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HIBCH mutations can cause Leigh-like disease with combined deficiency of multiple mitochondrial respiratory chain enzymes and pyruvate dehydrogenase.

Ferdinandusse S, Waterham HR, Heales SJ, Brown GK, Hargreaves IP, Taanman JW, Gunny R, Abulhoul L, Wanders RJ, Clayton PT, Leonard JV, Rahman S - Orphanet J Rare Dis (2013)

Bottom Line: Specific spectrophotometric enzyme assay revealed HIBCH activity to be below detectable limits in cultured skin fibroblasts from both brothers.Direct Sanger sequence analysis demonstrated a novel homozygous pathogenic missense mutation c.950G <A; p.Gly317Glu in the HIBCH gene, which segregated with infantile-onset neurodegeneration within the family.HIBCH deficiency, a disorder of valine catabolism, is a novel cause of the multiple mitochondrial dysfunctions syndrome, and should be considered in the differential diagnosis of patients presenting with multiple RC deficiencies and/or pyruvate dehydrogenase deficiency.

View Article: PubMed Central - HTML - PubMed

Affiliation: Metabolic Unit, Great Ormond Street Hospital, London, UK. shamima.rahman@ucl.ac.uk.

ABSTRACT

Background: Deficiency of 3-hydroxy-isobutyryl-CoA hydrolase (HIBCH) caused by HIBCH mutations is a rare cerebral organic aciduria caused by disturbance of valine catabolism. Multiple mitochondrial respiratory chain (RC) enzyme deficiencies can arise from a number of mechanisms, including defective maintenance or expression of mitochondrial DNA. Impaired biosynthesis of iron-sulphur clusters and lipoic acid can lead to pyruvate dehydrogenase complex (PDHc) deficiency in addition to multiple RC deficiencies, known as the multiple mitochondrial dysfunctions syndrome.

Methods: Two brothers born to distantly related Pakistani parents presenting in early infancy with a progressive neurodegenerative disorder, associated with basal ganglia changes on brain magnetic resonance imaging, were investigated for suspected Leigh-like mitochondrial disease. The index case had deficiencies of multiple RC enzymes and PDHc in skeletal muscle and fibroblasts respectively, but these were normal in his younger brother. The observation of persistently elevated hydroxy-C4-carnitine levels in the younger brother led to suspicion of HIBCH deficiency, which was investigated by biochemical assay in cultured skin fibroblasts and molecular genetic analysis.

Results: Specific spectrophotometric enzyme assay revealed HIBCH activity to be below detectable limits in cultured skin fibroblasts from both brothers. Direct Sanger sequence analysis demonstrated a novel homozygous pathogenic missense mutation c.950G

Conclusions: HIBCH deficiency, a disorder of valine catabolism, is a novel cause of the multiple mitochondrial dysfunctions syndrome, and should be considered in the differential diagnosis of patients presenting with multiple RC deficiencies and/or pyruvate dehydrogenase deficiency.

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HIBCH deficiency leads to accumulation of hydroxy-C4-carnitine. (a) Valine degradation pathway. 3-Hydroxy-isobutyrylCoA hydrolase (HIBCH) catalyses the fifth step of valine catabolism. HIBCH deficiency leads to accumulation of 3-hydroxy-isobutyryl carnitine, which is detected as hydroxy-C4-carnitine by tandem mass spectrometry. (b) Plasma acylcarnitine analysis by tandem mass spectrometry. Left panel: normal acylcarnitine profile; Right panel: acylcarnitine profile from Patient 2 with accumulating hydroxy-C4-carnitine indicated by arrow.
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Figure 1: HIBCH deficiency leads to accumulation of hydroxy-C4-carnitine. (a) Valine degradation pathway. 3-Hydroxy-isobutyrylCoA hydrolase (HIBCH) catalyses the fifth step of valine catabolism. HIBCH deficiency leads to accumulation of 3-hydroxy-isobutyryl carnitine, which is detected as hydroxy-C4-carnitine by tandem mass spectrometry. (b) Plasma acylcarnitine analysis by tandem mass spectrometry. Left panel: normal acylcarnitine profile; Right panel: acylcarnitine profile from Patient 2 with accumulating hydroxy-C4-carnitine indicated by arrow.

Mentions: Neurological features of cerebral organic acidurias (disorders of degradation of the carbon skeleton of amino acids) can be clinically and radiologically indistinguishable from mitochondrial encephalomyopathies caused by primary RC deficiencies; seizures, neurological regression and bilateral symmetrical basal ganglia lesions may occur in both groups of disorders [7-10]. 3-Hydroxy-isobutyryl-CoA hydrolase (HIBCH) is a mitochondrial enzyme that catalyses the fifth step of valine catabolism, the conversion of 3-hydroxy-isobutyryl-CoA to 3-hydroxy-isobutyrate (FigureĀ 1a). HIBCH deficiency has previously been reported in only two patients [11,12]. We now describe two new genetically confirmed cases (siblings), one of whom presented with combined defects of multiple RC enzymes and the pyruvate dehydrogenase complex (PDHc). This potentially represents a new disease mechanism mimicking the multiple mitochondrial dysfunctions syndrome, namely degradation of multiple enzymes resulting from accumulation of a toxic metabolite methacrylyl-CoA that is postulated to reduce mitochondrial enzyme activities by reacting with exposed thiol groups.


HIBCH mutations can cause Leigh-like disease with combined deficiency of multiple mitochondrial respiratory chain enzymes and pyruvate dehydrogenase.

Ferdinandusse S, Waterham HR, Heales SJ, Brown GK, Hargreaves IP, Taanman JW, Gunny R, Abulhoul L, Wanders RJ, Clayton PT, Leonard JV, Rahman S - Orphanet J Rare Dis (2013)

HIBCH deficiency leads to accumulation of hydroxy-C4-carnitine. (a) Valine degradation pathway. 3-Hydroxy-isobutyrylCoA hydrolase (HIBCH) catalyses the fifth step of valine catabolism. HIBCH deficiency leads to accumulation of 3-hydroxy-isobutyryl carnitine, which is detected as hydroxy-C4-carnitine by tandem mass spectrometry. (b) Plasma acylcarnitine analysis by tandem mass spectrometry. Left panel: normal acylcarnitine profile; Right panel: acylcarnitine profile from Patient 2 with accumulating hydroxy-C4-carnitine indicated by arrow.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4222069&req=5

Figure 1: HIBCH deficiency leads to accumulation of hydroxy-C4-carnitine. (a) Valine degradation pathway. 3-Hydroxy-isobutyrylCoA hydrolase (HIBCH) catalyses the fifth step of valine catabolism. HIBCH deficiency leads to accumulation of 3-hydroxy-isobutyryl carnitine, which is detected as hydroxy-C4-carnitine by tandem mass spectrometry. (b) Plasma acylcarnitine analysis by tandem mass spectrometry. Left panel: normal acylcarnitine profile; Right panel: acylcarnitine profile from Patient 2 with accumulating hydroxy-C4-carnitine indicated by arrow.
Mentions: Neurological features of cerebral organic acidurias (disorders of degradation of the carbon skeleton of amino acids) can be clinically and radiologically indistinguishable from mitochondrial encephalomyopathies caused by primary RC deficiencies; seizures, neurological regression and bilateral symmetrical basal ganglia lesions may occur in both groups of disorders [7-10]. 3-Hydroxy-isobutyryl-CoA hydrolase (HIBCH) is a mitochondrial enzyme that catalyses the fifth step of valine catabolism, the conversion of 3-hydroxy-isobutyryl-CoA to 3-hydroxy-isobutyrate (FigureĀ 1a). HIBCH deficiency has previously been reported in only two patients [11,12]. We now describe two new genetically confirmed cases (siblings), one of whom presented with combined defects of multiple RC enzymes and the pyruvate dehydrogenase complex (PDHc). This potentially represents a new disease mechanism mimicking the multiple mitochondrial dysfunctions syndrome, namely degradation of multiple enzymes resulting from accumulation of a toxic metabolite methacrylyl-CoA that is postulated to reduce mitochondrial enzyme activities by reacting with exposed thiol groups.

Bottom Line: Specific spectrophotometric enzyme assay revealed HIBCH activity to be below detectable limits in cultured skin fibroblasts from both brothers.Direct Sanger sequence analysis demonstrated a novel homozygous pathogenic missense mutation c.950G <A; p.Gly317Glu in the HIBCH gene, which segregated with infantile-onset neurodegeneration within the family.HIBCH deficiency, a disorder of valine catabolism, is a novel cause of the multiple mitochondrial dysfunctions syndrome, and should be considered in the differential diagnosis of patients presenting with multiple RC deficiencies and/or pyruvate dehydrogenase deficiency.

View Article: PubMed Central - HTML - PubMed

Affiliation: Metabolic Unit, Great Ormond Street Hospital, London, UK. shamima.rahman@ucl.ac.uk.

ABSTRACT

Background: Deficiency of 3-hydroxy-isobutyryl-CoA hydrolase (HIBCH) caused by HIBCH mutations is a rare cerebral organic aciduria caused by disturbance of valine catabolism. Multiple mitochondrial respiratory chain (RC) enzyme deficiencies can arise from a number of mechanisms, including defective maintenance or expression of mitochondrial DNA. Impaired biosynthesis of iron-sulphur clusters and lipoic acid can lead to pyruvate dehydrogenase complex (PDHc) deficiency in addition to multiple RC deficiencies, known as the multiple mitochondrial dysfunctions syndrome.

Methods: Two brothers born to distantly related Pakistani parents presenting in early infancy with a progressive neurodegenerative disorder, associated with basal ganglia changes on brain magnetic resonance imaging, were investigated for suspected Leigh-like mitochondrial disease. The index case had deficiencies of multiple RC enzymes and PDHc in skeletal muscle and fibroblasts respectively, but these were normal in his younger brother. The observation of persistently elevated hydroxy-C4-carnitine levels in the younger brother led to suspicion of HIBCH deficiency, which was investigated by biochemical assay in cultured skin fibroblasts and molecular genetic analysis.

Results: Specific spectrophotometric enzyme assay revealed HIBCH activity to be below detectable limits in cultured skin fibroblasts from both brothers. Direct Sanger sequence analysis demonstrated a novel homozygous pathogenic missense mutation c.950G

Conclusions: HIBCH deficiency, a disorder of valine catabolism, is a novel cause of the multiple mitochondrial dysfunctions syndrome, and should be considered in the differential diagnosis of patients presenting with multiple RC deficiencies and/or pyruvate dehydrogenase deficiency.

Show MeSH
Related in: MedlinePlus