Molecular diagnosis of Alpers syndrome

Department of Medicine, University of California, San Diego, San Diego, California, United States
Journal of Hepatology (Impact Factor: 11.34). 08/2006; 45(1):108-16. DOI: 10.1016/j.jhep.2005.12.026
Source: PubMed


Alpers syndrome is a developmental mitochondrial DNA depletion syndrome leading to fatal brain and liver disease in children and young adults. Mutations in the gene for the mitochondrial DNA polymerase (POLG) have recently been shown to cause this disorder.
The POLG locus was sequenced in 15 sequential probands diagnosed with Alpers syndrome. In addition, the POLG mutations found to cause Alpers syndrome in the 20 cases published to date were analyzed.
POLG DNA testing accurately diagnosed 87% (13/15=87%: 95% confidence interval=60-98%) of cases. Five new POLG amino acid substitutions (F749S, R852C, T914P, L966R, and L1173fsX) were found that were associated with Alpers syndrome in five unrelated kindreds, and 14 different allelic combinations of POLG mutations were found to cause Alpers syndrome in the 20 probands published to date. The most common Alpers-causing mutation was the A467T substitution, located in the linker region of the pol gamma protein, which accounted for about 40% of the alleles and was present in 65% of the patients. All patients with POLG mutations had either the A467T or the W748S substitution in the linker region.
Screening for A467T and W748S substitutions in POLG now constitutes the most rapid and sensitive test available for confirming the clinical diagnosis of Alpers syndrome.

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    • "The A467Tmutation is estimated to occur in 36% of all alleles associated with POLG disease. (Ferrari et al. 2005; Horvath et al. 2006; Nguyen et al. 2006; de Vries et al. 2007; Wong et al. 2008). In the general population, the frequency of the A467T mutation has been found to exist in between 0.2% to 1% of asymptomatic European populations (Van Goethem et al. 2001; Luoma et al. 2005; Winterthun et al. 2005; Horvath et al. 2006). "
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    ABSTRACT: The inability to replicate mitochondrial genomes (mtDNA) by the mitochondrial DNA polymerase (pol γ) leads to a subset of mitochondrial diseases. Many mutations in POLG, the gene that encodes pol γ, have been associated with mitochondrial diseases such as myocerebrohepatopathy spectrum (MCHS) disorders, Alpers-Huttenlocher syndrome, myoclonic epilepsy myopathy sensory ataxia (MEMSA), ataxia neuropathy spectrum (ANS), and progressive external ophthalmoplegia (PEO). This chapter explores five important topics in POLG-related disease: (1) clinical symptoms that identify and distinguish POLG-related diseases, (2) molecular characterization of defects in polymerase activity by POLG disease variants, (3) the importance of holoenzyme formation in disease presentation, (4) the role of pol γ exonuclease activity and mutagenesis in disease and aging, and (5) novel approaches to therapy and avoidance of toxicity based on primary research in pol γ replication.
    Cold Spring Harbor perspectives in biology 04/2013; 5(4). DOI:10.1101/cshperspect.a011395 · 8.68 Impact Factor
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    • "According to the early description of the disease by Huttenlocher et al. [3] and later descriptions by Harding [5] [28], liver involvement without exposure to valproic acid has comprised one of the defining features. Furthermore, the histochemical changes induced by valproic acid are identical to those observed without exposure (Table 1) [5] [7]. The pathologic features of Alpers-Huttenlocher syndrome are Figure 1. "
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    ABSTRACT: Alpers-Huttenlocher syndrome is an uncommon mitochondrial disease most often associated with mutations in the mitochondrial DNA replicase, polymerase-γ. Alterations in enzyme activity result in reduced levels or deletions in mitochondrial DNA. Phenotypic manifestations occur when the functional content of mitochondrial DNA reaches a critical nadir. The tempo of disease progression and onset varies among patients, even in identical genotypes. The classic clinical triad of seizures, liver degeneration, and progressive developmental regression helps define the disorder, but a wide range of clinical expression occurs. The majority of patients are healthy before disease onset, and seizures herald the disorder in most patients. Seizures can rapidly progress to medical intractability, with frequent episodes of epilepsia partialis continua or status epilepticus. Liver involvement may precede or occur after seizure onset. Regardless, eventual liver failure is common. Both the tempo of disease progression and range of organ involvement vary from patient to patient, and are only partly explained by pathogenic effects of genetic mutations. Diagnosis involves the constellation of organ involvement, not the sequence of signs. This disorder is relentlessly progressive and ultimately fatal.
    Pediatric Neurology 03/2013; 48(3):167-78. DOI:10.1016/j.pediatrneurol.2012.09.014 · 1.70 Impact Factor
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    • "The common POLG p.A467T mutation has previously been reported as a homozygous mutation in ataxia, sensory neuropathy, dysphagia, epilepsy, Alpers disease, progressive external ophthalmoplegia (PEO), and sensory ataxic neuropathy, dysarthria, and opthalmoparesis (http:// and in trans with p.L966R (Nguyen et al., 2006). We found POLG p.A467T mutation in trans with p.R417T associated with intractable epilepsy with status epilepticus as the first manifestation of the disease without any liver symptoms leading to severe epileptic encephalopathy and death at the age of 2.5 years. "
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    ABSTRACT: Purpose To assess the frequency and clinical features of childhood-onset intractable epilepsy caused by the most common mutations in the POLG gene, which encodes the catalytic subunit of mitochondrial DNA polymerase gamma. Methods Children presenting with nonsyndromic intractable epilepsy of unknown etiology but without documented liver dysfunction at presentation were eligible for this prospective, population-based study. Blood samples were analyzed for the three most common POLG mutations. If any of the three tested mutations were found, all the exons and the exon–intron boundaries of the POLG gene were sequenced. In addition, we retrospectively reviewed the notes of patients presenting with intractable epilepsy in which we had found POLG mutations. All available clinical data were collected by questionnaire and by reviewing the medical records. Key Findings We analyzed 213 blood DNA samples from patients fulfilling the inclusion criteria of the prospective study. Among these, five patients (2.3%) were found with one of the three common POLG mutations as homozygous or compound heterozygous states. In addition, three patients were retrospectively identified. Seven of the eight patients had either raised cerebrospinal fluid (CSF) lactate (n = 3) or brain magnetic resonance imaging (MRI) changes (n = 4) at presentation with intractable epilepsy. Three patients later developed liver dysfunction, progressing to fatal liver failure in two without previous treatment with sodium valproate (VPA). Furthermore, it is worth mentioning that one patient presented first with an autism spectrum disorder before seizures emerged. Significance Mutations in POLG are an important cause of early and juvenile onset nonsyndromic intractable epilepsy with highly variable associated manifestations including autistic features. This study emphasizes that genetic testing for POLG mutations in patients with nonsyndromic intractable epilepsies is very important for clinical diagnostics, genetic counseling, and treatment decisions because of the increased risk for VPA-induced liver failure in patients with POLG mutations. We recommend POLG gene testing for patients with intractable seizures and at least one elevated CSF lactate or suggestive brain MRI changes (predominantly abnormal T2-weighted thalamic signal) with or without status epilepticus, epilepsia partialis continua, or liver manifestations typical for Alpers disease, especially when the disease course is progressive.
    Epilepsia 02/2013; 54(6). DOI:10.1111/epi.12115 · 4.57 Impact Factor
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