Redefining phenotypes associated with mitochondrial DNA single deletion.

Area of Science:

• Genetics and Molecular Biology
• Neurology
• Rare Diseases

Background:

• Single large-scale deletions of mitochondrial DNA (mtDNA) are linked to Progressive External Ophthalmoplegia (PEO), Kearns-Sayre Syndrome (KSS), and Pearson syndrome.
• The term 'PEO plus' is used clinically but lacks a precise definition for patients with PEO and multisystem involvement.
• Accurate classification of these mtDNA deletion syndromes is crucial for research and patient care.

Purpose of the Study:

• To establish precise clinical definitions for phenotypes associated with single mtDNA deletions.
• To refine the classification of patients with PEO and KSS spectrum disorders.
• To improve patient categorization for future natural history studies and clinical trials.

Main Methods:

• Retrospective analysis of a large cohort (228 patients) from the "Nation-wide Italian Collaborative Network of Mitochondrial Diseases" database.
• Development of new diagnostic criteria for PEO and a "KSS spectrum" category.
• Classification of patients based on the newly defined criteria.

Main Results:

• Single mtDNA deletions constitute approximately one-third of mtDNA-related diseases in the studied cohort.
• New criteria allowed classification of nearly all patients: 64.5% PEO, 31.6% KSS spectrum (including 6.6% classic KSS), and 2.6% Pearson syndrome.
• Deletion length correlated positively with KSS spectrum, while heteroplasmy inversely correlated with age at onset.

Conclusions:

• The proposed phenotype definitions for PEO and KSS spectrum offer a more homogeneous patient categorization.
• These refined classifications are valuable for future research, including natural history studies and clinical trials for mtDNA deletion syndromes.
• Improved classification enhances understanding of the clinical spectrum of single mtDNA deletion disorders.