Isolated Periodic‐Paralysis‐Like Syndrome in a Kinship With a Pathogenic <i>MT‐ATP6</i> Variant: A Case Report

Using the electrochemical gradient generated by the mitochondrial respiratory chain, complex V (F1FO ATP synthase) generates cellular energy—adenosine triphosphate (ATP). Complex V comprises 18 subunits, with ATP6 and ATP8—components of the FO domain—encoded by mitochondrial DNA (mtDNA; NC_012920.1). Pathogenic variants in MT-ATP6 cause varied, often multisystemic, phenotypes including Leigh syndrome; neuropathy, ataxia and retinitis pigmentosa (NARP); chronic progressive external ophthalmoplegia (CPEO) among others, with variable age of onset [1, 2]. Periodic paralysis (PP) is usually associated with inherited defects in ion-channel-encoding genes CACNA1S, SCN4A, and KCNJ2. Pathogenic variants in which account for 60%–70% of patients with the PP-phenotype [3]. Episodic weakness has been reported in individuals with MT-ATP6 variants; however, these cases have thus far been distinguishable from PP by the additional presence of neuropathy [4]. Permanent plasma membrane depolarisation and altered permeability to potassium demonstrated in patient-derived fibroblasts, offered a potential biochemical basis for the symptom of episodic weakness [4]. We describe a patient with a familial isolated PP-like syndrome without neuropathy or other systemic features due to a pathogenic MT-ATP6 variant. The 43-year-old proband was born to non-consanguineous, asymptomatic parents and had one similarly affected brother. She reported episodic weakness induced by either prolonged rest or exertion. Her parents reported that at 2 years she pushed on her thighs to climb stairs. She was able to partake in school sports but was unable to walk back to class afterwards. She described triggers including prolonged sitting upright, exertion, infections or menstruation. Attacks were more likely to happen after drinking alcohol. The episodes would last 0.5–24 h. Weakness developed proximally in the legs, less frequently in the arms and would worsen with use. Muscles felt sore and tight during an attack. Weakness was not evident between attacks. By carefully managing levels of activity throughout the day and avoiding triggers, attack frequency was greatly reduced by adulthood. Neurological examination was normal except for absent lower limb reflexes. Nerve conduction studies of the median and peroneal motor, and sural sensory nerves, were normal. Needle electromyography of the first dorsal interosseous of the hand, vastus lateralis and tibialis anterior muscles revealed mildly enlarged motor unit potentials and a slightly diminished interference pattern. McManis long-exercise test revealed a 19% decrement post-exercise in the left adductor digiti minimi, less than the 40% threshold typically seen in PP. This pattern may be observed in patients with genetically proven PP with infrequent attacks [5]. Muscle biopsy showed type-I and type-II fiber-type grouping and normal respiratory chain function (Figure 1). Whole mitochondrial genome sequencing in blood revealed a missense variant in MT-ATP6 (m.8851T>C-p.(Trp109Arg) (NC_012920.1)) with 61% heteroplasmy. Screening of muscle-derived DNA using a pyrosequencing assay that permits quantitation of mtDNA heteroplasmy identified the variant at a level of 62% in skeletal muscle. Whole exome sequencing was normal. We report a patient with a novel phenotype of an isolated PP-like syndrome associated with the m.8851T>C MT-ATP6 variant. This variant is classified as likely pathogenic and is present on Mitomap (https://www.mitomap.org/), GnomAD (https://gnomad.broadinstitute.org/) and HELIX (https://www.helix.com/MITO) databases with extremely low frequencies. Affecting a highly conserved amino acid, in silico analysis supports pathogenicity. Additionally, functional studies support a detrimental effect on ATP synthase function [6]. Furthermore, the variant has been linked with a range of mitochondrial presentations including Charcot–Marie–Tooth and Leigh syndrome [1]. This report of a PP-like presentation reiterates there is significant variability in phenotype with identical genetic variants [1]. Despite subtle indicators of nerve involvement (lower limb areflexia, fiber-type grouping on biopsy), there has been no progression to clinical neuropathy over 40 years. Heteroplasmy and threshold effect are often used to explain some of the heterogeneity in phenotypic severity and presentation in mitochondrial disease. Our patient had 62% heteroplasmy in muscle. Previously reported patients with episodic weakness and progressive neuropathy were homoplasmic for their variants [4]. The heteroplasmic threshold required to cause disease differs between mitochondrial variants, some such as m.9035T>C and m.8993T>C being higher versus m.8993T>G [1]. The threshold required to cause disease with m.8851T>C is unclear; however, a symptomatic individual with motor axonal neuropathy was reported with 68% heteroplasmy in blood and 69% in urine while their sister (60% heteroplasmy) remained asymptomatic [7]. Muscle biopsy may aid interpretation of pathogenicity in such cases. In patients with a PP phenotype a genetic diagnosis remains elusive in 30%–40% despite confirmation of disease by clinical and electrophysiological criteria [3]. Our case demonstrates that mitochondrial diagnoses should be considered even in the absence of neuropathy or other more typical features of mitochondrial disease. Eva Tallon: original draft writing, data acquisition and interpretation, review and editing. Sinéad M. Murphy: conception, review and editing, data acquisition, supervision. Robert W. Taylor: review and editing, data analysis and interpretation. Michael Alexander: data acquisition, analysis and interpretation, review and editing. John McHugh: data analysis and interpretation, review and editing. Michael Farrell: data analysis and interpretation, review and editing. Jack P. Baines: data analysis and interpretation, review and editing. Sila Hopton: data analysis and interpretation, review and editing. Emma L. Blakely: data analysis and interpretation, review and editing. All the authors have reviewed and approved the final version. The authors have nothing to report. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. The authors declare no conflicts of interest. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.