# Administrative Supplement for Leigh Syndrome Spectrum Expert Panel Curation

> **NIH NIH U24** · CHILDREN'S HOSP OF PHILADELPHIA · 2020 · $77,978

## Abstract

PROJECT SUMMARY. Mitochondrial disease is a highly phenotypically and genetically heterogeneous group
of progressive, multi-system disorders affecting 1 in 4,300 people due to impaired cellular energy metabolism.
Many mitochondrial disorders fall within the NICHD high priority clinical domain, which involves a broad
spectrum of neurodevelopmental disabilities including autism. The common pediatric mitochondrial disease
presentations termed Leigh syndrome (LS) or Leigh-like syndrome (LLS), which can be caused by mutations in
approximately 90 genes across both nuclear and mitochondrial genomes, are linked with intellectual and
neurodevelopmental disabilities, infection susceptibility that often precipitates neurodevelopmental regression,
metabolic strokes in basal ganglia and deep brain structures at any point in childhood including, in some
cases, in the newborn period that is associated with primary lactic acidosis from birth and early demise, with an
overall 35% mortality in childhood. Establishing an accurate genetic diagnosis of these diverse pediatric
mitochondrial encephalopathy syndromes is critically important, as an increasing number have clinical
actionability involving initiation or avoidance of specific medications, cofactors, or diets. Accurate diagnosis
currently remains challenging, as there is no expertly-curated and comprehensive catalogue of pathogenic LS,
LLS, and other gene mutations to guide diagnosis and clinical actionability. Since 2012, the project PIs have
co-led the international Mitochondrial Disease Sequence Data Resource (MSeqDR) consortium to organize
and curate mitochondrial disease genomic knowledge, analysis and sharing tools, and phenotypes. This
organized MSeqDR community structure and committed international expertise is now poised to collaboratively
curate genes and variants relevant to the most prevalent and treatable mitochondrial LS and LLS pediatric
encephalopathy syndromes using ClinGen resources and curation tools. Aim 1. To complete gene-disease
association expert curation for all pediatric mitochondrial encephalopathy syndromes with
neurodevelopmental disability in the Leigh and Leigh-like spectrum. We will utilize the ClinGen gene
curation tools and frameworks to review the gene-disease relationship for approximately 90 genes that cause
LS, LLS, and other pediatric mitochondrial encephalopathy syndromes. We have brought together 32 leading
international experts from 11 countries to collaboratively analyze all relevant data and achieve consensus in
this important gene-disease curation effort. Aim 2. To expertly curate variants in the most prevalent and
treatable pediatric-onset mitochondrial encephalopathy nuclear and mtDNA genes. Nuclear genes
causing the most prevalent (SURF1, POLG, FBXL4) and treatable (SLC19A3, BTD, PDSS2, PDHA1, TPK1,
ACAD9, ETHE1, HIBCH) pediatric-onset LS and LLS will be prioritized. In addition, our global network of
leading mtDNA disease experts will evaluate the mtDNA variant...

## Key facts

- **NIH application ID:** 10225911
- **Project number:** 3U24HD093483-03S1
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** MARNI J FALK
- **Activity code:** U24 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $77,978
- **Award type:** 3
- **Project period:** 2020-08-01 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10225911

## Citation

> US National Institutes of Health, RePORTER application 10225911, Administrative Supplement for Leigh Syndrome Spectrum Expert Panel Curation (3U24HD093483-03S1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10225911. Licensed CC0.

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