Alpers-Huttenlocher Syndrome

Abstract

Alpers-Huttenlocher syndrome is an uncommon mitochondrial disease most often associated with mutations in the mitochondrial DNA replicase, polymerase gamma. Alterations in enzyme activity result in reduced levels and/or deletions within the mitochondrial DNA with phenotypic manifestations occurring when the functional content of mitochondrial DNA reaches a critical nadir. The tempo of disease progression and onset varies among patients, even those with identical genotypes. The classical clinical triad of seizures, liver degeneration, and progressive developmental regression helps define the disorder, but there is a wide range of clinical expression. The majority of patients are healthy before the disease onset with seizures heralding 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 onset of seizures. 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 partially explained by the pathogenic effects of a given genetic mutation(s). Diagnosis is made by the constellation of organ involvement, not the sequence of symptoms. This disorder is relentlessly progressive and ultimately fatal.

Clinical effects of chemical exposures on mitochondrial function

“…Although harmful exposure to environmental pollutants is ubiquitous among all populations, disease manifestation occurs in only a subset of the population. Interaction between environmental factors and genetic predisposition e.g., ecogenetic variants (Saneto et al, 2013) is therefore likely to be a necessary prerequisite to disease manifestation. While the specific causative agents and underlying mechanisms that lead to diseases are not fully understood, a growing body of epidemiologic and animal model studies support a link between environmental exposure and neurologic, metabolic, respiratory, cancer, developmental and reproductive toxicity in humans.…”

Inherited mitochondrial genomic instability and chemical exposures

“…One such disease is Alpers syndrome, a childhood mtDNA depletion disorder associated with mutations in POLG (Nguyen et al 2006; Uusimaa et al 2013; Zhang et al 2011). The characteristic triad of symptoms in Alpers syndrome are epilepsy, liver disease and progressive developmental regression (Saneto et al 2013). Valproic acid is a common drug used to treat epilepsy and bipolar disorder.…”

Mitochondrial Hepatopathies: Advances in Genetics, Therapeutic Approaches, and Outcomes

“…Genetic heterogeneity and exposure to environmental factors (including medications) may explain the wide variation in clinical presentation. Assays of respiratory chain complex concentrations reveal complex 1 deficiency, 27 and genotyping shows 2 pathologic mutations in the POLG gene. 25,27 …”