Case 3 -
Mitochondrial DNA Depletion Syndrome (primarily Hepatic) with Metabolic Hepatopathy
University of British Columbia
Vancouver, British Columbia
Click on each slide thumbnail image for an enlarged view
A male infant was born at term gestation following a normal pregnancy and was normal in early infancy.
The mother in a previous marriage had one normal child, a girl, now 6 years old and healthy. The baby
under discussion is the second born with her current spouse; the first born, a male, developed
progressively worsening liver failure and died at 9 months – an etiologic diagnosis was not established.
This the second male baby presented at 3 months with poor feeding, irritability, lethargy and jaundice.
The infant had hepatomegaly of 4 cm. Investigations demonstrated hypoglycemia, conjugated
hyperbilirubinemia, elevated alkaline phosphatase 574 (normal 110-320 units), AST 190 (normal 20-60
units), ALT 144 (6-50 units), GGT 624, amino acid analysis, abnormal but not specific and in keeping with
liver disease, organic acid analysis normal, alpha feto protein elevated (300,000 units), very long chain
fatty acids, normal, lactate elevated , 7.6 units, no ketosis, ammonia elevated, 40 units, prolonged PT,
total carnitine normal, free carnitine markedly reduced , 0.8 (normal 30.3 – 40.5) acyl carnitine profile
normal, 93.1. All studies for an infectious etiology were negative. Muscle and liver biopsies were
done; the muscle biopsy by H and E, histochemistry and electron microscopy was normal. Mitochondrial DNA
depletion was documented in liver, but not in fibroblasts. A mutation in the deoxyguanosine kinase (dGK)
gene was excluded.
Case 3 - Figure 1 - The light microscopic slides of liver show steatosis cholestasis and minimal portal mononuclear inflammation. The electron microscopic photograph demonstrates hepatic mitochondrial pleomorphism.
Case 3 - Figure 2 - The light microscopic slides of liver show steatosis cholestasis and minimal portal mononuclear inflammation. The electron microscopic photograph demonstrates hepatic mitochondrial pleomorphism.
Case 3 - Figure 3 - The light microscopic slides of liver show steatosis cholestasis and minimal portal mononuclear inflammation. The electron microscopic photograph demonstrates hepatic mitochondrial pleomorphism.
Case 3 - Figure 4 - The light microscopic slides of liver show steatosis cholestasis and minimal portal mononuclear inflammation. The electron microscopic photograph demonstrates hepatic mitochondrial pleomorphism.
The liver biopsy is demonstated in the slides. The liver biopsy was obtained before the DNA studies
were done. The interpretation favoring a metabolic disorder (endogenous toxic) or perhaps exogenous
toxic insult, was based especially on the findings of steatosis and abnormal mitochondria.
Cholestatsis, modest numbers of hepatocellular giant cells , apoptotic cells, mild ductular
proliferation and portal fibrosis and minimal inflammation were present too. Some hepatocytes had an
oncocytic quality. The histopathologic differential diagnosis because of giant cells, cholestasis and
inflammation may include so called Neonatal Hepatitis but the finding of steatosis and abnormal
mitochondria should move one to consider the metabolic disorders of Hereditary Tyrosinemia, Galactosemia,
Peroxisomopathies, and Mitochondriopathies. A disorder of bile acid synthesis was considered less likely
because of the presence of steatosis.
Metabolic hepatopathy, with steatosis (microvesicular), cholestasis, abnormal mitochondria,
Final Clinical-Pathologic Diagnosis - Mitochondrial DNA depletion syndrome (primarily hepatic) with metabolic hepatopathy
Mitochondrial DNA depletion syndromes are rare and only have been known to exist for about the last
decade.1-3 The defect is not in the mtDNA but is quantitative and leads to impaired function of the
respiratory chain. The depletion is not maternally inherited but is autosomal recessive or perhaps
autosomal dominant with incomplete penetration. The defect causing the depletion lies in the nuclear DNA
and can be corrected in complementation studies by using normal nuclei. 4
Patients with mitochondrial DNA depletion manifest differently depending on the tissue(s) affected..4
Some will have myopathy, encephalopathy, hepatopathy, or renal tubulopathy in combination or sometimes
with one predominating or expressed singly. Few have had isolated or predominating hepatic disease.5
Navajo neurohepatopathy seems to be a newcomer to the group 6
Depletion of mtDNA is known to be present in the fetus in as much as it has been identified in
amniocytes and yet manifestations do not occur in the fetus or immediate newborn period and pregnancies
are usually normal.7 The defective control of mtDNA seems to appear after birth.
There are many many genes that control mtDNA. 8 Poulton et al demonstrated that the human
mitochondrial transcription factor A (TFAM) was deficient in cells depleted of mtDNA.9 This factor
regulates transcription and replication of mtDNA. Its deficiency may be a signal of or a cause of mtDNA
depletion. Mitochondrial DNA synthesis requires a supply of deoxyribonucleotides that come from a
salvage pathway regulated by two mitochondrial enzymes, deoxyguanosine kinase and thymidine kinase that
together are capable of providing all four deoxyribonecleotides. The deoxyguanosine kinase gene maps to
a region at chromosome 2p13 and has been found mutated in the hepatocerebral form of mt DNA depletion 10 Salviati
et al describe similar patients including one with a missense mutation that had isolated
hepatopathy. .11 Saada et al describe mt DNA depletion myopathy due to deletion in the thymidine
kinase gene.12 Mitochondrial DNA depletion also may be acquired. Patients treated with nucleoside
analogs can develop lactic acidosis and hepatic steatosis secondary to mtDNA depletion that is due to the
analog inhibition of DNA polymerase. 13
Hepatic pathological changes of mtDNA depletion consistently feature steatosis and abnormal
mitochondria in the small number reported.10,14, personal experience At onset the liver may have a
giant cell hepatitis appearance but with steatosis that should signal an underlying metabolic
derangement. As the liver disease progresses fibrosis and micronodular cirrhosis evolves and in the
brother of our case a small hepatoblastoma arose. Hepatocellular giant cells, cholestasis, cytoplasmic
and cannalicular, occur and unlike Idiopathic Neonatal Hepatitis some hepatocytes develop an oncocytic
appearance. Notably, and representing a good argument for undertaking electron microscopy on liver
biopsies, the mitochondria in mtDNA depletion are increased in number, pleomorphic, have rarifed matrix,
and reduced and dilated cristae. This finding coupled with steatosis and oncocytic hepatocytes should
raise the strong possibility of a mitochondrial-metabolic disorder. Histocytochemistry will reveal
reduced activity of those enzymes mtDNA encoded, such as cytochrome c oxidase, although a mosaic pattern
may be found.14 Southern blot analysis is required to demonstrate mtDNA depletion.
- Moraes CT, Shanske S, Tritschler H-J
et al. mtDNA depletion with variable tissue expression: a novel genetic abnormality in mitochondrial
disease. Am J Hum Genet 1991; 48: 492-501
- Mazziotta MRM, Ricci E, Bertini E et al. Fatal
infantile liver failure associated with mitochondrial DNA depletion. J Pediatr 1992; 121: 896-901
- Tritschler H-J, Andreeta F, Moraes CT, et al Mitochondrial myopathy of childhood with depletion of
mitochondrial DNA. Neurology 1992; 42: 209-217
- Taanman J-W, Bodnar AG, Cooper JM, et al.
Molecular mechanisms in mitochondrial DNA depletion syndrome. Hum Molec Genet 1997; 6: 935-942
- Ducluzeau P-H, Lachaux A, Bouvier R et al. Depletion of mitochondrial DNA associated with infantile
cholestasis and progressive liver fibrosis. J Hepat 1999; 30: 149-155
- Vu TH, Tanji K, Holve
SA et al. Navajo neurohepatopathy: a mitochondrial DNA depletion syndrome? Hepatology 2001; 34:
- Blake JC, Taanman J-W, Morris AMM et al. Mitochondrial DNA depletion syndrome is
expressed in amniotic fluid cell cultures. Am J Path 1999; 155: 67-70
- Suomalainen A, Kaukonen
J. Diseases caused by nuclear genes affecting mtDNA stability. Am J Med Genet 2001; 106 ( suppl)
- Poulten J, Morten K, Freeman-Emmerson C et al Deficiency of the human mitochondrial
transcription factor h-mtTFA in infantile mitochondrial myopathy iis associated with mtDNA depletion.
Hum Molec Genet 1994; 3: 1763-1769
- Mandel H, Szargel R, Labay V et al. The deoxguanosine
kinasr gene is mutated in individuals with depleted hepatocerebral mitochondrial DNA. Nature Genet 2001;
- Salviati L, Sacconi S, Mancuso M et al. Mitochondrial DNA depletion and dGK gene
mutations. Ann Neurol 2002; 52: 311-317
- Saada A, Shaag A, Mandel H et al. Mutant
mitochondrial thymidine kinase in mitochondrial DNA depletion myopathy. Nature Genet 2001; 29:
- Cote HC, Brumme ZL, Craib KJ et al. Changes in mitochondrial DNA as a marker of
nucleoside toxicity in HIV-infected patients. N Engl J Med 2002; 346: 811-820
J, Muntau A, Schafer S et al. Depletion of mitochondrial DNA in the liver of an infant with neonatal
giant cell hepatitis. Hum Pathol 2002; 33: 247-253