Objective: To report a case of dropped head syndrome (DHS) associated with both Parkinson’s Disease (PD) and biopsy-proven mitochondrial myopathy in a patient carrying coexisting MT-TE (m.14709T>C) and MT-ND1 (m.3733G>A) variants, a combination not previously reported.

Background: DHS is characterized by weakness of the neck extensor muscles and severe cervicothoracic kyphosis. The differential is broad and can be categorized into neurological, neuromuscular, or muscular etiologies.  Mitochondrial dysfunction has been implicated in both myopathic and neurodegenerative processes, including PD. Here we describe the first report of a patient who presented with DHS related to PD and myopathy with coexistent variants in MT-TE and MT-ND1.

Method: Case report

Results: This is a Caucasian woman who developed a progressive head drop at age 68, followed by gait imbalance, stiffness, and impaired dexterity. DaT scan was positive and she was diagnosed with PD. Examination at age 73 showed profound atrophy of her neck extensor muscles, deltoid, infraspinatus and supraspinatus muscles. EMG showed myopathic units in the proximal arm, leg, scapular, and neck extensor muscles. Genetic testing for FSHD1/FSHD2 was negative, but she was found to have a pathogenic variant in the MT-TE gene (m.14709T>C) and a likely pathogenic variant in the MT-ND1 gene (m.3733G>A). Muscle biopsy of the deltoid showed excessive cox-deficient fibers suggestive of mitochondrial dysfunction.

MT-ND1 encodes for subunit 1 of mitochondrial complex I and is most commonly implicated in Leber hereditary optic neuropathy, but its pathogenicity in myopathy has also been reported [2, 3, 5]. MT-TE encodes a mitochondrial tRNA for glutamic acid; cases of both congenital and adult-onset myopathy have been reported in individuals with variants at position 14709 [4]. While there have been no reports linking these two variants to parkinsonism, there is growing evidence of a connection between mitochondrial dysfunction and PD, including studies demonstrating decreased complex I activity in dopaminergic neurons of the substantia nigra in PD patients [1].

Conclusion: This case highlights a rare presentation of DHS arising from the combined effects of mitochondrial myopathy and neurodegeneration. It also serves as the first reported co-presentation of the MT-TE and MT-ND1 variants in a patient with biopsy-confirmed mitochondrial myopathy.

References: 1. Gautier CA, Corti O, Brice A. Mitochondrial dysfunctions in Parkinson’s disease. Rev Neurol (Paris). 2014 May;170(5):339-43. doi: 10.1016/j.neurol.2013.06.003. Epub 2013 Oct 9. PMID: 24119854.
2. GeneCards. (n.d.). MT‑ND1 gene – Mitochondrially encoded NADH: ubiquinone oxidoreductase core subunit 1. Retrieved from https://www.genecards.org/cgi-bin/carddisp.pl?gene=MT-ND1
3. Gorman GS, Blakely EL, Hornig-Do HT, Tuppen HA, Greaves LC, He L, Baker A, Falkous G, Newman J, Trenell MI, Lecky B, Petty RK, Turnbull DM, McFarland R, Taylor RW. Novel MTND1 mutations cause isolated exercise intolerance, complex I deficiency and increased assembly factor expression. Clin Sci (Lond). 2015 Jun;128(12):895-904. doi: 10.1042/CS20140705. PMID: 25626417; PMCID: PMC4613521.
4. Hanna MG, Nelson I, Sweeney MG, Cooper JM, Watkins PJ, Morgan-Hughes JA, Harding AE. Congenital encephalomyopathy and adult-onset myopathy and diabetes mellitus: different phenotypic associations of a new heteroplasmic mtDNA tRNA glutamic acid mutation. Am J Hum Genet. 1995 May;56(5):1026-33. PMID: 7726155; PMCID: PMC1801468.
5. Ng YS, Thompson K, Loher D, Hopton S, Falkous G, Hardy SA, Schaefer AM, Shaunak S, Roberts ME, Lilleker JB, Taylor RW. Novel MT-ND Gene Variants Causing Adult-Onset Mitochondrial Disease and Isolated Complex I Deficiency. Front Genet. 2020 Feb 25;11:24. doi: 10.3389/fgene.2020.00024. PMID: 32158465; PMCID: PMC7052259.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/dropped-head-syndrome-from-combined-mt-te-and-mt-nd1-mitochondrial-variants/