Clinical management of a granulomatous tubulointerstitial nephritis associated with a bilateral granulomatous anterior uveitis: A challenging case report and review of the literature.

Acute granulomatous tubulointerstitial nephritis (GTIN) is a rare finding in renal biopsy. Differential diagnosis is facilitated when GTIN is associated with granulomatous bilateral anterior uveitis (GBAU). Nevertheless, differentiation between a rare form of granulomatous tubulointerstitial nephritis and uveitis syndrome (TINU) and sarcoidosis can be challenging. We report a case of biopsy-proven GTIN with concomitant GBAU, leading to a dead-end diagnosis. We discuss workup and propose a diagnostic algorithm based on a literature review. We also report a successful treatment of ophthalmologic and renal relapse using mycophenolate mofetil.

5-Year outcomes of the prospective and randomized CISTCERT study comparing steroid withdrawal to replacement of cyclosporine with everolimus in de novo kidney transplant patients.

Withdrawal of either steroids or calcineurin inhibitors are two strategies to reduce treatment-related side effects and improve long-term outcomes of kidney transplantation. The CISTCERT study compared the efficacy and safety of these two strategies. In this multicenter, randomized controlled trial, 151 incident kidney transplant recipients received cyclosporine (CsA), mycophenolic acid (MPA), and steroids during three months, followed by either steroid withdrawal (CsA/MPA) or replacement of cyclosporine with everolimus (EVL) (EVL/MPA/steroids). 5-year patient survival (89% vs. 86%; P = NS) and death-censored graft survival (95% vs. 96%; P = NS) were comparable in the CsA/MPA and EVL/MPA/steroids arm, respectively. 51 CrEDTA clearance was comparable in the intention-to-treat analysis, but in the on-treatment population, the EVL/MPA/steroids arm exhibited a superior 51 CrEDTA clearance at 1 and 5 years after transplantation (61.6 vs. 52.4, P = 0.05 and 59.1 vs. 46.2ml/min/1.73 m2 , P = 0.042). Numerically more and more severe rejections were observed in the EVL/MPA/steroids arm, which also experienced a higher incidence of posttransplant diabetes (26% vs. 6%, P = 0.0016) and infections. No significant differences were observed in cardiovascular outcomes and malignancy. Both regimens provide an excellent long-term patient survival and graft survival. Regarding graft function, EVL/MPA/steroids is an attractive strategy for patients with good tolerability who remain free of rejection. (ClinicalTrials.gov number: NCT00903188; EudraCT Number 2007-005844-26).

Bony palmar ridges of the phalanges of the human fingers.

PURPOSE: On imaging studies, bony ridges can be seen at the palmar aspect of the phalanges of the fingers. Our purpose was to address the following: (1) which structures insert on to the ridges and what is the histological appearance? (2) Is there a difference between the different fingers? (3) Is there a correlation between the ridges and age? MATERIALS AND METHODS: Two observers retrospectively evaluated 270 radiographs (135 men; 135 women; mean age 44 years), and 33 CT scans (22 men; 11 women; mean age 46 years). Three cadaveric hands were also studied. The ridges were graded using a 4-point scale. A Chi-square test was used to compare the different fingers (p < 0.05) and to study the prominence of the ridges in relation to age (p < 0.05). RESULTS: On histology with routine stains the A2 pulley was inserted on the ridges of the proximal phalanx, and the flexor superficialis and A4 pulley on the ridges of the middle phalanx. On histology, the insertion showed a transition zone consisting of fibrocartilage. The prominence of the ridges was significantly different between fingers with III and IV categorized higher than II and III. There was a significant correlation with age for all fingers except for the middle phalanx of II and III. CONCLUSION: The bony palmar ridges have characteristics of enthesophytes. They correspond to the insertion site of the A2 pulley, and the flexor superficialis tendon and A4 pulley, at the proximal and middle phalanx, respectively. The ridges become more prominent with age, and their prominence is different between the fingers with III and IV categorized higher than II and V.

Unraveling the spectrum of inflammatory myofibroblastic tumors in the lung: A comprehensive case series highlighting endobronchial, pleural, and lung parenchymal tumors.

Objectives: Diverse cases of inflammatory myofibroblastic tumors (IMTs) in the lung (pleural, endobronchial, and parenchymal) are presented while discussing the (preoperative) diagnostic challenges and treatment modalities. Other objectives include emphasizing the significance of gene rearrangements and highlighting the multidisciplinary approach in addressing IMTs. Methods: Four cases of IMT in the lung are presented, including a young adolescent girl with an ETV6-neurotrophic tyrosine receptor kinase 3 (NTRK3) gene rearrangement, a 5-year-old boy with challenging preoperative diagnosis, and 2 middle-aged women with respectively pleural and endobronchial tumors with one peribronchial relapse. Results: The cases demonstrate the diverse clinical presentations and diagnostic complexities associated with IMT in the lung. Surgical resection remains the primary treatment modality, with complete resection leading to a cure in most patients. Unfortunately, aggressive relapse can occur, as in our last case of an endobronchial tumor. Frozen section may confirm the presence of malignant cells perioperatively and impact further treatment. The presence of gene rearrangements, such as ETV6-NTRK3, suggests potential therapeutic implications. Conclusions: Early detection and complete surgical removal of IMT are crucial for effective treatment. Identifying gene rearrangements such as ETV6-NTRK3 holds promise for targeted therapies. Diagnostic challenges, including the controversy of biopsies and preoperative evaluations, underscore the importance of a multidisciplinary approach. Anatomopathological recognition of IMT stays demanding. Close surveillance is necessary due to potential relapse, whereas frozen section perioperatively can help further treatment. This case series emphasizes the diagnostic challenges and therapeutic considerations for IMT in the lung.

Comparison of trichostatin A and valproic acid treatment regimens in a mouse model of kidney fibrosis.

Histone deacetylase (HDAC) inhibitors are promising new compounds for the therapy of fibrotic diseases. In this study we compared the effect of two HDAC inhibitors, trichostatin A and valproic acid, in an experimental model of kidney fibrosis. In mice, doxorubicin (adriamycin) can cause nephropathy characterized by chronic proteinuria, glomerular damage and interstitial inflammation and fibrosis, as seen in human focal segmental glomerulosclerosis. Two treatment regimens were applied, treatment was either started prior to the doxorubicin insult or delayed until a significant degree of proteinuria and fibrosis was present. Pre-treatment of trichostatin A significantly hampered glomerulosclerosis and tubulointerstitial fibrosis, as did the pre-treatment with valproic acid. In contrast, the development of proteinuria was only completely inhibited in the pre-treated valproic acid group, and not in the pre-treated trichostatin A animals. In the postponed treatment with valproic acid, a complete resolution of established doxorubicin-induced proteinuria was achieved within three days, whereas trichostatin A could not correct proteinuria in such a treatment regimen. However, both postponed regimens have comparable efficacy in maintaining the kidney fibrosis to the level reached at the start of the treatments. Moreover, not only the process of fibrosis, but also renal inflammation was attenuated by both HDAC inhibitors. Our data confirm a role for HDACs in renal fibrogenesis and point towards a therapeutic potential for HDAC inhibitors. The effect on renal disease progression and manifestation can however be different for individual HDAC inhibitors.

Scleroderma renal crisis triggered by ibuprofen: Insights on complement-directed therapy.

Scleroderma renal crisis is a severe complication of systemic sclerosis with a poor prognosis. Therefore, identifying precipitating factors is essential. Among known risk factors, only few are reversible. On the contrary, anti-C5 therapy appears effective, at least in some cases. We describe a 59-year-old man with diffuse cutaneous systemic sclerosis who developed life-threatening scleroderma renal crisis following ibuprofen administration. Despite aggressive management, he did not improve. Renal biopsy have displayed features of thrombotic microangiopathy but no complement deposition. We then discuss the pathomechanism of scleroderma renal crisis that could drive eculizumab treatment since some renal biopsies exhibit complement deposits and others do not.

Valproic acid attenuates proteinuria and kidney injury.

Inhibitors of histone deacetylase (HDAC) have anti-inflammatory and antifibrotic effects in several organs and tissues, but their effect on the progression of renal disease is unknown. Here, we studied the effect of valproic acid in adriamycin-induced nephropathy in mice. Administration of valproic acid before kidney injury prevented the development of proteinuria and the onset of glomerulosclerosis. Even after postponing treatment until the peak of adriamycin-induced proteinuria, valproic acid rapidly decreased the quantity of proteinuria and attenuated the progression of renal disease. Valproic acid abrogated the decrease in glomerular acetylation observed during adriamycin-induced nephropathy. Furthermore, valproic acid attenuated the significant upregulation of profibrotic and proinflammatory genes, the deposition of collagen, and the infiltration of macrophages into the kidney. Valproic acid decreased glomerular apoptosis and proliferation induced by adriamycin. Ultrastructural studies further supported the protective effect of valproic acid on podocytes in this model. Taken together, these data suggest that HDACs contribute to the pathogenesis of renal disease and that HDAC inhibitors may have therapeutic potential in CKD.

Kidney Stones, Proteinuria and Renal Tubular Metabolic Acidosis: What Is the Link?

Kidney stone disease represents a rare cause of chronic kidney disease (2−3%) but has severe clinical consequences. Type 1 renal tubular acidosis is a strong lithogenic condition mainly related to primary Sjögren syndrome. This study aimed to illustrate an unusual presentation of Sjögren syndrome to improve the knowledge about rare kidney stone diseases, and to provide clues for the diagnostic approach in this specific condition. We report the case of a 35-year-old Indian woman with severe nephrocalcinosis and chronic kidney disease with tubular proteinuria who presented for metabolic assessment. We found advanced chronic kidney disease, low serum bicarbonate, permanent alkaline urine with pH at ~7.1, and severe hypocitraturia corresponding to type 1 renal tubular acidosis. The erythrocyte sedimentation rate was high. Serological screening for HAV, HBV, HCV, HIV, EBV was negative and complement was normal. Autoimmune screening showed antinuclear antibodies (>1/1.280) with anti-SSA, anti-SSA/Ro52 and anti-SSB antibodies. Genetic testing excluded an inherited cause of renal tubular acidosis. A renal biopsy showed moderate chronic tubulo-interstitial nephritis without any glomerular involvement. Primary Sjögren syndrome with significant renal involvement was considered, and corticosteroids were then subsequently initiated in combination with potassium citrate with vitamin D substitution. Only partial improvement was observed in electrolytes disturbance. After 15 months, her renal function remained stable. In conclusion, nephrocalcinosis could be the first manifestation of severely impacting diseases such as primary Sjögren syndrome. Chronic kidney disease, bilateral nephrocalcinosis, and metabolic acidosis can be linked through type 1 renal tubular acidosis. Therefore, autoimmune screening for Sjögren syndrome should be considered in such cases.

Case Report: Homozygous Pathogenic Variant P209L in the TTC21B Gene: A Rare Cause of End Stage Renal Disease and Biliary Cirrhosis Requiring Combined Liver-Kidney Transplantation. A Case Report and Literature Review.

Background: Ciliopathies are rare diseases causing renal and extrarenal manifestations. Here, we report the case of a ciliopathy induced by a homozygous pathogenic variant in the TTC21B gene. Case Description: A 47-year-old patient started hemodialysis for chronic kidney disease (CKD) of unknown origin. She presented with early onset of hypertension, pre-eclampsia, myopia and cirrhosis. Renal biopsy showed mild interstitial fibrosis, tubular atrophy, and moderate arteriosclerosis while liver pathology demonstrates grade B biliary cirrhosis. Family history revealed several cases of early-onset severe hypertension and one case of end-stage renal disease (ESRD) needing kidney transplantation at twenty years of age. Clinical exome sequencing showed homozygosis for the pathogenic variant c.626C>T (p.Pro209Leu) in the TTC21B gene. The patient underwent combined liver-renal transplantation with an excellent renal and hepatic graft outcome. Conclusions: TTC21B gene mutations can lead heterogeneous to clinical manifestations and represent an underappreciated cause of ESRD. The paradigm in diagnosis of CKD of early onset and/or of unknown origin is changing and genetic counseling should be performed in all patients and families that meet those criteria. Renal or combined liver-renal transplantation represents the best option for patients suffering from those diseases in terms of prognosis and quality of life.

Encrusted Uropathy: A Comprehensive Overview-To the Bottom of the Crust.

Encrusted uropathy is a rare subacute to chronic inflammatory disorder caused by infection with urease-producing bacteria, mainly Corynebacterium urealyticum. The disorder is characterized by urothelial deposition of struvite and carbonated apatite, resulting in encrustations and ulceronecrotic inflammation of the urothelium and surrounding tissues. Most commonly, encrusted uropathy is encountered in patients with predisposing conditions. The disease remains underdiagnosed. High urinary pH and negative conventional urine cultures should raise suspicion of the diagnosis. Prognosis is dependent on timely diagnosis and treatment installment, which consists of urological removal of encrustations in combination with urinary acidification and long-term antibiotic therapy.

CRBP-I in the renal tubulointerstitial compartment of healthy rats and rats with renal fibrosis.

BACKGROUND: Cellular retinol-binding protein I (CRBP-I), a member of the intracellular lipid-binding protein (iLBP) superfamily, is a specific marker of quiescent stellate cells in the healthy human liver. In the diseased fibrotic/cirrhotic liver, portal and septal myofibroblasts acquire CRBP-I expression, while activated hepatic stellate cells maintain their CRBP-I expression. Here, we investigate the distribution of CRBP-I in the renal cortex of healthy rats and rats with renal fibrosis. METHODS: Kidneys of healthy and adriamycin-treated rats were studied by immunohistochemistry, using antibodies against CRBP-I, desmin, vimentin and alpha-smooth muscle actin (alpha-SMA). Double stainings were done with immunofluorescence. Western blotting was performed to semi-quantify the expression levels of vimentin, desmin, alpha-SMA and CRBP-I. RESULTS: In the normal rat kidney, the convoluted proximal tubular epithelial cells express CRBP-I; no expression is found in the interstitium, nor in the glomeruli. In the adriamycin-induced fibrotic rat kidney, CRBP-I expression diminishes in the convoluted proximal tubular epithelial cells, whereas peritubular myofibroblasts in the interstitium acquire CRBP-I expression. CONCLUSIONS: In the tubulointerstitial compartment of the adriamycin-induced fibrotic rat kidney, CRBP-I is expressed in a different pattern than in the healthy rat kidney. As the convoluted proximal tubular epithelial cells dedifferentiate during fibrosis, CRBP-I expression decreases. Furthermore, de novo expression of CRBP-I is found in activated myofibroblast-like cells in the interstitium of adriamycin-treated rats. CRBP-I is therefore a useful marker to identify a subpopulation of activated/ myodifferentiated fibroblasts in the rat kidney.

Solid and pseudopapillary tumor of the pancreas--review and new insights into pathogenesis.

Solid pseudopapillary tumors (SPT) of the pancreas are rare neoplasms that occur mostly in young women. Despite of a low malignant potential, 10% to 15% of the cases have aggressive behavior with metastatic dissemination possibly leading to death. To date, no pathological factor can reliably predict the outcome of these tumours. Galectin-3, a major actor in the carcinogenesis of pancreatic ductal adenocarcinoma, has not been investigated in SPT. The presence of progesterone receptors is frequently reported in SPT, whereas that of estrogen receptor (ER) is unclear. We studied 5 cases of SPT consisting of 4 pancreatic tumors and 1 metastatic case. The morphological distinctive feature of metastatic nodules was the presence of polygonal or spindle cells with pleiomorphic nuclei and high mitotic count exhibiting a diffuse, infiltrative growth pattern. We found a strong expression of galectin-3 in all SPTs, whereas, interestingly, it was lower in metastatic nodules. Conversely, no galectin-3 expression was found in normal pancreatic endocrine cells or in neuroendocrine tumors. We suggest therefore that galectin-3 is a useful marker to distinguish SPT from neuroendocrine tumor, and also indicator of behavior because its low expression is associated with metastatic spreading. Moreover, the presence of galectin-3 in both SPT and pancreatic ducts rises the hypothesis of a posible ductal origin of these tumors. Specific antibodies for anti-ERalpha and anti-ERbeta demonstrated a strong expression of ERbeta whereas ERalpha was not detected. In conclusion, the present study brings the first evidence of the involvement of galectin-3 in SPT but also brought up clues which allowed to reconcile previously conflicting results on the presence of ER.

Identification of a novel HER3 activating mutation homologous to EGFR-L858R in lung cancer.

Somatic mutations found within the tyrosine kinase domain (TKD) of the human epidermal growth factor (HER) family of receptors have been implicated in the development and progression of non-small cell lung cancer (NSCLC). However, no conclusive reports have described pathogenic mutations in kinase-impaired HER3. Here, we report a case of an advanced chemotherapy-resistant NSCLC, harboring a novel HER3(V855A) somatic mutation homologous to the EGFR(L858R)activating mutation. Co-expression of HER3(V855A) and wild-type HER2 enhances ligand-induced transformation of murine and human cell lines, while HER-targeted inhibitors potently suppress mutant HER3 activity. Consistent with these observations, in silico computational modeling predicts that mutant V855A alters the kinase domain and c-terminal end of the HER3 protein. Taken together, these findings provide a basis for the clinical exploration of targeted therapies in HER3 mutant NSCLC and by extrapolation, in other cancers that more frequently carry somatic HER3 mutations.

Prospective Evaluation of First-Line Erlotinib in Advanced Non-Small Cell Lung Cancer (NSCLC) Carrying an Activating EGFR Mutation: A Multicenter Academic Phase II Study in Caucasian Patients (FIELT).

INTRODUCTION: Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibition is the preferred first-line treatment of advanced adenocarcinoma of the lung that harbors EGFR activating tyrosine kinase domain mutations. Most data available pertain to Asian populations in which such mutations are more prevalent. We report on the long-term results of first-line treatment with erlotinib in Caucasian patients with advanced adenocarcinoma of the lung that have a somatic EGFR mutation in their tumor. METHODS: Multicenter academic prospective phase II study with erlotinib in patients with an activating EGFR tyrosine kinase (TK) domain somatic mutation (any exon encoding the kinase domain) in the tumor and no prior treatment for their advanced disease. RESULTS: Phenotypic preselecting of 229 patients led to a high EGFR mutation detection rate of 24% of which 46 patients were included in the phase II study. With a progression free survival (PFS) of 81% at three months the study met its primary endpoint for presumed superiority over chemotherapy. With an overall median PFS of 11 months and a median overall survival (OS) of 23 months, the results compare favorably with results obtained in randomized studies using TKI in first line in EGFR mutation positive adenocarcinoma of the lung. CONCLUSION: The present study reinforces the use of EGFR tyrosine kinase inhibition (TKI) as a first line treatment of choice for advanced adenocarcinoma of the lung carrying an activating EGFR mutation. The mutation rate in preselected Caucasian patients is higher than previously reported. Issues relevant for clinical practice are discussed. TRIAL REGISTRATION: ClinicalTrials.gov NCT00339586.

Pulmonary Limited MPO-ANCA Microscopic Polyangiitis and Idiopathic Lung Fibrosis in a Patient with a Diagnosis of IgA Nephropathy.

We present a case of a male patient with chronic renal insufficiency, due to crescentic glomerulonephritis with IgA deposits, who successively developed (idiopathic) thrombocytopenic purpura (ITP) and MPO-ANCA microscopic polyangiitis (MPA) with pulmonary fibrosis. The patient presented with cough, weight loss, and dyspnea on exertion. CT imaging and pulmonary function tests were compatible with interstitial pneumonitis with pulmonary fibrosis. Laboratory results showed high MPO-ANCA titers; the urinary sediment was bland. The patient was treated successfully with cyclophosphamide and methyl-prednisolone. This unique case illustrates the diagnostic and therapeutic challenges of an unusual presentation of microscopic polyangiitis presenting first as isolated kidney disease with recurrence in the form of pneumonitis without renal involvement, in association with renal IgA deposits and ITP as coexisting autoimmune conditions.

Detection of EGFR-TK domain-activating mutations in NSCLC with generic PCR-based methods.

Somatic mutations in the epidermal growth factor receptor-tyrosine kinase (EGFR-TK) domain of non-small cell lung cancer (NSCLC) influence the responsiveness of these tumors to EGFR-TK inhibitors, indicating their usefulness as a predictive molecular marker. However, for mutation analysis, the amount of clinical material available from NSCLC patients is often very limited, suboptimally preserved, and composed of both normal and tumor cells. As a consequence, the total amount of recovered DNA is frequently very limited, with mutant alleles being often strongly underrepresented, and thus requiring highly sensitive methods for the detection of mutations. In the present study, EGFR mutation screening was performed on 210 NSCLC clinical samples by heminested polymerase chain reaction (PCR), followed by denaturing gradient gel electrophoresis (DGGE). Candidate mutations were further characterized by sequencing. Seventeen different types of pathogenic EGFR-TK domain mutations were detected in 55 of the 210 samples (26%). We reanalyzed 149 of the 155 samples in which no mutation was found by real-time PCR for the presence of recurrent exon 21 and exon 19 mutations using peptide nucleic acid probes in the PCR mix to increase sensitivity by mutant allele enrichment. Four additional samples with exon 19 mutations were detected. Thus, it is found that the relatively simple and inexpensive PCR-DGGE assay is already very sensitive for the detection of mutations in clinical samples, including samples with low tumor cellularity (10% or higher tumor cell content), although the sensitivity and speed of the assay can be further increased for a restricted panel of mutations by introducing peptide nucleic acid probes in the DGGE or real-time PCR-based assay.

Polygonal deformation of the dural sac in lumbar epidural lipomatosis: anatomic explanation by the presence of meningovertebral ligaments.

BACKGROUND AND PURPOSE: In patients with epidural lipomatosis, axial lumbar spine CT and MR images occasionally reveal a geometric, polygonal or stellar, shape of the dural sac. The purpose of this study was to define the anatomic structures responsible for this radiologic appearance. We hypothesized that meningovertebral ligaments could anchor the dura mater to the osteofibrous walls of the spinal canal and account for the geometric deformation of the dural sac. METHODS: The epidural spaces were examined in 15 adult cadaveric and seven aborted fetal lumbar spines. For macroscopic studies, 70 adult vertebral segments were separated and dissected by removing the extradural fat. For microscopic examination, axial histologic sections were obtained from 35 fetal and five adult undissected vertebral segments. RESULTS: Meningovertebral ligaments were observed in the median, paramedian, and lateral aspects of the anterior and posterior epidural spaces of both adult and fetal lumbar spines. These ligaments anchor the outer surface of the dura mater to the osteofibrous walls of the lumbar canal. They may form an irregular longitudinal septum partitioning the epidural space. Histologic examination demonstrated the fibroelastic composition of these ligaments and suggested their possible perivascular morphogenetic origin. CONCLUSION: The morphologic and topographic features of the meningovertebral ligaments explain the polygonal, stellar, or Y-shaped deformation of the dural sac observed on axial CT and MR images in patients with lumbar epidural lipomatosis.

miR-146a inhibits cell growth, cell migration and induces apoptosis in non-small cell lung cancer cells.

Aberrant expression of microRNA-146a (miR-146a) has been reported to be involved in the development and progression of various types of cancers. However, its role in non-small cell lung cancer (NSCLC) has not been elucidated. The aim of this study was to investigate the contribution of miR-146a to various aspects of the malignant phenotype of human NSCLCs. In functional experiments, miR-146a suppressed cell growth, induced cellular apoptosis and inhibited EGFR downstream signaling in five NSCLC cell lines (H358, H1650, H1975, HCC827 and H292). miR-146a also inhibited the migratory capacity of these NSCLC cells. On the other hand, miR-146a enhanced the inhibition of cell proliferation by drugs targeting EGFR, including both TKIs (gefitinib, erlotinib, and afatinib) and a monoclonal antibody (cetuximab). These effects were independent of the EGFR mutation status (wild type, sensitizing mutation or resistance mutation), but were less potent compared to the effects of siRNA targeting of EGFR. Our results suggest that these effects of miR-146a are due to its targeting of EGFR and NF-κB signaling. We also found, in clinical formalin fixed paraffin embedded (FFPE) lung cancer samples, that low expression of miR-146a was correlated with advanced clinical TNM stages and distant metastasis in NSCLC (P<0.05). The patients with high miR-146a expression in their tumors showed longer progression-free survival (25.6 weeks in miR-146a high patients vs. 4.8 weeks in miR-146a low patients, P<0.05). miR-146a is therefore a strong candidate prognostic biomarker in NSCLC. Thus inducing miR-146a might be a therapeutic strategy for NSCLC.

Early myoclonic epilepsy, hypertrophic cardiomyopathy and subsequently a nephrotic syndrome in a patient with CoQ10 deficiency caused by mutations in para-hydroxybenzoate-polyprenyl transferase (COQ2).

BACKGROUND: Primary coenzyme Q10 (CoQ10) deficiencies are heterogeneous autosomal recessive disorders. CoQ2 mutations have been identified only rarely in patients. All affected individuals presented with nephrotic syndrome in the first year of life. METHODS: An infant is studied with myoclonic seizures and hypertrophic cardiomyopathy in the first months of life and developed a nephrotic syndrome in a later stage. RESULTS: At three weeks of age, the index patient developed myoclonic seizures. In addition, he had hypertrophic cardiomyopathy and increased CSF lactate. A skeletal muscle biopsy performed at two months of age disclosed normal activities of the oxidative phosphorylation complexes. The child was supplemented with CoQ10 (5 mg/kg/day). At the age of four months, brain MR images showed bilateral increased signal intensities in putamen and cerebral cortex. After that age, he developed massive proteinuria. The daily dose of CoQ10 was increased to 30 mg/kg. Renal biopsy showed focal segmental glomerulosclerosis. Biochemical analyses of a kidney biopsy sample revealed a severely decreased activity of succinate cytochrome c reductase [complex II + III] suggesting ubiquinone depletion. Incorporation of labelled precursors necessary for CoQ10 synthesis was significantly decreased in cultured skin fibroblasts. His condition deteriorated and he died at the age of five months. A novel homozygous mutation c.326G > A (p.Ser109Asn) was found in COQ2. CONCLUSIONS: In contrast to previously reported patients with CoQ2 the proband presented with early myoclonic epilepsy, hypertrophic cardiomyopathy and only in a later stage developed a nephrotic syndrome. The phenotype of this patient enlarges the phenotypical spectrum of the multisystem infantile variant.