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At the Frontiers of Medicine
Published in Jo Bridgeman, Medical Treatment of Children and the Law, 2020
Charlie Gard appeared to be a healthy baby when he was born in August 2016. At eight weeks old, he was admitted to hospital and transferred to the care of GOSH where he remained on a ventilator and was fed by nasogastric tube for the rest of his short life. Charlie was diagnosed with an extremely rare, inherited, progressive condition, infantile onset encephalomyopathic mitochondrial DNA depletion syndrome, MDDS. Mitochondrial conditions affect the generation of the energy supply of cells,56 and in Charlie’s case, affected his ability to move, breathe, neurological functioning, and hearing.
Methylmalonic acidemia
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop
The cobalamin (Cbl) C and D represent a different type of disorder in which methylmalonic acidemia accompanies elevated concentrations of homocysteine and cystathionine in blood and urine (Chapter 4) [5]. In these groups, defective remethylation of homocysteine to methionine is the consequence of a failure to transform B12to either of the coenzymatically active derivatives, AdoCbl or methylcobalamin. Cbl F disease reflects abnormalities in the transport of cobalamin out of lysosomes, analogous to the defect that causes cystinosis. Methylmalonic aciduria is also seen in acquired deficiency of B12 [6], in pernicious anemia and in transcobalamin II deficiency [7]. In B12 deficiency and in intrinsic factor deficiency, the excretion of MMA in the urine is a more reliable index of depletion of body stores of cobalamin than the blood level of B12. Methylmalonic acidemia resulting from a defect in the metholmalonyl, CoA epimerase enzyme, long suspected to exist has now been documented by mutational analysis in a homozygous patient [8, 9]. Methylmalonic aciduria of modest degree has been the clue to a metabolic diagnosis in patients with succinyl CoA ligase (synthase) deficiency which leads to a mitochondrial DNA depletion syndrome [10–13]. This complex has two subunits, α and β, coded by genes SUCLA2 and SUCLG1. Mutations in both have been documented [11, 13].
Instability of Human Mitochondrial DNA, Nuclear Genes and Diseases
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
The case of MPV17 is even more intriguing. For the first time recessive mutations in MPV17 were described in 200645 and MPV17 protein was localized in the inner mitochondrial membrane. For many years new cases of mitochondrial DNA depletion syndrome with liver failure had been described, but the function of MPV17 was unknown. In 2015 we got closer to its function because it was proved that indeed MPV17 is an inner membrane protein acting as a non-selective channel with gating properties responding to different cellular signals like redox state, pH or membrane potential but it was still not known what type of molecules it transfers through the membrane46.
Liver Pathology in Mitochondrial Complex I Deficiency from Bi-Allelic Mutations in NDUFS2: A Report of Findings at Autopsy
Published in Fetal and Pediatric Pathology, 2020
Ashlie Rubrecht, William Clapp, Archana Shenoy
Hepatocellular cytoplasmic eosinophilia and microvesicular steatosis are well documented features of mitochondriopathy [3,5] and have also been demonstrated previously in a postmortem report of ACAD9 mutation associated mitochondrial complex I deficiency [1]. However, as demonstrated in Hazard et al.’s review of three cases of mitochondrial DNA depletion syndrome with different mutations and our case, these histologic findings may be seen across the spectrum of mitochondrial disorders and do not appear to be specific to any sub-group or mutation profile.
The Challenges of Discussing “Longshot” and “Fantasy” Treatments
Published in The American Journal of Bioethics, 2018
First, the separation between a longshot and a fantasy treatment is not always clear-cut, and there can be disagreement between the patient/family and the physician when making this designation. The case of Charlie Gard, the infant in Great Britain who captured the world's attention in early 2017, exemplifies this kind of conflict. Charlie presented with a very rare case of epileptic encephalomyopathy due to a mitochondrial DNA depletion syndrome. An experimental treatment for his condition was available. The family classified this treatment as a longshot, but Charlie's physicians felt it was a fantasy. This conflict led to numerous court cases, and the courts repeatedly sided with the hospital (The Brief 2017). Charlie ultimately passed away after care was withdrawn, but it remains unclear whether this therapy actually was a fantasy or a longshot. The experimental treatment initially being considered, nucleoside replacement therapy, had been used on other patients with a different mitochondrial DNA depletion syndrome and had even led to improved muscle strength and head support without any noted side effects in a 3-year-old (Cifuentes et al. 2016). Nevertheless, because of the rarity of Charlie's condition, this experimental treatment had never been used for a child with his specific mutation, and thus there was no literature to assist in the determination of whether this therapy was a longshot or a fantasy. In a quandary without data, how should we make this designation? What should be done if a patient/family disagrees with a physician's determination? Furthermore, do physicians always see eye-to-eye on whether a treatment is a longshot or a fantasy? In Charlie's case, based on the limited available data, it is likely he would have died with or without the experimental therapy. It would be a fantasy to think that the experimental therapy would have cured him. However, it would have been a longshot that the therapy could prolong his life and potentially lead to some improvement in muscle strength, as had been seen in patients with similar pathology.