Mitochondria-related neurodegenerative diseases have been implicated in the disruption of primary cilia function. Mutation in an intrinsic mitochondrial complex I component NDUFAF2 has been identified in Leigh syndrome, a severe inherited mitochondriopathy. Mutations in ARMC9, which encodes a basal body protein, cause Joubert syndrome, a ciliopathy with defects in the brain, kidney, and eye. Here, we report a mechanistic link between mitochondria metabolism and primary cilia signaling. We discovered that loss of NDUFAF2 caused both mitochondrial and ciliary defects in vitro and in vivo and identified NDUFAF2 as a binding partner for ARMC9. We also found that NDUFAF2 was both necessary and sufficient for cilia formation and that exogenous expression of NDUFAF2 rescued the ciliary and mitochondrial defects observed in cells from patients with known ARMC9 deficiency. NAD+ supplementation restored mitochondrial and ciliary dysfunction in ARMC9-deficient cells and zebrafish and ameliorated the ocular motility and motor deficits of a patient with ARMC9 deficiency. The present results provide a compelling mechanistic link, supported by evidence from human studies, between primary cilia and mitochondrial signaling. Importantly, our findings have significant implications for the development of therapeutic approaches targeting ciliopathies.

Spontaneous renal cyst hemorrhage is one of the clinical emergencies in peritoneal dialysis (PD) patients and is potentially life-threatening. The main complaints are sudden low back pain, paleness, and hypotensive shock with or without vomiting or fever. In contrast to inherited polycystic kidney disease, acquired cystic kidney disease (ACKD) secondary to chronic kidney disease is easily overlooked or delayed in clinical diagnosis and treatment, leading to severe clinical outcomes. We report three patients with spontaneous hemorrhage of ACKD in the peritoneal dialysis center at Peking University First Hospital. The common features are as follows, long history of dialysis, mild to severe low back pain, decrease in hemoglobulin, negative PD solutions, diagnosis established through computed tomography (CT), and continuing PD during treatment of ACKD hemorrhage. Treatments vary from conservative to unilaterally selective renal artery embolization. In this study, ACKD morbidity was investigated in PD patients. A total of 316 patients who had an abdominal ultrasound, CT, or magnetic resonance imaging (MRI) in the past 1 year were enrolled. Among them, 103 cases (32.9%) met the diagnostic criteria of ACKD. The morbidity rates were 27.5%, 37.8%, 43.8%, 59.1%, and 88.6%, when the dialysis history ranged from ≤3, >3 & ≤5, >5 & ≤7, >7 & ≤9, >9 years, respectively, showing a increasing trend. Most ACKD hemorrhages could be healed and got an acceptable prognosis after treatment, including rest, blood transfusion, selective renal artery embolization, or nephrectomy. We summarize the risk factors, including a long history of dialysis, anticoagulation or antiplatelet, and inflammation or stones of the urinary system, but with no difference in initial kidney diseases and gender. ACKD hemorrhage mainly includes intracapsular hemorrhage, cyst rupture, and spontaneous retroperitoneal hemorrhage. In addition, we also recommend an adaptive process for spontaneous kidney hemorrhage of diagnosis and treatment in peritoneal dialysis patients. The significance of these cases lies in the fact that patients with ACKD are potentially associated with complications such as cyst hemorrhage and malignancy. Thus, peritoneal dialysis physicians should place great importance on the surveillance of ACKD.

Tuberous sclerosis complex (TSC) presents with renal cysts and benign tumors, which eventually lead to kidney failure. The factors promoting kidney cyst formation in TSC are poorly understood. Inactivation of carbonic anhydrase 2 (Car2) significantly reduced, whereas, deletion of Foxi1 completely abrogated the cyst burden in Tsc1 KO mice. In these studies, we contrasted the ontogeny of cyst burden in Tsc1/Car2 dKO mice vs. Tsc1/Foxi1 dKO mice. Compared to Tsc1 KO, the Tsc1/Car2 dKO mice showed few small cysts at 47 days of age. However, by 110 days, the kidneys showed frequent and large cysts with overwhelming numbers of A-intercalated cells in their linings. The magnitude of cyst burden in Tsc1/Car2 dKO mice correlated with the expression levels of Foxi1 and was proportional to mTORC1 activation. This is in stark contrast to Tsc1/Foxi1 dKO mice, which showed a remarkable absence of kidney cysts at both 47 and 110 days of age. RNA-seq data pointed to profound upregulation of Foxi1 and kidney-collecting duct-specific H+-ATPase subunits in 110-day-old Tsc1/Car2 dKO mice. We conclude that Car2 inactivation temporarily decreases the kidney cyst burden in Tsc1 KO mice but the cysts increase with advancing age, along with enhanced Foxi1 expression.

The evolving landscape of clinical genetics is becoming increasingly relevant in the field of nephrology. HNF1B-associated renal disease presents with a diverse array of renal and extrarenal manifestations, prominently featuring cystic kidney disease and diabetes mellitus. For the genetic analyses, whole exome sequencing (WES) and multiplex ligation-dependent probe amplification (MLPA) were performed. Bioinformatics analysis was performed with Ingenuity Clinical Insights software (Qiagen). The patient\'s electronic record was utilized after receiving informed consent. In this report, we present seven cases of HNF1B-associated kidney disease, each featuring distinct genetic abnormalities and displaying diverse extrarenal manifestations. Over 12 years, the mean decline in eGFR averaged -2.22 ± 0.7 mL/min/1.73 m2. Diabetes mellitus was present in five patients, kidney dysplastic lesions in six patients, pancreatic dysplasia, hypomagnesemia and abnormal liver function tests in three patients each. This case series emphasizes the phenotypic variability and the fast decline in kidney function associated with HNF-1B-related disease. Additionally, it underscores that complex clinical presentations may have a retrospectively straightforward explanation through the use of diverse genetic analytical tools.

BACKGROUND: Syndromic ciliopathies are a group of congenital disorders characterized by broad clinical and genetic overlap, including obesity, visual problems, skeletal anomalies, mental retardation, and renal diseases. The hallmark of the pathophysiology among these disorders is defective ciliary functions or formation. Many different genes have been implicated in the pathogenesis of these diseases, but some patients still remain unclear about their genotypes.
METHODS: The aim of this study was to identify the genetic causes in patients with syndromic ciliopathy. Patients suspected of or meeting clinical diagnostic criteria for any type of syndromic ciliopathy were recruited at a single diagnostic medical center in Southern Taiwan. Whole exome sequencing (WES) was employed to identify their genotypes and elucidate the mutation spectrum in Taiwanese patients with syndromic ciliopathy. Clinical information was collected at the time of patient enrollment.
RESULTS: A total of 14 cases were molecularly diagnosed with syndromic ciliopathy. Among these cases, 10 had Bardet-Biedl syndrome (BBS), comprising eight BBS2 patients and two BBS7 patients. Additionally, two cases were diagnosed with Alström syndrome, one with Oral-facial-digital syndrome type 14, and another with Joubert syndrome type 10. A total of 4 novel variants were identified. A recurrent splice site mutation, BBS2: c.534 + 1G > T, was present in all eight BBS2 patients, suggesting a founder effect. One BBS2 patient with homozygous c.534 + 1G > T mutations carried a third ciliopathic allele, TTC21B: c.264_267dupTAGA, a nonsense mutation resulting in a premature stop codon and protein truncation.
CONCLUSIONS: Whole exome sequencing (WES) assists in identifying molecular pathogenic variants in ciliopathic patients, as well as the genetic hotspot mutations in specific populations. It should be considered as the first-line genetic testing for heterogeneous disorders characterized by the involvement of multiple genes and diverse clinical manifestations.

BACKGROUND: Joubert syndrome (JS) is a rare genetic disorder that presents with various neurological symptoms, primarily involving central nervous system dysfunction. Considering the etiology of JS, peripheral nervous system abnormalities cannot be excluded; however, cases of JS accompanied by peripheral nervous system abnormalities have not yet been reported. Distinct radiological findings on brain magnetic resonance imaging were considered essential for the diagnosis of JS. However, recently, cases of JS with normal or nearly normal brain morphology have been reported. To date, there is no consensus on the most appropriate diagnostic method for JS when imaging-based diagnostic approach is challenging. This report describes the case of an adult patient who exhibited bilateral peroneal neuropathies and was finally diagnosed with JS through genetic testing.
METHODS: A 27-year-old man visited our outpatient clinic due to a gait disturbance that started at a very young age. The patient exhibited difficulty maintaining balance, especially when walking slowly. Oculomotor apraxia was observed on ophthalmic evaluation. During diagnostic workups, including brain imaging and direct DNA sequencing, no conclusive findings were detected. Only nerve conduction studies revealed profound bilateral peroneal neuropathies. We performed whole genome sequencing to obtain a proper diagnosis and identify the gene mutation responsible for JS.
CONCLUSIONS: This case represents the first instance of peripheral nerve dysfunction in JS. Further research is needed to explore the association between JS and peripheral nervous system abnormalities. Detailed genetic testing may serve as a valuable tool for diagnosing JS when no prominent abnormalities are detected in brain imaging studies.

BACKGROUND: Crizotinib, an oral first-generation tyrosine kinase inhibitor (TKI), is superior to systemic chemotherapy for the treatment of non-small cell lung cancer (NSCLC) with positive rearrangement of anaplastic lymphoma kinase (ALK). However, an increased incidence of renal and hepatic cysts has been reported in the patients on crizotinib treatment.
METHODS: Here, we describe a case of a 71-year-old Chinese women developed multiple cystic lesions in kidney and liver during crizotinib treatment for the primary and metastatic NSCLC. The renal and hepatic cysts were noted by CT scan 3 months after crizotinib treatment, which were spontaneously and significantly regressed after stopping crizotinib.
CONCLUSIONS: Based on literature review and our experience in this case report, we concluded that crizotinib-associated renal cyst (CARCs) has features of malignancy and abscess in radiographic imaging, and thus, pathological confirmation is necessary to avoid inappropriate treatment decision. In addition, to benefit the patients with progress-free survival (PFS), switching from crizotinib to alectinib is recommended for the treatment of NSCLC patients who developed CARCs.

OBJECTIVE: To investigate the value of photon-counting detector CT (PCD-CT) derived virtual non-contrast (VNC) reconstructions to identify renal cysts in comparison with conventional dual-energy integrating detector (DE EID) CT-derived VNC reconstructions.
METHODS: We prospectively enrolled consecutive patients with simple renal cysts (Bosniak classification-Version 2019, density ≤ 20 HU and/or enhancement ≤ 20 HU) who underwent multiphase (non-contrast, arterial, portal venous phase) PCD-CT and for whom non-contrast and portal venous phase DE EID-CT was available. Subsequently, VNC reconstructions were calculated for all contrast phases and density as well as contrast enhancement within the cysts were measured and compared. MRI and/or ultrasound served as reference standards for lesion classification.
RESULTS: 19 patients (1 cyst per patient; age 69.5 ± 10.7 years; 17 [89.5%] male) were included. Density measurements on PCD-CT non-contrast and VNC reconstructions (arterial and portal venous phase) revealed no significant effect on HU values (p = 0.301). In contrast, a significant difference between non-contrast vs. VNC images was found for DE EID-CT (p = 0.02). For PCD-CT, enhancement for VNC reconstructions was < 20 HU for all evaluated cysts. DE EID-CT measurements revealed an enhancement of > 20 HU in five lesions (26.3%) using the VNC reconstructions, which was not seen with the non-contrast images.
CONCLUSIONS: PCD-CT-derived VNC images allow for reliable and accurate characterization of simple cystic renal lesions similar to non-contrast scans whereas VNC images calculated from DE EID-CT resulted in substantial false characterization. Thus, PCD-CT-derived VNC images may substitute for non-contrast images and reduce radiation dose and follow-up imaging.

Joubert syndrome (JS) is a recessively inherited congenital ataxia characterized by hypotonia, psychomotor delay, abnormal ocular movements, intellectual disability, and a peculiar cerebellar and brainstem malformation, the \"molar tooth sign.\" Over 40 causative genes have been reported, all encoding for proteins implicated in the structure or functioning of the primary cilium, a subcellular organelle widely present in embryonic and adult tissues. In this paper, we developed an in vitro neuronal differentiation model using patient-derived induced pluripotent stem cells (iPSCs), to evaluate possible neurodevelopmental defects in JS. To this end, iPSCs from four JS patients harboring mutations in distinct JS genes (AHI1, CPLANE1, TMEM67, and CC2D2A) were differentiated alongside healthy control cells to obtain mid-hindbrain precursors and cerebellar granule cells. Differentiation was monitored over 31 days through the detection of lineage-specific marker expression by qRT-PCR, immunofluorescence, and transcriptomics analysis. All JS patient-derived iPSCs, regardless of the mutant gene, showed a similar impairment to differentiate into mid-hindbrain and cerebellar granule cells when compared to healthy controls. In addition, analysis of primary cilium count and morphology showed notable ciliary defects in all differentiating JS patient-derived iPSCs compared to controls. These results confirm that patient-derived iPSCs are an accessible and relevant in vitro model to analyze cellular phenotypes connected to the presence of JS gene mutations in a neuronal context.

This report presents the first case of nodular dermatofibrosis with renal cysts (NDRC) in a beagle. In this atypical case, the gene mutation associated with the disease was not present, the renal cysts showed dynamic changes in size and number, and the patient has greatly surpassed the NDRC life expectation.