Severe Visual Impairment Following CAR T-Cell Therapy in Two Individuals with Malignant Optic Nerve Infiltration.

We report two patients who displayed evidence of localized ocular inflammation after CAR T-cell infusion. To manage the resulting severe visual impairment, systemic corticosteroids were administered to both patients. This treatment led to a reduction in local inflammation and restored vision in one of the patients.

Identification of disease-causing variants by comprehensive genetic testing with exome sequencing in adults with suspicion of hereditary FSGS.

In about 30% of infantile, juvenile, or adolescent patients with steroid-resistant nephrotic syndrome (SRNS), a monogenic cause can be identified. The histological finding in SRNS is often focal segmental glomerulosclerosis (FSGS). Genetic data on adult patients are scarce with low diagnostic yields. Exome sequencing (ES) was performed in patients with adult disease onset and a high likelihood for hereditary FSGS. A high likelihood was defined if at least one of the following criteria was present: absence of a secondary cause, ≤25 years of age at initial manifestation, kidney biopsy with suspicion of a hereditary cause, extrarenal manifestations, and/or positive familial history/reported consanguinity. Patients were excluded if age at disease onset was <18 years. In 7/24 index patients with adult disease onset, a disease-causing variant could be identified by ES leading to a diagnostic yield of 29%. Eight different variants were identified in six known genes associated with monogenic kidney diseases. Six of these variants had been described before as disease-causing. In patients with a disease-causing variant, the median age at disease onset and end-stage renal disease was 26 and 38 years, respectively. The overall median time to a definite genetic diagnosis was 9 years. In 29% of patients with adult disease onset and suspected hereditary FSGS, a monogenic cause could be identified. The long delay up to the definite genetic diagnosis highlights the importance of obtaining an early genetic diagnosis to allow for personalized treatment options including weaning of immunosuppressive treatment, avoidance of repeated renal biopsy, and provision of accurate genetic counseling.

Heterozygous COL4A3 Variants in Histologically Diagnosed Focal Segmental Glomerulosclerosis.

Introduction: Steroid-resistant nephrotic syndrome (SRNS) is one of the most frequent causes for chronic kidney disease in childhood. In ~30% of these cases a genetic cause can be identified. The histological finding in SRNS is often focal segmental glomerulosclerosis (FSGS). In rare cases, however, pathogenic variants in genes associated with Alport syndrome can be identified in patients with the histological finding of FSGS. Materials and Methods: Clinical information was collected out of clinical reports and medical history. Focused molecular genetic analysis included sequencing of COL4A5 and COL4A3 in the index patient. Segregation analysis of identified variants was performed in the parents and children of the index patient. Results: The female index patient developed mild proteinuria and microscopic hematuria in childhood (12 years of age). The histological examination of the kidney biopsies performed at the age of 21, 28, and 32 years showed findings partly compatible with FSGS. However, immunosuppressive treatment of the index patient did not lead to a sufficient reduction of in part nephrotic-range proteinuria. After the patient developed hearing impairment at the age of 34 years and her daughter was diagnosed with microscopic hematuria at the age of 6 years, re-examination of the index's kidney biopsies by electron microscopy revealed textural changes of glomerular basement membrane compatible with Alport syndrome. Molecular genetic analysis identified two missense variants in COL4A3 in a compound heterozygous state with maternal and paternal inheritance. One of them is a novel variant that was also found in the 6 year old daughter of the index patient who presented with microscopic hematuria. Discussion: We were able to show that a novel variant combined with a previously described variant in compound heterozygous state resulted in a phenotype that was histologically associated with FSGS. Molecular genetic analysis therefore can be essential to solve difficult cases that show an unusual appearance and therefore improve diagnostic accuracy. Additionally, unnecessary and inefficient treatment with multiple side effects can be avoided.