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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">A Nonsense Mutation in <italic>COQ9</italic> Causes Autosomal-Recessive Neonatal-Onset Primary Coenzyme Q<sub>10</sub> Deficiency: A Potentially Treatable Form of Mitochondrial Disease</title><author><name sortKey="Duncan, Andrew J" sort="Duncan, Andrew J" uniqKey="Duncan A" first="Andrew J." last="Duncan">Andrew J. Duncan</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Bitner Glindzicz, Maria" sort="Bitner Glindzicz, Maria" uniqKey="Bitner Glindzicz M" first="Maria" last="Bitner-Glindzicz">Maria Bitner-Glindzicz</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Meunier, Brigitte" sort="Meunier, Brigitte" uniqKey="Meunier B" first="Brigitte" last="Meunier">Brigitte Meunier</name><affiliation><nlm:aff id="aff2"></nlm:aff></affiliation></author><author><name sortKey="Costello, Harry" sort="Costello, Harry" uniqKey="Costello H" first="Harry" last="Costello">Harry Costello</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Hargreaves, Iain P" sort="Hargreaves, Iain P" uniqKey="Hargreaves I" first="Iain P." last="Hargreaves">Iain P. Hargreaves</name><affiliation><nlm:aff id="aff3"></nlm:aff></affiliation></author><author><name sortKey="L Pez, Luis C" sort="L Pez, Luis C" uniqKey="L Pez L" first="Luis C." last="L Pez">Luis C. L Pez</name><affiliation><nlm:aff id="aff4"></nlm:aff></affiliation></author><author><name sortKey="Hirano, Michio" sort="Hirano, Michio" uniqKey="Hirano M" first="Michio" last="Hirano">Michio Hirano</name><affiliation><nlm:aff id="aff4"></nlm:aff></affiliation></author><author><name sortKey="Quinzii, Catarina M" sort="Quinzii, Catarina M" uniqKey="Quinzii C" first="Catarina M." last="Quinzii">Catarina M. Quinzii</name><affiliation><nlm:aff id="aff4"></nlm:aff></affiliation></author><author><name sortKey="Sadowski, Michael I" sort="Sadowski, Michael I" uniqKey="Sadowski M" first="Michael I." last="Sadowski">Michael I. Sadowski</name><affiliation><nlm:aff id="aff5"></nlm:aff></affiliation></author><author><name sortKey="Hardy, John" sort="Hardy, John" uniqKey="Hardy J" first="John" last="Hardy">John Hardy</name><affiliation><nlm:aff id="aff6"></nlm:aff></affiliation></author><author><name sortKey="Singleton, Andrew" sort="Singleton, Andrew" uniqKey="Singleton A" first="Andrew" last="Singleton">Andrew Singleton</name><affiliation><nlm:aff id="aff7"></nlm:aff></affiliation></author><author><name sortKey="Clayton, Peter T" sort="Clayton, Peter T" uniqKey="Clayton P" first="Peter T." last="Clayton">Peter T. Clayton</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation><affiliation><nlm:aff id="aff8"></nlm:aff></affiliation></author><author><name sortKey="Rahman, Shamima" sort="Rahman, Shamima" uniqKey="Rahman S" first="Shamima" last="Rahman">Shamima Rahman</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation><affiliation><nlm:aff id="aff8"></nlm:aff></affiliation><affiliation><nlm:aff id="aff9"></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">19375058</idno><idno type="pmc">2681001</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2681001</idno><idno type="RBID">PMC:2681001</idno><idno type="doi">10.1016/j.ajhg.2009.03.018</idno><date when="2009">2009</date><idno type="wicri:Area/Pmc/Corpus">000424</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000424</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">A Nonsense Mutation in <italic>COQ9</italic> Causes Autosomal-Recessive Neonatal-Onset Primary Coenzyme Q<sub>10</sub> Deficiency: A Potentially Treatable Form of Mitochondrial Disease</title><author><name sortKey="Duncan, Andrew J" sort="Duncan, Andrew J" uniqKey="Duncan A" first="Andrew J." last="Duncan">Andrew J. Duncan</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Bitner Glindzicz, Maria" sort="Bitner Glindzicz, Maria" uniqKey="Bitner Glindzicz M" first="Maria" last="Bitner-Glindzicz">Maria Bitner-Glindzicz</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Meunier, Brigitte" sort="Meunier, Brigitte" uniqKey="Meunier B" first="Brigitte" last="Meunier">Brigitte Meunier</name><affiliation><nlm:aff id="aff2"></nlm:aff></affiliation></author><author><name sortKey="Costello, Harry" sort="Costello, Harry" uniqKey="Costello H" first="Harry" last="Costello">Harry Costello</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Hargreaves, Iain P" sort="Hargreaves, Iain P" uniqKey="Hargreaves I" first="Iain P." last="Hargreaves">Iain P. Hargreaves</name><affiliation><nlm:aff id="aff3"></nlm:aff></affiliation></author><author><name sortKey="L Pez, Luis C" sort="L Pez, Luis C" uniqKey="L Pez L" first="Luis C." last="L Pez">Luis C. L Pez</name><affiliation><nlm:aff id="aff4"></nlm:aff></affiliation></author><author><name sortKey="Hirano, Michio" sort="Hirano, Michio" uniqKey="Hirano M" first="Michio" last="Hirano">Michio Hirano</name><affiliation><nlm:aff id="aff4"></nlm:aff></affiliation></author><author><name sortKey="Quinzii, Catarina M" sort="Quinzii, Catarina M" uniqKey="Quinzii C" first="Catarina M." last="Quinzii">Catarina M. Quinzii</name><affiliation><nlm:aff id="aff4"></nlm:aff></affiliation></author><author><name sortKey="Sadowski, Michael I" sort="Sadowski, Michael I" uniqKey="Sadowski M" first="Michael I." last="Sadowski">Michael I. Sadowski</name><affiliation><nlm:aff id="aff5"></nlm:aff></affiliation></author><author><name sortKey="Hardy, John" sort="Hardy, John" uniqKey="Hardy J" first="John" last="Hardy">John Hardy</name><affiliation><nlm:aff id="aff6"></nlm:aff></affiliation></author><author><name sortKey="Singleton, Andrew" sort="Singleton, Andrew" uniqKey="Singleton A" first="Andrew" last="Singleton">Andrew Singleton</name><affiliation><nlm:aff id="aff7"></nlm:aff></affiliation></author><author><name sortKey="Clayton, Peter T" sort="Clayton, Peter T" uniqKey="Clayton P" first="Peter T." last="Clayton">Peter T. Clayton</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation><affiliation><nlm:aff id="aff8"></nlm:aff></affiliation></author><author><name sortKey="Rahman, Shamima" sort="Rahman, Shamima" uniqKey="Rahman S" first="Shamima" last="Rahman">Shamima Rahman</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation><affiliation><nlm:aff id="aff8"></nlm:aff></affiliation><affiliation><nlm:aff id="aff9"></nlm:aff></affiliation></author></analytic><series><title level="j">American Journal of Human Genetics</title><idno type="ISSN">0002-9297</idno><idno type="eISSN">1537-6605</idno><imprint><date when="2009">2009</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Coenzyme Q<sub>10</sub> is a mobile lipophilic electron carrier located in the inner mitochondrial membrane. Defects of coenzyme Q<sub>10</sub> biosynthesis represent one of the few treatable mitochondrial diseases. We genotyped a patient with primary coenzyme Q<sub>10</sub> deficiency who presented with neonatal lactic acidosis and later developed multisytem disease including intractable seizures, global developmental delay, hypertrophic cardiomyopathy, and renal tubular dysfunction. Cultured skin fibroblasts from the patient had a coenzyme Q<sub>10</sub> biosynthetic rate of 11% of normal controls and accumulated an abnormal metabolite that we believe to be a biosynthetic intermediate. In view of the rarity of coenzyme Q<sub>10</sub> deficiency, we hypothesized that the disease-causing gene might lie in a region of ancestral homozygosity by descent. Data from an Illumina HumanHap550 array were analyzed with BeadStudio software. Sixteen regions of homozygosity >1.5 Mb were identified in the affected infant. Two of these regions included the loci of two of 16 candidate genes implicated in human coenzyme Q<sub>10</sub> biosynthesis. Sequence analysis demonstrated a homozygous stop mutation affecting a highly conserved residue of <italic>COQ9</italic>, leading to the truncation of 75 amino acids. Site-directed mutagenesis targeting the equivalent residue in the yeast <italic>Saccharomyces cerevisiae</italic> abolished respiratory growth.</p></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Am J Hum Genet</journal-id><journal-title>American Journal of Human Genetics</journal-title><issn pub-type="ppub">0002-9297</issn><issn pub-type="epub">1537-6605</issn><publisher><publisher-name>Elsevier</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">19375058</article-id><article-id pub-id-type="pmc">2681001</article-id><article-id pub-id-type="publisher-id">AJHG376</article-id><article-id pub-id-type="doi">10.1016/j.ajhg.2009.03.018</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>A Nonsense Mutation in <italic>COQ9</italic> Causes Autosomal-Recessive Neonatal-Onset Primary Coenzyme Q<sub>10</sub> Deficiency: A Potentially Treatable Form of Mitochondrial Disease</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Duncan</surname><given-names>Andrew J.</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Bitner-Glindzicz</surname><given-names>Maria</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Meunier</surname><given-names>Brigitte</given-names></name><xref rid="aff2" ref-type="aff">2</xref></contrib><contrib contrib-type="author"><name><surname>Costello</surname><given-names>Harry</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Hargreaves</surname><given-names>Iain P.</given-names></name><xref rid="aff3" ref-type="aff">3</xref></contrib><contrib contrib-type="author"><name><surname>López</surname><given-names>Luis C.</given-names></name><xref rid="aff4" ref-type="aff">4</xref></contrib><contrib contrib-type="author"><name><surname>Hirano</surname><given-names>Michio</given-names></name><xref rid="aff4" ref-type="aff">4</xref></contrib><contrib contrib-type="author"><name><surname>Quinzii</surname><given-names>Catarina M.</given-names></name><xref rid="aff4" ref-type="aff">4</xref></contrib><contrib contrib-type="author"><name><surname>Sadowski</surname><given-names>Michael I.</given-names></name><xref rid="aff5" ref-type="aff">5</xref></contrib><contrib contrib-type="author"><name><surname>Hardy</surname><given-names>John</given-names></name><xref rid="aff6" ref-type="aff">6</xref></contrib><contrib contrib-type="author"><name><surname>Singleton</surname><given-names>Andrew</given-names></name><xref rid="aff7" ref-type="aff">7</xref></contrib><contrib contrib-type="author"><name><surname>Clayton</surname><given-names>Peter T.</given-names></name><xref rid="aff1" ref-type="aff">1</xref><xref rid="aff8" ref-type="aff">8</xref></contrib><contrib contrib-type="author"><name><surname>Rahman</surname><given-names>Shamima</given-names></name><email>s.rahman@ich.ucl.ac.uk</email><xref rid="aff1" ref-type="aff">1</xref><xref rid="aff8" ref-type="aff">8</xref><xref rid="aff9" ref-type="aff">9</xref><xref rid="cor1" ref-type="corresp">∗</xref></contrib></contrib-group><aff id="aff1"><addr-line><sup>1</sup>Mitochondrial Research Group, Clinical and Molecular Genetics Unit, UCL Institute of Child Health, London WC1N 1EH, UK</addr-line></aff><aff id="aff2"><addr-line><sup>2</sup>Centre de Génétique Moléculaire, CNRS, FRC3115, Avenue de la Terrasse, 91198 Gif-sur-Yvette, France</addr-line></aff><aff id="aff3"><addr-line><sup>3</sup>Neurometabolic Unit, National Hospital for Neurology, Queen Square, London WC1N 3BG, UK</addr-line></aff><aff id="aff4"><addr-line><sup>4</sup>Columbia University Medical Center, 1150 St. Nicholas Avenue, Russ Berrie Medical Pavilion, New York, NY 10032, USA</addr-line></aff><aff id="aff5"><addr-line><sup>5</sup>Division of Mathematical Biology, National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK</addr-line></aff><aff id="aff6"><addr-line><sup>6</sup>Department of Molecular Neuroscience and Reta Lila Weston Laboratories, Institute of Neurology, Queen Square, London WC1N 3BG, UK</addr-line></aff><aff id="aff7"><addr-line><sup>7</sup>Laboratory of Neurogenetics, National Institute of Aging, National Insitutes of Health, Bethesda, MD 20892, USA</addr-line></aff><aff id="aff8"><addr-line><sup>8</sup>Metabolic Unit, Great Ormond Street Hospital, London WC1N 3JH, UK</addr-line></aff><aff id="aff9"><addr-line><sup>9</sup>MRC Centre for Neuromuscular Diseases, Queen Square, London WC1N 3BG, UK</addr-line></aff><author-notes><corresp id="cor1"><label>∗</label>Corresponding author <email>s.rahman@ich.ucl.ac.uk</email></corresp></author-notes><pub-date pub-type="ppub"><day>15</day><month>5</month><year>2009</year></pub-date><volume>84</volume><issue>5</issue><fpage>558</fpage><lpage>566</lpage><history><date date-type="received"><day>28</day><month>1</month><year>2009</year></date><date date-type="rev-recd"><day>23</day><month>3</month><year>2009</year></date><date date-type="accepted"><day>24</day><month>3</month><year>2009</year></date></history><permissions><copyright-statement>© 2009 The American Society of Human Genetics. Published by Elsevier Ltd. All right reserved..</copyright-statement><copyright-year>2009</copyright-year><copyright-holder>The American Society of Human Genetics</copyright-holder><license><p>This document may be redistributed and reused, subject to <ext-link ext-link-type="uri" xlink:href="http://www.elsevier.com/wps/find/authorsview.authors/supplementalterms1.0">certain conditions</ext-link>.</p></license></permissions><abstract><p>Coenzyme Q<sub>10</sub> is a mobile lipophilic electron carrier located in the inner mitochondrial membrane. Defects of coenzyme Q<sub>10</sub> biosynthesis represent one of the few treatable mitochondrial diseases. We genotyped a patient with primary coenzyme Q<sub>10</sub> deficiency who presented with neonatal lactic acidosis and later developed multisytem disease including intractable seizures, global developmental delay, hypertrophic cardiomyopathy, and renal tubular dysfunction. Cultured skin fibroblasts from the patient had a coenzyme Q<sub>10</sub> biosynthetic rate of 11% of normal controls and accumulated an abnormal metabolite that we believe to be a biosynthetic intermediate. In view of the rarity of coenzyme Q<sub>10</sub> deficiency, we hypothesized that the disease-causing gene might lie in a region of ancestral homozygosity by descent. Data from an Illumina HumanHap550 array were analyzed with BeadStudio software. Sixteen regions of homozygosity >1.5 Mb were identified in the affected infant. Two of these regions included the loci of two of 16 candidate genes implicated in human coenzyme Q<sub>10</sub> biosynthesis. Sequence analysis demonstrated a homozygous stop mutation affecting a highly conserved residue of <italic>COQ9</italic>, leading to the truncation of 75 amino acids. Site-directed mutagenesis targeting the equivalent residue in the yeast <italic>Saccharomyces cerevisiae</italic> abolished respiratory growth.</p></abstract></article-meta></front><floats-wrap><fig id="fig1"><label>Figure 1</label><caption><p>Biosynthetic Pathway of Coenzyme Q<sub>10</sub></p></caption><graphic xlink:href="gr1"></graphic></fig><fig id="fig2"><label>Figure 2</label><caption><p>HPLC Analysis of Coenzyme Q<sub>10</sub> in Cultured Skin Fibroblasts</p><p>Reverse phase EC-HPLC chromatograms obtained from lipid extracts of cultured skin fibroblasts from (A) healthy control fibroblasts and (B) the patient. Retention times are coenzyme Q<sub>9</sub> = 10.45 min; coenzyme Q<sub>10</sub> = 14.15 min. The patient's trace clearly shows an additional peak at 13.22 min (arrow) not resulting from coenzyme Q<sub>9</sub> or coenzyme Q<sub>10</sub>, likely to be the result of accumulation of a metabolic intermediate of coenzyme Q<sub>10</sub> biosynthesis.</p></caption><graphic xlink:href="gr2"></graphic></fig><fig id="fig3"><label>Figure 3</label><caption><p>Sequence Analysis of <italic>COQ9</italic></p><p>Sequencing electropherograms showing homozygous c.730C→T mutation in the patient's genomic DNA (top) and healthy control genomic DNA (bottom). The mutation predicts a change from arginine to a stop codon at amino acid 244 of the protein.</p></caption><graphic xlink:href="gr3"></graphic></fig><fig id="fig4"><label>Figure 4</label><caption><p>Evolutionary Conservation Data for COQ9</p></caption><graphic xlink:href="gr4"></graphic></fig><fig id="fig5"><label>Figure 5</label><caption><p>Molecular Model of COQ9 in Homodimeric Form</p><p>One monomer is depicted in red, the other in blue. Figure created with Pymol.<xref rid="bib42" ref-type="bibr"><sup>42</sup></xref></p></caption><graphic xlink:href="gr5"></graphic></fig><fig id="fig6"><label>Figure 6</label><caption><p>Yeast Studies</p><p>Left: Growth on respiratory (glycerol) medium. Right: Growth on fermentable (glucose) medium selective for the plasmids. (a) Δcoq9 mutant+ empty plasmid; (b) Δcoq9 mutant+ pYcoq9 (yeast <italic>COQ9</italic>); (c) Δcoq9 mutant+ pYcoq9Stop (yeast <italic>coq9 K191X</italic>); (d) Δcoq9 mutant+ pHcoq9 (human <italic>COQ9</italic>). COQ9 genes were placed under the control of a constitutive promoter on a multicopy plasmid.</p></caption><graphic xlink:href="gr6"></graphic></fig><table-wrap position="float" id="tbl1"><label>Table 1</label><caption><p>Genes Implicated in the Biosynthesis of Human Coenzyme Q<sub>10</sub></p></caption><table frame="hsides" rules="groups"><thead><tr><th>Gene</th><th>Chromosomal Location</th><th>Protein</th></tr></thead><tbody><tr><td><italic>PDSS1</italic></td><td>10p12.1</td><td>decaprenyl-diphosphate synthase subunit 1</td></tr><tr><td><italic>PDSS2</italic></td><td>6q21</td><td>decaprenyl-diphosphate synthase subunit 2</td></tr><tr><td><italic>COQ2</italic></td><td>4q21.23</td><td>4-hydroxybenzoate polyprenyltransferase</td></tr><tr><td><italic>COQ3</italic></td><td>6q16.3</td><td>hexaprenyldihydroxybenzoate methyltransferase</td></tr><tr><td><italic>COQ4</italic></td><td>9q34.11</td><td>ubiquinone biosynthesis protein COQ4 homolog</td></tr><tr><td><italic>COQ5</italic></td><td>12q24.31</td><td>ubiquinone biosynthesis methyltransferase COQ5</td></tr><tr><td><italic>COQ6</italic></td><td>14q24.3</td><td>ubiquinone biosynthesis monooxygenase COQ6</td></tr><tr><td><italic>COQ7</italic></td><td>16p12.3</td><td>ubiquinone biosynthesis protein COQ7 homolog</td></tr><tr><td><italic>CABC1</italic></td><td>1q42.13</td><td>chaperone-activity of bc1 complex-like, mitochondrial precursor (Chaperone-ABC1-like) (aarF domain-containing protein kinase 3)</td></tr><tr><td><italic>COQ9</italic></td><td>16q13</td><td>ubiquinone biosynthesis protein COQ9</td></tr><tr><td><italic>COQ10A</italic></td><td>12q13.2</td><td>protein COQ10 A</td></tr><tr><td><italic>COQ10B</italic></td><td>2q33.1</td><td>protein COQ10 B</td></tr><tr><td><italic>ADCK1</italic></td><td>14q24.3</td><td>uncharacterized aarF domain-containing protein kinase 1</td></tr><tr><td><italic>ADCK2</italic></td><td>7q34</td><td>uncharacterized aarF domain-containing protein kinase 2</td></tr><tr><td><italic>ADCK4</italic></td><td>19q13.2</td><td>uncharacterized aarF domain-containing protein kinase 4</td></tr><tr><td><italic>ADCK5</italic></td><td>8q24.3</td><td>uncharacterized aarF domain-containing protein kinase 5</td></tr></tbody></table></table-wrap><table-wrap position="float" id="tbl2"><label>Table 2</label><caption><p>Coenzyme Q<sub>10</sub> Levels in Muscle and Cultured Skin Fibroblasts and Biosynthesis of CoQ<sub>10</sub> in Cultured Skin Fibroblasts</p></caption><table frame="hsides" rules="groups"><thead><tr><th>Coenzyme Q<sub>10</sub> Levels</th><th>Patient</th><th>Mean Control ± SD</th></tr></thead><tbody><tr><td>Muscle (pmol/mg protein)</td><td>37</td><td>241 ± 95 (range 140–580, n = 26)</td></tr><tr><td>Fibroblasts (pmol/mg protein)</td><td align="char">25.3</td><td>62 ± 14 (range 39–75, n = 5)</td></tr><tr><td>Fibroblasts (ng/mg protein)</td><td align="char">10.4</td><td>58 ± 10 (range 41–72, n = 15)</td></tr><tr><td>Biosynthesis of CoQ<sub>10</sub> in fibroblasts (Q<sub>10</sub> DPM/mg protein/day)</td><td>304, 480</td><td>3460 ± 505 (range 3022–4207, n = 6)</td></tr></tbody></table></table-wrap><table-wrap position="float" id="tbl3"><label>Table 3</label><caption><p>Regions of Homozygosity Observed in the Patient</p></caption><table frame="hsides" rules="groups"><thead><tr><th>Chromosome</th><th>Flanking SNPs</th><th>Length of Homozygous Region Mb</th><th>Candidate Genes Located in Region of Homozygosity</th></tr></thead><tbody><tr><td>1</td><td>rs12043991, rs1009658</td><td align="char">13.4</td><td><italic>CABC1</italic></td></tr><tr><td>2</td><td>rs6749901, rs3755021</td><td align="char">5</td><td></td></tr><tr><td>3</td><td>rs9883258, rs7636942</td><td align="char">3.2</td><td></td></tr><tr><td>3</td><td>rs1393555, rs9855944</td><td align="char">10.1</td><td></td></tr><tr><td>5</td><td>rs4498289, rs294580</td><td align="char">3.3</td><td></td></tr><tr><td>7</td><td>rs41943, rs17595350</td><td align="char">2.3</td><td></td></tr><tr><td>8</td><td>rs7013926, rs6474040</td><td align="char">6.6</td><td></td></tr><tr><td>12</td><td>rs4931594, rs10161491</td><td align="char">1.5</td><td></td></tr><tr><td>13</td><td>rs1314940, rs2025736</td><td align="char">15.7</td><td></td></tr><tr><td>16</td><td>rs7201926, rs36553</td><td align="char">10.6</td><td><italic>COQ9</italic></td></tr><tr><td>17</td><td>rs11078078, rs7212579</td><td align="char">16.8</td><td></td></tr><tr><td>17</td><td>rs2229611, rs6503398</td><td align="char">1.8</td><td></td></tr><tr><td>19</td><td>rs4807140, rs2240669</td><td align="char">2.4</td><td></td></tr><tr><td>19</td><td>rs1688021, rs10422365</td><td align="char">2.9</td><td></td></tr><tr><td>20</td><td>rs6021247, rs6022204</td><td align="char">1.5</td><td></td></tr><tr><td>22</td><td>rs136026, rs756638</td><td align="char">4.9</td><td></td></tr></tbody></table></table-wrap><table-wrap position="float" id="tbl4"><label>Table 4</label><caption><p>Genotype-Phenotype Correlation in Inherited Deficiency of Coenzyme Q<sub>10</sub> Biosynthesis</p></caption><table frame="hsides" rules="groups"><thead><tr><th>Gene</th><th>Number of Patients (Families)</th><th>Age at Onset</th><th>Clinical Features</th><th>MRI Features</th><th>Lactate mmol/l (Reference Range)</th><th>Coenzyme Q<sub>10</sub> Level (Reference Range)</th><th>Response to Exogenous Q<sub>10</sub> Supplementation</th><th>References</th></tr></thead><tbody><tr><td><italic>PDSS1</italic></td><td>2 (1)</td><td>1–2 y</td><td>deafness, bulimia, obesity, optic atrophy, valvulopathy, macrocephaly, peripheral neuropathy, MR</td><td>NR</td><td>B 2.1 at 22 y; 3.2 at 14 y (1.0–1.55)</td><td>Fb 4 pmol/mg (120 ± 32)</td><td>alive at 22 y (mild MR)</td><td><xref rid="bib15" ref-type="bibr"><sup>15</sup></xref></td></tr><tr><td><italic>PDSS2</italic></td><td>1</td><td>3 mo</td><td>Leigh syndrome, nephropathy</td><td>bilateral symmetrical T2 hyperintensity in BG</td><td>B 7.5 (<2.0)</td><td>M 4.6 ng/mg (32.1 ± 6.8); Fb 6.7 ng/mg (52.2 ± 9.1)</td><td>no clinical response; died at 8 mo (refractory status epilepticus)</td><td><xref rid="bib13" ref-type="bibr"><sup>13</sup></xref></td></tr><tr><td><italic>COQ2</italic></td><td>2 (1)</td><td>9–12 mo</td><td>encephalomyopathy, nephropathy</td><td>cerebellar atrophy and stroke-like lesions</td><td>B + CSF N</td><td>M 12 ng/mg (32.1 ± 6.7); Fb 18–19 ng/mg (105 ± 14)</td><td>dramatic improvement of neurological manifestations; renal transplant at 3 y in proband; renal disease responded to early treatment in younger sibling</td><td><xref rid="bib14 bib22" ref-type="bibr"><sup>14,22</sup></xref></td></tr><tr><td><italic>COQ2</italic></td><td>2 (2)</td><td>18 mo</td><td>steroid-resistant nephropathy</td><td>N</td><td>B N</td><td>M 12 pmol/mg (17.6–49.2); KC 4.5 pmol/mg (26–180)</td><td>neurologically normal during 8 mo of treatment</td><td><xref rid="bib16" ref-type="bibr"><sup>16</sup></xref></td></tr><tr><td></td><td></td><td>5 d</td><td>acute renal failure, progressive epileptic encephalopathy</td><td>cortical and subcortical stroke-like lesions</td><td>CSF 11.8 (1.1–2.4)</td><td>M 0.8 pmol/mg (17.6–49.2); KC 3.7 pmol/mg (26–180)</td><td>no clinical response; died at 6 mo (respiratory failure).</td><td></td></tr><tr><td><italic>COQ2</italic></td><td>1</td><td>birth</td><td>neurological distress, liver failure, nephrotic syndrome, anemia, pancytopaenia, IDDM, seizures</td><td>NR</td><td>B 22.7 (1.0–1.55)</td><td>Fb 29 pmol/mg(120 ± 32)</td><td>no clinical response; died at 12 d (multiorgan failure)</td><td><xref rid="bib15" ref-type="bibr"><sup>15</sup></xref></td></tr><tr><td><italic>CABC1</italic></td><td>2 (2)</td><td><18 mo</td><td>proximal muscle weakness, cerebellar ataxia, strabismus, ptosis, seizures</td><td>cerebellar atrophy and posterior cerebral cortical and subcortical hyperintensities (both patients)</td><td>B 3.0 (1.0–1.55); CSF 4.0 (<2.0)</td><td>M 2.6–9.4 pmol/mg (32.2 ± 9.8); Fb 125 pmol/mg (120 ± 32)</td><td>severe neurological deterioration and EPC (alive at 16 y and 14 y)</td><td><xref rid="bib17" ref-type="bibr"><sup>17</sup></xref></td></tr><tr><td><italic>CABC1</italic></td><td>7 (4)</td><td>3–11 y</td><td>cerebellar ataxia, exercise intolerance</td><td>cerebellar atrophy</td><td>B N – 7.8 (0.5–2.2)</td><td>M 12.6 ng/mg (n = 1) (27.6 ± 4.4); Fb 29–69 ng/mg (n = 3) (58.5 ± 4.1)</td><td>mild improvement of ataxia (only one patient treated)</td><td><xref rid="bib18" ref-type="bibr"><sup>18</sup></xref></td></tr><tr><td><italic>COQ9</italic></td><td>1</td><td>birth</td><td>neonatal lactic acidosis, seizures, global developmental delay, hypertrophic cardiomyopathy, renal tubular dysfunction</td><td>cerebral + cerebellar atrophy</td><td>B 19.4 (0.9–1.9)</td><td>M 37 pmol/mg (140–580); Fb 25.3 pmol/mg (39–75)</td><td>no clinical response; died at 2 y</td><td><xref rid="bib5" ref-type="bibr"><sup>5</sup></xref>; this report</td></tr></tbody></table><table-wrap-foot><fn><p>Abbreviations: B, blood; BG, basal ganglia; CSF, cerebrospinal fluid; d, days; EPC, epilepsia partialis continua; Fb, fibroblast; IDDM, insulin-dependent diabetes mellitus; KC, kidney cortex; M, muscle; mo, months; MR, mental retardation; N, normal; NR, not reported; y, years.</p></fn></table-wrap-foot></table-wrap></floats-wrap></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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