ICNC Abstracts, ICNC 2018

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Leigh-like syndrome due to homoplasmic m.8993T>G variant with hypocitrullinemia and unusual biochemical features suggestive of multiple carboxylase deficiency (MCD)
Maina Padmanabha Kava, Barry Lewis, Lawrence Greed, Shanti Balasubramaniam

Last modified: 2018-09-09


Leigh syndrome (LS) is a genetically heterogeneous, relentlessly progressive, devastating neurodegenerative disorder. 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 5 ½ year-old boy who had an abnormal newborn screening with increased 3-hydroxyisovalerylcarnitine (C5-OH). Subsequent persistent increases of plasma C5-OH and propionylcarnitine (C3) as well as fluctuating urinary markers were suggestive of MCD. Enzymology, mutational analysis of HLCS and BTD genes and biotin uptake studies were normal. At 13 months of age he displayed psychomotor delay, central hypotonia, myopathy, failure to thrive, recurrent episodes of decompensation with metabolic keto-lactic acidosis, hypocitrullinemia and an episode of hyperammonemia. Whole exome sequencing was non-contributory. Identification of de novo homoplasmic MT-ATP6 m.8993T>G mutations in muscle and blood led to the diagnosis of Leigh-like syndrome. Complex IV activity was mildly decreased in skeletal muscle. Apart from a small lactate doublet on spectroscopy, brain MRI was normal. Biotin treatment was associated with improved patient activity levels, alertness, and attainment of developmental milestones, despite lack of biochemical improvements.

Persistent increases of plasma C3 and C5-OH have previously been reported in only one other patient with this homoplasmic mutation. This unique biochemical phenotype may serve as a potential marker for mitochondrial disorders due to m.8993T>G or other MT-ATP6 mutations associated LS, facilitating rapid diagnosis through targeted mutation analysis and minimize invasive tissue biopsies for respiratory chain studies. Trail of oral biotin is also  warranted.


Leigh-like syndrome ;biotin ;hypocitrullinemia

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