Abstract
Pathogenic variants in the LONP1 gene have been associated with CODAS syndrome (Cerebral, Ocular, Dental, Auricular, and Skeletal Anomalies Syndrome). A recent report identified the first newborn case with LONP1-related mitochondrial cytopathy due to a compound heterozygous pathogenic variant in LONP1 without features of CODAS. The proband had manifested with severe congenital lactic acidosis and profound multiple respiratory chain complex activity deficiencies associated with the quantitative loss of mtDNA copy number in muscle. A subsequent report identified two siblings with regression during infancy, profound hypotonia and muscle weakness, severe intellectual disability, progressive cerebellar atrophy, where muscle biopsy showed an electron dense mitochondrial inclusions without ragged-red fibers and normal electron transport chain enzyme activities. Here, we report an additional case of autosomal recessive mitochondrial cytopathy due to a homozygous missense variant in LONP1 that was identified on whole exome sequencing (c.810G > A; p.D463N). The proband, a 20-year-old male born to consanguineous parents, presented with global developmental delay, emotional outbursts, speech and swallowing difficulties, hypotonia, and ataxia since childhood. Muscle biopsy showed massive granular bodies, increased oxidative stress, and autophagic block and reduced mitochondrial state 3 respiration. We have identified another case of LONP1-related mitochondrial cytopathy further confirming a neurological phenotype without CODAS features.
Highlights
LONP1 is a lon protease with substrate selectivity, which removes a variety of oxidatively damaged proteins in the mitochondria [1,2,3]
We describe an additional case of a severe mitochondrial cytopathy resulting from a homozygous missense variant in LONP1, and show an expected finding of massive intra-mitochondrial globular inclusions on muscle biopsy, likely representing protein that is not broken down through proteases, in keeping with LONP1 deficiency (Figure 1)
This mitochondrial defect did not result in the canonical histological (COX-negative, RRF, paracrystalline inclusions) or enzymatic features of a mitochondrial cytopathy; yet, the finding of large intra-mitochondrial electron densities and very significant reductions in high resolution respirometry determined activities were defining, and in keeping with the muscle findings of a previous report [8]
Summary
LONP1 is a lon protease with substrate selectivity, which removes a variety of oxidatively damaged proteins in the mitochondria [1,2,3]. LONP1 is necessary for mitochondrial proteostasis and gene expression maintenance [4]. Defects in LONP1 leads to accumulation of oxidatively damaged proteins, causing mitochondrial specific proteotoxicity [5]. The homozygous deletion of LonP1 causes early embryonic death [3]. A reduction of LONP1 activity was shown to have a significantly reduced respiratory chain complex activity, consistent with depletion of mtDNA, which encodes for key components of these respiratory chain complexes [5]
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