Neuronal Hyperexcitability in PKD: Treatment Using Parenteral Therapy
2021 Student Scholarship – Second Place Case Study
MATTHEW RENSHAW RUDDELL, ND
LESLIE FULLER, ND
Paroxysmal kinesigenic dyskinesia (PKD) is the most common paroxysmal movement disorder and is characterized by episodes of involuntary movements that are thought to be triggered by voluntary movements of the body.1 PKD is an inherited disorder caused by a mutation in the PRoline-Rich Transmembrane Protein 2 gene (PRRT2).1 The PRRT2 mutation is a loss-of-function and frameshift mutation that results in reduced mRNA stability. This mutation has been implicated in hemiplegic migraines, benign familial infantile epilepsy, and infantile convulsions.2,3 Treatment of PKD typically consists of anticonvulsive medications. However, in cases where patients struggle with severe fatigue, anticonvulsants may not be appropriate. Parenteral therapy offers an alternative modality that may assist in decreasing neuronal excitability.
This case study examined the probable link between PKD and systemic neuronal hyperexcitability, created by the PRRT2 mutation. This hyperexcitability includes sodium channel overactivation,4,5 increased synaptic transmission mediated by SNARE and SNAP25,6,7 and glutamate excitotoxicity due to the overexpression of GRIA1 receptors.8,9 In contrast to previous case reports on PKD,10 this paper postulates that the hyperexcitability caused by the PRRT2 mutation is present not only in the central nervous system, but also in the enteric nervous system, resulting in systemic symptomatology, and that the disorder can be effectively treated with parenteral therapy.
In May 2020, a 64-year-old postmenopausal, Caucasian female presented to the NUNM clinic with PKD and irritable bowel syndrome (IBS) that had persisted for 18 years, since 2002. She had first presented to the clinic in April of 2015, at which time Dr Fuller initiated parenteral therapy. Prior to this point, the PKD had been so severe that she had been non-ambulatory for multiple years, with extremely limited activities of daily living.
In 2002, the patient experienced her first episode of PKD after a presumed hemiplegic migraine that left her unconscious at her home. A thorough workup ruled out stroke and myocardial infarction. Brain magnetic resonance imaging (MRI) was normal, and anti-nuclear antibodies (ANA), lupus anticoagulant panel, and cardiolipin antibodies were all negative. The only noteworthy findings were elevations in high-sensitivity C-reactive protein (hs-CRP) and erythrocyte sedimentation rate (ESR). Within the year, her neurologist diagnosed PKD based on her symptoms of dysarthria, aphasia, discoordination, and chorea. Symptoms consistent with IBS included episodic, purgative bowel movements of unformed stool, which first occurred following her initial hemiplegic migraine and which often accompanied or preceded PKD episodes.
Past medical history included chronic fatigue syndrome (CFS), but the patient’s family history was negative for PKD, tremors, seizures, stroke, multiple sclerosis, Parkinson’s disease, and chorea. The patient was offered anticonvulsants by her neurologist, which she declined due to her preexisting, severe fatigue. The patient was finally diagnosed with IBS in 2013. Prior to the initiation of parenteral therapy in 2015, the patient had undergone genetic testing through a previous physician. Results revealed a homozygous, loss-of-function mutation in the NBPF3 gene, 2 heterozygous loss-of-function mutations in the MTHFR gene (A1298C and the C677T), and a homozygous loss-of-function mutation in the glutamate decarboxylase-1 (GAD1) gene. These mutations have been correlated with low absorption and use of pyridoxine (vitamin B6), reduced production of active folate (vitamin B9), and decreased conversion of glutamate to gamma-aminobutyric acid (GABA), respectively.11-14
The patient initiated parenteral therapy in April of 2015, the components of which are listed in Table 1. Infusions took place on a monthly basis.
Table 1. Parenteral Formula, April 2015-March 2020
|Parental Formula Ingredients||Concentration (mg/mL)||Volume (mL)|
|Carrier liquid||(Sterile water)||45|
|B12 H/M||1000 µg||1/1|
|Vitamin C (non-corn-derived)||200 / 500||4|
|Magnesium sulfate||200 / 500||4|
Niacinamide 100 mg/mL)
Follow-up & Outcomes
After initiating parenteral therapy in April 2015, the patient began experiencing some relief of symptoms of both PKD and IBS. With monthly infusions, near-resolution of her symptoms was achieved between September 2018 and March 2020. At that point, the clinic was forced to close due to COVID-19. As a result of the closure, the patient had a 3-month gap in receiving parenteral treatments. Approximately 6 weeks after clinic closure, consistent PKD and IBS episodes returned (see Table 3 for a timeline).
When the clinic reopened in May 2020, the patient had regressed. Parenteral therapy was reinitiated on a biweekly basis. Near-resolution of symptoms was achieved after 2 treatments and was maintained for 4 months, at which point her symptoms again became uncontrolled. The formula was then modified to include an additional 500 mg magnesium sulfate, and with a doubling of the dosages of dexpanthenol, pyridoxine, methylcobalamin/hydroxocobalamin, and selenium. The dosages of vitamins B and C were tripled, and carnitine and zinc sulfate were also added (see Table 2). Once again, the patient experienced symptom resolution.
Table 2. Parenteral Formula, October 2020-(ongoing)
|Augmented Formula Ingredients||Concentration (mg/mL)||Volume (mL)|
|Carrier liquid||(Sterile water)||200|
|B12 H/M||1000 µg||1/2|
|Vitamin C (non-corn-derived)||200 / 500||12|
|Magnesium sulfate||200 / 500||5|
Niacinamide 100 mg/mL)
Serial infusions with parenteral nutrients helped the patient become ambulatory and regain her independence, and removed many of her daily physical limitations. She described the change in her life, as a result of parenteral therapy, as a “miracle” and she was emphatic about the improvement it had made in her quality of life. On multiple occasions after the clinic closure and reopening, the patient had PKD episodes in-office, which caused symptoms of dysarthria, aphasia, discoordination, chorea, and extreme fatigue. Complete resolution of symptoms, with the exception of the extreme fatigue, occurred following each treatment.
Table 3. Timeline
|Mar 2002||Hemiplegic migraine followed by onset of symptoms, consistent with PKD and IBS|
|Oct 2002||Symptoms remained. Brain MRI and laboratory workup unremarkable.|
|2002-2004||Patient non-ambulatory due to severity and frequency of symptomatic episodes|
|2005-2014||ADLs severely limited due to PKD and IBS episodes|
|Early 2015||Identified homozygous mutations in NBPF3 and glutamate decarboxylase-1 (GAD1) genes, and heterozygous mutations in MTHFR gene (A1298C and C677T)|
|Apr 2015||Initiation of parenteral therapy relieved symptoms of PKD and IBS with first treatment|
|Sep 2018||Near-resolution of symptoms achieved between monthly parenteral treatments|
|Mar 2020||Clinic closed due to COVID-19. Patient unable to receive monthly parenteral therapy. PKD and IBS symptoms returned after 6 weeks.|
|May 2020||Clinic re-opened, and patient resumed parenteral therapy every 2 weeks. Near-resolution of symptoms achieved within 6 weeks, with 2-week treatment intervals.|
|Oct 2020||Symptoms re-emerged with 2-week intervals. Treatments augmented with increased doses of vitamins B and C, magnesium, selenium, and carnitine. Patient re-achieved symptom resolution.|
Research on PKD has demonstrated that the principle causative factor is a frameshift mutation in the PRRT2 gene,1,2 which results in decreased mRNA stability and functionality.3 This loss-of-function mutation leads to PRRT2 deficiency in the skin, gut, and cerebellum, resulting in hyperexcitability of Nav+ 1.2 and Nav+ 1.6 channels and a significant increase in synaptic transmission.4,5 This, coupled with decreased SNARE complex inhibition (via SNAP25 modulation), due to the same PRRT2 mutation, leads to heightened responses to mechanical stimuli in the viscera, muscles, and epidermis.4-7 The PRRT2 mutation also results in increased GRIA1 expression, which leads to increased glutamate release and reception, neuronal hyperexcitability, and excitotoxicity.8,9 This is corroborated by findings of increased levels of aspartate and glutamate in the plasma of PKD patients.8
Patients with PKD often present with IBS and chronic fatigue. To the best of our knowledge, no case reports exist linking these 2 conditions with PKD’s causative PRRT2 mutation. We hypothesized that there might be a common pathophysiology between PKD and IBS, stemming from the cellular alterations due to the PRRT2 mutation, which result in systemic neuronal hyperexcitability and, in turn, excitotoxicity and severe chronic fatigue. This could also offer a pathophysiological explanation for the closely-timed episodes of IBS and PKD.
Our hypothesis of enteric and central neuronal hyperexcitability and excitotoxicity was reinforced by the reestablishment of symptomatic control in this case, initially with the old parenteral formula and then with the new, augmented formula. The mechanisms involved were likely the same in both cases and were simply a matter of magnitude due to the availability of critical nutrients that were administered. These mechanisms include neuronal inhibition offered by magnesium, which has been shown to protect against neuronal excitotoxicity,15 as well as the key roles particularly of pyridoxine (vitamin B6), in transamination, such as the conversion of glutamate into alpha-ketoglutarate, and of glutamate into gamma-aminobutyric acid (GABA). Genetic testing in this patient indicated the likelihood of reduced absorption and utilization of vitamin B6, as well as decreases in methylation and in the conversion of glutamate into GABA; these changes appear to be at least partially inherent to the PRRT2 mutation and the PKD presentation.
Coupled with the previously discussed changes caused by the PRRT2 mutation, the MTHFR and NBPF3 mutations likely resulted in severe deficiencies in vitamin B6, methylfolate (vitamin B9) and methylcobalamin (vitamin B12), as well as significantly elevated levels of plasma glutamate and markedly low levels of plasma GABA. These altered levels could explain the extreme sensitivity of the patient and her sudden IBS and PKD episodes, which were often simultaneous or consecutive in occurrence. Due to the cellular nature of these biochemical alterations, these changes would likely be present in both the enteric and central nervous systems, causing hyperexcitability and excitotoxicity and leading to episodes of IBS, PKD, and extreme fatigue.
Other possible therapeutic strategies, in addition to parenteral therapy, include other means of blocking glutamate signaling, similar to B vitamins and magnesium. Furthermore, the diterpene alkaloids from Aconite moldavicum have been shown to reduce Nav+ 1.2 activity by approximately 50%, and carvacrol from Origanum (oregano) species inhibits a variety of Nav+ channels, including Nav+ 1.2 and Nav+ 1.6.16,17
Strengths of this case report include long-term patient follow-up as well as circumstances that forced the patient to temporarily discontinue parenteral treatments. We considered the interrupted course of treatment a strength because it allowed us to determine how long the treatment effect lasts and what nutrients are most important for the resolution of IBS and PKD symptoms in a patient presenting with both. Limitations of this case report include the limited research on the effect of the PRRT2 mutation on the enteric nervous system. Moreover, the patient’s diagnosis of PKD was complicated by a diagnosis of CFS, but it seems likely that this diagnosis was a result of the mutations in the PRRT2, MTHFR, and NBPF3 genes. This case demonstrates the critical importance of parenteral therapy in cases where there is complex, systemic, cellular dysfunction of genetic origin, as it can provide at least temporary symptom relief, especially when other therapies are inaccessible or prove ineffective.
The PRRT2 mutation identified in PKD may also be responsible for IBS in patients with paroxysmal movement disorders, due to alterations in synaptic and glutamate signaling, as well as sodium channel excitability that leads to systemic neuronal excitotoxicity and causes extreme fatigue. Further genetic testing is valuable in cases where systemic neuronal hyperexcitability is observed, since it can help direct targeted parenteral therapies that can improve patients’ quality of life and enable them to resume their ADLs. This case suggests that parenteral therapy is an important therapeutic option in patients with PKD and should be considered when fatigue and/or IBS is present, especially when other genetic mutations that contribute to neuronal excitability are identified.
Acknowledgements: Thank you to the National University of Natural Medicine for making this clinical experience possible. This case report was written using the CARE (CAse REport) guidelines.18
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- Israel MR, Tanaka BS, Castro J, et al. NaV1.6 regulates excitability of mechanosensitive sensory neurons. J Physiol. 2019;597(14):3751-3768.
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- Coleman J, Jouannot O, Ramakrishnan SK, et al. PRRT2 Regulates Synaptic Fusion by Directly Modulating SNARE Complex Assembly. Cell Rep. 2018;22(3):820-831.
- Tan GH, Liu YY, Wang L, et al. PRRT2 deficiency induces paroxysmal kinesigenic dyskinesia by regulating synaptic transmission in cerebellum. Cell Res. 2018;28(1):90-110.
- Li M, Niu F, Zhu X, et al. PRRT2 mutant leads to dysfunction of glutamate signaling. Int J Mol Sci. 2015;16(5):9134-9151.
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- Bruton A, Fuller L. Paroxysmal Kinesigenic Dyskinesia Symptoms Markedly Reduced with Parenteral Vitamins and Minerals: A Case Report. Perm J. 2019;23:19.036.
- Tanaka T, Scheet P, Giusti B, et al. Genome-wide Association Study of Vitamin B6, Vitamin B12, Folate, and Homocysteine Blood Concentrations. Am J Hum Genet. 2009;84(4):477-482.
- Servy E, Menezo Y. The Methylene Tetrahydrofolate Reductase (MTHFR) isoform challenge. High doses of folic acid are not a suitable option compared to 5 Methyltetrahydrofolate treatment. Clin Obstet Gynecol Reprod Med. 2017;3(6):1-6.
- Neuray C, Maroofian R, Scala M, et al. Early-infantile onset epilepsy and developmental delay caused by bi-allelic GAD1 variants. Brain. 2020;143(8):2388-2397.
- Asada H, Kawamura Y, Maruyama K, et al. Cleft palate and decreased brain ?-aminobutyric acid in mice lacking the 67-kDa isoform of glutamic acid decarboxylase. Proc Natl Acad Sci U S A. 1997;94(12):6496-6499.
- Kirkland AE, Sarlo GL, Holton KF. The role of magnesium in neurological disorders. Nutrients. 2018;10(6):730.
- Borcsa B, Fodor L, Csupor D, et al. Diterpene alkaloids from the roots of Aconitum moldavicum and assessment of Nav 12 sodium channel activity of Aconitum alkaloids. Planta Med. 2014;80(2-3):231-236.
- Horishita T, Ogata Y, Horishita R, et al. Carvacrol inhibits the neuronal voltage-gated sodium channels Nav1.2, Nav1.6, Nav1.3, Nav1.7, and Nav1.8 expressed in Xenopus oocytes with different potencies. J Pharmacol Sci. 2020;142(4):140-147.
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Matthew Renshaw Ruddell, ND was a 4th-year naturopathic medical student at NUNM in Portland, OR, at the time of this writing. Dr. Renshaw Ruddell, who plans to complete a full-time residency after graduation, is interested in pediatrics, veteran care, nature cure, and traditional naturopathy. While at NUNM, he served in the Oregon Army National Guard as an infantryman in the 2/162 infantry battalion based in Springfield, OR. Dr Renshaw Ruddell is a veteran of the US Army Infantry. His long-term career aspirations include setting up a private practice and working with the local police force to develop a response team trained to handle mental health emergencies.
Leslie Fuller, ND is a 2009 graduate of NCNM (now NUNM). Dr Fuller has focused on sports medicine, neurologic disability, and IV therapy for well over a decade. During this time she has worked with patients with spinal cord injury, cerebral palsy, and stroke, and helped able-bodied individuals become the best athletes possible. Dr Fuller continues to lecture at NUNM on the topics of neurology, pain management, and IV therapy. Her clinic time remains focused on IV therapy as a primary modality. She remains connected to several nonprofit disability groups throughout Oregon and is excited by the potential impact of naturopathic medicine on the field of neurological rehabilitation.