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(068) FLNC Variant in a Patient with Schizophrenia and Recurrent Neuroleptic Malignant Syndrome and Catatonia


Paul A. Parcon, MD, PhD – Resident Physician, University of Arkansas for Medical Sciences

Jeffrey Clothier Clothier, MD, DFAPA – Professor, Department of Psychiatry, UAMS DEPT OF PSYCHIATRY

Amy Grooms, MD – Assistant Professor, University of Arkansas for Medical Sciences


Kent Mckelvey, Jr, MD – Rockefeller Chair in Clinical Genetics, University of Arkansas for Medical Sciences


Presenting Author: Paul Parcon, MD, PhD, University of Arkansas for Medical Sciences
Co-Author: Jeffrey Clothier Clothier, MD, DFAPA, UAMS DEPT OF PSYCHIATRY
Co-Author: Amy Grooms, MD, FACLP, University of Arkansas for Medical Sciences
Co-Author: Lou Ann Eads, MD, UAMS
Co-Author: Kent Mckelvey, Jr, MD, University of Arkansas for Medical Sciences


Background: Neuroleptic Malignant Syndrome (NMS) is marked by sudden onset of rigidity, elevated temperature, autonomic dysfunction, and confusion. Altered homeostasis of intracellular calcium is one proposed etiology.

Method: We present a 52 year old female with a diagnosis of ‘catatonic schizophrenia’ and epilepsy, who presented on several occasions with high CK (up to 30,730 IU/L), rigidity and fevers. Workup included inconclusive LP, MRI studies, negative autoimmune encephalitis labs. Treatment with various neuroleptics including clozapine, lithium and other mood stabilizers had limited success. Over the years she has a cognitive and physical decline. The NMS reactions occurred with antipsychotics including clozapine. She had an episode free period during while treated with ECT. Her overall course was one of decline.

Evidence of mitochondrial dysfunction was indicated by an elevated lactate:pyruvate ratio of 58 and elevated lactate and ammonia (Parikh, 2015). Exome analysis of nuclear and mitochondrial DNA was done. There were two alleles identified as potentially pathogenic. The first was a variant of TPO (Thyroid Peroxidase enzyme gene). The second gene was FLNC gene (Filamin C). Filamin C is an actin-binding like protein responsible for the condition known as myofibrillar myopathy type 5 (MFM-5), a condition that presents ages 37 to 57 (Furst, 2013). The patient was heterozygous for a variant that included a substitution of arginine for proline at position 1526. The location was on Chromosome 7q32.1. This variant has not previously been reported. In-silico analyses of the structure predicted a deleterious effect.

Pimavanserin was started. The anticonvulsant was changed to levetiracetam due to the minimal impact on mitochondria compared to other anticonvulsants (Mithal, 2017). The pimavanserin was partially effective and low dose clozapine was added. Clozapine has a minimal impact on mitochondria among antipsychotic agents (Anglin, 2012). There is less rigidity and a more muscle control noted. She is now able to verbalize more easily and is calmer. CKs and the serum lactate have normalized.

Discussion: Filamin C which is expressed primarily in the skeletal and cardiac muscles. As a structural protein, variants can be expressed as an autosomal dominant conditions (Furst, 2013). A review of the literature identified a small cohort in Belgium that had co-occurrence of frontotemporal dementia with the MFM-5. (Janssens, 2015)

Conclusion: The mitochondria are important in intracellular calcium homeostasis. Calcium is important in muscle contractions. The impact of psychiatric medications on mitochondrial function is variable (Anglin, 2012). Selection of the least toxic agents along with cardiac monitoring is important.

1. Furst, DO, et al: Filamin C-related myopathies: pathology and mechanisms. Acta Neuropathol (2013) 125:33–46
2. Janssens, J et al: Investigating the role of filamin C in Belgian patients with frontotemporal dementia linked to GRN deficiency in FTLD-TDP brains, Acta Neuropathologica Communications (2015) 3:68.

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