Polymerase gamma deficiency (POLG): Clinical course in a child with two stage evolution from infantile myocerebrohepatopathy spectrum to an Alpers syndrome and neuropathological findings of Leigh's encephalopathy

Division of Paediatric Neurology, Centre Hospitalier de Luxembourg, Luxembourg.
European journal of paediatric neurology: EJPN: official journal of the European Paediatric Neurology Society (Impact Factor: 2.3). 02/2012; 16(5):542-8. DOI: 10.1016/j.ejpn.2012.01.013
Source: PubMed


Description of the clinical course in a child compound heterozygous for POLG1 mutations, neuropathology findings and results of dietary treatment based on fasting avoidance and long chain triglycerides (LCT) restriction.
At 3(1/2) months of age the patient presented with severe hypoglycemia, hyperlactatemia, moderate ketosis and hepatic failure. Fasting hypoglycemia occurred 8 h after meals. The hypoglycemia did not respond to glucagon. She was supplemented with IV glucose and/or frequent feedings, but developed liver insufficiency which was reversed by long-chain triglyceride (LCT) restriction. Alpha-foeto-protein (AFP) levels were elevated and returned to low values after dietary treatment. Liver biopsy displayed cirrhosis, bile ductular proliferation, steatosis, isolated complex IV defect in part of the liver mitochondria, and mitochondrial DNA depletion (27% of control values). Two heterozygous mutations (p. [Ala467Thr] + p. [Gly848Ser]) were found in the POLG1 gene. At 3 years of age she progressively developed refractory mixed type seizures including a focal component and psychomotor regression which fulfilled the criteria of Alpers syndrome (AS) although the initial presentation was compatible with infantile myocerebrohepatopathy spectrum (MCHS). She died at 5 years of age of respiratory insufficiency. Neuropathologic investigation revealed lesions in the right striatal area and the inferior colliculi typical for Leigh's encephalopathy.
The present patient showed an evolution from infantile MCHS to AS, and dietary treatment seemed to slow the progression of liver failure. In spite of the late clinical features of AS, it extends the neuropathological spectrum of AS and polymerase gamma deficiency (POLG) to Leigh syndrome lesions.

Download full-text


Available from: Emmanuel Scalais, Nov 30, 2015
  • Source
    • "Interestingly the authors describe that their patient did not respond to glucagon, a response that could be consistent with GDE deficiency depending on the fasting time. Due to the many similarities between our patient and the one previously published (Roels et al. 2009; Scalais et al. 2012), one may speculate whether our findings are genotype specific. A search of the Human DNA Polymerase Gamma Mutation Database ( for p.[A467T]+p.[G848S] revealed 18 additional published cases. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Intermittent hypoglycemia has been described in association with Alpers' syndrome, a disorder caused by mutations in the mitochondrial DNA polymerase gamma gene. In some patients hypoglycemia may define the initial disease presentation well before the onset of the classical Alpers' triad of psychomotor retardation, intractable seizures, and liver failure. Correlating with the genotype, POLG pathogenicity is a result of increased mitochondrial DNA mutability, and mitochondrial DNA depletion resulting in energy deficient states. Hypoglycemia therefore could be secondary to any metabolic pathway affected by ATP deficiency. Although it has been speculated that hypoglycemia is due to secondary fatty acid oxidation defects or abnormal gluconeogenesis, the exact underlying etiology is still unclear. Here we present detailed studies on carbohydrate metabolism in an Alpers' patient who presented initially exclusively with intermittent episodes of hypoglycemia and ketosis. Our results do not support a defect in gluconeogenesis or fatty acid oxidation as the cause of hypoglycemia. In contrast, studies performed on liver biopsy suggested abnormal glycogenolysis. This is shown via decreased activities of glycogen brancher and debrancher enzymes with normal glycogen structure and increased glycogen on histology of the liver specimen. To our knowledge, this is the first report documenting abnormalities in glycogen metabolism in a patient with Alpers' syndrome.
    Full-text · Article · Nov 2013
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: To highlight differences between early-onset and adult mitochondrial depletion syndromes (MDS) concerning etiology and genetic background, pathogenesis, phenotype, clinical presentation and their outcome. MDSs most frequently occur in neonates, infants, or juveniles and more rarely in adolescents or adults. Mutated genes phenotypically presenting with adult-onset MDS include POLG1, TK2, TyMP, RRM2B, or PEO1/twinkle. Adult MDS manifest similarly to early-onset MDS, as myopathy, encephalo-myopathy, hepato-cerebral syndrome, or with chronic progressive external ophthalmoplegia (CPEO), fatigue, or only minimal muscular manifestations. Diagnostic work-up or treatment is not at variance from early-onset cases. Histological examination of muscle may be normal but biochemical investigations may reveal multiple respiratory chain defects. The outcome appears to be more favorable in adult than in early-onset forms. Mitochondrial depletion syndromes is not only a condition of neonates, infants, or juveniles but rarely also occurs in adults, presenting with minimal manifestations or manifestations like in the early-onset forms. Outcome of adult-onset MDS appears more favorable than early-onset MDS.
    Preview · Article · Sep 2013 · The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques
  • [Show abstract] [Hide abstract]
    ABSTRACT: Alpha-fetoprotein (AFP) is present in fetal serum in concentrations up to 5,000,000 μg/l. After birth, AFP gene expression is turned down with a subsequent fall of the serum concentrations of this albumin-like protein to 'adult values' of circa 0.5-15 μg/l from the age of 2 years onwards. Irrespective of its assumed important functions, individuals with AFP deficiency appear fully healthy. The other way around, the presence of AFP in the circulation after the first years of life doesn't seem to harm, since individuals with 'hereditary persistence of AFP' are also without clinical abnormalities. During pregnancy, AFP (in maternal serum) has long been recognized as a marker for congenital anomalies of the fetus. Equally well known is AFP as biomarker for hepatocellular carcinoma and some other malignancies. There are at least four neurodegenerative disorders, all inherited as autosomal recessive traits and characterized by the presence of cerebellar ataxia, abnormal ocular movements, and neuropathy, for which an elevated concentration of serum AFP is an important diagnostic biomarker. The availability of a reliable biomarker is not only important during screening or diagnostic processes, but is also relevant for objective follow-up during (future) therapeutic interventions.
    No preview · Article · Sep 2013 · European journal of paediatric neurology: EJPN: official journal of the European Paediatric Neurology Society
Show more