LAUSR

In 2005, we reported on three patients in whom we suspected a nephrotic syndrome (NS) of mitochondrial origin [1]. Patients 2 and 3 died soon after birth due to a cardiogenic shock. The first patient was quite different (for detailed report, see ref. [1]). The main features were as follows: He was born hypotrophic (2140 g, 49 cm), after an uneventful pregnancy from healthy non-consanguineous parents. The placenta weighed 800 g. During the first days of life, he exhibited clinical and biological signs of a moderate congenital cortico-resistant NS. Renal biopsy at 1 month of age showed diffuse mesangial proliferation and focal tubular dilatation. Search for classical etiologies of congenital NS failed to find any infectious origin, signs of a syndromic NS, or maternal pathologies. Genetic testing, made with classical techniques in 2006 (SCCP, Pr C. Antignac Paris) only demonstrated a NPHS1 mutation in the heterozygous state, also found in the asymptomatic father and considered a variant of undetermined pathogenicity (c.2014g>A; p. Ala 672Thr). Symptomatic treatment during the first months of life allowed an uneventful evolution withweekly albumin infusion. But, after appearance of chronic renal insufficiency, around 1.5 years of life, he exhibited severe hypertension, clinical cardiac and neurological signs associated with acidosis, possibly suggestive of mitochondrial dysfunction. The cardiac pathology was a dilated cardiomyopathy without hypertrophy. Biochemical and enzymological studies ofmitochondria were compatible with such a hypothesis and spectrophotometric analysis demonstrated complex II andV deficiency in the kidney and an isolated complex II deficiency in the endomyocardium. Polarographic and spectrophotometric studies of isolated mitochondria of skeletal muscle and cultured skin fibroblasts were in the normal range. The quinone-dependent activities (segments I + III or G3P + III and II + III) were normal in muscle, liver, kidney, and fibroblasts, and thus no indication for congenital Q10 deficiency was given. No mutation of mitochondrial DNAwas found with two complementary strategies (Surveyor® and MitoChip®) (completed after publication of ref. [1]). Interestingly, mitochondrial symptoms, in particular cardiac myocardiopathy, persisted even after bi nephrectomies (18 and 22 months of life) and correction of hypertension, with a cardiac fractional shortening as low as 12%.Myocardial function improved under carnitine supplementation (to 45%), but did not return to normal values.When he was 4 years old, with a growth retardation of − 2SD, he received a cadaveric renal graft. At present, he is 20 years old; his renal function is good (creatininemia = 102 μmol/l), without recurrence of proteinuria. No carnitine supplementation was required after renal transplantation; the patient never presented again acidosis and cardiac function remains normal. Since 5 years of age, a progressive deafness of unknown origin was detected, but no other clinical or biological disorders of mitochondrial dysfunction appeared, and growth retardation regressed (at present 160 cm and 49 kg; − 1SD). The answer to this question can be found at https://doi.org/10.1007/ s00467-019-04217-7.