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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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Related in: MedlinePlus

Homozygous HIBCH mutation in patients 1 and 2. Sequence electropherograms of HIBCH gene. Top panel: Control; Second (from top) panel: Patient 1; Third panel: Patient 2; Fourth panel: Mother; Fifth panel: Father. Both patients are homozygous for the c.950G <A mutation, whilst the parents are heterozygous.
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Figure 4: Homozygous HIBCH mutation in patients 1 and 2. Sequence electropherograms of HIBCH gene. Top panel: Control; Second (from top) panel: Patient 1; Third panel: Patient 2; Fourth panel: Mother; Fifth panel: Father. Both patients are homozygous for the c.950G <A mutation, whilst the parents are heterozygous.

Mentions: Sequence analysis revealed a novel homozygous missense mutation c.950G <A;p.Gly317Glu in the HIBCH gene on chromosome 2q32.3 in both Patients 1 and 2 (Figure 4). The mutation is absent in the dbSNP and 1000 genomes databases (which includes 200 Pakistani alleles), affects an amino acid residue highly conserved among different species and is predicted by the SIFT software as deleterious and by the Polyphen-2 software as probably damaging. Parents and the maternal aunt and uncle were all heterozygous for the c.950G <A mutation. Patients 1 and 2 were also homozygous for two known single nucleotide polymorphisms within the HIBCH gene: c.2T <C;p.Met1? (disruption main translation initiation codon; initiation 5 codons downstream). and c.136A <G;p.Thr46Ala. The reported Minor Allele Frequencies for the two polymorphisms are for c.2T <C: T = 0.3988 (European American) and C = 0.4557 (African American); and for c.136A <G: A = 0.2407 (European American) and A = 0.3443 (African American).


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)

Homozygous HIBCH mutation in patients 1 and 2. Sequence electropherograms of HIBCH gene. Top panel: Control; Second (from top) panel: Patient 1; Third panel: Patient 2; Fourth panel: Mother; Fifth panel: Father. Both patients are homozygous for the c.950G <A mutation, whilst the parents are heterozygous.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Homozygous HIBCH mutation in patients 1 and 2. Sequence electropherograms of HIBCH gene. Top panel: Control; Second (from top) panel: Patient 1; Third panel: Patient 2; Fourth panel: Mother; Fifth panel: Father. Both patients are homozygous for the c.950G <A mutation, whilst the parents are heterozygous.
Mentions: Sequence analysis revealed a novel homozygous missense mutation c.950G <A;p.Gly317Glu in the HIBCH gene on chromosome 2q32.3 in both Patients 1 and 2 (Figure 4). The mutation is absent in the dbSNP and 1000 genomes databases (which includes 200 Pakistani alleles), affects an amino acid residue highly conserved among different species and is predicted by the SIFT software as deleterious and by the Polyphen-2 software as probably damaging. Parents and the maternal aunt and uncle were all heterozygous for the c.950G <A mutation. Patients 1 and 2 were also homozygous for two known single nucleotide polymorphisms within the HIBCH gene: c.2T <C;p.Met1? (disruption main translation initiation codon; initiation 5 codons downstream). and c.136A <G;p.Thr46Ala. The reported Minor Allele Frequencies for the two polymorphisms are for c.2T <C: T = 0.3988 (European American) and C = 0.4557 (African American); and for c.136A <G: A = 0.2407 (European American) and A = 0.3443 (African American).

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