Muscle Biopsy #2 March 2010
Mitochondrial Disease
Garrett's muscle biopsy is back, and here is the skinny:
We first evaluated Garrett in October of 2009 for concerns of a possible mitochondrial disorder. Prior muscle biopsy had demonstrated increased numbers of mitochondria and increased neutral lipids. Additional testing for a mitochondrial disorder was not performed. At that visit, we requested a series of laboratory studies to investigate for biomarkers of mitochondrial dysfunction. Garrett’s laboratory studies demonstrated a marked elevation in lactic acid (results was 49, normal value is 4-16 mg/dl).
Following receipt of these studies it was recommended that Garrett have a repeat muscle biopsy performed to evaluate for mitochondrial dysfunction. Muscle biopsy was performed at Children’s Memorial Hermann Hospital in Houston, Texas on 04/13/2010. Pathology demonstrated a mild increase in the number of mitochondria with mild degeneration of membranous organelles. The mitochondria appeared to be under stress with prominent cristae and enlargement of the intracristal spaces. Electron transport chain analysis showed slight reductions in activity without a clear deficit in respiratory function:
Citrate synthase activity was 118% of the mean
Complex I activity was 109% of the mean
Complex I+III total activity was 68% of the mean
Complex II activity was 61% of the mean
Complex II+III activity was 54% of the mean
Complex IV activity was 149% of the mean
Although not diagnostic by itself, the focal deficit in Complex II+III activity might be indicative of a mitochondrial disorder.
Additional studies performed included mtDNA quantification. This showed that Garrett’s mtDNA content is 53% of control. For a true depletion syndrome, we generally expect to see a reduction to <50% of control. Like the electron transport chain testing, this finding is not diagnostic as a stand alone, but is suggestive of a mitochondrial disorder.
DNA studies testing for deletions and duplications were normal. Mitochondrial DNA sequencing was normal.
In summarizing these results, Garrett does have several features of a mitochondrial disorder. Clinically he has a myopathy with impaired language development and a history of GI dysmotility (constipation and delayed gastric emptying). His muscle biopsy showed mitochondria under stress with a suggestion of decreased function in either Complex II or III. In addition, his mitochondrial DNA content was low (52%), but not low enough to be diagnostic of a depletion syndrome (typically less than 50%). Lastly, he does have elevated lactate levels consistent with mitochondrial dysfunction.
Unfortunately, mitochondrial disorders are notoriously difficult to diagnose in young children and often the clinical picture does not become clear until they are much older. Based on my experience, I do believe that Garrett has a mitochondrial disorder and would recommend pursuing additional DNA analysis for some of the more common depletion syndromes.
We first evaluated Garrett in October of 2009 for concerns of a possible mitochondrial disorder. Prior muscle biopsy had demonstrated increased numbers of mitochondria and increased neutral lipids. Additional testing for a mitochondrial disorder was not performed. At that visit, we requested a series of laboratory studies to investigate for biomarkers of mitochondrial dysfunction. Garrett’s laboratory studies demonstrated a marked elevation in lactic acid (results was 49, normal value is 4-16 mg/dl).
Following receipt of these studies it was recommended that Garrett have a repeat muscle biopsy performed to evaluate for mitochondrial dysfunction. Muscle biopsy was performed at Children’s Memorial Hermann Hospital in Houston, Texas on 04/13/2010. Pathology demonstrated a mild increase in the number of mitochondria with mild degeneration of membranous organelles. The mitochondria appeared to be under stress with prominent cristae and enlargement of the intracristal spaces. Electron transport chain analysis showed slight reductions in activity without a clear deficit in respiratory function:
Citrate synthase activity was 118% of the mean
Complex I activity was 109% of the mean
Complex I+III total activity was 68% of the mean
Complex II activity was 61% of the mean
Complex II+III activity was 54% of the mean
Complex IV activity was 149% of the mean
Although not diagnostic by itself, the focal deficit in Complex II+III activity might be indicative of a mitochondrial disorder.
Additional studies performed included mtDNA quantification. This showed that Garrett’s mtDNA content is 53% of control. For a true depletion syndrome, we generally expect to see a reduction to <50% of control. Like the electron transport chain testing, this finding is not diagnostic as a stand alone, but is suggestive of a mitochondrial disorder.
DNA studies testing for deletions and duplications were normal. Mitochondrial DNA sequencing was normal.
In summarizing these results, Garrett does have several features of a mitochondrial disorder. Clinically he has a myopathy with impaired language development and a history of GI dysmotility (constipation and delayed gastric emptying). His muscle biopsy showed mitochondria under stress with a suggestion of decreased function in either Complex II or III. In addition, his mitochondrial DNA content was low (52%), but not low enough to be diagnostic of a depletion syndrome (typically less than 50%). Lastly, he does have elevated lactate levels consistent with mitochondrial dysfunction.
Unfortunately, mitochondrial disorders are notoriously difficult to diagnose in young children and often the clinical picture does not become clear until they are much older. Based on my experience, I do believe that Garrett has a mitochondrial disorder and would recommend pursuing additional DNA analysis for some of the more common depletion syndromes.
Muscle Biopsy #1 December 2006
Garrett had a muscle biopsy at the same time he had his g-button placed. It was tested, and his Houston pediatrician called me extatic to share that of a whole bunch of bad things she had warned us it could reveal, he had the ONE thing that was not so bad. It was called Congenital Fiber Type DIsproportion, or CFTD. It meant that his type I muscle fibers were too small and outnumbered the type II fibers. At that age, they should have all been same size and equal proportion. SO the lab report read:
1) Predominance in number and smallness in size of type I fibers
2) Increased mitochondria, mild to moderate
3) Increased neurtal lipid, mild
SO the pathologist called it CFTD, but then in October 2008 when we trveled to the Mayo Clinic in Rohester, MN to see a physician specializingin Congenital Myasthenic Syndrome, this diagnosis was withdrawn as the size difference between type I and type II fibers was not enough to be able to diagnose him with CFTD.
When Dr. Koenig read the pathology report from the Mayo clinic where it ws reviewed, she said the sample would be too old and the slides too faded to offer her the information she needed. Second biopsy was completed in March, 2010. See results above.
1) Predominance in number and smallness in size of type I fibers
2) Increased mitochondria, mild to moderate
3) Increased neurtal lipid, mild
SO the pathologist called it CFTD, but then in October 2008 when we trveled to the Mayo Clinic in Rohester, MN to see a physician specializingin Congenital Myasthenic Syndrome, this diagnosis was withdrawn as the size difference between type I and type II fibers was not enough to be able to diagnose him with CFTD.
When Dr. Koenig read the pathology report from the Mayo clinic where it ws reviewed, she said the sample would be too old and the slides too faded to offer her the information she needed. Second biopsy was completed in March, 2010. See results above.