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  • Updated 05.19.2023
  • Released 09.15.2014
  • Expires For CME 05.19.2026

POLG-related disorders



Alpers-Huttenlocher syndrome (AHS) is caused by pathogenic variants in POLG, the nuclear gene encoding the mitochondrial polymerase gamma. Although Alpers-Huttenlocher syndrome has a restricted neuro-hepatic clinical definition, pathogenic variants in this gene can result in a broad range of clinical presentations that involve not only the brain and liver, but the rest of the central and peripheral nervous system as well as the cardiac, endocrine, gastrointestinal, ophthalmologic, and reproductive systems. These disorders, referred to as POLG-related disorders, may present at any age. The allelic variants in POLG are usually expressed in an autosomal recessive manner, but some are expressed as dominant traits. Unfortunately, only supportive treatments are available, although clinical trials are ongoing. To date, there are no FDA approved therapies for POLG-related disorders.

Key points

• Polymerase gamma is the only human polymerase able to replicate mitochondrial DNA (mtDNA), and pathogenic variants in POLG are responsible for a host of symptoms that result from mitochondrial DNA depletion (ie, a reduction in mtDNA copy number).

• Alpers-Huttenlocher syndrome generally presents between 2 and 4 years of age with a rapidly progressive and medically intractable epilepsy. A second, smaller peak of disease presentation occurs between 17 and 24 years of age.

• Alpers-Huttenlocher syndrome usually causes progressive encephalopathy associated with refractory epilepsy, cortical visual loss, pyramidal signs, movement disorders, and neuropathy. Brain MRI changes include generalized atrophy, cerebellar atrophy, thalamic/pulvinar lesions, the “peri-Rolandic sign,” and stroke-like lesions usually in the posterior/occipital lobe.

• Hepatic involvement is common in Alpers-Huttenlocher syndrome, but the onset may be delayed years to decades after the first clinical symptoms. Fulminant liver failure may occur due to exposure to valproic acid or other hepatically cleared medications, or due to other stressors such as fever/infection..

• There are over 300 pathogenic variants in POLG that are expressed in both recessive and dominant inheritance patterns. Most of these are point mutations but deletions also exist. In those disorders caused by the recessively expressed alleles, the number of potential combinations is nearly limitless, which may explain the variability in the spectrum of clinical presentations. There may be some consistent genotype-phenotype correlations which can aid in prognosis.

• The additional clinical phenotypes beyond Alpers-Huttenlocher syndrome were clinically defined prior to understanding the etiology of POLG pathogenic variants, and there is overlap between these disorders. POLG-related disorders is now recognized as a continuum rather than six separate clinically defined syndromes.

Historical note and terminology

The original description of what is now known as Alpers-Huttenlocher syndrome was made by Alfons Maria Jakob (45). The following year Bernard Alpers, a student of Jakob’s, published a clinical-pathological report of a 4-month-old girl with typical development who developed intractable seizures in the context of a 1-month illness (01). Alpers’ description lead to the recognition of the disease and fostered further reports, although initial descriptions of this disease likely occurred earlier (09). The eponym of Alpers disease was given in 1963, and it was later renamed Alpers poliodystrophy (35). Hints as to the pathophysiology of this disorder did not exist until 1972, when ultrastructural studies showed giant and disorganized mitochondria in neurons from patients with the disorder (76). In 1976 Peter Huttenlocher first reported the hepatic features of the disease and elevated CSF protein, and he suggested that it was a monoallelic and autosomal recessive disorder based on recurrence in family members (43). Several reports suggested this disorder was linked to abnormalities in metabolism, such as abnormal pyruvate metabolism, citric acid cycle dysfunction, electron transport chain dysfunction, or isolated cytochrome c oxidase activity (72; 73; 26; 99). However, these biochemical findings provided only secondary evidence of mitochondrial dysfunction and, in retrospect, did not identify the primary cause of the illness.

The first extensive review of the clinical features, electrophysiology, and pathology of this disorder described the course of 32 patients with distinctive liver and brain pathology. Other important features in the manuscript described typical early development followed by an insidious onset of developmental delay, failure to thrive, bouts of vomiting, and pronounced hypotonia (35). Typically, the clinical course became rapidly progressive soon after the onset of seizures. Liver involvement was variable; in some patients it preceded seizure onset, and in others it occurred at the terminal stages of the disease (20). The postmortem liver findings demonstrated a characteristic combination of pathogenic features, and examination of the cerebral cortex revealed variability but a constant involvement of the calcarine cortex with microscopic changes, including spongiosis, neuronal loss, and astrocytosis that involved all cortical layers (35; 65).

In 1996, POLG was characterized and cloned as the gene encoding for polymerase gamma, the only polymerase involved in mtDNA replication (75; 52). This discovery ushered in the molecular era of mitochondrial DNA depletion disorders. However, the clinical implications for POLG were not yet known. A few years later, biochemical studies provided evidence that mtDNA depletion was involved in Alpers-Huttenlocher syndrome (63). In 2001, the first firm evidence of a human illness, progressive external ophthalmoplegia (PEO) linked to autosomal recessive pathogenic variants in POLG, was published (92). In retrospect, a report two years earlier described the first nuclear gene disorder causing progressive external ophthalmoplegia with multiple mitochondrial DNA deletions—the disorder known as mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). The importance of this discovery is that pathologic variants in the TYMP gene, which encodes for thymidine phosphorylase, cause alterations in nucleotide pools, resulting in mtDNA replication infidelity and subsequent mtDNA depletion (67). More than 70 years passed between Alpers’ first description of Alpers-Huttenlocher syndrome and Naviaux’s 2004 description of pathogenic variants in POLG in two unrelated families with Alpers-Huttenlocher syndrome (62). These data provided the full pathophysiology of the phenotype, including the identification of the genetic etiology and the physiologic changes associated with reduced mtDNA content, also known as mtDNA depletion. Within the next four years, a number of publications outlined the full spectrum and clinical descriptions of POLG disorders, including descriptions of both dominant and recessive pathogenic variants in 61 patients that can cause a wide spectrum of clinical symptoms (98). A review article was published by Saneto and colleagues in 2013, followed by GeneReviews articles, which are updated every few years.

POLG-related disorders are now recognized as a continuum of overlapping clinical phenotypes, all named before the molecular basis of these disorders was known. The onset of symptoms ranges from infancy to late adulthood. Establishing the diagnosis requires two (biallelic) pathogenic variants for autosomal recessive disease and one pathogenic variant for autosomal dominant disease. Also important to note that some pathogenic variants have been reclassified over time and that previously published pathogenic variants have been reclassified to benign and vice versa. In addition, in order to prove biallelic inheritance, parental testing needs to confirm parents are each carriers, as some variants can coexist on one allele (in cis) and be inherited from the same parent, and thus not inherited in an autosomal recessive manner (in trans).

The expressivity of POLG disease varies by age of onset and disease severity. The clinical presentation is influenced by a combination of factors that include the specific gene mutation(s), region of the mutation within the gene, genetic background and epigenetic effects, environmental factors, and the age of onset. The neurologic features include encephalopathy and/or dementia, seizures, migrainous headache, visual loss, pyramidal and extrapyramidal motor dysfunction, movement disorders (ataxia, myoclonus, chorea, and dystonia), and neuropathy. Systemic features include cardiomyopathy, gastrointestinal and bladder dysautonomia, hepatic dysfunction, and gonadal failure and other endocrinopathies (42). The POLG disorders can be classified into several recognizable and described phenotypes, yet symptoms overlap among individuals, even those with identical mutations (25; 41; 42; 90; 13; 98; 06; 84; 39). Some affected individuals will present with a classically recognized syndrome, whereas others can have some, but not all, of the signs and symptoms of the classic syndromes.

Given the growing clinical phenotypes in the literature, all with significant overlap, a new study of 155 patients affected by POLG pathogenic variants was published to demonstrate the spectrum of clinical features in the largest known cohort of patients (39). The authors recognized a continuum of symptoms and stratified patients into one of three groups based on age of onset of symptoms to identify clinical phenotype and prognosis. Those presenting before 12 years of age had liver involvement (87%), seizures (84%), and feeding difficulties (84%) as main symptoms. Those between 12 to 40 years old had ataxia (90%), peripheral neuropathy (84%), and seizures (71%) as main symptoms. Those presenting after age 40 years had ptosis (95%), progressive external ophthalmoplegia (89%), and ataxia (58%) as major symptoms. Poor prognosis was associated with younger age of onset, epilepsy, and autosomal recessive disease from compound heterozygote variants.

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