Phenotype and natural history of mitochondrial membrane protein-associated neurodegeneration

Area of Science:

• Neurogenetics
• Neurodegenerative diseases
• Rare diseases

Background:

• Mitochondrial membrane protein-associated neurodegeneration (MPAN) is an ultra-rare neurogenetic disorder within the neurodegeneration with brain iron accumulation (NBIA) group.
• Understanding the natural history and progression of MPAN is crucial for developing effective therapeutic strategies and clinical trial designs.
• Current knowledge regarding MPAN's clinical phenotype, disease progression, and optimal outcome measures for research is limited.

Purpose of the Study:

• To define the clinical phenotype and disease progression of Mitochondrial membrane protein-associated neurodegeneration (MPAN) using cross-sectional and longitudinal data.
• To assess the rate of disease progression in MPAN patients using standardized rating scales.
• To estimate sample sizes required for future clinical trials in MPAN.

Main Methods:

• Cross-sectional and longitudinal data were collected from 85 MPAN patients enrolled in the TIRCON registry and cohort study, with functional outcome data from 45 patients.
• Linear mixed-effect modeling (LMEM) was employed to calculate annual progression rates for the Unified Parkinson's Disease Rating Scale (UPDRS), Barry-Albright Dystonia (BAD) scale, Schwab and England Activities of Daily Living (SE-ADL) scale, and the Pediatric Quality of Life Inventory (PedsQL).
• Analysis included assessment of symptom onset, frequency, and progression over time to characterize the disease's natural history.

Main Results:

• The median age of onset for MPAN was 9 years, with a median diagnostic delay of 5 years. Common early symptoms include gait disturbance (99%), pyramidal involvement (95%), and dysarthria (90%).
• After 16 years of disease, 50% of patients required wheelchair dependency. LMEM indicated an average annual progression rate of 4.5 points on the total UPDRS.
• The SE-ADL scale and PedsQL showed significant declines (3.9%, 2.14, and 2.05 points annually, respectively), while the BAD scale showed no significant progression. No distinct patient subpopulations were identified.

Conclusions:

• Cross-sectional findings clarify the order and frequency of MPAN symptoms, aiding diagnosis, shortening delays, and improving patient/caregiver counseling.
• Longitudinal data establish the natural history of MPAN, identify responsive outcomes for trials, and highlight the need for MPAN-specific assessment tools.
• Sample size estimations derived from this study will guide the design of upcoming clinical trials for MPAN.