POLG-related mitochondrial disorders …

Amy Goldstein MD

Neurogenetic Disorders

Updated 12.22.2025
Released 09.15.2014
Expires For CME 12.22.2028

POLG-related mitochondrial disorders

Author: Amy Goldstein MD

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Editor: Deepa S Rajan MD

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POLG-related mitochondrial disorders

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Introduction

Overview

POLG-related disease is a variable condition that is best described as a spectrum, with those most severely affected having early-onset progressive and severe neurologic concerns, typically including refractory epilepsy and liver failure (historically called Alpers-Huttenlocher syndrome), and those less severely affected having eye muscle weakness later in life. Other common symptoms include peripheral neuropathy, ataxia, and gastrointestinal dysmotility. Classification is based on age of symptom debut (under 12 years of age, 12 to 40 years of age, and over 40 years of age), presence or absence of epilepsy, and autosomal recessive or autosomal dominant inheritance. Unfortunately, only supportive treatments are available, although clinical trials are ongoing. There are no FDA-approved therapies for POLG-related disorders at this time.

Key points

	• Polymerase gamma is the only human polymerase able to replicate mitochondrial DNA, 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) or multiple large mtDNA deletions.
	• Seizures generally present between 2 and 4 years of age with rapidly progressive and medically intractable epilepsy. Preexisting symptoms can include hypotonia and developmental delay. A second peak of disease presentation occurs between 17 and 24 years of age with a female predominance and may be triggered by illness or exposure to estrogen-containing oral contraceptive pills and worsened by menses or pregnancy.
	• Brain MRI changes include generalized atrophy, cerebellar atrophy, thalamic lesions, the “peri-Rolandic sign,” and cortical focal lesions usually in the posterior/occipital lobe.
	• 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 mainly in autosomal recessive inheritance patterns. Most of these are point mutations but rare deletions exist. There may be some consistent genotype-phenotype correlations that can aid in prognosis, and online tools are available.
	• POLG-related disorders are now recognized as a continuum rather than separate clinically defined syndromes, and the age of debut symptom, presence or absence of epilepsy, and inheritance patterns are used as the most important prognostic factors according to recent literature.

Historical note and terminology

The original description of Alpers-Huttenlocher syndrome was made by Alfons Maria Jakob (42). 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 led to the recognition of the disease and fostered further reports, although initial descriptions of this disease likely occurred earlier (07). The eponym of Alpers disease was given in 1963, and it was later renamed Alpers poliodystrophy (30). 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 (79). 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 (40). 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 (74; 75; 24; 98). 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 (30). 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 (19). 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 (30; 66).

In 1996, POLG was characterized and cloned as the gene encoding for polymerase gamma, the only polymerase involved in mtDNA replication (77; 51). 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 depletion (68). 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 physiological changes associated with reduced mtDNA content (copy number), also classifying POLG as a mitochondrial mtDNA depletion syndrome. Within the next 4 years, a number of publications outlined the full spectrum and clinical descriptions of POLG-related mitochondrial disorders, including descriptions of both dominant and recessive pathogenic variants in 61 patients that can cause a wide spectrum of clinical symptoms (97). A review article was published by Saneto and colleagues in 2013 (80), followed by GeneReviews articles, which are updated every few years; the last update in February 2024 reflects the current understanding of overlapping phenotypes and considers age of onset to be correlated with clinical phenotypes and overall prognosis (35; 12).

Given the growing description of clinical phenotypes in the literature, all with significant overlap, there was a growing need to simplify the classification of POLG. Hikmat proposed a new classification scheme in a study of 155 patients in seven European countries affected by POLG pathogenic variants, which demonstrated the spectrum of clinical features in the largest known cohort of patients published to date (35). The authors stratified patients into one of three groups based on age of debut symptoms, which correlated with clinical phenotype and prognosis. Those presenting with debut symptoms before 12 years of age had liver involvement (87%), seizures (84%), and feeding difficulties (84%) as their overall main symptoms. Those presenting with debut symptoms between 12 to 40 years old had ataxia (90%), peripheral neuropathy (84%), and seizures (71%) as their overall main symptoms. Those presenting with debut symptoms after age 40 years of age had ptosis (95%), progressive external ophthalmoplegia (89%), and ataxia (58%) as their overall main symptoms. Poor prognosis was associated with younger age of onset, epilepsy, and autosomal recessive disease from compound heterozygote variants (as opposed to homozygous variants).

Another retrospective review of 40 pediatric patients in France discovered three clinical phenotypes correlating with survival (78). There were no genotype-phenotype correlations. The first phenotype included 24 patients with neurologic symptoms, some needing urgent neurointensive care for epilepsy management; other neurologic symptoms included dystonia, cerebellar ataxia, and peripheral neuropathy. The neuropathy was described as Guillain-Barre syndrome and chronic inflammatory demyelinating polyneuropathy given the presence of elevated CSF protein and diffuse enhancement of nerve roots on post-gadolinium contrast MRI spine of cranial nerve roots and cauda equina seen in six patients. The second phenotype included gastrointestinal symptoms, with vomiting, gastroparesis, and chronic intestinal pseudo-obstruction; patients presented later in age and had longer survival. Patients in this group did not develop epilepsy. The third phenotype included hepatopathy symptoms; these patients had the earliest age of onset and shortest survival (death by 3 months to 10 years old), with the hepatopathy frequently precipitated by valproate administration for seizures. The mortality rate for the entire cohort of 40 patients was 85%; only six of 40 survived.

Clinical manifestations

Presentation and course

POLG is inherited mainly as an autosomal recessive condition in which two variants are needed in a compound heterozygous (or homozygous) state (in trans). Some variants can be found in cis (on the same allele) (eg, Thr251Ile + Pro587Leu), so familial segregation studies (ie, testing the parents or other family members) is necessary to prove the inheritance pattern of the variants. There are several more common variants seen, with endless combinations of variants given that over 300 variants in POLG have been reported in the Human DNA Polymerase Gamma Mutation Database. Five variants are responsible for over 70% of affected individuals: p.Ala467Thr, p.Gly848Ser, p.Thr251Ile + p.Pro587Leu (in cis), p.Trp748Ser, and p.Thr914Pro (with respective frequencies 36%, 8%, 7.5%, 6.3%, and 3.4%) (76).

Autosomal dominant disease is rare, and the variants are specific.

Pathogenic mutations in POLG

(From: National Institute of Environmental Health Sciences.)

POLG is one of the most frequent genetic causes of mitochondrial epilepsy, which can start at any age and may be provoked by fever or infection, may be spontaneous in onset, or may be under hormonal influence (94; 76; 37). Seizures are the initial (debut) symptom in 50% of childhood-onset cases (03), with more than 80% of children having epilepsy at disease onset in some case series (34). Adults with epilepsy may also have POLG variants, although it has been reported with a much lower frequency: 7% in one cohort (3/42) (94). The seizure types and EEG findings have been very well characterized, with focal, generalized, myoclonic, and epilepsia partialis continua reported as well as a proclivity for the occipital lobe (90; 12). In a large retrospective review of 372 patients with POLG and epilepsy, the authors found a bimodal age distribution, with a large peak in early childhood (median age of onset: 2 years, range: 1 month – seventh decade) and a second peak in adolescence (03). In this review, seizure types were available for 229 patients and described as focal motor in 64%, myoclonic in 58%, generalized status epilepticus in 49%, and focal motor status in 34%. The bimodal age of distribution has been proposed to be influenced by hormones, especially with onset of puberty in females (37).

EEG findings have included a pathognomonic pattern of unilateral occipital rhythmic high-amplitude delta with superimposed (poly)spikes (RHADS), which has been described in a cohort of children (96). Other EEG patterns include intermittent continuous spike-wave, occipital lobe predominance, focal discharges or slowing, or multifocal abnormalities (03; 76; 12).

POLG patient (EEG)

EEG findings in a POLG patient demonstrating occipital spike and polyspike morphology. (Contributed by Dr. Bruce H Cohen.)

Neuroimaging of POLG, and specifically the syndrome known as Alpers-Huttenlocher syndrome, has been well described in previous literature (20; 03; 02; 25). Imaging may be normal early in the disease, with eventual gliosis and then global atrophy involving both the cortex and the cerebellum. Acutely, lesions may be seen in the occipital lobes (bilateral or unilateral) and often involve the thalami concurrently, with a frequent pattern of unilateral occipital and thalamic involvement. Peri-Rolandic cortex is also frequently involved (25). Anagnostou and colleagues described neuroimaging findings in 136 patients with POLG-related epilepsy: 43% had a stroke-like lesion (T2/FLAIR of cortical/subcortical areas, mainly of the occipital lobe). Additional areas of the brain involved included thalamus (37%), basal ganglia (14%), cerebellum (17%), generalized brain or cerebellar atrophy (28%), and cerebral white matter changes (7%) (03).

Examination of cerebrospinal fluid may show elevated protein, decreased CSF folate (5-MTHF), and elevated CSF neopterin among other immune markers, including oligoclonal bands, suggesting a possible immune pathogenesis (18; Harris and Walsh 2010; 32). Hasselmann and colleagues published a case of a 3.5-year-old who presented in status epilepticus; at 30 months old, the child presented with severe developmental delay, hypotonia, and ataxia with an IQ of 75 (32). Genetic testing revealed biallelic variants in POLG (p.A467T + p.G848S). Laboratory evaluation showed elevated CSF neopterin, elevated IL-6, IL-8, and IFN-gamma, low CSF 5-MTHF, and elevated CSF protein of 2.9 g/l (normal range 0.1–0.3 g/l). The patient was treated with leucovorin (as 5-formyl-tetrahydrofolate), escalating to a final dose of 4 mg/kg/BID. Over the next 17 months, the seizure frequency decreased, communication skills improved, and CSF IL-6 and IFN-gamma were reduced, but the IL-8 peak persisted. The child died at 5.5 years old of unknown cause. This was the first report of several inflammatory biomarkers being elevated in POLG, as well as treatment with folinic acid. Subsequent literature suggests a greater role of the inflammasome, with activation of the cGAS-STING pathway, delayed type I interferon response, increased IL-6 response to viruses, as well as elevated ISI-27, all of which may help explain some of the neuroinflammatory phenotypes that have been recognized over time, such as Guillain-Barre syndrome and CIDP-type neuropathies (44; 47; 78). To date, there are no treatment trials for additional immunomodulatory medications for POLG.

Interestingly, anemia has been noted at high prevalence in some of the early-onset patients with POLG in published cohorts and as a potential risk factor for status epilepticus in those cohorts (34; 50).

Growth differentiation factor 15 (GDF-15) has been proposed as a biomarker of mitochondrial disease for diagnosis, to correlate with disease severity and progression, and has been used to evaluate efficacy of interventional therapies in clinical trials, with a reported AUC of 0.8228 and 0.9927 in patients with mitochondrial disease (23; 99; 60; 73; 72).

In an open-label trial of nucleoside therapy for POLG patients, serum GDF-15 levels were noted to be increased at baseline for five of 10 subjects, with a mean GDF-15 level of 1031 pg/ml (normal < 750 pg/ml) (72). GDF-15 levels were obtained at 1-, 2-, 3-, and 6-month time points, and the mean level decreased to 729 pg/ml at 6 months, which the authors reported as “estimated difference: 200; 95% CI: 12–infinite; p = 0.048.” However, in reviewing the data, one subject continued to have a GDF-15 over 6000 throughout the study, and one subject went from 2354 to 1301 to 961 to 935, then back up to 1866 at 6 months.

GDF-15 as a biomarker for a previous CHOP cohort had an AUC of 0.731 (95%CI: 0.610–0.853), which performed similarly to CK and lactate, with a sensitivity of 52% and specificity of 90% for mitochondrial myopathy (22). In this patient cohort of mitochondrial myopathy subjects, GDF-15 did not correlate well with strength testing or 6-minute walk test distance.

GDF-15 performed well as a biomarker in a study of 50 patients with mitochondrial myopathy, four of whom have POLG (two autosomal dominant and two autosomal recessive) (58). GDF-15 levels in this study had a mean of 3396 pg/mL (SD: 1873), with the POLG patients having a mean of 3270 (range 2653–4270 pg/mL) with normal lactate and CK levels.

Neuropsychiatric symptoms include mood disorders, such as major depression, anxiety, and somatization (29; 37). POLG-related disease has a large impact on health-related quality of life and mental health. Fifteen patients with POLG aged 16 to 83 years old had lower scores in every domain as measured by standardized patient-reported outcome measures (RAND-36) when compared to the general population (37).

Hikmat and colleagues reported on 155 patients with POLG, seen across seven European centers, and described the major symptoms by age of onset (35). For those with age of onset under 12 years old, which was 54% of the cohort, the most common symptoms included hepatopathy (87%), seizures (84%), feeding difficulties (84%), and hypotonia (79%). For those with age of onset between 12 and 40 years old, which was 34% of the cohort, the most common symptoms were ataxia (90%), peripheral neuropathy (84%), seizures (71%), and stroke-like episodes (54%). For those with age of onset over 40 years old, which was 12% of the cohort, the most common symptoms were ptosis (95%), progressive external ophthalmoplegia (89%), ataxia (58%), and peripheral neuropathy (65%). The most common symptoms across the total cohort were neurologic (90%), which included epilepsy (69%), and seizure subtypes of focal (92%), focal to secondary generalization with tonic-clonic seizures (85%), myoclonic (74%), epilepsia partialis continua (57%), and status epilepticus (78%). The most common neuroimaging abnormalities found among this cohort were reported as generalized atrophy (59%) and cortical focal lesions (54%). Ophthalmology issues were reported in 74% and gastrointestinal problems in 63%. The earlier the onset of disease, the worse the prognosis. Patients with epilepsy and those with compound heterozygous variants carried significantly worse prognosis; those without epilepsy and those with homozygous variants (especially in the linker region) had better prognosis.

To further understand status epilepticus in POLG, Hikmat and colleagues reported on a cohort of 194 patients with genetically confirmed POLG disease followed longitudinally at seven European centers: 67% (130/194) of the patients had epilepsy, and 77% (97/126) developed status epilepticus (36). Seizures reported were of several types: convulsive status epilepticus (97%), epilepsia partialis continua (67%), focal seizures (59%), generalized tonic-clonic seizures (55%), and myoclonic seizures (43%). The median age of onset of status epilepticus was 7 years old (range: 4 months to 57 years); status epilepticus was more frequent in those under 12 years old (61%) compared to those 12 to 40 years old (38%). There was a bimodal distribution with a first peak at under 5 years old and a second peak in adolescence between 14 and 16 years old, with a female predominance. Of those who developed status epilepticus, seizures were the debut symptom in 43% (40/93); 63% were under 12 years old, and 7% were between 12 and 40 years old. Status epilepticus occurred spontaneously in 70%, or with infection in 28%, often presenting as the first symptom in early-onset cases. Those who developed status epilepticus frequently showed liver impairment (78%), muscle weakness (75%), ataxia (69%), and stroke-like episodes (57%). Blood and CSF lactate levels were elevated in about 40% of patients at disease onset. About 30% of patients had significantly low hemoglobin levels at disease onset. CSF protein was elevated in 72% of the patients at disease onset. EEG often showed occipital epileptiform activity (66%), whereas brain MRI abnormalities were seen in 64% of cases at status epilepticus onset, with cortical focal lesions being the most common finding (67%) followed by thalamic lesions (47%) and generalized atrophy (33%). Survival outcomes were poor, with only 23% of patients with status epilepticus alive at the time of data collection. Mortality was higher in those with epilepsy, though status epilepticus itself did not directly affect mortality. Median survival after status epilepticus onset was 5 months for early-onset cases, 6 months for juvenile- to adult-onset cases, and 2 months for those developing status epilepticus after the age of 40. This study highlights the need for early recognition and aggressive management of status epilepticus in POLG disease and suggests considering POLG disease in children and young adults presenting with new-onset refractory status epilepticus (NORSE).

Rotig and colleagues published a study on a cohort of 40 children followed at a single center (CARAMMEL, France, 2003–2023) with biallelic pathogenic POLG variants (78). All had early onset of symptoms, ranging from birth to 5 years, with a median onset at 9 months. The disease had a progressively fatal course, with a median lifespan of 14.25 months and median age at death of 20 months, although six children survived beyond 4 years. Initial symptoms included failure to thrive, motor delay, unsteady gait, vomiting, and seizures. They described three clinical phenotypes: hepatic, neurologic, and digestive. Hepatic had the earliest onset (1.8 months) and shortest survival (8 months), with no survivors. Neurologic had later onset (15.5 months) and longer survival (31.5 months), with four survivors. Digestive had an intermediate onset (6 months) and longest survival (42.5 months), with two survivors. Neurologic complications were common, with 24 patients experiencing seizures, myoclonic epilepsy, and status epilepticus, sometimes triggered by valproate use. Four had classic rhythmic high-amplitude delta activity with superimposed (poly) spikes (RHADS) on EEG. Dystonia, cerebellar ataxia, peripheral neuropathy, and absent deep tendon reflexes were observed; there were six cases consistent with Guillain-Barré syndrome with elevated CSF protein, abnormal nerve conduction study, and polyradiculoneuropathy. Brain and spine MRIs were mostly normal, but post-gadolinium imaging revealed cranial nerve and cauda equina enhancement, suggesting an inflammatory component. Severe digestive symptoms, including swallowing difficulties, vomiting, GERD, constipation, pseudo-obstruction, cachexia, and gastroparesis, were noted in eight patients, none of whom developed seizures. Genetic analysis identified 32 pathogenic POLG variants, though no clear genotype-phenotype correlation was found. Elevated plasma lactate (31/35) and CSF lactate (13/15) levels were common, and the study emphasized the importance of early diagnosis and avoiding valproate.

Prognosis and complications

The disease progression is variable in both timing and rapidity. Because of the myriad variant mutation combinations, modifying genetic factors, and environmental influences, it is not possible to predict the rate of progression.

For those with early-onset epilepsy, there is a progressive neurodegenerative course. There will be loss of neurologic function culminating in cognitive decline, spastic tetraparesis from corticospinal tract involvement, movement disorders from extrapyramidal track involvement, cortical visual loss, and, ultimately, death. The rate of neurodegeneration varies and is marked by periods of stability. The degree of dementia is often difficult to assess because of frequent seizures and high doses of anticonvulsants that can cloud the sensorium. The reported life expectancy from onset of first symptoms ranges from 3 months to 12 years, but this varies on both the underlying illness and intensity of medical intervention (13).

Based on age of presentation and presence or absence of epilepsy, those under 12 years have the worst prognosis, those between 12 and 40 years have a better prognosis than early-onset, and those older than 40 years at disease onset have the best prognosis.

Prognosis is based on genotype-phenotype correlations, and previously published cases are available in a publicly available database, which can be accessed at the following website: https://mitomap.org/polg/. The POLG Pathogenicity Prediction Server aims to provide the most current available information regarding the pathogenicity of POLG variants based on a clustering model and was first published by Nurminen and colleagues (69). However, many publications prior to and afterwards have not seen strong genotype-phenotype correlations.

Avoidance of valproic acid is necessary to prevent the hepatopathy and fulminant hepatic failure that can be associated with its use; however, hepatopathy may occur in the absence of valproic acid use. Hepatopathy may involve elevated liver enzymes and result in only a transaminitis; however, additional complications may include synthetic liver function, including coagulopathy.

Clinical vignette

The following case involves a summary of events that occurred in a patient with early-onset epilepsy and hepatopathy, and the case illustrates the spectrum of clinical manifestations that can occur in this illness.

The child was healthy until 3 years of age when his parents noted several staring spells over the course of a month. He became increasingly irritable and distractible during this time, as well. One evening it was noted that the right side of his face and right shoulder were twitching.

He was admitted to the hospital for evaluation of what was thought to be a partial seizure. His examination showed that he was nonverbal with altered mental status, but he would intermittently follow commands and had a nonlateralized motor examination. The head CT was normal. The brain MRI was normal except for mild enhancement of the left leptomeninges. The EEG showed intermittent left hemispheric slowing. CSF was acellular with normal glucose and moderately elevated protein. He was diagnosed with epilepsia partialis continua and treated with increasing dosages of phenobarbital and lorazepam. Over the next few days, the epilepsia partialis continua resolved, and the child was discharged on oral medication. The parents noted in retrospect that during the month of staring spells, he had lost some of his expressive language skills, and these did not recover over the next few months. He then had several hospitalizations for prolonged motor seizures, and they were treated with several other antiseizure medications, including fosphenytoin, phenytoin, levetiracetam, and lamotrigine. During this period, the child’s gait became mildly spastic and ataxic. When the seizures were well controlled, he regained some language function. His parents thought his personality was also returning to normal. A repeat brain MRI scan 3 months into the onset of the illness revealed cortical atrophy.

One month later, the child was readmitted with status epilepticus. After using increasing dosages of benzodiazepine and barbiturates to try to control the seizures, he was given a loading dose of sodium valproate. His seizures soon subsided, and he was discharged four days later on oral valproic acid and phenobarbital. Because of the general concern of liver toxicity with valproic acid use, the family was instructed to report any nausea, vomiting, confusion, or other mental changes. Three weeks later the child appeared to be lethargic, and alanine transaminase was found to be 1.5 times the upper limit of normal with normal liver synthetic studies, including ammonia, bilirubin, cholesterol, albumin, and prothrombin time. He was admitted to the hospital for evaluation and observation. The following morning his glucose (while on intravenous fluids containing 5% dextrose) was 42 mg/dL, and his alanine transaminase was 800 u/L. Over the next several days he developed florid liver failure. IV levocarnitine was instituted at a dose of 300 mg per kg per day, and rapid whole genome testing was ordered. The child was evaluated by the liver transplant service, deemed a good transplant candidate, and received a living donor liver transplant from his father’s liver within 3 days. Over the following week, the child recovered and returned to his baseline neurologic state, although his seizures continued as the valproic acid was not restarted after the liver transplant. Genetic testing revealed known pathogenic variants in POLG, p.Ala467Thr and p.Gly848Ser, and the diagnosis of POLG-related mitochondrial disease syndrome was confirmed.

Over the next two years, the child had numerous hospitalizations for status epilepticus. He lost his ability to swallow and became fully G-tube-fed. The examination showed a steady loss of pyramidal function with increasing spasticity, chorea, myoclonus, and dystonia. He became cortically blind due to repeated cortical focal lesions of the occipital lobe and lost communication skills. He was admitted with aspiration pneumonia, and, at that time, his parents declined ventilation, so he was treated with mask BiPAP therapy. After consultation with the ethics team and the palliative care service, the family decided not to have a tracheostomy placed and favored home-based palliative care services. The child died peacefully from hypoventilation after what was likely an aspiration event. Of note, liver transplantation is now generally contraindicated in POLG-related disorders due to the poor prognosis following liver transplantation, especially in younger patients with epilepsy.

Biological basis

Etiology and pathogenesis

Ultimately, the triggering factor in disease manifestation is the reduction in mitochondrial function due to a loss of mtDNA-produced proteins, tRNA and rRNA. The reduction in mtDNA products compromises the manufacture of ATP and, therefore, critical energy production required for cellular function. Once a critical nadir of ATP is reached, cellular function and survival are compromised. Depending on the energy demands of the cell, organs become dysfunctional and disease symptoms are manifested.

The unique physiological properties of the mitochondria, in part, give rise to the varied phenotypic manifestations of POLG diseases. The sole mtDNA replicase is POLG. When genetic pathogenic variants occur in the nuclear-encoded POLG gene, the integrity of the replication, editing, and repair of mtDNA is compromised. The portion of the POLG gene that harbors the pathogenic variant plays a large role in POLG malfunctions and has been mapped out by clusters (POLG Pathogenicity Prediction Server).

The phenotype of disease is usually correlated with the degree of mtDNA depletion within the mitochondrion. Due to the heterogeneity of numbers of mitochondria per cell and mtDNA copies per mitochondrion, differing symptoms arise at distinctive times within tissues as mtDNA is depleted or compromised in integrity. The complexity of the phenotype of POLG variants is due to the position of the pathogenic variant, the degree of mtDNA depletion, and unclear factors, including environmental and toxin exposure (which may include infection, fever, hormones, etc).

Polymerase gamma 1 protein (pol γ) is the only known DNA polymerase in the mammalian mitochondria and is responsible for mtDNA replication and repair (43; 27; 49). Pol γ is synthesized in the cell nucleus and transported to its inner membrane location. In the inner membrane, it associates with other nuclear-encoded proteins that make up the mtDNA replisome and nucleoids. Pol γ has three distinct DNA activities: a 5’->3’ DNA polymerase, a 3’->5’ exonuclease, and a 5’-deoxyribose phosphate lyase activity. The exonuclease activity (catalytic domain) is located within the N-terminal regions and is connected by a linker region to the C-terminal domain, which contains the 5’-3’ polymerase activity. The polymerase region has three subdomains named palm, fingers, and thumb. The C-terminal domain contains the 5’-3’-polymerase activity as well as the 5’-deoxyribose phosphate lyase activity. The exact location of the 5’-deoxyribose phosphate lyase activity within the C-terminal region is unknown (54). There are three motifs within the exonuclease region, I, II, and III, and three within the polymerase region, A, B, and C, which are essential for full pol γ activity (43; 27). Within the linker region, there are two regions required for full activity: the accessory protein interacting domain (AID) located toward the N-terminal part of the linker region and the intrinsic processivity subdomain (IP) located distally in the linker region (toward the C-terminal).

Functional and structural domains of the polymerase gamma protein

The N-terminal domain (NTD) region contains the mitochondrial targeting sequence. The thumb subdomains (T) of the protein are located between the exonuclease and linker region, as well as within the polymerase region. The exonucle...

Holoenzyme. The holoenzyme of pol γ is a heterotrimer comprised of one molecule of pol γ associated with two molecules of POLG2 (77; 51). POLG2, the 55 kDa accessory protein enhances the processivity (the average number of nucleotides added by the enzyme per association-disassociation with the template DNA) of the holoenzyme (52). One site of POLG2 association is with the linker region at the AID subdomain of the catalytic subunit (52). This interaction increases the DNA-binding affinity of the holoenzyme. The second POLG2 protein makes limited contact with pol γ and is labeled the distal accessory site (52). Interaction of POLG2 to this distal site enhances the polymerization rate of the holoenzyme (52). The replisome complex also comprises the mtDNA helicase PEO1 (Twinkle), a single-stranded DNA binding protein, mtSSB, and a number of accessory proteins and transcription factors (27).

POLG genetics. Although there are some pathogenic variants in POLG that are associated with autosomal dominant disease, the majority of POLG-related disorders are autosomal recessive disorders. Both copies of POLG are expressed in mammalian cells, and monoallelic expression of wild-type POLG is sufficient to avoid disease (10). Homozygote dominant POLG mutations, or even a dominant POLG mutation with a recessive mutation, have not been described, suggesting that these possible mutation combinations are likely embryonic lethal.

Recessive mutations in POLG occur as homozygous or compound heterozygous pathogenic variants. In general, compound heterozygous variants usually induce a more severe phenotype, whereas homozygous recessive variants are associated with milder and later-onset disease (65; 27; 35). However, both compound heterozygous variants as well as homozygous variants have been associated with severe early-onset POLG-related mitochondrial disease.

Epidemiology

It is estimated that the minimum birth frequency of children who will develop mitochondrial disease is approximately 1 in 5000 (84). Of this population, up to 25% will develop POLG disease (Chinnery and Zeviani 2007). A best estimate of prevalence is between 1 in 51,000 to about 1 in 100,000 (14; 61). Clearly, more reliable population studies are needed to more reliably estimate the incidence and prevalence of POLG. POLG pathogenic variants are thought to be one of the most common cause of inherited mitochondrial disease, and it is estimated that 2% of the population harbors a POLG pathogenic variant (76).

Population estimates of common POLG mutations. Elegant population studies have demonstrated that the common pathogenic variants p.Ala467Thr and p.Trp748Ser arose from a common ancestor within various populations of Northern European descent (28). The carrier frequency of p.Ala467Thr is estimated to be as high as 0.6% in Belgium and 1% in Norway, and the p.Trp748Ser frequency is estimated to be 1:125 in Finland (93; 29; 28; 95). POLG variants have been found in many other ethnic groups (26; 82; 59).

As more patients are described with POLG mutations, it is possible that more “hot spot” regions of POLG will be uncovered. Using crude estimates of the gene frequency of the most common mutations, members of these Northern European populations have about a 2% risk of carrying a pathogenic (heterozygote) mutation, suggesting a disease frequency of about 1:10,000.

Gender. Males and females seem to be equally affected with Alpers-Huttenlocher syndrome (92; 89; 97; 83).

Ecogenetic structural nucleotide variants (ESNV). One possible emerging mechanism for phenotypic variability is the presence of silent nucleotide polymorphisms or ESNVs that alter disease expression depending on environmental or epigenetic factors. When present, a particular POLG genotype will remain clinically silent unless specific conditions are present that can either lead to disease or modify the phenotype. The polymorphic nature of POLG suggests that ESNVs may exist (83). Two ENSVs have been described in the Northern European population: p.E1143G and p.Q1236H (39; 08; 86). p.E1143G has a frequency of approximately 4.5%, and p.Q1236H has a frequency of approximately 8.6%, of the Northern European population. These variants are almost nonexistent in the Asian, sub-Saharan African, or African-American populations (80). The presence of the ESNV p.E1134G has been demonstrated to increase the catalytic rate for incoming nucleotides as well as to increase intrinsic stability in in vitro studies (09). When present in cis with certain pathological mutations, especially with the p.W748S mutation, p.E1143G can lessen the disease severity and delay the age of onset by enhancing enzyme activity (39; 08). This same ESNV can also increase the liver’s sensitivity to valproic acid exposure, which appears counterintuitive to the disease-lessening effect. Thus, the p.E1143G ESNV can be a disease modifier by either enhancing enzyme activity or compromising liver function, depending on other genetic factors and environmental exposures. As with p.E1143G, the presence of p.Q1236H was proposed to induce liver failure with exposure to valproic acid. It is estimated that the presence of either p.E1143G or p.Q1236H increases valproic acid sensitivity more than 20-fold (32). However, as p.Q1236H was originally reported as a neutral polymorphism and has a known prevalence of 8.3% in the European population, 14.8% to 15.9% in the Finnish population, and about 1% in Africans and Asians, it is not thought to contribute to valproic acid-induced hepatotoxicity (41).

A question arises as to whether either ENSV is wholly or partially responsible for hastening liver failure from exposure to valproic acid in POLG. Six previously reported patients with Alpers-Huttenlocher syndrome and liver failure did not have either ESNV (82). There are rare reports of long-term use of valproic acid exposure with POLG mutation(s) without liver failure (89). Whether other valproic acid-sensitive ENSVs exist, and the full understanding of valproic acid-induced liver failure, remain unknown.

Prevention

Mutations inducing POLG diseases are uncommon in the population. As with most autosomal recessive disorders, the expression of these diseases is rare. The finding of an individual within a family is likely unique within that family. However, once an individual is identified, common Mendelian genetics would dictate the probability of another family member being affected. Once an individual is identified, genetic counseling is recommended for family planning.

There is an autosomal dominant pattern of inheritance in the condition of autosomal dominant progressive external ophthalmoplegia. Individuals with this form of POLG disease would herald more prompt genetic counseling as multiple individuals within that family have a higher probability of having the gene mutation and, hence, a higher likelihood of expressing the disease.

Currently, we do not have any preventative medications to ameliorate the symptoms of POLG disease. Management of disease is purely symptomatic. Patients with POLG disease have been treated with investigational medications in multi-institutional trials, including the following medications: vincerinone (EPI-743/PTC-743; Bioelectron Technologies), cysteamine bitartrate (RP-103; Horizon Pharmaceuticals), elamipretide (SS-31, MTP-131; Stealth Biotherapeutics), and omaveloxolone (RTA-408; Reata Pharmaceuticals). To date, none of these investigational products have shown efficacy nor met their primary outcome measure in a randomized clinical trial for POLG-RMD. Results of these trials have not yet been published.

Elamipretide (Stealth Biotherapeutics) is in a phase 3 trial for patients with replisome defects, including adults with POLG, as the previous phase 3 trial did not meet primary endpoints (improvement in 6-minute walk test) but suggested possible improvement in a subset of patients with mtDNA replisome defects (46). Post-hoc analysis of the data from the previous trial was utilized to develop a new clinical trial targeting a smaller subset of patients with nuclear replisome defects (45).

Omaveloxolone (Reata Pharmaceuticals) did not meet primary endpoints in a clinical trial of adults with primary mitochondrial myopathy (56); however, it was approved by the FDA for Friedreich ataxia (55).

Pekeles and colleagues published the results of an open-label, single-arm, phase 2 clinical trial on the safety and efficacy of deoxynucleoside therapy in a cohort of patients after a 6-month treatment window (72). These interim data include reporting on the first 10 patients with POLG-related disorders given oral therapy of deoxycytidine and deoxythymidine and outcome measures of the Newcastle Mitochondrial Disease Scale, DGF-15, EEG, seizure diary, additional lab studies, and adverse events. This study remains ongoing and is registered at clinicaltrials.gov: NCT04802707.

PZL-A is a small molecule that can bind and restore normal enzymatic activity to the most common POLG pathogenic variants, thereby activating mtDNA synthesis (91). Preclinical models have been completed in pediatric patient cells. A structurally similar compound, PX578, has been developed by Pretzel Therapeutics and is currently in phase I trials in humans, with a planned phase 2 trial in the near future.

Diagnostic workup

Genetic testing. Sequencing and deletion studies of POLG should be performed if POLG-related disorder is suspected. The use of gene sequencing has more importance in these syndromes than in other biochemical disorders because there are no specific or sensitive biochemical markers for POLG disease. Disease-causing variants in POLG remain the most sensitive and specific methods of confirming the diagnosis of POLG-related disorders. Single-gene testing is outdated, and this is best done as whole exome or whole genome sequencing in trio (both parents), when possible, as segregating the variants within the family for autosomal recessive variants is extremely important in POLG.

Electron transport chain enzymology. Depression of electron transport chain enzymatic activities in muscle and liver are not specific for POLG; this is an insensitive method of diagnosis, especially early in the course of the illness. Reports have demonstrated a variable pattern of electron transport chain defects, ranging from completely normal to single and multiple electron transport chain deficiencies (65; 16).

The variability of electron transport chain complex enzyme activity is likely related to the stage of disease and the tissue tested. As the disease progresses, abnormal electron transport chain enzyme deficiencies become more pronounced, as the catalytic subunits of the various complexes encoded by mtDNA are either not produced or have abnormal protein function. Although electron transport chain enzymology may be abnormal, the lack of sensitivity and specificity suggests electron transport chain activity should not be used to screen or diagnose.

Mitochondrial DNA content. The mtDNA copy number in POLG patients is 3% to 40% of normal, but this is also a function of what tissue is tested, the specific variant, and the stage of the illness (62; 21; 85; 87). The use of mtDNA content may seem useful for diagnosis, but it is not sensitive or specific for POLG because mtDNA content may be normal early in the disease process. Muscle and liver mtDNA depletion may lag behind disease symptoms. Some mutations impair the fidelity of the transcript and render the mtDNA as a functionless copy instead of altering the mtDNA content. In this case, the mtDNA content will be normal. If mtDNA content is analyzed, it should be measured in liver and muscle tissue, as POLG variants do not always induce mtDNA depletion in blood (17). As the disease progresses, almost all POLG patients will begin to demonstrate mtDNA depletion or mtDNA multiple deletions, which require mtDNA genome testing instead of content. Rare exceptions have been reported in patients with POLG who had mtDNA deletions without mtDNA depletion (48). Therefore, the finding of mtDNA depletion may be helpful in diagnosis, but its absence cannot be used to exclude POLG. Typically, childhood-onset POLG has mtDNA depletion, whereas adult-onset POLG has mtDNA multiple deletions; however, the absence of these findings does not rule out POLG.

Electroencephalogram and seizures.

POLG patient (EEG)

EEG findings in a POLG patient demonstrating occipital spike and polyspike morphology. (Contributed by Dr. Bruce H Cohen.)

Well-described and specific EEG findings and seizure semiology early in the disease course may suggest POLG-related mitochondrial disease (POLG-RMD) as a diagnosis. Severe seizures with occipital lobe predominance of epileptiform discharges that evolve into status epilepticus and/or epilepsia partialis continua, combined with psychomotor delay, occur frequently in POLG-RMD and do not in other illnesses; therefore, these findings should signal the possibility of POLG-RMD (20; 96; 82). Only a few epileptic syndromes, including Panayiotopoulos syndrome; Gastaut syndrome; Lafora disease; celiac disease; mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS); myoclonic epilepsy with ragged-red fibers (MERRF); epilepsy with bilateral occipital calcifications; idiopathic photosensitive occipital epilepsy; and malformations of cortical development have a posterior head predominance of spike/polyspike and wave epileptiform discharges (88). This combination of epileptiform location and seizure semiology should also signal the clinician to confirm that POLG is negative on genetic testing before starting valproic acid.

Neuroimaging. Neuroimaging findings are nonspecific but can be helpful in diagnosis. Head CT and brain MRI may be normal early in the course of the disease, but MR imaging changes reflect acute and chronic pathological changes as the disease progresses. The occipital location of EEG abnormalities and neuronal loss/gliosis can sometimes be seen on brain MRI as hyperintensity on T2-weighted and FLAIR sequences in the occipital regions that suggest mitochondrial dysfunction. When the seizures are uncontrolled, T2-weighted and FLAIR hyperintensities are often prominent in the thalami and basal ganglia (96), as well as the inferior olivary nuclei (33). There may also be a transient resolution of MRI changes with normalization of the signal changes (81). However, as the disease progresses, MRI imaging demonstrates cortical atrophy reflecting the pathological changes in the basal ganglia and brainstem induced by the disease (30; 48). Some patients have cerebellar atrophy, which corresponds to the prominent Purkinje cell loss seen in autopsy cases (30). In a systematic review of neuroimaging in 136 patients with POLG-related epilepsy, stroke-like lesions in the cortex were found in 43%, in addition to lesions in the thalamus (37%), basal ganglia (14%), cerebellum (17%), as well as generalized atrophy (28%). Of note, some patients had normal imaging results, emphasizing that a normal brain MRI does not exclude POLG-related disease (03). Additional studies on MRI findings include a review of 13 children with epilepsy (including epilepsia partialis continua) and POLG pathogenic variants (25). The most common findings include abnormal signal changes in the thalamus (77%) and perirolandic cortex (54%), in addition to rapid volume loss (77%) on subsequent imaging. Hikmat and colleagues found the following in the cohort of POLG with status epilepticus: MRI brain was abnormal in 55 of 86 (64%) patients at status epilepticus onset, with focal lesions of the cortex and subcortical areas the most common finding (55 of 77, 67%) (36). Some had thalamic lesions (n=36 of 77, 47%) or generalized cerebral atrophy (n=10 of 30, 33%).

The diagnosis of POLG-RMD takes a great deal of clinical acumen. The clinical expression of signs and symptoms varies in timing, intensity, and severity. Clinical suspicion is needed early in the course of diagnosis as the sequence of symptoms may be distinctive for each patient. However, the constellation of clinical symptoms will eventually be expressed, and POLG sequencing will confirm the diagnosis.

Management

Treatment of manifestations. Once the diagnosis of a POLG-related disorder is established, it is important to perform a systemic initial evaluation to determine the extent of neurologic and systemic involvement.

Table 1. Initial Evaluation for Patients with POLG-related disorders

Brain MRI; early studies may appear normal Electroencephalogram (EEG); consider video-EEG if subclinical seizures are suspected Ophthalmologic examination Audiology Gastroenterology Physical medicine and rehabilitation Physical therapy, occupational therapy, or speech therapy Psychotherapy (mood disorders prevalent)
	• Nutritional assessment • Swallow study if any signs of bulbar dysfunction are present • Liver evaluation (blood)
		- Glucose - Ammonia - Amino acids - Bilirubin (conjugated and unconjugated) - Albumin - Cholesterol - Carnitine studies - Coagulation studies (prothrombin time-INR) - Ultrasound - Enzymes (ALT, GGT, AST)
Routine laboratory: complete blood count, comprehensive metabolic panel, urine analysis Mitochondrial biomarkers (if available): GDF-15, FGF-21, glutathione (total, reduced, oxidized) Inflammatory markers: cytokine studies Pulmonary function tests Polysomnogram Electrocardiogram
Note: Not all testing is necessary for every patient, and this list should serve as a guide.

Because the illness requires different types of therapy and generally involves different organ systems, it is reasonable to assemble a treatment team.

Table 2. Treatment Team for Patients with POLG-related disorders

• Primary care provider
• Medical genetics
• Neurology
• (+/- epileptologist)
• Physical, occupational, or speech therapy
• Gastroenterologist (+/- hepatologist)
• Pulmonologist (+/- sleep specialist)
• Physiatrist
• Ophthalmologist
• Palliative care medicine

Treatment is limited to symptom management and supportive care. It is critical that the family be informed about the critical nature of this illness as soon as the family is able to absorb the diagnosis. The global perspective of care should be palliative-oriented, even if death is not imminent. Quality-of-life issues are important to discuss, specifically whether to institute invasive therapy, such as a gastrostomy tube, or tracheostomy before major clinical changes occur.

Childhood-onset POLG with epilepsy ultimately progresses to fatal encephalopathy or liver failure. Because variable levels of intensive treatment are available, these options should be discussed openly with the family. Supportive care could include the placement of a gastrostomy feeding tube for medication, hydration, or nutrition. Different levels of ventilator support may include less invasive treatments such as continuous positive airway pressure (CPAP), bilevel positive airway pressure (BiPAP), assisted nasal ventilation, intubation or placement of a tracheostomy, and use of mechanical ventilation. These issues are complex because the maximal degree of medical support that is acceptable can vary among parents. In addition, a procedure that is minimally invasive, such as the institution of BiPAP, can lead to a quality-of-life improvement. However, such interventions may ultimately escalate towards tracheostomy placement and mechanical ventilation because each decision requires painful reflection, and the parents may hope that the escalation will reverse the progression of the disease or have an equivalent restoration of the quality of life that previous, less invasive interventions formerly provided. Nonetheless, as the disease progresses, the benefits of more invasive interventions may have a diminishing impact on the child’s quality of life. Involvement of palliative care services can maintain the process of iterative discussions about the family’s goals, support the family and care team with these discussions, and help implement the decisions. In larger hospitals, rehabilitation units are often where family members learn to care for their loved ones with new gastrostomy tubes and ventilatory support. Most patients utilize rehabilitative services that help to maintain neurologic function for as long as possible, including occupational, physical, or speech therapies.

Consultations with a gastroenterologist and nutrition therapy early in the disease course are necessary to address feeding and nutritional issues and to assess and manage liver dysfunction. Surgical placement of a gastric feeding tube, when oral feeding becomes impaired, can maintain nutritional status or prevent aspiration of oral feedings. However, given the ultimate course of the illness, some families may wish to forego the placement of a feeding tube.

Hypoventilation is common in POLG and can exist long before anyone has observed frank apnea or clinical signs of hypercarbia. Assessment of both daytime and nocturnal ventilatory function can be performed for evidence of central or obstructive apnea. Depending on the severity of the findings, the use of CPAP or BiPAP may improve the quality of life in these children. Tracheostomy placement with or without varying use of artificial ventilation is a consideration for some cases, but families may wish to allow the natural course of the illness to proceed without these invasive and usually lifelong approaches.

Attempts should be made to control the seizures as best as possible. However, refractory epilepsy, especially epilepsia partialis continua, may be impossible to control with any treatment, and the side effects of treatment may outweigh any clinical benefit. Epilepsia partialis continua may be confused with movement disorders as it may not correlate with EEG changes, and epilepsia partialis continua may also warrant imaging as it can indicate a new cortical focal lesion. There is no evidence that newer antiseizure medications, such as lamotrigine, topiramate, oxcarbazepine, or levetiracetam, offer a better therapeutic benefit over the older medications (phenobarbital, phenytoin, carbamazepine, primidone, felbamate); however, the newer medications tend to be less sedating, may require less processing by the liver, and may have fewer drug-drug interactions. Valproic acid and sodium divalproate should be avoided (05; 82; 15). Because other antiseizure medications have also been implicated in accelerating liver deterioration, it is reasonable to monitor liver transaminase levels every 2 to 4 weeks after introducing any new medications.

Status epilepticus is common in POLG, and in a large multinational retrospective study of 195 patients of whom 130 had epilepsy, status epilepticus was identified in 97 of them (77%), with a median age of onset of 7 years (36). Status epilepticus was the presenting symptom of the disease in 40 patients (43%) and developed during the course of the disease in 53 (57%). Seizure semiology included convulsive status in 94% and epilepsia partialis continua in 67%. Associated comorbidities included liver impairment (78%), ataxia (69%), and stroke-like episodes (57%). Status epilepticus was typically refractory or super-refractory in 66%, and the presence of seizures was associated with significantly higher mortality compared to those without seizures.

Treatment for status epilepticus is known to be refractory, and most patients need several antiseizure medications. In the study by Hikmat and colleagues, six was the median number of antiseizure medications used during a single status epilepticus episode (range two to 11) with 62% of patients on more than six antiseizure medications (36). Treatments included antiseizure medications, anesthesia medications, immunomodulators, and ketogenic diet. Ketogenic diet was started during status epilepticus in 13 patients and reported to be effective in two older patients. Immunomodulators given during status epilepticus consisted of prednisolone (16), immunoglobulin (four), ACTH (two), plasmapheresis (one), tacrolimus (one), with no difference in seizure control or long-term survival; however, the authors acknowledge that giving these agents late and under treatment-resistant conditions does not prove lack of efficacy and that prospective trials are warranted. There are insufficient data for vagus nerve stimulation and transcranial direct current stimulation in POLG-related epilepsy, although transcranial direct current stimulation was used successfully in one teenager with focal motor status (64) but, unfortunately, not in another (57).

Movement disorders are common. Some, such as chorea and athetosis, may cause pain or psychological stress. Muscle relaxants and pain medications, including narcotics, would be advised in this circumstance. Some movement disorders can be treated with dopaminergic medication, such as levodopa-carbidopa or tetrabenazine. Therefore, a trial of either of these medications can be considered, if medically indicated.

Visual loss is common in POLG-RMD and is usually attributable to the destruction of the calcarine cortex. This occurs at variable states of the illness. There is no specific therapy available.

Standard treatment for liver failure can include small frequent meals or continuous feeding to compensate for impaired gluconeogenesis. In addition, reducing dietary protein to a minimum, use of non-absorbable sugars to create an osmotic diarrhea, and the use of conjugating agents to treat hyperammonemia may be helpful. Because levocarnitine may have some benefit in the setting of liver failure, and because of its low toxicity, some recommend its use from the time of diagnosis (06). The use of mitochondrial supplements, including vitamins and cofactors, has not been proven to be helpful specifically in POLG spectrum disorders, but most clinicians and families prefer to start some combination of these supplements (71). An updated paper on mitochondrial supplements based on preclinical data in animal models suggests a core cocktail followed by additional components based on genetic etiology or symptoms (04). For POLG these would include folinic acid (see below) and N-acetylcysteine for the hepatopathy that might be aided by improved glutathione levels and, therefore, improved the ability to handle oxidative stress (similar to treatment of Tylenol overdose).

CSF folate deficiency has been reported in POLG-related disorders, so some advocate testing the CSF for folate deficiency, which requires a lumbar puncture and treatment with folinic acid (calcium leucovorin) if there is a deficiency (32). From a practical standpoint, CSF folate deficiency can occur at any point in the disease process, and monitoring CSF folate a few times a year is not practical; therefore, initiating empiric treatment at the time of diagnosis is reasonable.

Studies by Hikmat and Rotig both noted anemia at the time of status epilepticus in their pediatric population (35; 78). Whether this was coincidental or perhaps causal in some way is poorly understood, but checking a complete blood count periodically and treating anemia is prudent.

In a mouse model of POLG disease, forced exercise resulted in clear clinical, biochemical, and pathological benefits and clearly delayed disease manifestations. Whether exercise can help modify the disease in humans remains to be proven, and it would certainly be difficult to institute as a therapy in most patients.

There are no guidelines available to suggest the best frequency for monitoring common laboratory values, and there is no one biomarker for diagnosis, prognosis, or management of POLG-related mitochondrial disorders. Testing should be guided by clinical features, and the proposed schedule should be modified if the clinical course is stable. Blood counts, electrolytes, and liver enzymes are reasonable to check every few months. Once there is an elevation in liver enzymes, it is reasonable to begin monitoring liver function (preprandial serum glucose concentration), ammonia, GGTP, albumin, bilirubin (free and conjugated), cholesterol, and prothrombin time/INR every few months. There is no clear evidence that either lactic acid or plasma amino acids assist in management, but some clinicians find value in these tests. Other testing should be performed as clinically necessary, such as liver ultrasound, EEG, brainstem auditory evoked potential, swallowing evaluation, polysomnography, and pulmonary function tests. However, because subclinical hypoventilation is common, it is reasonable to obtain a baseline polysomnogram and repeat this test every year or so or if clinical suspicion arises. Finally, subclinical seizures can mimic an encephalopathic state, so any acute change in sensorium, if lasting more than a few hours, should be evaluated with an EEG or a continuous EEG, if available. There seems to be little value in using brain MRI or head CT results to monitor the progression of the disease.

Media

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Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

Amy Goldstein MD

Dr. Goldstein of University of Pennsylvania Perelman School of Medicine and Children’s Hospital of Pittsburgh received a consulting fee from UCB.
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Editor

Deepa S Rajan MD

Dr. Rajan of UPMC Children's Hospital of Pittsburgh has no relevant financial relationships to disclose.
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Former Authors

Bruce H Cohen MD
Russell P Saneto PhD DO
Tyler Reimschisel MD

Patient Profile

Age range of presentation: Alpers-Huttenlocher syndrome: 2 to 44 years (two peaks, before 4 years, and 12 to 16 years)

ANS, SANDO, MIRAS, MEMSA: 13 to 44 years

arPEO: 19 to 64 years

adPEO: 45 to 65+ years

Myocerebrohepatopathy: 1 to 23 months
Sex preponderance: male=female in younger groups

females 60%: males 40% after age 12
Heredity: autosomal dominant

autosomal recessive

heredity typical

sporadic mutations occur
Population groups selectively affected: Australia

Central Europe

New Zealand

Northwestern Europe

United States
Occupation groups selectively affected: None

ICD & OMIM codes

ICD-10: Alpers disease: G31.81
ICD-11: Mitochondrial DNA depletion syndromes: 5C53.20
OMIM: Mitochondrial DNA depletion syndrome 1 (MNGIE type); MTDPS1: #603041

Mitochondrial DNA depletion syndrome 4A (Alpers type); MTDPS4A: #203700

Mitochondrial DNA depletion syndrome 4B (MNGIE type); MTDPS4B: #613662

Polymerase, DNA, gamma; POLG: #174763

Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis; SANDO: #607459

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POLG-related mitochondrial disorders

Associated Disorders

Ataxia
Axonal sensorimotor neuropathy
Cardiomyopathy
Cataract
Chorea
- Cortical blindness
- Dementia
- Depression
- Diabetes
- Exercise intolerance
- Focal motor seizures
- Gastrointestinal dysmotility
- Generalized seizures
- Liver failure
- Migraine
- Myoclonus
- Parkinsonism
- Primary ovarian failure
- Primary testicular failure
- Proximal myopathy
- Psychosis
- Ptosis and external ophthalmoparesis (PEO or CPEO)
- Retinopathy
- Sensorineural deafness
- Sensory neuropathy/ganglionopathy
- Stroke-like episodes

Differential Diagnosis

Mutations in POLG, POLG2, and C10orf2 (previously referred to as PEO1 or TWINKLE)
Mutations in TP1, TK2, DGUOK, SUCLA1, SUCLG2, ANT1, RRM2B, and MPV17

Also Relevant

Ataxia
Epilepsia partialis continua of Kozhevnikov
Epilepsy in mitochondrial disorders
Febrile seizures
Myoclonic seizures
- Myoclonus
- Myoclonus epilepsy with ragged-red fibers
- Valproic acid

POLG-related mitochondrial disorders

Cite this article

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Diagnostic workup

Management

Table 1. Initial Evaluation for Patients with POLG-related disorders

Table 2. Treatment Team for Patients with POLG-related disorders

Special considerations

Pregnancy

Anesthesia

Media

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

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Questions or Comment?

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