Red Flags in Primary Mitochondrial Diseases: What Should We Recognize?

**Background:** Primary mitochondrial diseases (PMDs) are a group of genetic metabolic disorders caused by impaired oxidative phosphorylation (OXPHOS), with a prevalence of approximately 1 in 4300. Pathogenic variants in mitochondrial DNA (mtDNA) and over 400 nuclear genes can cause PMDs, leading to vast clinical heterogeneity. High-energy-demand tissues like muscle, brain, and heart are most affected. Diagnosis is challenging due to variable age of onset, tissue-specific manifestations, and complex genetics. This narrative review aims to outline 'red flags'—clinical features that should raise suspicion for PMDs—to help clinicians navigate diagnostic complexity.

**Methods:** The authors conducted a narrative review of the literature, synthesizing evidence on common clinical manifestations of PMDs. They focused on neurological, gastrointestinal, cardiovascular, renal, endocrine, and other systemic features, summarizing pathogenetic mechanisms, syndromic associations, and genetic etiologies for each red flag. Key data sources included the Nation-wide Italian Collaborative Network of Mitochondrial Diseases database and other cohort studies.

**Key Results:** Neurological red flags include progressive external ophthalmoplegia (PEO), which occurs in syndromes like Kearns-Sayre syndrome (KSS) and is often associated with mtDNA deletions or POLG1 mutations. Exercise intolerance affects >20% of mitochondrial patients, with one-third showing elevated creatine kinase. Stroke-like episodes (SLEs) define MELAS syndrome, with ~80% linked to the m.3243A>G mutation; POLG1-related SLEs are more aggressive. Bilateral brainstem lesions characterize Leigh syndrome (LS), affecting ~1 in 36,000 births, often due to complex IV deficiency (e.g., SURF1 mutations). Epilepsy occurs in 10–40% of adults and 60% of pediatric PMD patients, commonly in MELAS, MERRF, and Alpers-Huttenlocher syndrome. Movement disorders like ataxia and parkinsonism are frequent; ataxia is seen in KSS, MILS, MERRF, and POLG-related disorders. Migraine prevalence is 35% in PMD patients, higher than the general population. Peripheral neuropathy occurs in one-third of patients, often in KSS, MNGIE, and MERRF. Cognitive decline is reported in MELAS (≥90% dementia), MERRF, LS, and NARP. Optic atrophy is hallmark of LHON (m.11778G>A most common) and ADOA (OPA1 mutations); pigmentary retinopathy is key in KSS and MIDD. Sensorineural hearing loss is common in MELAS, KSS, MERRF, and MIDD, and can be aminoglycoside-induced with m.1555A>G.

Gastrointestinal red flags include acute liver failure, especially in Alpers-Huttenlocher syndrome (POLG1 mutations) and mitochondrial depletion syndromes (DGUOK, MPV17). Severe dysmotility/pseudo-obstruction is characteristic of MNGIE (TYMP mutations) and also seen in MELAS. Cardiovascular red flags: cardiomyopathies occur in 20–40% of PMD patients (hypertrophic most common), with poorer prognosis; seen in MELAS (30–32%) and LS (18–21%). Arrhythmias and conduction defects are frequent in KSS and cPEO; Wolff-Parkinson-White syndrome is noted in MELAS. Renal red flags: tubulopathies (e.g., Fanconi syndrome) are common with large-scale mtDNA deletions; glomerulopathies (focal segmental glomerulosclerosis) occur with m.3243A>G. Endocrine red flags: diabetes mellitus is reported in 0.5–2.9% of the population with m.3243A>G, and is frequent in MIDD, MELAS, and KSS. Other endocrine signs include hypothyroidism, hypoparathyroidism, and premature ovarian failure (POLG-related). Additional red flags: lactic acidosis is present in 30–50% of PMD patients, more common in children; cachexia occurs in MELAS and MNGIE; multiple systemic lipomatosis is linked to MERRF (m.8344A>G); short stature affects 73% of children with m.3243A>G.

**Clinical Implications:** Recognizing these red flags is essential for early diagnosis of PMDs, which can guide genetic testing and management. Family history, neuroimaging, and laboratory biomarkers (e.g., lactate) support diagnosis. While current therapies are largely supportive, emerging treatments include idebenone for LHON, omaveloxolone for Friedreich's ataxia, and gene therapy (e.g., AAV2-ND4 for LHON). Clinicians should suspect PMDs in any multisystem disorder, especially with neurological, ocular, or endocrine involvement, and avoid mitochondrial-toxic drugs like valproate in POLG1 patients.