An update on Alpers-Huttenlocher syndrome: pathophysiology of disease and rational treatment designs

ABSTRACT

Introduction: Alpers-Huttenlocher syndrome (AHS) is a unique nuclear DNA-encoded mitochondrial disease. Clinically, after normal development the syndrome is manifested by psychomotor decline, medically refractory seizures, and hepatopathy. The disease is caused by biallelic recessive mutations in the mitochondrial DNA polymerase catalytic subunit, polymerase gamma 1 (POLG1), which is relentlessly progressive with death occurring several years after diagnosis.

Areas covered: The consistency of neuropathology, biochemical, genetic, and clinical findings are discussed. However, the lack of phenotype and genotype correlations, presence of ecovariants, and multiple environmental influences create variable onset of symptoms and degrees of clinical expression. Coupled with the low prevalence of AHS, standard clinical trials are not possible and treatment modalities must be extrapolated from other mitochondrial and clinical diseases or animal models.

Expert opinion: Currently, treatment is mostly supportive. Animal models of AHS are sorely needed. However, there are hints to possible disease-altering treatments based on animal and in vitro and other disease treatment studies. In a worm model of POLG1 dysfunction, the cardiac medication clofilium tosylate can correct the deficit. Exosomes made from stem cells can deliver genes and protein products to muscle cells and presumably neurons. These studies begin the journey toward possible treatments.

KEYWORDS:

• Mitochondrial disease
• polymerase gamma 1 (POLG1)
• Alpers-Huttenlocher syndrome
• nuclear-encoded
• epilepsy
• mitochondrial DNA replication

Article highlights

• Polymerase gamma is the only human polymerase able to replicate mitochondrial DNA and mutations in the replicase POLG1 are responsible for most all patients with Alpers-Huttenlocher syndrome.

• Alpers-Huttenlocher syndrome usually causes progressive encephalopathy associated with drug-resistant seizures, cortical visual loss, pyramidal signs, myoclonus, and hepatopathy.

• Alpers-Huttenlocher syndrome generally presents between 2 and 4 years of age with a rapidly progressive and drug-resistant epilepsy. A second, smaller number of patients present between 17 and 24 years of age.

• There are over 180 pathological variants in POLG1 that are expressed in both dominant and recessive inheritance patterns. Alpers-Huttenlocher syndrome is expressed an autosomal recessive biallelic disorder. The location of variants within the POLG1 gene and whether the variants are homozygous or heterozygous, may explain some of the variability in the spectrum of clinical presentation.

• Hepatic involvement is common in Alpers-Huttenlocher syndrome, but the onset is variable and may be delayed years from illness onset. Valproic acid exposure accelerates hepatic involvement in most all patients and should be avoided.

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Declaration of interest

R. Saneto is partially supported by an NIH grant U54NS078059 and has also participated in clinical trials for Bioelectron Technologies and Stealth Biotherapeutics. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.