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Navajo neurohepatopathy(MTDPS6)

MedGen UID:
338045
Concept ID:
C1850406
Disease or Syndrome
Synonyms: 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
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): MPV17 (2p23.3)
OMIM®: 256810
Orphanet: ORPHA255229

Definition

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 GTR]

Additional descriptions

From GeneReviews
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.  https://www.ncbi.nlm.nih.gov/books/NBK92947
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.  https://ghr.nlm.nih.gov/condition/mpv17-related-hepatocerebral-mitochondrial-dna-depletion-syndrome

Clinical features

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)
Recurrent corneal erosions
MedGen UID:
56353
Concept ID:
C0155119
Disease or Syndrome
The presence of recurrent corneal epithelial erosions. Although most corneal epithelial defects heal quickly, some may show recurrent ulcerations.
Abnormality of the foot
MedGen UID:
8888
Concept ID:
C0016506
Anatomical Abnormality
Alterations or deviations from normal shape or size which result in a disfigurement of the foot.
Acral ulceration and osteomyelitis leading to autoamputation of digits
MedGen UID:
324836
Concept ID:
C1837603
Finding
Ulceration and osteomyelitis of the distal parts of the limbs associated with necrosis and spontaneous detachment of digits or parts of digits.
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.
Short stature
MedGen UID:
87607
Concept ID:
C0349588
Finding
A height below that which is expected according to age and gender norms. Although there is no universally accepted definition of short stature, many refer to \
Diarrhea
MedGen UID:
8360
Concept ID:
C0011991
Sign or Symptom
Abnormally increased frequency of loose or watery bowel movements.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormal enlargement of the liver.
Liver Cirrhosis
MedGen UID:
7368
Concept ID:
C0023890
Disease or Syndrome
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.
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.
Liver Failure, Acute
MedGen UID:
58125
Concept ID:
C0162557
Disease or Syndrome
A form of rapid-onset LIVER FAILURE, also known as fulminant hepatic failure, caused by severe liver injury or massive loss of HEPATOCYTES. It is characterized by sudden development of liver dysfunction and JAUNDICE. Acute liver failure may progress to exhibit cerebral dysfunction even HEPATIC COMA depending on the etiology that includes hepatic ISCHEMIA, drug toxicity, malignant infiltration, and viral hepatitis such as post-transfusion HEPATITIS B and HEPATITIS C.
Macrovesicular hepatic steatosis
MedGen UID:
373290
Concept ID:
C1837256
Finding
A form of hepatic steatosis characterized by the presence of large, lipid-laden vesicles in the affected hepatocytes.
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.
Reye syndrome-like episodes
MedGen UID:
340530
Concept ID:
C1850413
Finding
Repeated occurrences of acute noninflammatory encephalopathy and fatty degenerative liver failure.
Microvesicular hepatic steatosis
MedGen UID:
376784
Concept ID:
C1850415
Finding
A form of hepatic steatosis characterized by the presence of small, lipid-laden vesicles in the affected hepatocytes.
Prolonged neonatal jaundice
MedGen UID:
347108
Concept ID:
C1859236
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.
Cerebellar ataxia
MedGen UID:
849
Concept ID:
C0007758
Sign or Symptom
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).
Dystonia
MedGen UID:
3940
Concept ID:
C0013421
Sign or Symptom
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.
Areflexia
MedGen UID:
115943
Concept ID:
C0234146
Finding
A finding indicating the complete absence of neurological reflexes.
Pain insensitivity
MedGen UID:
488855
Concept ID:
C0344307
Finding
Inability to perceive painful stimuli.
Hyporeflexia
MedGen UID:
195967
Concept ID:
C0700078
Sign or Symptom
Reduction of neurologic reflexes such as the knee-jerk reaction.
Sensorimotor neuropathy
MedGen UID:
207266
Concept ID:
C1112256
Disease or Syndrome
Painless fractures due to injury
MedGen UID:
325208
Concept ID:
C1837602
Finding
An increased tendency to fractures following trauma, with fractures occurring without pain.
Decreased number of peripheral myelinated nerve fibers
MedGen UID:
346872
Concept ID:
C1858285
Finding
A loss of myelinated nerve fibers in the peripheral nervous system (in general, this finding can be observed on nerve biopsy).
Cognitive delay
MedGen UID:
351243
Concept ID:
C1864897
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.
Muscular hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
A condition of decreased tone of the skeletal muscles and diminished resistance to passive stretching.
Distal muscle weakness
MedGen UID:
355271
Concept ID:
C1864696
Finding
Reduced strength of the musculature of the distal extremities.
Osteomyelitis leading to amputation due to slow healing fractures
MedGen UID:
351263
Concept ID:
C1864975
Finding
Abnormality of the immune system
MedGen UID:
867388
Concept ID:
C4021753
Anatomical Abnormality
An abnormality of the immune system.
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
A decreased concentration of glucose in the blood.
Increased susceptibility to fractures
MedGen UID:
234655
Concept ID:
C1390474
Finding
An abnormally increased tendency to fractures of bones caused by an abnormal reduction in bone strength that is generally associated with an increased risk of fracture.
Painless fractures due to injury
MedGen UID:
325208
Concept ID:
C1837602
Finding
An increased tendency to fractures following trauma, with fractures occurring without pain.
Osteomyelitis leading to amputation due to slow healing fractures
MedGen UID:
351263
Concept ID:
C1864975
Finding
Acral ulceration and osteomyelitis leading to autoamputation of digits
MedGen UID:
324836
Concept ID:
C1837603
Finding
Ulceration and osteomyelitis of the distal parts of the limbs associated with necrosis and spontaneous detachment of digits or parts of digits.
Prolonged neonatal jaundice
MedGen UID:
347108
Concept ID:
C1859236
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.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
Follow this link to review classifications for Navajo neurohepatopathy in Orphanet.

Recent clinical studies

Etiology

Choi YR, Hong YB, Jung SC, Lee JH, Kim YJ, Park HJ, Lee J, Koo H, Lee JS, Jwa DH, Jung N, Woo SY, Kim SB, Chung KW, Choi BO
BMC Neurol 2015 Oct 5;15:179. doi: 10.1186/s12883-015-0430-1. PMID: 26437932Free PMC Article
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. PMID: 20074988

Diagnosis

Bitting CP, Hanson JA
Acta Gastroenterol Belg 2016 Sep-Dec;79(4):463-469. PMID: 28209105
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. 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. 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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