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Genetic etiologies of mitochondrial hepatopathies presenting in neonates or infants

Genetic etiologies of mitochondrial hepatopathies presenting in neonates or infants
Mutation/syndrome Defect Onset/age of presentation Hepatic presentation Neurologic features Other features Diagnostic tests

DGUOK[1-3]

MIM #251880		 mtDNA depletion; complex I, III, IV Acute/early neonatal Neonatal liver failure, progressive cholestasis, neonatal hemochromatosis, hepatocellular carcinoma risk; can have isolated liver disease Hypotonia, developmental regression, nystagmus Lactic acidosis, hypoglycemia DGUOK sequence analysis

POLG[4,5]

MIM #203700		 mtDNA depletion; complex I, III, IV Acute/neonatal Neonatal liver failure, micro- or macrovesicular steatosis, cirrhosis Encephalopathy, seizures, myopathy, neuropathy, blindness, developmental regression Vomiting, GERD POLG sequence analysis or panel

MPV17/Navajo neurohepatopathy[6,7]

MIM #256810		 mtDNA depletion; complex I, III, IV Acute/neonatal Isolated neonatal/infant liver failure or in multisystem syndrome Progressive sensorimotor neuropathy; CNS white matter lesions Acidosis, FTT, corneal anesthesia/abrasions, acral mutilation MPV17 sequence analysis or panel

TWINKLE (C10ORF2)[8,9]

MIM #271245		 mtDNA depletion DNA helicase Acute/neonatal Neonatal liver failure, cirrhosis, elevated liver enzymes Encephalopathy (athetosis, ataxia, seizures), sensory neuropathy, deafness   C10ORF2 TWINKLE sequence analysis

TRMU[10,11]

MIM #613070		 Decreased mito translation (tRNA-modifying enzyme); complex I, III, IV Acute/neonatal Neonatal liver failure; some recover, possibly with cirrhosis     TRMU sequence analysis

TSFM, EFG1, EF-Tu, MRPS16[12]

MIM #609060		 Decreased mito translation (elongation) Acute/neonatal Liver dysfunction in infancy, hepatomegaly Hypotonia, dystonia Hypertrophic cardiomyopathy, tubulopathy Sequencing individual genes, eg, TSFM or exome sequencing

SUCLG1[13]

MIM #245400		 mtDNA depletion abnormal succinate synthesis; complex I, III, IV Acute/neonatal Neonatal liver failure, episodic liver failure Hypotonia/myopathy (progressive), hearing loss Acidosis, elevated methylmalonic acid SUCLG1 sequence analysis

BCS1L[14]

MIM #603358		 Complex III assembly deficiency Acute/neonatal Neonatal liver failure, cholestasis, hepatic iron overload   Growth failure, aminoaciduria, lactic acidosis, early death (GRACILE syndrome) BCS1L sequence analysis

SCO1[15]

MIM #220110		 Complex IV deficiency Acute/neonatal Neonatal liver failure, hepatomegaly Hypotonia Acidosis SCO1 sequence analysis

FARS2[16]

MIM #614946		 Phenylalanyl tRNA synthetase Acute/neonatal Neonatal liver failure (Alpers-like) Intractable seizures, encephalopathy   FARS2 sequence analysis on Nexgen

SLC25A20[17]

MIM #212138 		Carnitine acylcarnitine translocase deficiency (carnitine, FAO) Acute/neonatal Neonatal liver failure, steatohepatitis Myopathy Hypoglycemia, cardiomyopathy SLC25A20 sequence analysis

HADHA/LCHAD or trifunctional protein deficiency[18]

MIM #609015		 FAO defect Acute Hepatomegaly, fatty liver, elevated LFTs, cholestasis, liver failure, ALF Encephalopathy, peripheral neuropathy Acidosis, hypoglycemia, pigmentary retinopathy HADHA sequence analysis

CPT I deficiency[19]

MIM #255120		 Carnitine cycle FAO defect Acute/infancy Hepatomegaly, liver failure episodes Reye-like episodes of encephalopathy Hypoketotic hypoglycemia CPTIA sequence analysis

CPT II deficiency[19,20]

MIM #600649		 Carnitine cycle FAO defect Acute/severe neonatal Liver failure in infancy Seizures Hypoketotic hypoglycemia, cardiomyopathy, myopathy CPT2 sequence analysis
ALF: acute liver failure; CNS: central nervous system; CPT: carnitine palmitoyltransferase; FAO: fatty acid oxidation; FTT: failure to thrive; GERD: gastroesophageal reflux disease; GRACILE: growth retardation, aminoaciduria, cholestasis, iron overload, lactic acidosis, and early death; HADHA: hydroxyacyl-CoA deHase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase alpha subunit; LCHAD: long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency; LFTs: liver function tests; mtDNA: mitochondrial DNA; tRNA: transfer ribonucleic acid.
References:
  1. Dimmock DP, Zhang Q, Dionisi-Vici C, et al. Clinical and molecular features of mitochondrial DNA depletion due to mutations in deoxyguanosine kinase. Hum Mutat 2008; 29:330.
  2. 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.
  3. Pronicka E, Weglewska-Jurkiewicz A, Taybert J, et al. Post mortem identification of deoxyguanosine kinase (DGUOK) gene mutations combined with impaired glucose homeostasis and iron overload features in four infants with severe progressive liver failure. J Appl Genet 2011; 52:61.
  4. Saneto RP, Naviaux RK. Polymerase gamma disease through the ages. Dev Disabil Res Rev 2010;16:163–74.
  5. Tang S, Wang J, Lee N-C, et al. Mitochondrial DNA polymerase g mutations: an ever expanding molecular and clinical spectrum. J Med Genet 2011; 48:669.
  6. 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.
  7. Wong LJ, Brunetti-Pierri N, Zhang Q, et al. Mutations in the MPV17 gene are responsible for rapidly progressive liver failure in infancy. Hepatology 2007; 46:1218.
  8. Spinazzola A, Invernizzi F, Carrara F, et al. Clinical and molecular features of mitochondrial DNA depletion syndromes. J Inherit Metab Dis 2009; 32:143.
  9. Hakonen AH, Isohanni P, Paetau A, et al. Recessive Twinkle mutations in early onset encephalopathy with mtDNA depletion. Brain 2007; 130:3032.
  10. Schara U, von Kleist-Retzow JC, Lainka E, et al. Acute liver failure with subsequent cirrhosis as the primary manifestation of TRMU mutations. J Inherit Metab Dis 2011; 34:197.
  11. Zeharia A, Shaag A, Pappo O, et al. Acute infantile liver failure due to mutations in the TRMU gene. Am J Hum Genet 2009; 85:401.
  12. Vedrenne V, Galmiche L, Chretien D, et al. Mutation in the mitochondrial translation elongation factor EFTs results in severe infantile liver failure. J Hepatol 2012; 56:294.
  13. Van Hove JL, Saenz MS, Thomas JA, et al. Succinyl-CoA ligase deficiency: a mitochondrial hepatoencephalomyopathy. Pediatr Res 2010; 68:159.
  14. Kotarsky H, Karikoski R, Morgelin M, et al. Characterization of complex III deficiency and liver dysfuntion in GRACILE syndryome caused by a BCS1L mutation. Mitochondrion 2010; 10:497.
  15. 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.
  16. Elo JM, Yadavalli SS, Euro L, et al. Mitochondrial phenylalanyl-tRNA synthetase mutations underlie fatal infantile Alpers encephalopathy. Hum Mol Genet 2012; 21:4521.
  17. Lopriore E, Reinoud JBJG, Verhoeven NM, et al. Carnitine-acylcarnitine translocase deficiency: phenotype, residual enzyme activity and outcome. Eur J Pediatr 2001; 160:101.
  18. den Boer MEJ, Wanders RJA, Morris AAM, et al. Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: clinical presentation and follow-up of 50 patients. Pediatrics 2002; 109:99.
  19. Longo N, Amat di San Filippo C, Pasquali M. Disorders of carnitine transport and the carnitine cycle. Am J Med Genet C Semin Med Genet 2006; 142C:77.
  20. Olpin SE, Afifi A, Clark S, et al. Mutation and biochemical analysis in carnitine palmitoyltransferase type II (CPT II) deficiency. J Inherit Metab Dis 2003; 26:543.

Reproduced with permission from: Molleston JP, Sokol RJ, Karnsakul W, et al. Childhood Liver Disease Research Education Network (ChiLDREN). Evaluation of the child with suspected mitochondrial liver disease. J Pediatr Gastroenterol Nutr 2013; 57:269. DOI: 10.1097/MPG.0b013e31829ef67a. Copyright © 2013 ESPGHAN and NASPGHAN. Unauthorized reproduction of this material is prohibited.

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