This case describes an almost three-decade-long diagnostic mystery that was ultimately solved by multidisciplinary clinical suspicion and comprehensive genetic analysis. The patient’s pattern of neurological, muscular, cardiac, and respiratory symptoms led to multiple misdiagnoses which are often the case in mitochondrial disorders. More than half of patients with mitochondrial disease receive one or more incorrect diagnoses before the true cause is found [13]. The underlying disease was uncovered through a combination of high clinical suspicion and broad genome-wide testing which confirmed MERRF-spectrum mitochondrial disease.

Classically, MERRF begins in childhood or adolescence with a mean onset in the early 20s [3]. Onset in middle-aged adults is rare. A large German registry found that the oldest onset among 34 MERRF patients to be 48 years [3]. Our patient, who did not develop overt myoclonic symptoms until his 50s, is an outlier that expands the phenotypic spectrum of MERRF into late adulthood. Among typical MERRF cases, only a subset develops the full “triad” of myoclonus, generalized seizures, and ataxia. In the German cohort, for example, these classic features were present in about 60 – 70% of patients. Instead, many patients exhibit other signs including sensorineural hearing loss, psychiatric or cognitive changes, and even respiratory muscle impairment [3]. Our patient’s presentation was consistent with the broader spectrum of MERRF symptoms. He has stimulus-sensitive myoclonus and ataxia, but no prolonged epileptic seizures. He also had developed progressive proximal muscle weakness with paraspinal atrophy, cardiomyopathy with atrial fibrillation, and restrictive respiratory dysfunction. This array of findings, spanning neurological and systemic domains, strongly pointed to a mitochondrial disorder as the unifying diagnosis.

The earliest misdiagnosis was labeling the patient’s jerking movements as primary generalized epilepsy. In retrospect, these episodes were likely nonepileptic myoclonus related to MERRF, which can be precipitated by photic stimulation or alcohol and may show generalized EEG spike-wave activity [2]. Photosensitive myoclonus in mitochondrial disease can be mistaken as epilepsy, as in this case. The patient was treated for epilepsy for over 15 years before video-EEG monitoring demonstrated the absence of epileptic ictal activity.

An additional diagnostic challenge was a variant of uncertain significance detected in the DES gene (c.250G>A, p.Gly84Ser) on a neuromuscular gene panel. Given the patient’s progressive proximal weakness, paraspinal muscle atrophy on MRI, reduced vital capacity, and cardiomyopathy, a late-onset desmin-related myofibrillar myopathy (desminopathy) was considered. Desminopathies cause combined skeletal muscle, cardiac, and respiratory muscle involvement, often presenting with limb-girdle weakness, restrictive lung disease, and dilated cardiomyopathy or arrhythmias [14]. Desminopathy does not typically produce stimulus-sensitive myoclonus, seizures, or cerebellar ataxia. Ultimately, the DES variant was ruled out as the source of the patient’s constellation of symptoms. This emphasizes the importance of correlating genetic findings with the entire clinical picture before ascribing causality.

A definitive diagnosis was achieved with comprehensive genetic testing that included the mitochondrial genome. Whole-genome sequencing identified a heteroplasmic m.8344A>G mutation in the MT-TK gene at a 62% variant load, which confirmed that the patient’s illness was a MERRF-spectrum mitochondrial disease. While a muscle biopsy may have demonstrated the hallmark ragged red fibers seen in MERRF, it was not necessary once the genetic diagnosis was found [1]. With the m.8344A>G mutation unifying the clinical picture, previously puzzling aspects of the case became clear. For instance, the early “peripheral neuropathy” symptoms and imbalance were likely manifestations of a mild neuropathic component of MERRF (which commonly includes peripheral neuropathy) [1], and the apparent EEG abnormalities in 2005 were consistent with photosensitive myoclonic activity rather than idiopathic epilepsy. The multi-organ involvement is consistent with MERRF’s spectrum, which is known to affect the heart and breathing musculature in addition to the nervous system [2].

This case highlights several important lessons for clinical practice. First, clinicians should keep mitochondrial disorders in the differential diagnosis of unexplained multisystem syndromes, even in older adults. Our patient’s age at diagnosis (late 60s) is unusual but demonstrative: mitochondrial disease is not purely pediatric and can remain latent until later in life [3]. Second, a targeted approach to genetic testing may miss the culprit in complex cases. In hindsight, standard gene panels and exomes focused on nuclear DNA did not detect the mtDNA mutation. It required broad whole-genome sequencing, with dedicated mtDNA analysis, to finally identify the cause. Third, the case illustrates the value of interdisciplinary and technology-augmented analysis. The synthesis of data from neurology, pulmonology, cardiology, imaging, and electrophysiology raised suspicion for a single unifying disorder.