ABSTRACT
Liver involvement, a common feature in childhood mitochondrial hepatopathies, particularly in the neonatal period, may manifest as neonatal acute liver failure, hepatic steatohepatitis, cholestasis, or cirrhosis with chronic liver failure of insidious onset. There are usually significant neuromuscular symptoms, multisystem involvement, and lactic acidemia. The liver disease is usually progressive and eventually fatal. Current medical therapy of mitochondrial hepatopathies is largely ineffective, and the prognosis is usually poor. The role of liver transplantation in patients with liver failure remains poorly defined because of the systemic nature of the disease that does not respond to transplantation. Several specific molecular defects (mutations in nuclear genes such as SCO1, BCS1L, POLG, DGUOK, and MPV17 and deletion or rearrangement of mitochondrial DNA) have been identified in recent years. Prospective, longitudinal multicenter studies will be needed to address the gaps in our knowledge in these rare liver diseases.
KEYWORDS
Mitochondrial hepatopathies - genetics - pathogenesis
REFERENCES
1
Chinnery P F, DiMauro S.
Mitochondrial hepatopathies.
J Hepatol.
2005;
43
207-209
2
Sokol R J, Treem W R.
Mitochondria and childhood liver diseases.
J Pediatr Gastroenterol Nutr.
1999;
28
4-16
3
DiMauro S, Schon E A.
Mitochondrial respiratory-chain diseases.
N Engl J Med.
2003;
348
2656-2668
4
Johns D R.
Mitochondrial DNA and disease.
N Engl J Med.
1995;
333
638-644
5
Morris A A, Taanman J W, Blake J et al..
Liver failure associated with mitochondrial DNA depletion.
J Hepatol.
1998;
28
556-563
6
Labarthe F, Dobbelaere D, Devisme L et al..
Clinical, biochemical and morphological features of hepatocerebral syndrome with mitochondrial DNA depletion due to deoxyguanosine kinase deficiency.
J Hepatol.
2005;
43
333-341
7
Sutovsky P, Moreno R D, Ramalho-Santos J, Dominko T, Simerly C, Schatten G.
Ubiquitin tag for sperm mitochondria.
Nature.
1999;
402
371-372
8
Sutovsky P, Van Leyen K, McCauley T, Day B N, Sutovsky M.
Degradation of paternal mitochondria after fertilization: implications for heteroplasmy, assisted reproductive technologies and mtDNA inheritance.
Reprod Biomed Online.
2004;
8
24-33
9
Skladal D, Halliday J, Thornburn D R.
Minimum birth prevalence of mitochondrial respiratory chain disorders in children.
Brain.
2003;
126
1905-1912
10
Darin N, Oldfors A, Moslemi A R, Holme E, Tulinius M.
The incidence of mitochondrial encephalomyopathies in childhood: clinical features and morphological, biochemical, and DNA abnormalities.
Ann Neurol.
2001;
49
377-383
11
Cormier-Daire V, Chretien D, Rustin P et al..
Neonatal and delayed-onset liver involvement in disorders of oxidative phosphorylation.
J Pediatr.
1997;
130
817-822
12
Garcia-Cazorla A, De Lonlay P, Nassogne M C, Rustin P, Touati G, Saudubray J M.
Long-term follow-up of neonatal mitochondrial cytopathies: a study of 57 patients.
Pediatrics.
2005;
116
1170-1177
13
Holve S, Hu D, Shub M, Tyson R W, Sokol R J.
Liver disease in Navajo neuropathy.
J Pediatr.
1999;
135
482-493
14
Leonard J V, Shapiro A HV.
Mitochondrial respiratory chain disorders. I: mitochondrial DNA defects.
Lancet.
2000;
355
299-304
15
Von Kleist-Retzow J C, Cormier-Daire V, Viot G et al..
Antenatal manifestations of mitochondrial respiratory chain deficiency.
J Pediatr.
2003;
143
208-212
16
Moraes C T, Shanske S, Tritschler H J et al..
mtDNA depletion with variable tissue expression: a novel genetic abnormality in mitochondrial diseases.
Am J Hum Genet.
1991;
48
492-501
17
Bakker H D, Scholte H R, Dingemans K P, Spelbrink J N, Wijburg F A, Van der Bogert C.
Depletion of mitochondrial deoxyribonucleic acid in a family with fatal neonatal liver disease.
J Pediatr.
1996;
128
683-687
18
Narkewicz M R, Sokol R J, Beckwith B, Sondheimer J, Silverman A.
Liver involvement in Alpers disease.
J Pediatr.
1991;
119
260-267
19
Boyd S G, Harden A, Egger J, Pampiglione G.
Progressive neuronal degeneration of childhood with liver disease (“Alpers' disease”): characteristic neurophysiological features.
Neuropediatrics.
1986;
17
75-80
20
Tzoulis C, Engelsen B A, Telstad W et al..
The spectrum of clinical disease caused by the A467T and W748S POLG mutations: a study of 26 cases.
Brain.
2006;
129
1685-1692
21
Harding B N.
Progressive neuronal degeneration of childhood with liver disease (Alpers-Huttenlocher syndrome): a personal review.
J Child Neurol.
1990;
5
273-287
22
Egger J, Harding B N, Boyd S G, Wilson J, Erdohazi M.
Progressive neuronal degeneration of childhood (PNDC) with liver disease.
Clin Pediatr (Phila).
1987;
26
167-173
23
Gauthier-Villars M, Landrieu P, Cormier-Daire V et al..
Respiratory chain deficiency in Alpers syndrome.
Neuropediatrics.
2001;
32
150-152
24
Pearson H A, Lobel J S, Kocoshis S A et al..
A new syndrome of refractory sideroblastic anemia with vacuolization of marrow precursors and exocrine pancreatic dysfunction.
J Pediatr.
1979;
95
976-984
25
Morikawa Y, Matsuura N, Kakudo K, Higuchi R, Koike M, Kobayashi Y.
Pearson's marrow/pancreas syndrome: a histological and genetic study.
Virchows Arch A Pathol Anat Histopathol.
1993;
423
227-231
26
Krahenbuhl S, Kleinle S, Henz S et al..
Microvesicular steatosis, hemosiderosis and rapid development of liver cirrhosis in a patient with Pearson's syndrome.
J Hepatol.
1999;
31
550-555
27
Majander A, Suomalainen A, Vettenranta K et al..
Congenital hypoplastic anemia, diabetes, and severe renal tubular dysfunction associated with a mitochondrial DNA deletion.
Pediatr Res.
1991;
30
327-330
28
Cormier-Daire V, Bonnefont J P, Rustin P et al..
Mitochondrial DNA rearrangement with onset as chronic diarrhea with villous atrophy.
J Pediatr.
1994;
124
63-70
29
Singleton R, Helgerson S D, Snyder R D et al..
Neuropathy in Navajo children: clinical and epidemiologic features.
Neurology.
1990;
40
363-367
30
Robinson B H.
Lactic acidemia and mitochondrial disorders.
Mol Genet Metab.
2006;
89
3-13
31
Kreisberg R A.
Glucose-lactate inter-relations in man.
N Engl J Med.
1972;
287
132-137
32
Rustin P, Chretien D, Bourgeron T et al..
Biochemical and molecular investigations in respiratory chain deficiencies.
Clin Chim Acta.
1994;
228
35-51
33
Holt I J, Harding A E, Morgan-Hughes J A.
Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies.
Nature.
1988;
331
717-719
34
Cormier V, Rustin P, Bonnefont J P et al..
Hepatic failure in disorders of oxidative phosphorylation with neonatal onset.
J Pediatr.
1991;
119
951-954
35
Bohm M, Pronicka E, Karczmarewicz E et al..
Retrospective, multicentric study of 180 children with cytochrome c oxidase deficiency.
Pediatr Res.
2006;
59
21-26
36
Taanman J W.
Human cytochrome c oxidase: structure, function, and deficiency.
J Bioenerg Biomembr.
1997;
29
151-163
37
Valnot I, Osmond S, Gigarel N et al..
Mutations of the SCO1 gene in mitochondrial cytochrome c oxidase deficiency with neonatal-onset hepatic failure and encephalopathy.
Am J Hum Genet.
2000;
67
1104-1109
38
Sacconi S, Salviati L, Sue C M et al..
Mutation screening in patients with isolated cytochrome c oxidase deficiency.
Pediatr Res.
2003;
53
224-230
39
De Lonlay P, Valnot I, Barrientos A et al..
A mutant mitochondrial respiratory chain assembly protein causes complex III deficiency in patients with tubulopathy, encephalopathy and liver failure.
Nat Genet.
2001;
29
57-60
40
De Meirleir L, Seneca S, Damis E et al..
Clinical and diagnostic characteristics of complex III deficiency due to mutations in the BCS1L gene.
Am J Med Genet A.
2003;
121
126-131
41
Moraes C T, Shanske S, Tritschler H J et al..
mtDNA depletion with variable tissue expression: a novel genetic abnormality in mitochondrial diseases.
Am J Hum Genet.
1991;
48
492-501
42
Jullig M, Eriksson S.
Mitochondrial and submitochondrial localization of human deoxyguanosine kinase.
Eur J Biochem.
2000;
267
5466-5472
43
Wang L, Munch-Petersen B, Herrstrom Sjoberg A et al..
Human thymidine kinase 2: molecular cloning and characterisation of the enzyme activity with antiviral and cytostatic nucleoside substrates.
FEBS Lett.
1999;
443
170-174
44
Mandel H, Szargel R, Labay V et al..
The deoxyguanosine kinase gene is mutated in individuals with depleted hepatocerebral mitochondrial DNA.
Nat Genet.
2001;
29
337-341
45
Saada A, Shaag A, Mandel H, Nevo Y, Eriksson S, Elpeleg O.
Mutant mitochondrial thymidine kinase in mitochondrial DNA depletion myopathy.
Nat Genet.
2001;
29
342-344
46
Salviati L, Sacconi S, Mancuso M et al..
Mitochondrial DNA depletion and dGK gene mutations.
Ann Neurol.
2002;
52
311-317
47
Ferrari G, Lamantea E, Donati A et al..
Infantile hepatocerebral syndromes associated with mutations in the mitochondrial DNA polymerase-γA.
Brain.
2005;
128
723-731
48
Horvath R, Hudson G, Ferrari G et al..
Phenotypic spectrum associated with mutations of the mitochondrial polymerase γ gene.
Brain.
2006;
129
1674-1684
49
Spinazzola A, Viscomi C, Fernandez-Vizarra E et al..
MPV17 encodes an inner mitochondrial membrane protein and is mutated in infantile hepatic mitochondrial DNA depletion.
Nat Genet.
2006;
38
570-575
50
Naviaux R K, Nguyen K V.
POLG mutations associated with Alpers' syndrome and mitochondrial DNA depletion.
Ann Neurol.
2004;
55
706-712
51
Nguyen K V, Sharief F S, Chan S SL, Copeland W C, Naviaux R K.
Molecular diagnosis of Alpers syndrome.
J Hepatol.
2006;
45
108-116
52
Kaguni L S.
DNA polymerase γ: the mitochondrial replicase.
Annu Rev Biochem.
2004;
73
293-320
53
Naviaux R K, Nyhan W L, Barshop B A et al..
Mitochondrial DNA polymerase gamma deficiency and mtDNA depletion in a child with Alpers' syndrome.
Ann Neurol.
1999;
45
54-58
54
Lamantea E, Tiranti V, Bordoni A et al..
Mutations of mitochondrial DNA polymerase gammaA are a frequent cause of autosomal dominant or recessive progressive external ophthalmoplegia.
Ann Neurol.
2002;
52
211-219
55
Vu T H, Tanji K, Holve S A et al..
Navajo neurohepatopathy: a mitochondrial DNA depletion syndrome?.
Hepatology.
2001;
34
116-120
56
Karadimas C L, Vu T H, Holve S A et al..
Navajo neurohepatopathy is caused by a mutation in the MPV17 gene.
Am J Hum Genet.
2006;
79
544-548
57
Rotig A, Cormier V, Blanche S et al..
Pearson's marrow-pancreas syndrome: a multisystem mitochondrial disorder in infancy.
J Clin Invest.
1990;
86
1601-1608
58
Sano T, Ban K, Ichiki T et al..
Molecular and genetic analyses of two patients with Pearson's marrow-pancreas syndrome.
Pediatr Res.
1993;
34
105-110
59
Jacobs LJAM, Jongbloed R JE, Wijburg F A et al..
Pearson syndrome and the role of deletion dimers and duplications in the mtDNA.
J Inherit Metab Dis.
2004;
27
47-55
60 MITOMAP .A Human Mitochondrial Genome Database. Atlanta, GA; Center for Molecular Medicine, Emory University http://Available at: www.mitomap.org Accessed October 24, 2006
61
Muraki K, Sakura N, Ueda H, Kihara H, Goto Y.
Clinical implications of duplicated mtDNA in Pearson syndrome.
Am J Med Genet.
2001;
98
205-209
62
Gillis L A, Sokol R J.
Gastrointestinal manifestations of mitochondrial disease.
Gastroenterol Clin North Am.
2003;
32
789-817
63
Chinnery P, Majamaa K, Turnbull D, Thorburn D.
Treatment for mitochondrial disorders (review).
Cochrane Database Syst Rev.
2006;
(1)
CD004426
64
Mahoney D J, Parise G, Tarnopolsky M A.
Nutritional and exercise-based therapies in the treatment of mitochondrial disease.
Curr Opin Clin Nutr Metab Care.
2002;
5
619-629
65
Hart P E, Lodi R, Rajagopalan B et al..
Antioxidant treatment of patients with Freidreich ataxia: four year follow-up.
Arch Neurol.
2005;
62
621-626
66
Eleff S, Kennaway N G, Buist N R et al..
31P NMR study of improvement in oxidative phosphorylation by vitamin K3 and C in a patient with a defect in electron transport at complex III in skeletal muscle.
Proc Natl Acad Sci USA.
1984;
81
3529-3533
67
Chen R S, Huang C C, Chu N S.
Coenzyme Q10 treatment in mitochondrial encephalomyopathies: short-term double-blind, crossover study.
Eur Neurol.
1997;
37
212-218
68
Muller W, Reimers C D, Berninger T et al..
Coenzyme Q10 in ophthalmoplegia plus: a double blind, cross over therapeutic trial.
J Neurol Sci.
1990;
98(suppl)
442
69
Frei B, Kim M C, Ames B N.
Ubiquinol-10 is an effective lipid-soluble antioxidant at physiological concentrations.
Proc Natl Acad Sci USA.
1990;
87
4879-4883
70
Rodriguez M C, MacDonald J R, Mahoney D J, Parise G, Beal M F, Tarnopolsky M A.
Beneficial effects of creatinine, CoQ(10), and lipoic acid in mitochondrial disorders.
Muscle Nerve.
2007;
35
235-242
71
Rustin P, Bonnet D, Rotiq A, Munnich A, Sidi D.
Idebenone treatment in Freidreich patients: one-year-long randomized placebo-controlled trial.
Neurology.
2004;
62
524-525
72
Di Rocco M, Lamba L D, Minniti G, Caruso U, Naito E.
Outcome of thiamine treatment in a child with Leigh disease due to thiamine-responsive pyruvate dehydrogenase deficiency.
Eur J Paediatr Neurol.
2000;
4
115-117
73
Bugiani M, Lamantea E, Invernizzi F et al..
Effects of riboflavin in children with complex II deficiency.
Brain Dev.
2006;
28
576-581
74
Stacpoole P W, Kerr D S, Barnes C et al..
Controlled clinical trial of dichloroacetate for treatment of congenital lactic acidosis in children.
Pediatrics.
2006;
117
1519-1531
75
Oguro H, Iijima K, Takahashi K et al..
Successful treatment with succinate in a patient with MELAS.
Intern Med.
2004;
43
427-431
76
Schols L, Zange J, Abele M et al..
L-carnitine and creatine in Freidreich's ataxia: a randomized, placebo-controlled crossover trial.
J Neural Transm.
2005;
112
789-796
77
Kornblum C, Schroder R, Muller K et al..
Creatine has no beneficial effect on skeletal muscle energy metabolism in patients with single mitochondrial DNA deletions: a placebo-controlled, double-blind 31P-MRS crossover study.
Eur J Neurol.
2005;
12
300-309
78
Mowat D, Kirby D M, Kamatu K R, Kan A, Thorburn D R, Christodoulou J.
Respiratory chain complex III deficiency with pruritus, a novel vitamin responsive clinical feature.
J Pediatr.
1999;
134
352-354
79
Sokal E M, Sokol R, Cormier V et al..
Liver transplantation in mitochondrial respiratory chain disorders.
Eur J Pediatr.
1999;
158(suppl 2)
S81-S84
80
Thomson M, McKiernan P, Buckels J, Mayer D, Kelly D A.
Generalised mitochondrial cytopathy is an absolute contraindication to orthotopic liver transplant in childhood.
J Pediatr Gastroenterol Nutr.
1998;
26
478-481
81
Dubern B, Broue P, Dubinsson C et al..
Orthotopic liver transplantation for mitochondrial respiratory chain disorders: a study of 5 children.
Transplantation.
2001;
71
633-637
82
Delarue A, Paut O, Guys J-M et al..
Inappropriate liver transplantation in a child with Alpers-Huttenlocher syndrome misdiagnosed as valproate-induced acute liver failure.
Pediatr Transplant.
2000;
4
67-71
83 Cholestatic Liver Disease Consortium (CLiC) .Available at: http://rarediseasesnetwork.epi.usf.edu/clic/index.htm Accessed February 4, 2007
Ronald J SokolM.D.
Section of Pediatric Gastroenterology, Hepatology, and Nutrition, Box B290, The Children's Hospital
1056 E. 19th Avenue, Denver, CO 80218