eISSN: 2084-9869
ISSN: 1233-9687
Polish Journal of Pathology
Current issue Archive Manuscripts accepted About the journal Supplements Editorial board Abstracting and indexing Subscription Contact Instructions for authors Publication charge Ethical standards and procedures
Editorial System
Submit your Manuscript
SCImago Journal & Country Rank
2/2021
vol. 72
 
Share:
Share:
Letter to the Editor

Adult-onset, isolated respiratory chain complex-IV deficiency with mild manifestations

Josef Finsterer
1
,
Michael Winklehner
2

  1. Klinikum Landstrasse, Messerli Institute, Vienna, Austria
  2. Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Vienna, Austria
Pol J Pathol 2021; 72 (2): 185-189
Online publish date: 2021/09/30
Article file
- 12-PJP-01963.pdf  [3.31 MB]
Get citation
 
PlumX metrics:
 

Introduction

Mitochondrial disorders (MIDs) are most frequently due to mutations in genes encoding respiratory chain complex subunits or assembly factors [1]. Biochemically, isolated or combined complex deficiencies are delineated. The second most frequent type of the isolated respiratory chain complex deficiencies is the isolated respiratory chain complex-IV deficiency (ICIVD) [2, 3]. ICIVD usually manifests clinically as a severe, multisystem mitochondrial disorder (MID) [2, 3, 4] and only rarely with mild manifestations (Table I) [5]. Here we present an adult with late-onset ICIVD with slowly progressive, discrete clinical manifestations. The patient is a 57-years-old Caucasian male, who developed myalgias of the thighs upon exercise and recurrently elevated creatine-kinase (CK) up to 1000 U/l (n, < 190U/l) since age 48 years. Later on, he additionally developed cramping of the calves. His further history was positive for diabetes treated with alogliptin/metformin and gliclazid, hyperuricemia, hyperlipidemia treated with diet, arterial hypertension, treated with amlodipine, unilateral retinal detachment, transient hypothyroidism, hypogonadism, and an unilateral hearing fall. Diabetes was well controlled with a HbA1c value of 6.7.
Clinical neurologic exam revealed mild, left-sided ptosis, reduced tendon reflexes on the upper limbs, and sore limb muscles. Nerve conduction studies were normal. A first needle electromyography (EMG) showed only non-specific abnormalities. A follow-up EMG showed neurogenic changes. Serum lactate was normal. Muscle biopsy from the left vastus lateralis muscle revealed mild, non-specific, myopathic changes with scattered atrophic muscle fibers, isolated ring fibers and a single COX-negative muscle fiber (Fig. 1A-E). Normal sarcolemmal immunoreactivity was detected for most muscle dystrophy-relevant proteins. The ultrastructural study by electron microscopy revealed a subsarcolemmal increase of lipopigment and accumulation of slightly enlarged mitochondria with focal, small, electron-dense condensations; typical paracrystalline inclusions were not identified (Fig. 1F-G). Biochemical investigations of the muscle homogenate revealed ICIVD with reduced cytochrome-c oxidase (COX) activity of 46.4 U/g NCP (n, 112-351 U/g NCP). Transthoracic echocardiography at ages 51 years and 56 years revealed mild concentric thickening of the left ventricular myocardium. Cerebral MRI showed non-specific, gliotic spots, in a fronto-parietal distribution. A non-syndromic MID was diagnosed and treatment with coenzyme-Q (CoQ) 400mg/d was begun at age 53 years. His family history was positive for diabetes (mother), Parkinson’s disease (mother), dementia (mother), myocloni (brother), hyper-CKemia (brother), and muscle soreness (brother).
ICIVD has been repeatedly reported (Table I) and manifests in the majority of cases with severe clinical manifestations, such as a rapidly progressive, infantile-onset, multiorgan MID, with early death. Syndromic [5] and non-syndromic ICIVD phenotypes [6] have been reported. Contrary to most of the previous descriptions, the index patient manifested with only a mild and slowly progressive phenotype. Myopathy, diabetes, hypothyroidism, hypogonadism, and hypoacusis have been previously reported as manifestations of an ICIVD (Table I) [7, 8]. Particularly myopathy is a common feature of ICIVD (Table I) [2, 7, 9]. Diabetes has been only rarely reported in association with ICIVD (Table I). Hypothyroidism and hypoacusis are common features in MIDs but have been hardly found in patients with ICIVD. Whether hyperlipidemia, arterial hypertension, and retinal detachment are truly attributable to the underlying metabolic defect, remains speculative but it is increasingly recognised that particularly arterial hypertension can be a primary or secondary manifestation of a MID [10]. Additionally, retinal detachment has been recently reported in association with MELAS. The second, neurogenic EMG despite metabolic myopathy is no contradiction and could be explained by muscle fiber hypertrophy, increased dispersion of the motor endplates, and slowed or inhomogeneous propagation of action potentials along the muscle fiber membranes.
The vast majority of patients with ICIVD has an onset at infancy, usually within the first year of life (Table I). Even patients with congenital ICIVD have been reported (Table I). Only few patients have an onset in childhood and even patients with an adult onset have been communicated (Table 1). The genetic cause of ICIVD is heterogeneous and includes mutations in various genes including mtDNA genes (MT-CO1, MT-CO2, MT-CO3) and nuclear genes (COA3, COA7, COX4I1, COX5A, COX6B1, COX10, COX15, COX18, COX20, PET100, PET117, SCO1, SCO2, SURF1, TACO1, FASTKD2, LRPPRC, and FARS2) (Table I). Assuming that the index patient’s condition was inherited from the mother, diabetes, Parkinson’s disease, and dementia in the mother were regarded as clinical manifestations of her MID. However, the mother neither underwent clinical nor para-clinical investigations for MID. The brother of the index patient most likely had inherited the disease as well, given recurrent hyper-CKemia, muscle cramps, muscle soreness, and myocloni. Unfortunately, the brother did not consent to further diagnostic work-up for a MID. Despite these limitations, the family history and the clinical manifestations of the index patient, his mother, and his brother, suggest a maternally transmitted MID.
In conclusion, this case shows that ICIVD may manifest in adulthood with only mild manifestations and may take a slowly progressive course. Patients with mild hyper-CKemia and mild, multisystem manifestations, including muscular symptoms, profit from muscle biopsy and biochemical investigations of the muscle homogenate. In the vast majority of the cases, ICIVD is due to mutations in nuclear genes encoding COX subunits, transcription factors, or assembly factors.

Acknowledgements

We thank Dr. Ellen Gelpi from the Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, for supplementary investigations.
The authors declare no conflicts of interest.

References

1. Rahman J, Rahman S. Mitochondrial medicine in the omics era. Lancet 2018; 391: 2560-2574.
2. Debray FG, Lambert M, Chevalier I, et al. Long-term outcome and clinical spectrum of 73 pediatric patients with mitochondrial diseases. Pediatrics 2007; 119: 722-733.
3. Scaglia F, Towbin JA, Craigen WJ, et al. Clinical spectrum, morbidity, and mortality in 113 pediatric patients with mitochondrial disease. Pediatrics 2004; 114: 925-931.
4. Pillai NR, AlDhaheri NS, Ghosh R, et al. Biallelic variants in COX4I1 associated with a novel phenotype resembling Leigh syndrome with developmental regression, intellectual disability, and seizures. Am J Med Genet A 2019; 179: 2138-2143.
5. Rossmanith W, Freilinger M, Roka J, et al. Isolated cytochrome c
6. oxidase deficiency as a cause of MELAS. BMJ Case Rep 2009; 2009: bcr08.2008.0666.
7. Renkema GH, Visser G, Baertling F, et al. Mutated PET117 causes complex IV deficiency and is associated with neurodevelopmental regression and medulla oblongata lesions. Hum Genet 2017; 136: 759-769.
8. Roos S, Sofou K, Hedberg-Oldfors C, et al. Mitochondrial complex IV deficiency caused by a novel frameshift variant in MT-CO2 associated with myopathy and perturbed acylcarnitine profile. Eur J Hum Genet 2019; 27: 331-335.
9. Lamperti C, Diodato D, Lamantea E, et al. MELAS-like encephalomyopathy caused by a new pathogenic mutation in the mitochondrial DNA encoded cytochrome c oxidase subunit I. Neuromuscul Disord 2012; 22: 990-994.
10. Zierz CM, Baty K, Blakely EL, et al. A Novel Pathogenic Variant in MT-CO2 Causes an Isolated Mitochondrial Complex IV Deficiency and Late-Onset Cerebellar Ataxia. J Clin Med 2019; 8: 789.
11. Zhou M, Xue L, Chen Y, et al. A hypertension-associated mitochondrial DNA mutation introduces an m1G37 modification into tRNAMet, altering its structure and function. J Biol Chem 2018; 293: 1425-1438.
Copyright: © 2021 Polish Association of Pathologists and the Polish Branch of the International Academy of Pathology This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0) License (http://creativecommons.org/licenses/by-nc-sa/4.0/), allowing third parties to copy and redistribute the material in any medium or format and to remix, transform, and build upon the material, provided the original work is properly cited and states its license.
Quick links
© 2024 Termedia Sp. z o.o.
Developed by Bentus.