ADCK4-Associated Glomerulopathy Causes Adolescence-Onset FSGS

Area of Science:

• Genetics
• Nephrology
• Biochemistry

Background:

• Hereditary defects in coenzyme Q10 biosynthesis can lead to nephrotic syndrome.
• These defects may present as isolated cases or part of multiorgan disorders.
• ADCK4 mutations are a newly identified cause of nephrotic syndrome.

Purpose of the Study:

• To investigate the role of ADCK4 mutations in patients with steroid-resistant nephrotic syndrome (SRNS).
• To characterize the clinical phenotype and disease progression in patients with ADCK4 mutations.
• To establish ADCK4-related glomerulopathy as a differential diagnosis for adolescent SRNS.

Main Methods:

• Genetic screening of 534 patients with SRNS for mutations in ADCK4.
• Clinical data collection and analysis of 26 patients from 12 families with identified ADCK4 mutations.
• Comparison of disease progression with mutations in WT1 and NPHS2.

Main Results:

• Recessive ADCK4 mutations were found in 1.9% of screened SRNS cases.
• Patients predominantly exhibited a renal-limited phenotype, with some experiencing neurological or visual issues.
• ADCK4 nephropathy typically presented in adolescence with FSGS on biopsy, progressing to ESRD in the third decade.

Conclusions:

• ADCK4-related glomerulopathy is a significant genetic cause of SRNS, particularly in adolescents.
• The disease course is characterized by rapid CKD progression during adolescence.
• ADCK4 mutations should be considered in the differential diagnosis of adolescent SRNS/FSGS and CKD of unknown origin.