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
page: 59

PATIENT REPORT

The patient is the first child of non-consanguineous parents (father has hypothyroidism and mother was treated for anxiety disorder), born from an uneventful pregnancy. Birth weight was 4.2 kg, and the perinatal period was normal. In early infancy, poor weight gain was observed. Thorough diagnostic evaluation was initiated at six months of age due to failure to thrive, muscular hypotonia, motor delay and recurrent bronchiolitis. The laboratory analyses revealed hyperlactatemia (2.53 mmol/l), hypokalaemia (2.8 mmol/l), absence of other electrolyte abnormalities in serum (table 1) and tubular loss of potassium and magne- sium (table 2). The aldosterone level was normal. Serum creatine level and estimated glomerular filtration rates were normal at the time of the first evaluation. The ultrasound exam showed hyperechoic, normal sized kidneys. After discharge he was lost to follow-up until two years of age when he was readmitted with an elevated creatinine level, reduced estimated glomerular filtrate rate, normochromic anaemia, metabolic acidosis and hyperka- laemia. Urine abnormalities pointed to tubular dysfunction (table 2). Aldosterone, renin and cortisol concentrations were within normal range, while decreased plasma concen- tration of parathyroid hormone (PTH) was accompanied by normal calcemia. The association of chronic renal disease with devel- opmental delay of unknown aetiology prompted genetic testing. Two novel heterozygous variants in the TARS2 gene were detected by means of whole exome sequencing: c.1298T>G (p.Phe438Cys) missense variant derived from the mother and the c.1931A>T (p.Asp644Val) missense variant derived from the father). At the age of 2.5 years the boy, was admitted due to generalized seizures associated with fever, severe metabolic acidosis and electrolyte imbal- ance (hyponatremia of 121 mmol/L, hypomagnesemia 0,5 mmol/L and hypophosphatemia 0,5 mmol/L). At the time he had elevated serum lactate (3.61 mmol/L). Pneumonia was verified, and during the treatment acute pancreatitis devel- oped with hyperglycaemia requiring the insulin therapy. A moderate progression of chronic kidney disease was noted during this metabolic crisis (creatinine 164 mcmol/L) with subsequent polyuria. Urinary analysis showed persistent tu- bular dysfunction. The boy’s overall condition deteriorated into encephalopathy. A brain MRI examination detected a pathologically increased signal of the brain parenchyma on T2/DVI/FLAIR sequences, in the projection of the basal ganglia, thalamus, hippocampus, substantia nigra, mesence- phalic crus bilaterally, as well as in the posterior aspects of the pons and white matter of the cerebellum (figure 1). Mild supratentorial ventriculomegaly was described as well as a consequence of brain parenchyma reduction in the patient. An electroencephalogram showed diffuse slowing of basal activity of delta type without clear epileptic discharge. Slow recovery of neurologic functions ensued over the course of several weeks, while hyperglycaemia proved to be transi- tory, thus the insulin treatment was stopped. Treatment during the disease included dietary modi- fication, erythropoietin, calcitriol, ion-exchange resin, a “mitochondrial cocktail” of supplements and vitamins, and antiseizure medication. Thyroxine supplementation was introduced in response to hypothyroidism, detected at 4 years of age during a regular follow-up visit. Dosage of thyroxine had to be adjusted over time due to the wors- ening of thyroid function. Currently, at 4.5 years of age, the boy weighs 11 kg (below 3 standard deviations), has severe motor and verbal delay, and end stage CKD with generalized tubulopathy. We referred the patient to another paediatric centre that provides renal replacement therapy. The dynamics of the serum/plasma and urine laboratory findings during the course of the disease is presented in table 1 and table 2.

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