Viviana Palazzo

Key Points: Anti–slit autoantibody profiles identified different podocytopathy phenotypes, with anti-podocin/KIRREL1 associated with FSGS and steroid resistance. Anti-nephrin, anti-podocin, and anti-KIRREL1 testing improved risk stratification, identifying patients at a risk of CKD and post-transplant recurrence. Background: Anti-nephrin, anti-podocin, and anti-KIRREL1 antibodies are increasingly recognized as causes of autoimmune podocytopathies, yet autoantibody-specific clinical phenotypes remain poorly defined. Methods: We conducted a multicenter study integrating serology and super-resolution microscopy in 471 samples, including 213 cases with 146 kidney biopsies (minimal change n =63, FSGS n =83), and sera from 128 patients (minimal changes n =30, FSGS n =42, idiopathic nephrotic syndrome or isolated proteinuria n =56), including 61 paired specimens plus 258 controls (75 kidney biopsies, 200 sera, including 17 paired specimens). Paired specimens were used to assess ELISA performance by comparing serum results with IgG colocalization of target proteins within the filtration slit using receiver operating characteristic curves. All assays showed high specificity but lower sensitivity than super-resolution microscopy. Clinical features and long-term outcomes associated with individual autoantibodies and their combinations were also evaluated. Results: Anti–slit diaphragm antibodies were detected in 67/213 patients: 63% had anti-nephrin, 9% anti-podocin, or 3% anti-KIRREL1 antibodies only, while 25% had multiple autoantibodies. Isolated anti-nephrin antibodies were associated with minimal changes (91%), steroid sensitivity (88%), and absence of CKD over 120 months. In contrast, anti-podocin and/or anti-KIRREL1 antibodies correlated with FSGS (84%), steroid resistance (58%), CKD progression (36%), and kidney failure (24%). Among 26 transplant recipients with FSGS, early post-transplant recurrence occurred in 83% of autoantibodies carriers and in 5% of the others. Recurrent patients showed anti-podocin/KIRREL1 antibodies, with or without anti-nephrin. Conclusions: These findings suggest that anti-podocin and anti-KIRREL1 antibodies associate with steroid resistance, FSGS, and disease recurrence after transplantation in autoimmune podocytopathies.

Monocentric retrospective case series to describe clinical and molecular peculiarities in a series of pediatric patients in attempting a possible genotype-phenotype correlation. We included 13 pediatric patients from 7 unrelated families (ages 1-18) with biallelic pathogenic and likely pathogenic variants in RDH12 gene. For all our patients segregation analyses were performed in their parents and affected siblings. According to their cooperation, patients underwent a complete ophtalmic examination and imaging with full field standard electroretinography (ffERG), spectral domain optical coherence tomography (SD-OCT) and fundus autofluorescence (FAF). According to previous studies, we did not observe a conclusive genotype-phenotype correlation in our series, nevertheless we reported 2 new RDH12 likely pathogenic variants. Also, we report clinical data on pediatric patients, with the fundus imaging in the youngest child (2 yo) described in the literature in whom retinal dystrophic changes are already present. This study includes a collection of genotypic and phenotypic data from children with RDH12-associated IRD. These findings will help further characterize RDH12-related retinopathy. Determining the time window of onset of dystrophic changes is critical to research the correct timing for administering possible therapies. More extensive and functional studies are needed in view of the opportunity of gene replacement therapy for RDH12 associated IRD.

Context: Cytochrome C oxidase (COX) is the fourth component of the respiratory chain and is located within the internal membrane of mitochondria. COX deficiency causes an inherited mitochondrial disease with significant genetic and phenotypic heterogeneity. Four clinical subtypes have been identified, each with distinct phenotypes and genetic variants. Mitochondrial complex IV deficiency nuclear type 4 (MC4DN4) is a form of COX deficiency associated with pathogenic variants in the SCO1 gene. Case description: We describe three patients with MC4DN4 with developmental and epileptic encephalopathy (DEE), hypopituitarism, and SCO1 pathogenic variants. These patients’ phenotypes considerably differ from previously reported MC4DN4 phenotypes as they associate DEE with progressive hypopituitarism and survival beyond the first months after birth. Pituitary deficiency in these patients progressively worsened and mainly involved growth hormone secretion and thyroid function. Conclusions: Our findings expand knowledge of phenotypic variability in MC4DN4 and suggest that SCO1 is a candidate gene for genetic hypopituitarism and DEE. Significance statement: Our paper describes three patients affected by MC4DN4 with hypopituitarism and developmental and epileptic encephalopathy (DEE), two features that have never been associated with this condition. In addition, we reviewed the clinical features of all previous cases of MC4DN4 to give the other clinicians a wide picture of the clinical phenotype of this genetic disease. We hope that the publication of our data may help others to identify this disease and consider the chance to analyze the SCO1 gene in cases of DEE associated with pituitary dysfunction. Our article contributes to expanding the spectrum of genetic hypopituitarism and proposes a model to explain an association between this condition, mitochondrial anomalies, and neurodevelopmental defects.

Oculocutaneous albinism is an autosomal recessive disorder characterized by the presence of typical ocular features, such as foveal hypoplasia, iris translucency, hypopigmented fundus oculi and reduced pigmentation of skin and hair. Albino patients can show significant clinical variability; some individuals can present with only mild depigmentation and subtle ocular changes. Here, we provide a retrospective review of the standardized clinical charts of patients firstly addressed for evaluation of foveal hypoplasia and slightly subnormal visual acuity, whose diagnosis of albinism was achieved only after extensive phenotypic and genotypic characterization. Our report corroborates the pathogenicity of the two common TYR polymorphisms p.(Arg402Gln) and p.(Ser192Tyr) when both are located in trans with a pathogenic TYR variant and aims to expand the phenotypic spectrum of albinism in order to increase the detection rate of the albino phenotype. Our data also suggest that isolated foveal hypoplasia should be considered a clinical sign instead of a definitive diagnosis of an isolated clinical entity, and we recommend deep phenotypic and molecular characterization in such patients to achieve a proper diagnosis.

Bartter (BS) and Gitelman (GS) syndrome are autosomal recessive inherited tubulopathies, whose clinical diagnosis can be challenging, due to rarity and phenotypic overlap. Genotype–phenotype correlations have important implications in defining kidney and global outcomes. The aim of our study was to assess the diagnostic rate of whole-exome sequencing (WES) coupled with a bioinformatic analysis of copy number variations in a population of 63 patients with BS and GS from a single institution, and to explore genotype-phenotype correlations. We obtained a diagnostic yield of 86% (54/63 patients), allowing disease reclassification in about 14% of patients. Although some clinical and laboratory features were more commonly reported in patients with BS or GS, a significant overlap does exist, and age at onset, preterm birth, gestational age and nephro-calcinosis are frequently misleading. Finally, chronic kidney disease (CKD) occurs in about 30% of patients with BS or GS, suggesting that the long-term prognosis can be unfavorable. In our cohort the features associated with CKD were lower gestational age at birth and a molecular diagnosis of BS, especially BS type 1. The results of our study demonstrate that WES is useful in dealing with the phenotypic heterogeneity of these disorders, improving differential diagnosis and genotype-phenotype correlation.

Type 1 Chiari malformation (C1M) is characterized by cerebellar tonsillar herniation of 3–5 mm or more, the frequency of which is presumably much higher than one in 1000 births, as previously believed. Its etiology remains undefined, although a genetic basis is strongly supported by C1M presence in numerous genetic syndromes associated with different genes. Whole-exome sequencing (WES) in 51 between isolated and syndromic pediatric cases and their relatives was performed after confirmation of the defect by brain magnetic resonance image (MRI). Moreover, in all the cases showing an inherited candidate variant, brain MRI was performed in both parents and not only in the carrier one to investigate whether the defect segregated with the variant. More than half of the variants were Missense and belonged to the same chromatin-remodeling genes whose protein truncation variants are associated with severe neurodevelopmental syndromes. In the remaining cases, variants have been detected in genes with a role in cranial bone sutures, microcephaly, neural tube defects, and RASopathy. This study shows that the frequency of C1M is widely underestimated, in fact many of the variants, in particular those in the chromatin-remodeling genes, were inherited from a parent with C1M, either asymptomatic or with mild symptoms. In addition, C1M is a Mendelian trait, in most cases inherited as dominant. Finally, we demonstrate that modifications of the genes that regulate chromatin architecture can cause localized anatomical alterations, with symptoms of varying degrees.

Hyperkalaemia hypertension and metabolic acidosis in children can pose a challenge of both diagnosis and management. This case chronicles the diagnostic journey of a 2-year-old girl with hyperkalaemia associated with hypertension and metabolic acidosis accidentally detected during a viruses.