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Polish Journal of Pathology
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vol. 72
Letter to the Editor

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

Josef Finsterer
Michael Winklehner

Klinikum Landstrasse, Messerli Institute, Vienna, Austria
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
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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.


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.


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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.
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