Abstract
Hereditary defects of coenzyme Q10 biosynthesis cause steroid-resistant nephrotic syndrome (SRNS) as part of multiorgan involvement but may also contribute to isolated SRNS. Here, we report 26 patients from 12 families with recessive mutations in ADCK4. Mutation detection rate was 1.9% among 534 consecutively screened cases. Patients with ADCK4 mutations showed a largely renal-limited phenotype, with three subjects exhibiting occasional seizures, one subject exhibiting mild mental retardation, and one subject exhibiting retinitis pigmentosa. ADCK4 nephropathy presented during adolescence (median age, 14.1 years) with nephrotic-range proteinuria in 44% of patients and advanced CKD in 46% of patients at time of diagnosis. Renal biopsy specimens uniformly showed FSGS. Whereas 47% and 36% of patients with mutations in WT1 and NPHS2, respectively, progressed to ESRD before 10 years of age, ESRD occurred almost exclusively in the second decade of life in ADCK4 nephropathy. However, CKD progressed much faster during adolescence in ADCK4 than in WT1 and NPHS2 nephropathy, resulting in similar cumulative ESRD rates (>85% for each disorder) in the third decade of life. In conclusion, ADCK4-related glomerulopathy is an important novel differential diagnosis in adolescents with SRNS/FSGS and/or CKD of unknown origin.
Keywords: glomerulopathy, genetic renal disease, focal segmental glomerulosclerosis, familial nephropathy, mitochondria
Mitochondrial cytopathies are clinically and genetically heterogeneous disorders. Although most mitochondriopathies involve multiple organ systems and often present with prominent neurologic and myopathic features in childhood, a few exhibit organ-selective phenotypes.1 In the kidney, mitochondriopathies typically cause proximal tubulopathy2; however, glomerular dysfunction has been reported with mitochondrial DNA mutations in the tRNALEU gene and coenzyme Q biosynthesis defects.2–5 Coenzyme Q (ubiquinone; CoQ10) is a component of the mitochondrial respiratory chain,4 a potent lipophilic antioxidant, and a cofactor for mitochondrial dehydrogenases and in pyrimidine nucleoside biosynthesis. CoQ10 is synthesized ubiquitously through a multienzyme complex at the inner mitochondrial membrane. Mutations in several genes encoding enzymes of the CoQ10 biosynthetic pathway (COQ2, COQ6, and PDSS2) are associated with a glomerular phenotype. These have been collectively termed CoQ10 glomerulopathies.2 Recently, recessive mutations in ADCK4 (AarF Domain Containing Kinase-4) have been added to this list as a novel cause of steroid-resistant nephrotic syndrome (SRNS).6 ADCK4 interacts with components of the CoQ10 biosynthesis pathway, and patients with ADCK4 mutations have reduced cellular CoQ10 content.6,7 The selective glomerular phenotype of patients with ADCK4 mutations may be the result of relative enrichment of ADCK4 and lacking expression of the related protein ADCK3 in podocytes, whereas ADCK3 expression exceeds that of ADCK4 in most other body tissues.6
We identified a new patient cohort with ADCK4 glomerulopathy among 534 consecutive SRNS cases. ADCK4 mutations were found in ten patients (1.9%) from mostly consanguineous families. In five families the mutation was found in further affected siblings (Supplemental Figure 1: Families III–VII). Two additional families comprising nine affected subjects in whom ADCK4 mutations were identified by genome-wide linkage analysis or exome sequencing (Supplemental Figure 1: Families I, II), yielding a total cohort of 26 patients. Mutational analysis revealed four novel sequence variants and three previously reported homozygous mutations, namely c.645delT, c.1199_1200dupA, and c.532C>T; p.(Arg178Trp) substitution.6 The novel c.1339dupG variant was found in four apparently unrelated Kurdish families originating from a region in southeast Turkey, suggesting a founder effect. Bioinformatic information on the novel variants is given in Table 1 and the online supplement.
Table 1.
Summary of bioinformatic analyses of the detected novel sequence variants
| Novel variant | Residue change | Protein domain | MAFa | Conservation | Human Splicing Finder 3.0 | Grantham difference score | PolyPhen score | SIFT score | Mutation taster prediction |
|---|---|---|---|---|---|---|---|---|---|
| c.293T>G | p.(Leu98Arg) | transmembrane (helical) | 0 (not reported) 0.3%b | highly conserved, within conserved region | mutation in early exonic positions potentially breaking ESE site | 102 | 1.0 probably damaging | 0 damaging | disease causing |
| c.929C>T | p.(Pro310Leu) | kinase (ABC1 subdomain) | 0 (not reported) | highly conserved | mutation in late exonic positions potentially breaking ESE site | 98 | 1.0 probably damaging | 0 damaging | disease causing |
| c.1493_1494CC>AA | p.(Ala498Glu) | – | 0 (not reported) | low conservation | potential creation of exonic ESE site | 93 | 0.173 benign | 0 damaging | disease causing |
| c.1339dupG | p.(Glu447Glyfs10) | – | <1:10,000 0.3%b | highly conserved | potential activation of exonic cryptic acceptor site, or alteration of exonic ESE site, or creation of exonic ESS site | NA | NA | NA | disease causing |
ESE, exonic splicing enhancer; ESS, exonic splicing silencer; NA, not applicable.
MAF, minor allele frequency; estimation based on data of 2577 individual genomes cataloged by the 1000 Genomes Project; 6503 samples collected at NHLBI Exome Sequencing Project and data from 60,706 individuals aggregated by the Exome Aggregation Consortium (ExAC; http://exac.broadinstitute.org); (accessed January 31, 2015).
In-house allele frequency database representative for Turkish population (collection of 373 individual genomes; accessed October 22, 2014).
The phenotypic profile is summarized in Table 2. The disease first manifested in adolescence, typically with mild to moderate proteinuria with no or mild edema. However, advanced CKD was present in almost half of patients at time of diagnosis and progression to ESRD occurred in 22 of the 26 patients within a median of 9 (interquartile range 0–44) months from diagnosis. Hematuria was present at time of diagnosis in 25% of patients, including one case with a chief complaint of macroscopic hematuria accompanied by only trace proteinuria. FSGS was diagnosed in all biopsies, including two differentiated as collapsing and tip lesion subtypes.
Table 2.
Comparison of clinical characteristics at time of diagnosis and prospective kidney survival of patients with ADCK4-related SRNS versus patients with NPHS2- and WT1-related glomerulopathy from the PodoNet Registry8
| ADCK4 SRNS | NPHS2 SRNS | WT1 SRNSd | |
|---|---|---|---|
| n | 26 | 140 | 66 |
| Age at first reported manifestation, years | 14.1 (10.8–17.0) | 3.4 (1.1–6.6)d | 2.0 (0.7–5.4)d |
| Asymptomatic, incidental diagnosis | 26.9% | 22.9% | 28.1% |
| Edema (none/mild/moderate/severe) | 54/42/4/0% | 48/17/16/19% | 47/19/24/10% |
| Proteinuria (subnephrotic/nephrotic range) | 57.1/43.9% | 14.9/85.1%d | 19.4/80.6%c |
| Hematuria | 25.0% | 44.0% | 26.3% |
| Hypertension | 30.8% | 15.7% | 41.5%b |
| CKD stage 3–5 | 46.1%a | 13.6%a,d | 23.4%a,b |
| including RTT: | 26.9%a | 2.9%a,d | 15.6%a |
| Age at start of RRT, years | 16.1 (13.7–18.0)a | 12.9 (7.6–19.4)a,d | 10.9 (2.3–17.0)a,d |
| Histopathological diagnosis | |||
| FSGS/global glomerulosclerosis | 61.5% | 49.3% | 45.0% |
| Diffuse mesangial sclerosis | 0 | 0.7% | 33.3%d |
| Mesangioproliferative GN | 0 | 12.9% | 4.5% |
| Minimal change GN | 0 | 10.7% | 1.5% |
| Other | 0 | 5.0% | 3.0% |
| No data/ not performed | 38.5% | 21.4% | 13.7% |
| Neurologic abnormalities (seizures, NI, behavioral problems) | 24.0% | 5.0%c | 6.1%bb |
| Congenital organ abnormalities | CAKUT 4.0% | CAKUT 0% | CAKUT 42.2%d |
| Other 8.0% | Other 5.7% | Other 4.5% |
Data are given as median (interquartile range) or percentage. Sixty-one of the patients with WT1 mutations were previously described by Lipska et al. (2014)9
Percentages given are relative to all observation with information on a specific variable.
P<0.05.
P<0.01.
P<0.001.
Signs and symptoms compatible with neurologic dysfunction were reported in six patients (Supplemental Table 1). Mild mental retardation and agoraphobia were each present in one case and two siblings had primary nocturnal enuresis. Three patients developed electroencephalogram-confirmed seizures, including two while on dialysis. One subject was eventually diagnosed with hypertension-related reversible posterior encephalopathy whereas the other two require continued anticonvulsive therapy. One patient presented with retinitis pigmentosa. No histories of hearing problems, cardiomyopathy, muscle weakness, optical nerve atrophy, or hematologic or endocrinologic abnormalities were reported in any patient. Serum lactate was episodically elevated in 4 of 11 patients tested, and transient creatine kinase elevation was noted in two patients during episodes of AKI.
The clinical phenotype of ADCK4-related glomerulopathy was compared with the phenotypes of the two most common genetic podocytopathies, i.e., NPHS2- and WT1-associated nephropathies (Figure 1, Table 2). Patients with ADCK4-related glomerulopathy were significantly older at time of diagnosis, with no cases manifesting before 5 years of age, and they presented with less severe proteinuria and less edema than WT1- or NPHS2-associated disease. Hypertension was less common than in WT1 nephropathy. FSGS was the histopathologic diagnosis in all biopsied ADCK4 cases, whereas diagnoses other than FSGS were commonly observed at time of diagnosis in NPHS2 (Mesangioproliferative GN, Minimal change GN) and WT1 nephropathy (diffuse mesangial sclerosis). In ADCK4 patients, advanced CKD at time of diagnosis was more prevalent than in NPHS2. Of patients with ADCK4 disease, 38.5% presented with CKD5, compared with 15.6% of WT1 and 2.9% of NPHS2 cases (P<0.001). Whereas 47% of WT1 and 36% of NPHS2 patients progressed to ESRD before reaching 10 years of age, ESRD occurred almost exclusively in the second decade of life in ADCK4 nephropathy (Figure 1). However, CKD progression was much faster during adolescence in ADCK4 than in WT1 and NPHS2 nephropathy, resulting in similar cumulative ESRD rates (>85%) for the three genetic forms of SRNS in the third decade of life. Neurologic deficits were more frequent in ADCK4 disease. Renal and urinary tract malformations occurred almost exclusively in WT1. Other congenital anomalies, mostly heart structural defects, were anecdotally reported in all groups.
Figure 1.
Age at attainment of ESRD by genetic cause of glomerulopathy. Thirty-five patients with ADCK4 glomerulopathy (current series plus nine previously published cases6), 140 cases of NPHS2-associated SRNS and 66 cases of WT1-associated SRNS from PodoNet Registry.8,9
Immunosuppressive therapy was applied in 11 cases, of which only in two siblings an apparent partial initial response to oral steroids was reported. One patient progressed to ESRD at age 14 years, where-as the other is still on conservative therapy 8 years after diagnosis of SRNS and is currently on cyclosporin and angiotensin-converting enzyme inhibition, with persistent proteinuria of 2.5 g/m2 per day. Two patients were diagnosed while still being asymptomatic with only minimal proteinuria and normal kidney function, thanks to the identification of ADCK4 mutations in older siblings with established CKD. These subjects were started on CoQ10 supplementation soon after diagnosis and demonstrated a decrease of proteinuria by 50% and 80%, respectively, within 6 weeks of treatment (Figure 2, Supplemental Materials).
Figure 2.
Changes in albuminuria after starting CoQ10 supplementation in patients with early-stage ADCK4 glomerulopathy. Changes shown for two subjects detected in the asymptomatic early stage of the disease as a result of our study (further presented in Supplemental Material).
Our assembly and detailed phenotypic characterization of the largest ADCK4 nephropathy cohort to date allowed us to demonstrate or corroborate several features that make ADCK4 disease unique among the hereditary glomerulopathies in general and among those related to mitochondrial dysfunction in particular. In patients with mutations in PDSS2, COQ2, and COQ6, the other mitochondriopathy genes associated with SRNS, renal symptoms usually occur as part of a multisystemic disease complex encompassing progressive encephalopathy, ataxia, seizures, mental retardation, deafness, retinopathy, hypertrophic cardiomyopathy, and generalized myopathy.1–5,10 By contrast, ADCK4 disease typically manifests as an isolated nephropathy with only occasional extrarenal symptomatology. Combining our cohort with five previously published cases with available data on extrarenal involvement,6 we oversee 30 patients from 17 families with detailed phenotypic information. Among these, 15 patients (50%) never showed any extrarenal system involvement. Three patients presented seizures (thereof two while on dialysis), and two patients each had mild mental retardation and behavioral problems. Two cases of goiter and single cases of retinitis pigmentosa and a lupus-like syndrome were reported. Occasionally observed transient mild elevations of lactate and creatine kinase during AKI are of questionable specificity and relevance.
Hence, within the wide spectrum of mitochondrial disorders ADCK4 mutations lead to the most selective glomerular involvement, possibly related to preferential enrichment of ADCK4 in podocytes. The cytosolic as well as mitochondrial localization of ADCK4 protein in podocytes has led to speculation that ADCK4 may exert additional functions other than CoQ10 biosynthesis.6 Notwithstanding the preferential renal phenotype, patients diagnosed with ADCK4 nephropathy should undergo systematic and repeated screening for subclinical extrarenal symptoms.
Our systematic screening of more than 500 prospective SRNS cases suggests that ADCK4 nephropathy may be the third most common hereditary cause of SRNS, with a detection rate of one in 50 patients compared with one in eight for NPHS28 and one in 18 for WT1.9 The renal phenotype of ADCK4 disease is characterized by an insidious onset at adolescence with mild to moderate proteinuria and absence of relevant edema in the majority of cases. As a consequence of the oligosymptomatic early course, advanced CKD is often present at the time of diagnosis. The comparison of renal survival of patients with ADCK4, WT1, and NPHS2 glomerulopathies respectively demonstrates the unusual evolution of renal function in the mitochondriopathy, with almost all patients progressing to ESRD between 12 and 23 years of age. Hence, at the current stage of knowledge SRNS progressing toward ESRD in the first decade of life almost rules out ADCK4 disease, whereas ADCK4 nephropathy is an important differential diagnosis to consider in cases of adolescent-onset multidrug-resistant proteinuria with FSGS on biopsy. In this group, where genetic causes are found in less than 10% of cases by conventional screening,11,12 mutations in ADCK4 may be as common as those in NPHS2 and WT1. Of course, the experience derived from the first two disease cohorts comprising patients from 20 families with 15 different mutations is still limited. It remains to be seen whether the sug-gested detection rate will be confirmed and whether the uniform disease pattern will diversify with the identification of more patients and mutations.
The CoQ10 glomerulopathies represent the first hereditary forms of SRNS for which a causative molecular therapy is potentially available. Oral CoQ10 supplementation may reverse proteinuria and stabilize kidney function if applied early in the disease course.5,6,10,13 The commonly late diagnosis of ADCK4 disease so far has precluded efficient therapy in most affected patients. This situation may change in the near future with earlier diagnosis thanks to increased awareness of the disease entity, inclusion of the mitochondrial genes in routinely performed next generation sequencing (NGS) panel screening, and proteinuria screening of asymptomatic siblings of affected patients as accomplished in two children in this report. Both subjects indeed demonstrated a significant decrease of proteinuria on CoQ10 supplementation, raising hopes that timely treatment may preserve podocyte and kidney function in children with ADCK4 nephropathy.
Based on the preliminary evidence presented here, we propose to perform ADCK4 sequencing, ideally as part of NGS panel screening, in all patients with adolescent-onset proteinuric kidney disease in whom autoimmune etiologies have been ruled out on clinical and biochemical grounds. Genetic screening should be prioritized over kidney biopsy, particularly in cases of familial disease occurrence or parental consanguinity.
In conclusion, ADCK4 glomerulopathy is a novel cause of adolescent-onset SRNS caused by defective CoQ10 biosynthesis in podocytes. This recessive Mendelian disease may present with signs and symptoms of systemic mitochondrial dysfunction, but more often manifests as isolated FSGS. Despite the late clinical manifestation, rapid progression to end-stage renal disease is common. Early diagnosis will help to identify children at early disease stages who are eligible for oral CoQ10 supplementation.
Concise Methods
ADCK4 screening was performed in 534 consecutive SRNS patients from the PodoNet Registry and in-house biobanks at Nec-ker Hospital in Paris, France, the Hacettepe University Nephrogenetics Laboratory, Ankara, Turkey, and the Molecular Genetics Unit at Bioscientia, Ingelheim, Germany. Clinical information was available for 349 patients, including 233 unrelated patients negative for mutations in the first-line SRNS-associated genes (NPHS2, exons 8–9 of WT1) and 116 not previously tested individuals.
The PodoNet, Necker, and Bioscientia cohorts underwent high-throughput sequencing using custom-designed multi-gene NGS panels for FSGS and related glomerulopathies. Sequencing was performed using the MiSeq/HiSeq platform (Illumina, San Diego, CA). All findings were verified by Sanger sequencing, which was also used to test eligible family members.
Comparator cohorts with SRNS related to mutations in NPHS2 (n=140) or WT1 (n=66) were extracted from the PodoNet Registry.8,9
Whole-genome linkage analysis using 250K single nucleotide polymorphism array (Affymetrix, Santa Clara, CA) followed by homozygosity mapping using VIGENOS software was performed in two index families (Supplemental Figure 1: Families I and II). Illumina TruSeq Exome Enrichment Kit was used for paired-end whole exome sequencing performed on an Illumina HiSeq 2000 sequencing system (Illumina, San Diego, CA).
Detailed clinical information on renal and extrarenal symptoms was obtained on all ADCK4 patients by way of a standardized questionnaire. The patient-level data are given in Supplemental Table 1. Statistical analyses were performed using the STATISTICA 9.1 (StatSoft; Tulsa, OK) data analysis software system.
Disclosures
None.
Supplementary Material
Acknowledgments
The research leading to these results has received funding from the European Community’s Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 2012-305608 (EURenOmics), from Bundesministerium für Bildung und Forschung (BMBF) through the e-Rare initiative (PodoNet), the Polish Ministry of Science and Education (grant N402631840). F.O. was supported by the Scientific and Technological Research Council of Turkey (grant 108S417) and by the Hacettepe University Infrastructure Projects (grant 06A101008 and 011A101003).
Footnotes
Published online ahead of print. Publication date available at www.jasn.org.
This article contains supplemental material online at http://jasn.asnjournals.org/ lookup/suppl/doi:10.1681/ASN.2014121240/-/DCSupplemental.
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