Balkan Journal of Medical Genetics

EXPANDING THE PHENOTYPIC SPECTRUM: CHRONIC KIDNEY DISEASE IN A PATIENT WITH COMBINED OXIDATIVE PHOSPHORYLATION DEFECT 21
Paripović A, Maver A, Stajić N, Putnik J, Ostojić S, Alimpić B, Ilić N, Sarajlija A
*Corresponding Author: Adrijan Sarajlija MD, PhD, Clinical Genetics Outpatient Clinic, Mother and Child Health Care Institute “Dr Vukan Čupić”, Radoja Dakića 6-8, 11070 Novi Beograd, Serbia; University of Belgrade, Faculty of Medicine, Belgrade, Serbia, email:adrijans2004@yahoo.com
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DISCUSSION

The clinical presentations of the patients we have reported on so far are mostly in accordance with other cases of COXPD21 (1-5.) The key clinical features of this particular mitochondrial disorder (failure to thrive, devel- opment delay, muscle tone abnormalities, epilepsy) are all present in our patient. A spectrum of brain MRI changes has been described in patients with COXPD21. Therefore, our patient’s brain MRI scan revealed basal ganglia hyper intensity and generalized atrophy, resembling some of the more extensive findings thus reported (2,5). Our report focusses on the renal aspect of a patient’s phenotype, since the kidney’s involvement in COXPD21 has been described in seven cases so far (2,4). In one of the reports, the male patient of Syrian descent presented with renal tubular acidosis, diagnosed at 6 months of age along with delayed psychomotor development (4). Neph- rocalcinosis was observed at 12 months of age. In his early teenage years, the ultrasound showed small and scarred kidneys; the same patient was diagnosed stage III of CKD at 17 years of age. In the largest case series of COXPD21, a third of the patients had distal renal tubular acidosis (2). According to the data, none of them developed chronic kidney disease, despite half of them being of adult age. In contrast to previously reported patients, CKD was already present at two years of age and progressed into the end stage by the age of four. Moreover, the observed gener- alized tubulopathy differs our patient from COXPD21 patients with isolated renal tubular acidosis as the main tubular dysfunction. However, we can speculate that the origin of tubulopathy stems both from primary mitochon- drial disorder and from advanced CKD itself. Defects in the mitochondrial oxidative phosphor- ylation system are well-known genetic causes of renal dysfunction. Even though renal impairment can be the presenting feature of mitochondrial diseases, it is more commonly seen after the onset of neurological manifesta- tions (9). Renal impairment can occur at any age in patients with mitochondrial disease, but the median age of this specific organ involvement has been estimated at 12 years (6). Typically, laboratory abnormalities of urine detected during regular patient check-ups are the first sign of kidney involvement in these patients. In our patient, at the very early age of six months, tubular loss of potassium and magnesium was verified. This indicated potential dysfunc- tion of either thick ascending limb of the loop of Henle or distal tubule, even before the rise of urinary beta-2 microglobulin. Initially, there were no signs of proximal tubular dysfunction. Impairment of renal function was verified at two years of age in our patient and was consis- tent with both proximal and distal tubular dysfunctions. Full expression of Fanconi syndrome has been previously associated with mtDNA deletion syndromes, but also with diseases caused by nuclear DNA mutations affecting mito- chondrial functioning (6,10). The presence of glycosuria, hyperphosphaturia, generalized aminoaciduria and low- molecular-weight proteinuria in our patient was detected at the end stage of CKD. The progression of chronic kidney disease in our patient seemed to be facilitated during severe metabolic crisis occurring at the age of 2.5 years. Impairment of both proximal and distal renal tubules has been designated as generalized tubulopathy and described as such in sev- eral patients with mitochondriopathies (6). Interestingly, severe tubular dysfunction has been associated mostly with large mtDNA deletions, thereby contrasting to our patient’s disease, caused by the autosomal-recessive mu- tations in nuclear TARS2 gene. However, there have been reports of tubular impairment and chronic kidney disease in patients with mutations in SARS2 gene which encodes mitochondrial seryl-tRNA synthetase (11). This autoso- mal recessive mitochondrial disease, caused by SARS2 mutations, has been designated as HUPRA, an acronym based on the hallmarks of the disease (hyperuricemia, pulmonary hypertension, renal failure, alkalosis). Despite certain basic similarities in terms of abnormal mitochon- drial protein translation in both HUPRA and COXPD21, clinical presentations of the two diseases are distinct. Renal impairment has been the hallmark of HUPRA, while only a quarter of COXPD21 cases published so far had kidney involvement. The patient presented herein is the second verified case of CKD in COXPD21. The overall clinical course is similar to that of our patient. Tubular dysfunc- tion and early onset of CKD has been observed in several patients with mitochondrial genome mutations affecting tRNA synthesis (7,12). In a plethora of patients with re- spiratory chain assembly and function defects, kidney involvement was noted as part of the multisystem disease, with proximal tubulopathy being the most commonly en- countered renal phenotype (8). The genotype of our patient includes two variants of unknown significance in TARS2 gene detected by whole exome sequencing. After confirmation of combined het- erozygosity of the proband, we performed a segregation analysis, proving carriership of single variants in the par- ents. Both variants we found in TARS2 are designated as missense. According to one literature review of COXPD21 cases, carriers of biallelic missense variants in TARS2 had later disease presentation with longer survival (3). How- ever, a more recent study depicting 18 new patients with COXPD21 denied presence of any meaningful genotype- phenotype correlation (2). Although our patient had failure to thrive and delayed development early in infancy, his overall condition remained relatively stable over time, apart from one serious metabolic crisis at the age of 2.5 years. However, early and progressive CKD represents a key clinical feature in this particular patient, despite being non-typical for COXPD21. The presence of hypothyroidism in our patient has been demonstrated by elevated thyroid stimulating hor- mone level and low free thyroxine in blood. A neonatal screening test for congenital hypothyroidism was previ- ously negative. The level of thyroid peroxidase antibodies remained low, suggesting that the occurrence of hypothy- roidism is most probably the part of the multisystem pre- sentation of mitochondrial disease. Endocrine abnormali- ties represent one of the more prominent clinical features of mitochondrial diseases with hypothyroidism being pres- ent in approximately 6.3% of patients (13). Interestingly, defects in nuclear genes encoding mitochondrial protein pose a lower risk for hypothyroidism, when compared to mtDNA mutations (2.9% and 8.5%, respectively). The findings of the WES did not reveal any other genetic vari- ant that could be causative to hypothyroidism. Hypothy- roidism in the father is caused by Hashimoto thyroiditis and is most probably not related to the hypothyroidism in the proband. Subnormal levels of PTH found in context of overt CKD suggest hypoparathyroidism in our patient. Insufficiency of parathyroid secretion has been well es- tablished occurrence in mitochondrial disorders (14), but not in COXPD321 so far (2,3). The overall clinical course in the patient we report on corresponds well to the previously reported cases of TARS2 related COXPD21, especially in regard to neurological and developmental aspects of the disease. However, we point out the early occurrence CKD in our patient since it has been previously described in only a single case of COXPD21. The presence of overt hypothyroidism and hypoparathyroidism are additional phenotypic features that have not been reported on in patients with this spe- cific mitochondrial disorder before. We hope that this case report will add to the deeper knowledge of the phenotypic spectrum of COXPD21.

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