POLG-related disorders

Bruce H Cohen MD (Dr. Cohen of Children's Hospital Medical Center of Akron received consulting fees from Transgenomic, research grants from Edison Pharma, and honoraruims from the American Academy of Neurology and Motive Medical Intelligence.)
Russell P Saneto PhD DO (Dr. Saneto of Seattle Children's Hospital/University of Washington received research grants from Edison Pharmaceuticals and Biodex.)
Tyler Reimschisel MD, editor. (Dr. Reimschisel of Vanderbilt University has received contracted research grants from Shire and Vtesse.)
Originally released September 15, 2014; last updated October 29, 2015; expires October 29, 2018

This article includes discussion of POLG-related disorders, Alpers diffuse degeneration of cerebral gray matter with hepatic cirrhosis, Alpers progressive infantile poliodystrophy, Alpers syndrome, neuronal degeneration of childhood with liver disease, progressive (PNDC), Alpers-Huttenlocher syndrome (AHS), ataxia neuropathy spectrum (ANS), ataxia neuropathy syndrome, autosomal dominant progressive external ophthalmoplegia, autosomal recessive progressive external ophthalmoplegia, childhood myocerebrohepatopathy spectrum (MCH), chronic progressive external ophthalmoplegia plus, mitochondrial neurogastrointestinal encephalomyopathy, mitochondrial recessive ataxia syndrome (MIRAS), myoclonic epilepsy myopathy sensory ataxia (MEMSA), sensory ataxia, neuropathy, dysarthria, and ophthalmoplegia, spinocerebellar ataxia with epilepsy, and spinocerebellar ataxia with epilepsy syndrome (SCAE). The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

Alpers-Huttenlocher syndrome is caused by mutations in POLG, the gene encoding the mitochondrial polymerase gamma. Although Alpers-Huttenlocher syndrome has a restricted neuro-hepatic presentation, mutations in this same 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, and reproductive systems. These disorders, referred to in the broad term as POLG spectrum 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.

Key points

 

• Polymerase gamma is the only human polymerase able to replicate mitochondrial DNA, and mutations in POLG are responsible for a host of illnesses that result in mitochondrial DNA depletion.

 

• 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 repetitive seizures, cortical visual loss, pyramidal signs, movement disorders, and a neuropathy.

 

• Hepatic involvement is common in Alpers-Huttenlocher syndrome, but the onset may be delayed years to decades.

 

• There are over 150 mutations in POLG that are expressed in both recessive and dominant inheritance patterns. 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.

Historical note and terminology

The original description of what is now known as Alpers-Huttenlocher syndrome was made by Alfons Maria Jakob (Jakob 1930). 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 (Alpers 1931). Alpers's description lead to the recognition of the disease and fostered further reports, although initial descriptions of this disease likely occurred earlier (Bullard 1890). The eponym of Alpers disease was given in 1963, and it was later renamed Alpers poliodystrophy (Harding 1990). 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 (Sandback and Lerman 1972). 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 (Huttenlocher et al 1976). 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 (Prick et al 1981; Prick et al 1982; Gabreëls et al 1984; Wörle et al 1998). 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 (Harding 1990). 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 (Eggar et al 1987). 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 (Harding 1990; Nguyen et al 2006).

In 1996, POLG was characterized and cloned as the gene encoding for polymerase gamma, the only polymerase involved in mtDNA replication (Ropp and Copeland 1996; Lecrenier et al 1997). 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 (Naviaux et al 1999). In 2001, the first firm evidence of a human illness, progressive external ophthalmoplegia linked to autosomal recessive mutations in POLG mutations, was published (Van Goethem et al 2001). In retrospect, a report 2 years earlier described the first nuclear gene disorder causing progressive external ophthalmoplegia with mitochondrial DNA deletions--the disorder known as mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). The importance of this discovery is that pathologic mutations in the EGCF1 gene, which encodes for thymidine phosphorylase, cause alterations in nucleotide pools, resulting in mtDNA replication infidelity and subsequent mtDNA depletion (Nishino et al 1999). More than 70 years passed between Alpers's first description of Alpers-Huttenlocher syndrome and Naviaux's 2004 description of pathologic mutations in POLG in 2 unrelated families with Alpers-Huttenlocher syndrome (Naviaux and Nguyen 2004). These data provided the full pathophysiology of the phenotype, including the identification of the genetic etiology and the physiologic changes of reduced mtDNA content inducing mtDNA depletion. Within the next 4 years, a number of publications outlined the full spectrum and clinical descriptions of POLG disorders, including descriptions of both dominant and recessive mutations that can cause a wide spectrum of clinical disease (Wong et al 2008).

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 (Hudson and Chinnery 2006). The POLG disorders can be classified into several recognizable phenotypes, yet symptoms overlap among individuals, even those with identical mutations (Ferrari et al 2005; Horvath et al 2006; Hudson and Chinnery 2006; Tzoulis et al 2006; Chinnery and Zeviani 2008; Wong et al 2008; Blok et al 2009; Spinazzola and Zeviani 2009). Some affected individuals will present with the classic syndrome, whereas others can have some, but not all, of the signs and symptoms of the classic syndrome.

The content you are trying to view is available only to logged in, current MedLink Neurology subscribers.

If you are a subscriber, please log in.

If you are a former subscriber or have registered before, please log in first and then click select a Service Plan or contact Subscriber Services. Site license users, click the Site License Acces link on the Homepage at an authorized computer.

If you have never registered before, click Learn More about MedLink Neurology  or view available Service Plans.