Until relatively recently, mitochondrial disorders were considered to be obscure, exceptionally rare diseases affecting perhaps one or two per million of the population. Only a limited number of centers throughout the world had clinical and laboratory expertise in mitochondrial medicine, and a general lack of awareness of mitochondrial disease by non-specialist physicians left many patients undiagnosed. However, the complete sequencing of the human mitochondrial genome (mtDNA) followed by the identification of pathogenic mtDNA mutations and led to a huge surge in interest in human mitochondrial disease in the early 1990s. These advances paved the way for future epidemiological studies which clearly demonstrate that mitochondrial disorders are amongst the most common inherited human diseases.1
The last decade has been an age of enlightenment as far as mitochondrial pathology is concerned. Well established nuclear genetic diseases, such as Friedreich’s ataxia, Wilson disease, and autosomal recessive hereditary spastic paraplegia, have been shown to have a mitochondrial basis, and we are just starting to unravel the complex nuclear genetic disorders which directly cause mitochondrial dysfunction.2
In 1993, it was reported in the medical journal Genomics that mitochondrial DNA deletion had been identified in a case of Kearns-Sayre syndrome.3
In 1994, the Journal of Medical Genetics reported on the findings of Cormier-Daire and colleagues, summarizing: “The list of presenting features of mitochondrial disease expands even further with this report of two patients who presented with chronic dirrhoea during the second year of life. The gastrointestinal problems, initially attributed to gluten, cow’s milk protein intolerance, were severe enough to warrant parenteral nutrition in both cases.”4
In 1994, researchers also reported in the Journal of Medical Genetics on the case of a 15-year-old girl who had initially been misdiagnosed as having a psychosomatic disorder. Under close examination, she was found to have mitochondrial myopathy. As for how the initial misdiagnosis had come about, “In infancy she had a severe crisis of bone marrow depression, and as a child she suffered from hypersensitivity to light, increasing fatigue, and vertigo, signs that were initially thought to be psychosomatic.”
With respect to how the correct diagnosis was obtained, “Histological examination showed mitochondrial myopathy, and subsequent mitochondrial DNA (mtDNA) analysis showed a deletion of approximately 5500 base pairs in 35 to 40% of her muscle mtDNA.”5
Also in 1994, the Journal of Neurology, Neurosurgery, and Psychiatry reported on a patient who had been misdiagnosed by virtue of an MRI, and who was referred to evaluation for surgery for epilepsy as a result. The surgery, however, was prevented as further investigation showed a mitochondrial disorder.6
By the mid-1990s, Mitochondrial DNA deletions had “been found in the majority of patients with chronic progressive external ophthalmoplegia and Kearns-Sayre syndrome.”7
In 1997, researchers in Switzerland had devised a strategy based on long polymerase chain reaction “for detection and characterization of mitochondrial DNA” rearrangements in two patients with clinical signs suggesting Pearson syndrome and Kearns-Sayre syndrome, respectively, and another patient with myopathic symptoms of unidentified origin. In summarizing their results, they explained: “Using a strategy based on screening with long PCR we were able to detect and characterize high as well as low levels of mtDNA rearrangements in three patients.8
Also in 1997, researchers from the College of Physicians and Surgeons, Columbia University, New York, using the newly developed long polymerase chain reaction protocol in conjunction with Southern blot analyses, found dup-mtDNAs in most of the examined tissues from two autopsy patients. In both patients, they found an unusually high level of dup-mtDNA concentrated in the heart.9
In 1999, researchers optimistically noted in the Journal of Medical Genetics: “The last decade has been an age of enlightenment as far as mitochondrial pathology is concerned. Well established nuclear genetic diseases, such as Friedreich’s ataxia, Wilson disease, and autosomal recessive hereditary spastic paraplegia, have been shown to have a mitochondrial basis, and we are just starting to unravel the complex nuclear genetic disorders which directly cause mitochondrial dysfunction.”10
In early 2000, researchers at Hôpital Timone-Enfants, Marseille, France, reported on the case of a 3-yr-old boy received valproic acid for recurrent seizures. He developed coma and acute liver failure that were attributed to VPA toxicity, and underwent emergency orthotopic liver transplantation. Despite good graft function, his neurological state worsened and led to death a few months later.
They suspected a possible diagnosis of Alpers–Huttenlocher Syndrome, in view of ongoing neurologic deterioration and magnetic resonance imaging findings. As they explain it: “The syndrome, recessively inherited, associates brain degeneration with liver failure, and is now considered a mitochondrial disease.” They further explain that: “Enzyme activity deficiencies of the respiratory chain were identified in muscle mitochondria, as well as morphologic abnormalities of mitochondria in the explanted liver,” presenting guidelines for diagnosis intended “to differentiate the liver failure in AHS from that induced by genuine VPA toxicity.”11
Unfortunately, the promising research results that came about notwithstanding, in this particular case the diagnosis came too late for the child.
By August of 2000, researchers as the University of Zürich, Switzerland, published an admonition in Liver International, cautioning that mitochondrial diseases should “be considered as a risk factor for valproate-induced liver failure and be excluded before treatment with valproate.”12
In early 2004, Andrew M. Schaefer and colleagues reported that: “Until relatively recently, mitochondrial disorders were considered to be obscure, exceptionally rare diseases affecting perhaps one or two per million of the population. Only a limited number of centers throughout the world had clinical and laboratory expertise in mitochondrial medicine, and a general lack of awareness of mitochondrial disease by non-specialist physicians left many patients undiagnosed.”
Schaefer and colleagues noted that: “the complete sequencing of the human mitochondrial genome (mtDNA) followed by the identification of pathogenic mtDNA mutations and led to a huge surge in interest in human mitochondrial disease in the early 1990s. These advances paved the way for future epidemiological studies which clearly demonstrate that mitochondrial disorders are amongst the most common inherited human diseases.”
Also in 2004, researchers in Clinical Chemistry reported on a condition known as mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), an affliction caused by mutations in the gene encoding thymidine phosphorylase. Of particular note is that the researchers explained: “The clinical manifestations of MNGIE are recognizable and homogeneous, but in the early stages, the disease is often misdiagnosed.”13
In 2011, the journal Brain reported with regard to mitochondrial neurogastrointestinal encephalomyopathy that: “Despite increasing awareness of this illness, a high proportion of patients had been misdiagnosed.” They noted that early and accurate diagnosis of mitochondrial neurogastrointestinal encephalomyopathy, together with the timely treatment of acute intercurrent illnesses, may retard disease progression and increase the number of patients eligible for appropriate treatments.14
This is consistent with the findings of researchers at Columbia University Medical Center, New York, who explain: “The diagnosis of mitochondrial diseases poses challenges to clinicians due to their diverse and often complex clinical presentations. As a consequence these diseases are frequently misdiagnosed.”15
By 2013, tremendous progress had been made. Writing in Case Reports in Pediatrics, clinicians from Nationwide Children’s Hospital, at the Ohio State University College of Medicine, reported “a long term followup of a 10-year-old female presenting at 1 year of age with rickets initially misdiagnosed as vitamin D deficiency rickets.” Subsequently, they explain”
She was referred to the metabolic bone and genetics clinics at 5 years of age with severe genu valgum deformities of 24 degrees and worsening rickets. She had polyuria, polydipsia, enuresis, and bone pain. Diagnosis of hypophosphatemic rickets due to de Toni-Debré-Fanconi syndrome was subsequently made. Respiratory chain enzyme analysis identified a complex I mitochondrial deficiency as the underlying cause.
On a positive note, they concluded that notwithstanding her initial misdiagnosis: “Her excellent orthopaedic outcome despite late proper medical therapy is likely due to the intrinsic renal tubular defect that is more responsive to combined alkali, phosphate, and calcitriol therapy.”16
In March 2014, Italian Journal of Pediatrics reported that “mitochondrial dysfunction accounts for a large group of inherited metabolic disorders most of which are due to a dysfunctional mitochondrial respiratory chain and, consequently, deficient energy production.”
They noted further that “mitochondrial diseases can be caused by genetic defects in either the mitochondrial or the nuclear genome, or in the cross-talk between the two.” This impaired cross-talk, they explain, gives rise to so-called nuclear-mitochondrial intergenomic communication disorders, which result in loss or instability of the mitochondrial genome and, in turn, impaired maintenance of qualitative and quantitative mitochindrial DNA integrity. In children, most mitochondrial respiratory chain disorders are associated with nuclear gene defects rather than alterations in the mitochondrial DNA itself.17
“Mitochondrial disorders have the highest incidence among congenital metabolic diseases, and are thought to occur at a rate of 1 in 5000 births,” notes a recent article in the encyclopedic medical journal Biochimica et Biophysica Acta (BBA) – General Subjects. The journal recently devoted an entire issue to the subject of mitochondrial disorders.18
Australian researchers explain in the same journal that: “An expanding number of mitochondrial diseases are being recognized, despite their phenotypic diversity, largely due to improvements in methods to detect mutations in affected individuals and the discovery of genes contributing to mitochondrial function.”19
Clinicians in London explain that a more complete understanding of mitochondrial functioning “will be crucial in developing therapies for the plethora of diseases in which the pathophysiology is determined by mitochondrial dysfunction.”20
1 Andrew M. Schaefer et al., “The Epidemiology of Mitochondrial Disorders—past, Present and Future ,” Biochimica et Biophysica Acta (BBA) – Bioenergetics, Euromit 6 Special Issue, 1659, no. 2–3 (December 6, 2004): 115–20, doi:10.1016/j.bbabio.2004.09.005.
2 Patrick F. Chinnery et al., “Clinical Mitochondrial Genetics,” Journal of Medical Genetics 36, no. 6 (June 1, 1999): 425–36, doi:10.1136/jmg.36.6.425.
3 A M Remes et al., “Kearns-Sayre Syndrome Case Presenting a Mitochondrial DNA Deletion with Unusual Direct Repeats and a Rudimentary RNAase Mitochondrial Ribonucleotide Processing Target Sequence,” Genomics 16, no. 1 (April 1993): 256–58, doi:10.1006/geno.1993.1170.
4 Jill Clayton Smith, “Medical Genetics: Advances in Brief ,” Journal of Medical Genetics 31, no. 6 (June 1994): 504. Parenteral nutrition is ” the medical term for feeding through a vein,” according to Mayo Clinic Staff, “Tests and Procedures: Home Parenteral Nutrition Program (TPN) ,” Mayo Clinic, undated.
5 Søren Nørby et al., “Juvenile Kearns-Sayre Syndrome Initially Misdiagnosed as a Psychosomatic Disorder ,” Journal of Medical Genetics 31, no. 1 (1994): 45–50,
6 I Tuxhorn et al., “Reversible Cortical Oedema Mimicking Cortical Dysplasia in Mitochondrial Disorder.,” Journal of Neurology, Neurosurgery, and Psychiatry 57, no. 11 (November 1994): 1439, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1073210/.
7 T Klopstock et al., “3.1-Kb Deletion of Mitochondrial DNA in a Patient with Kearns-Sayre Syndrome,” Acta Neuropathologica 90, no. 2 (1995): 126–29.
8 S Kleinle et al., “Detection and Characterization of Mitochondrial DNA Rearrangements in Pearson and Kearns-Sayre Syndromes by Long PCR,” Human Genetics 100, no. 5–6 (October 1997): 643–50.
9 Bernard Fromenty et al., “High Proportions of mtDNA Duplications in Patients with Kearns-Sayre Syndrome Occur in the Heart,” American Journal of Medical Genetics 71, no. 4 (September 5, 1997): 443–52, doi:10.1002/(SICI)1096-8628(19970905)71:43.0.CO;2-G. (mtDNA duplication is shorthand for mitochondrail DNA duplication).
10 Chinnery et al., “Clinical Mitochondrial Genetics.”
11 A Delarue et al., “Inappropriate Liver Transplantation in a Child with Alpers-Huttenlocher Syndrome Misdiagnosed as Valproate-Induced Acute Liver Failure ,” Pediatric Transplantation 4, no. 1 (February 2000): 67–71.
12 Stephan Krähenbühl et al., “Mitochondrial Diseases Represent a Risk Factor for Valproate-Induced Fulminant Liver Failure ,” Liver 20, no. 4 (August 1, 2000): 346–48, doi:10.1034/j.1600-0676.2000.020004346.x.
13 Ramon Martı́ et al., “Definitive Diagnosis of Mitochondrial Neurogastrointestinal Encephalomyopathy by Biochemical Assays ,” Clinical Chemistry 50, no. 1 (January 1, 2004): 120–24, doi:10.1373/clinchem.2003.026179. The identification of Mitochondrial Neurogastrointestinal Encephalomyopathy is attributed to Okamura et al. See K Okamura et al., “Congenital Oculoskeletal Myopathy with Abnormal Muscle and Liver Mitochondria,” Journal of the Neurological Sciences 27, no. 1 (January 1976): 79–91. (describing “light-microscopic, histochemical and electron-microscopic findings showed abnormal mitochondria not only in the skeletal muscle, but also in liver cells”).
14 Caterina Garone, Saba Tadesse, and Michio Hirano, “Clinical and Genetic Spectrum of Mitochondrial Neurogastrointestinal Encephalomyopathy ,” Brain 134, no. 11 (November 1, 2011): 3326–32, doi:10.1093/brain/awr245.
15 Michio Hirano, Valentina Emmanuele, and Catarina M. Quinzii, “Mitochondrial Myopathies ,” in Neuromuscular Disorders, ed. Rabi N. Tawil MD and Shannon Venance MD FRCPCP (Wiley-Blackwell, 2011), 42–50..
16 Sasigarn A. Bowden et al., “Successful Medical Therapy for Hypophosphatemic Rickets due to Mitochondrial Complex I Deficiency Induced de Toni-Debré-Fanconi Syndrome,” Case Reports in Pediatrics 2013 (December 10, 2013), doi:10.1155/2013/354314.
17 Célia Nogueira et al., “Syndromes Associated with Mitochondrial DNA Depletion ,” Italian Journal of Pediatrics 40, no. 1 (April 3, 2014): 34, doi:10.1186/1824-7288-40-34.
18 A. Ohtake et al., “Diagnosis and Molecular Basis of Mitochondrial Respiratory Chain Disorders: Exome Sequencing for Disease Gene Identification,” Biochimica et Biophysica Acta (BBA) – General Subjects 1840, no. 4 (April 2014): 1355–59, doi:10.1016/j.bbagen.2014.01.025.
19 Christina Liang, Kate Ahmad, and Carolyn M. Sue, “The Broadening Spectrum of Mitochondrial Disease: Shifts in the Diagnostic Paradigm,” Biochimica et Biophysica Acta (BBA) – General Subjects 1840, no. 4 (April 2014): 1360–67, doi:10.1016/j.bbagen.2013.10.040.
20 Vassilios N. Kotiadis, Michael R. Duchen, and Laura D. Osellame, “Mitochondrial Quality Control and Communications with the Nucleus Are Important in Maintaining Mitochondrial Function and Cell Health,” Biochimica et Biophysica Acta (BBA) – General Subjects 1840, no. 4 (April 2014): 1254–65, doi:10.1016/j.bbagen.2013.10.041.