Milder clinical course of Type IV 3-methylglutaconic aciduria due to a novel mutation in TMEM70

Oleg A. Shchelochkov, Fang Yuan Li, Jing Wang, Hongli Zhan, Jeffrey Towbin, John Jefferies, Lee Jun Wong, Fernando Scaglia

Research output: Contribution to journalArticle

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Abstract

Mitochondrial disorders are a large and genetically heterogeneous group of disorders posing a significant diagnostic challenge. Only approximately 10-20% of patients have identifiable alterations in their mitochondrial DNA (mtDNA). The remaining ~ 80-90% of affected patients likely harbor mutations in nuclear genes, most of which are still poorly characterized, and therefore not amenable to efficient screening using currently available molecular methods.Here we present a patient, who has been followed since birth after presenting with neonatal hyperammonemia, lactic acidosis, Reye-like syndrome episodes, and ventricular tachyarrhythmia. Initial biochemical work-up revealed hyperalaninemia, normal plasma glutamine, mild orotic aciduria and significant amounts of urinary 3-methylglutaconic (3-MGC) and 3-methylglutaric (3-MGA) acids. Muscle biopsy demonstrated the presence of ragged-red fibers and non-specific structural abnormalities of mitochondria. The activities of respiratory chain enzymes (complexes I-IV) showed no deficiency. Mutational analysis of the entire mitochondrial genome did not reveal deleterious point mutations or large deletions. Long-term follow-up was significant for a later-onset hypertrophic cardiomyopathy, muscle weakness, and exercise intolerance. Although she had frequent episodes of Reye-like episodes in infancy and early childhood, mostly triggered by illnesses, these symptoms improved significantly with the onset of puberty.In the light of recent reports linking cases of type IV 3-methylglutaconic aciduria (3-MGCA) and hypertrophic cardiomyopathy to mutations in TMEM70, we proceeded with sequencing analysis of this gene. We identified one previously reported splice site mutation, c.317-2A>G and a novel mutation c.494G>A (p.G165D) in an evolutionarily conserved region predicted to be deleterious. This variant was not identified in 100 chromosomes of healthy control subjects and 200 chromosomes of patients with cardiomyopathies. Western blotting using a polyclonal antibody against ATP5J, subunit F6 of ATP synthase, on patient's skin fibroblasts showed undetectable amount of the ATP5J protein. In comparison to the previously reported cases, we note that our patient had normal growth parameters and cognitive development, absence of structural heart and urinary tract defects, no dysmorphic features, improvement of symptoms with age, and persistence of hypertrophic cardiomyopathy.

Original languageEnglish (US)
Pages (from-to)282-285
Number of pages4
JournalMolecular Genetics and Metabolism
Volume101
Issue number2-3
DOIs
StatePublished - Oct 1 2010

Fingerprint

Genes
Chromosomes
Mutation
Muscle
Hypertrophic Cardiomyopathy
Mitochondria
Biopsy
Fibroblasts
Ports and harbors
Glutamine
Mitochondrial DNA
Skin
Screening
Adenosine Triphosphate
Reye Syndrome
Hyperammonemia
Plasmas
Mitochondrial Diseases
Lactic Acidosis
Defects

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Endocrinology

Cite this

Milder clinical course of Type IV 3-methylglutaconic aciduria due to a novel mutation in TMEM70. / Shchelochkov, Oleg A.; Li, Fang Yuan; Wang, Jing; Zhan, Hongli; Towbin, Jeffrey; Jefferies, John; Wong, Lee Jun; Scaglia, Fernando.

In: Molecular Genetics and Metabolism, Vol. 101, No. 2-3, 01.10.2010, p. 282-285.

Research output: Contribution to journalArticle

Shchelochkov, Oleg A. ; Li, Fang Yuan ; Wang, Jing ; Zhan, Hongli ; Towbin, Jeffrey ; Jefferies, John ; Wong, Lee Jun ; Scaglia, Fernando. / Milder clinical course of Type IV 3-methylglutaconic aciduria due to a novel mutation in TMEM70. In: Molecular Genetics and Metabolism. 2010 ; Vol. 101, No. 2-3. pp. 282-285.
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