Drivers of Diagnostic Delay in Mitochondrial Disease: Missed Recognition of Canonical Features

TL;DR

This study finds that most diagnostic delays in mitochondrial disease occur because doctors fail to recognize early symptoms, not due to testing limitations.

Contribution

The study identifies missed recognition of canonical features as a key driver of diagnostic delay in mitochondrial disease.

Findings

Most delays occurred between symptom onset and clinical suspicion (mean 8.17 years).

Delays decreased sharply with later birth and symptom-onset years.

Canonical features like seizures and stroke were documented years before diagnosis.

Abstract

Diagnostic delay is common in mitochondrial disease, and its drivers remain unclear despite advances in molecular diagnostics. We retrospectively analyzed 61 individuals with molecularly confirmed mitochondrial disease at the Mount Sinai Mitochondrial Disease Clinic, diagnosed after 2016. Diagnostic delay was partitioned into intervals from symptom onset to clinical suspicion, and from suspicion to molecular diagnosis. Demographic, phenotypic, and genetic data were abstracted from health records, and Human Phenotype Ontology terms were compared before and after diagnosis using ClinPhen. Most delays occurred between symptom onset and clinical suspicion (mean 8.17 years) rather than after suspicion (mean 1.28 years), yielding a mean total delay of 8.22 years (median 3.0). Delay decreased sharply by year of birth (r = −0.99, p < 49.92 × 10−39) and symptom onset (r = −0.96, p < 8.14 × 10−27), but showed no meaningful trend with year of diagnosis. Canonical features such as seizures, hypotonia, and stroke were frequently documented years before suspicion, underscoring missed opportunities. Diagnostic delay may reflect missed recognition rather than testing limitations. Systematic capture of early phenotypes and AI/NLP‐based mining of electronic health records could proactively flag patients for reflexive sequencing, shortening diagnostic delay.

Most of the delay occurred before clinical suspicion: mean onset to clinical suspicion 8.17 years, versus mean suspicion to molecular diagnosis 1.28 years (mean total delay 8.22 years; median 3.0 years).Delays have shortened sharply across birth and symptom‐onset cohorts: year of birth versus delay r = −0.99 (p < 49.92 × 10−39) and symptom‐onset year versus delay r = −0.96 (p < 8.14 × 10−27), while year of molecular diagnosis showed no association (r = 0.07, p = 0.653).Canonical features were often documented years before recognition: seizures in 41% with mean lead time 1.8 years before diagnosis; global developmental delay 36% with 3.7 years; hypotonia 36% with 2.1 years; stroke 27% with 4.0 years.

Most of the delay occurred before clinical suspicion: mean onset to clinical suspicion 8.17 years, versus mean suspicion to molecular diagnosis 1.28 years (mean total delay 8.22 years; median 3.0 years).

Delays have shortened sharply across birth and symptom‐onset cohorts: year of birth versus delay r = −0.99 (p < 49.92 × 10−39) and symptom‐onset year versus delay r = −0.96 (p < 8.14 × 10−27), while year of molecular diagnosis showed no association (r = 0.07, p = 0.653).

Canonical features were often documented years before recognition: seizures in 41% with mean lead time 1.8 years before diagnosis; global developmental delay 36% with 3.7 years; hypotonia 36% with 2.1 years; stroke 27% with 4.0 years.

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