TIMMDC1 – Leigh syndrome

Leigh syndrome is an early-onset mitochondrial encephalopathy characterized by neurodevelopmental regression, hypotonia, respiratory failure, and characteristic basal ganglia lesions. TIMMDC1 encodes a complex I assembly factor, and biallelic loss-of-function variants have been implicated in autosomal recessive Leigh syndrome (TIMMDC1; Leigh syndrome).

Initial functional assessment of a homozygous nonsense TIMMDC1 variant (c.673C>T (p.Arg225Ter)) demonstrated a hypomorphic impact on complex I assembly but retained rescue capacity in knockout cells, and the clinical presentation was indistinguishable from PDHX-related Leigh syndrome, arguing against a dual diagnosis in that patient (PMID:30981218).

Definitive genetic evidence emerged with discovery of a homozygous deep intronic variant (c.597-1340A>G) segregating in two affected siblings presenting with hypotonia and respiratory insufficiency, confirming aberrant splicing and complex I deficiency by muscle biopsy and clinical phenotype (PMID:33278652). A second unrelated family harbored compound heterozygous variants, including a novel nonsense change c.385C>T (p.Arg129Ter) and the same deep intronic allele, in two affected brothers with rapidly progressive Leigh syndrome (PMID:33278652).

Further functional studies in patient fibroblasts from a consanguineous family with the deep intronic variant c.597-1340A>G demonstrated near-complete loss of TIMMDC1 protein, compromised complex I activity, and restoration of normal splicing, protein levels, and mitochondrial function following antisense oligonucleotide correction (PMID:35091571).

Collectively, at least 4 probands from two unrelated families exhibit biallelic TIMMDC1 variants, with segregation in 4 affected relatives and concordant functional data confirming loss-of-function as the disease mechanism. A hypomorphic C-terminal truncation was shown to be insufficient for disease causation, highlighting the necessity of rigorous functional interpretation.

Key take-home: Biallelic loss-of-function TIMMDC1 variants cause autosomal recessive Leigh syndrome; targeted antisense therapy offers a potential precision treatment avenue.

References

• Human Mutation • 2019 • A patient with homozygous nonsense variants in two Leigh syndrome disease genes: Distinguishing a dual diagnosis from a hypomorphic protein-truncating variant. PMID:30981218
• European Journal of Medical Genetics • 2021 • Deep intronic TIMMDC1 variant delays diagnosis of rapidly progressive complex I deficiency. PMID:33278652
• NPJ Genomic Medicine • 2022 • Oligonucleotide correction of an intronic TIMMDC1 variant in cells of patients with severe neurodegenerative disorder. PMID:35091571

Evidence Based Scoring (AI generated)