Leigh-Like Syndrome Due to Homoplasmic m.8993T>G Variant with Hypocitrullinemia and Unusual Biochemical Features Suggestive of Multiple Carboxylase Deficiency (MCD)

Abstract

Leigh syndrome (LS), or subacute necrotizing encephalomyelopathy, is a genetically heterogeneous, relentlessly progressive, devastating neurodegenerative disorder that usually presents in infancy or early childhood. A diagnosis of Leigh-like syndrome may be considered in individuals who do not fulfil the stringent diagnostic criteria but have features resembling Leigh syndrome.We describe a unique presentation of Leigh-like syndrome in a 3-year-old boy with elevated 3-hydroxyisovalerylcarnitine (C5-OH) on newborn screening (NBS).Subsequent persistent plasma elevations of C5-OH and propionylcarnitine (C3) as well as fluctuating urinary markers were suggestive of multiple carboxylase deficiency (MCD). Normal enzymology and mutational analysis of genes encoding holocarboxylase synthetase (HLCS) and biotinidase (BTD) excluded MCD. Biotin uptake studies were normal excluding biotin transporter deficiency. His clinical features at 13 months of age comprised psychomotor delay, central hypotonia, myopathy, failure to thrive, hypocitrullinemia, recurrent episodes of decompensation with metabolic keto-lactic acidosis and an episode of hyperammonemia. Biotin treatment from 13 months of age was associated with increased patient activity, alertness,

Mutational Analysis and mtDNA Haplogroup Characterization in Three Serbian Cases of Mitochondrial Encephalomyopathies and Literature Review

“…Moreover, phenotypic heterogeneity has been recorded in m.8993T>G carriers [61,62]. Our study supports the literature which displays the occurrence of m.8993T>G mutation in sporadic cases with rapid segregation toward homoplasmy [63][64][65]; it is noticeable in a single generation and reported in about 1/5 LS cases [66]. Other differential diagnoses for LS were excluded [67][68][69].…”

Leigh Syndrome: Spectrum of Molecular Defects and Clinical Features in Russia

“…Changes in the spectrum of organic acids are relatively non-specific and include high concentrations of the Krebs cycle metabolites: 2-hydroxyisobutyrate, 3-hydroxybutyrate, 2-oxoglutaric acid, lactate, pyruvate, fumarate, succinate, etc. In cases with PDHA1 -associated LS, a high level of alanine in blood is frequently observed and for the m.8993T>C/G variant low citrulline in blood (2/10; 20%) was noted which was previously reported in the literature [ 21 ].…”

MT‐ATP6 mitochondrial disease identified by newborn screening reveals a distinct biochemical phenotype

“…These disorders classically present with severe, life‐threatening hyperammonemia in the newborn period; however, early identification and medical management of affected individuals can dramatically improve outcomes. Decreased citrulline is also a feature of certain mitochondrial disorders (Atkuri et al, 2009), including MT‐ATP6 mitochondrial disease (Balasubramaniam et al, 2016; Larson et al, 2019; Mori et al, 2014; Peretz et al, 2021), such that affected individuals may similarly be identified through NBS. Like proximal UCDs, MT‐ATP6 mitochondrial disease can have a severe neonatal presentation, and therefore the ability to efficiently identify and differentiate these disorders is important for providing appropriate medical management to symptomatic newborns, as well as guidance for family members.…”

“…There are several reports of infants diagnosed with MT‐ATP6 mitochondrial disease after initially presenting in metabolic crisis with features of Leigh syndrome for whom a NBS abnormality was reported (Balasubramaniam et al, 2016; Larson et al, 2019; Mori et al, 2014). Such reports have aided in the recognition of NBS abnormalities associated with MT‐ATP6 mitochondrial disease, which include various permutations of decreased citrulline, elevated 3‐hydroxyisovaleryl‐(C5‐OH) and/or propionyl‐(C3) acylcarnitine(s), with variability likely reflecting differences in NBS panels and cutoff levels between states.…”