Distinct Clinical Courses and Shortened Lifespans in Childhood-Onset DNA Polymerase Gamma Deficiency

Abstract

Background and objectives: DNA polymerase subunit gamma (POLG) deficiency is likely the most frequent cause of nuclear-encoded mitochondrial disorders. POLG-related disorders reportedly constitute a spectrum of overlapping phenotypes from infancy to late adulthood. We retrospectively reviewed natural histories for 40 children carrying biallelic pathogenic POLG variants.

Methods: The patients were identified by the French coordinating center for mitochondrial disorders (CARAMMEL), making this a large monocentric series on childhood-onset POLG deficiency.

Results: Three patterns of clinical course and survival were observed, distinguished by main category of symptoms: neurologic, hepatic, and gastrointestinal. A total of 24 patients needed urgent neurointensive care for tonic-clonic seizures, myoclonic epilepsy, and status epilepticus, occasionally precipitated by valproate administration. Other neurologic symptoms included dystonia, cerebellar ataxia, and peripheral neuropathy. We report 6 POLG-deficient patients with polyradiculoneuropathy mimicking subacute Guillain-Barré syndrome and provide postgadolinium MRI evidence of diffuse cranial nerve root and cauda equina enhancement, suggesting these disorders have an inflammatory component. Children presenting with enteral nervous system involvement had vomiting, gastroparesis, and chronic intestinal pseudo-obstruction. They had later ages of onset and lived much longer. Primarily, hepatic presentations had the earliest onset and shortest survivals. Secondary hepatic failure was frequently precipitated by valproate administration given before diagnosis to patients with focal impaired awareness seizures or absence of seizures. These POLG deficiencies were often fatal, with age at death ranging from 3 months to 10 years, with a significant difference in survival between the 3 clinical forms; 6 of the 40 children did survive. No genotype-phenotype correlations were found for the 3 clinical course types.

Discussion: The study demonstrates the prevalence of neurologic presentation and the extent of central, peripheral, and autonomous nervous system involvement in 60% of patients. Most of the patients with early onset and rapidly fatal hepatic failure did not live long enough to develop neurologic symptoms. The study revealed a new clinical form of POLG deficiency presenting with neurodigestive symptoms with longer lifespan. We also propose that POLG deficiency should be considered in children presenting with unexplained polyradiculoneuropathy, demyelinating neuropathy, and elevated CSF protein. Finally, valproate administration remains a notable cause of avoidable death in POLG-deficient patients.

Figure 1. Onset Symptoms and Causes of Death

Onset symptoms and causes of death in 40 children with biallelic pathogenic POLG variants. FTT = failure to thrive. The percentages represent the respective frequencies of each symptom.

Figure 2. Clinical Symptoms

Frequency of clinical symptoms and therapeutic interventions in patients with biallelic pathogenic POLG variants. CIPO = chronic intestinal pseudo-obstruction; EN = enteral nutrition; FTT = failure to thrive; PEN = parenteral nutrition. The percentages represent the respective frequencies of each symptom.

Figure 3. Brain MRI of P33, P36, and P38

Sagittal T1 postgadolinium spine MRI in 3 patients with biallelic pathogenic POLG variants, respectively, aged 3 months (P33, A), 17 months (P36, B), and 16 months (P38, C). Arrows indicate enhancement of the caudal nerve roots. Axial T1 postgadolinium brain MRI in P33 (D) shows (from top to bottom) abnormal enhancement of cisternal oculomotor nerves, cisternal trigeminal nerves, and bilateral intracanalicular facial nerves (arrows).

Figure 4. Survival of POLG Patients

Kaplan-Meier estimator of survival according to clinical forms of POLG deficiency. H: hepatic (n = 8), N: neurologic (n = 24), and D: digestive (n = 8) forms. The difference in survival between the 3 clinical forms is significant (p = 0.004). The differences between hepatic and digestive forms (p = 0.006) and hepatic and neurologic forms are significant (p = 0.008). The difference between digestive and neurologic forms is not significant (p = 0.01). Test for trends between the 3 groups is significant (p = 0.0025). Median and range of age of disease onset and death are shown below graph.

Figure 5. POLG Mutations

POLG mutations. Top: splice variations and large deletion in cDNA. Bottom: amino acid changes in protein. Recurrent variations associated with neurologic (N), hepatic (H), and digestive (D) clinical courses indicated in pink, green, and orange, respectively.