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Year : 2019  |  Volume : 67  |  Issue : 1  |  Page : 259--260

Complex heterozygous polymerase gamma mutation and cerebral folate deficiency in a child with refractory partial status

Debopam Samanta1, Raghu Ramakrishnaiah2, Richard E Frye1,  
1 Neurology Section, Department of Pediatrics, University of Arkansas for Medical Sciences, Little rock, Arkansas, USA
2 Division of Neuroradiology and Pediatric Radiology, University of Arkansas for Medical Sciences, Little rock, Arkansas, USA

Correspondence Address:
Dr. Debopam Samanta
1 Children's Way, Little rock, Arkansas - 72202

How to cite this article:
Samanta D, Ramakrishnaiah R, Frye RE. Complex heterozygous polymerase gamma mutation and cerebral folate deficiency in a child with refractory partial status.Neurol India 2019;67:259-260

How to cite this URL:
Samanta D, Ramakrishnaiah R, Frye RE. Complex heterozygous polymerase gamma mutation and cerebral folate deficiency in a child with refractory partial status. Neurol India [serial online] 2019 [cited 2019 Jul 17 ];67:259-260
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Full Text


An 18-year-old Caucasian young male, with a past medical history of mild intellectual impairment and well-controlled epilepsy, was transferred to our intensive care unit from another hospital with complaints of intractable left-sided epilepsia partialis continua (EPC) and progressive encephalopathy for 7 days. He was treated with several antiepileptic medications such as midazolam infusion, fosphenytoin, levetiracetam, lacosamide, pentobarbital infusion, clonazepam, topiramate, sodium valproate, and ketogenic diet with no definite improvement in his frequency of seizures. Initial brain magnetic resonance imaging (MRI) [Figure 1] prompted a working diagnosis of acute disseminated encephalomyelitis (ADEM); however, high dose steroids with their subsequent tapering, immunoglobulin, plasmapheresis, and rituximab were used with no significant improvement in the outside hospital.{Figure 1}

Due to the disproportionately severe encephalopathy compared to his lesion burden in the brain and the atypical presence of EPC, further laboratory tests were done which revealed elevated blood lactate and pyruvate. The cerebrospinal fluid specimen demonstrated elevated levels (158 mg/dl) of protein and low 5-methyltetrahydrofolate (5-MTHF) level. Treatment with oral leucovorine was started due to concerns of secondary cerebral folate deficiency. Follow-up MRI studies on day 7 and day 17 [Figure 2]a and [Figure 2]b showed waxing and waning pattern of signal abnormality. Progressive cerebral volume loss and secondary expansion of the ventricles were noted, which was attributed to steroid-induced parenchymal volume loss. Day 45 follow-up MRI study [Figure 2]c and [Figure 2]d showed resolution of T2 signal changes with progressive global cerebral parenchymal atrophy.{Figure 2}

He had a prolonged 4-month course in the pediatric intensive care unit before passing away.

Posthumously, whole exome sequencing revealed compound heterozygote POLG mutation-p.W748S (c. 2243 G > C) mutation inherited from mother and p.S305R (c. 915 C > G) inherited from father.

Mitochondrial dysfunction, including POLG mutation, is an important cause of EPC in the pediatric population. In one large case series of 26 patients with POLG mutation, one patient had evolving lesions in the left occipital and right motor cortex followed by prefrontal cortex, similar to our case.[1] In another study by Engleston et al., 2 out of 19 patients had EPC with MRI findings of evolving contralateral frontoparietal lesions.[2]

Extremely low cerebrospinal fluid 5-MTHF level in our patient suggested a diagnosis of cerebral folate deficiency syndrome. Several mitochondrial disorders have been associated with secondary cerebral folate deficiency due to failure of the ATP-dependent active transport of 5-MTHF across the choroid plexus epithelial cells. This choroid plexus dysfunction may also explain the high protein content of cerebrospinal fluid in our patient. Etiology of demyelination-like lesions is still unknown, however, myelin basic protein methylation defect secondary to folate deficiency may cause instability of myelin with subsequent demyelination.[3] This information has particular clinical significance as a high dose of folinic acid supplementation may provide benefit in these patients.

This case highlights the importance of identification of POLG mutation in the setting of EPC, especially in patients with a prior diagnosis of intellectual impairment or epilepsy. POLG mutation should be considered in the presence of waxing waning T2 abnormality in the brain, which may initially suggest changes due to infection, inflammation, or postictal abnormality. It is important to identify these cases early as valproic acid administration for seizure control can be catastrophic with development of hepatic failure. Diagnosis of this entity is also vital for family counselling purposes. This case also suggested that secondary cerebral folate deficiency syndrome can be present in patients with POLG mutation and folinic acid can be used as potential therapy. Further research is needed if administration of folinic acid, earlier in the disease course, can change prognosis in this devastating disease.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.


1Tzoulis C, Engelsen BA, Telstad W, Aasly J, Zeviani M, Winterthun S, et al. The spectrum of clinical disease caused by the A467T and W748S POLG mutations: A study of 26 cases. Brain 2006;129:1685-92.
2Engelsen BA, Tzoulis C, Karlsen B, Lillebø A, Laegreid LM, Aasly J, et al. POLG1 mutations cause a syndromic epilepsy with occipital lobe predilection. Brain 2008;131:818-28.
3Garcia-Cazorla A, Quadros EV, Nascimento A, Garcia-Silva MT, Briones P, Montoya J, et al. Mitochondrial diseases associated with cerebral folate deficiency. Neurology 2008;70:1360-2.