Hypoglycemia
MedGen UID:
505016
Concept ID:
CN001757
Finding
A decreased concentration of glucose in the blood.
Abnormality of the immune system
MedGen UID:
427926
Concept ID:
CN002465
Finding
An abnormality of the immune system.
Distal muscle weakness
MedGen UID:
140883
Concept ID:
C0427065
Finding
Muscular hypotonia
MedGen UID:
504768
Concept ID:
CN001147
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.
Acral ulceration and osteomyelitis leading to autoamputation of digits
MedGen UID:
376785
Concept ID:
C1850417
Finding
Abnormality of the foot
MedGen UID:
427893
Concept ID:
CN001600
Finding
An abnormality of the skeleton of foot.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews

Recent clinical studies

Etiology

Wong LJ
Semin Neurol 2012 Feb;32(1):55-61. Epub 2012 Mar 15 doi: 10.1055/s-0032-1306387. PMID: 22422207
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. [Epub ahead of print] PMID: 20074988

Diagnosis

Wong LJ
Semin Neurol 2012 Feb;32(1):55-61. Epub 2012 Mar 15 doi: 10.1055/s-0032-1306387. PMID: 22422207
Holve S, Hu D, Shub M, Tyson RW, Sokol RJ
J Pediatr 1999 Oct;135(4):482-93. PMID: 10518083

Prognosis

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. [Epub ahead of print] PMID: 20074988
Holve S, Hu D, Shub M, Tyson RW, Sokol RJ
J Pediatr 1999 Oct;135(4):482-93. PMID: 10518083

Clinical prediction guides

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. [Epub ahead of print] PMID: 20074988
Holve S, Hu D, Shub M, Tyson RW, Sokol RJ
J Pediatr 1999 Oct;135(4):482-93. PMID: 10518083

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