Alport syndrome: an update.

Purpose Of Review: The recent widespread availability of genetic testing has resulted in the diagnosis of many more people with Alport syndrome. This increased recognition has been paralleled by advances in understanding clinical consequences, genotype-phenotype correlations and in the development of new therapies.

Recent Findings: These include the international call for a change of name to 'Alport spectrum' which better reflects the diverse clinical features seen with autosomal dominant and X-linked Alport syndrome; the demonstration of how common Alport syndrome is in people with haematuria, proteinuria, or kidney failure; the inability of current genetic testing to detect all pathogenic variants in suspected Alport syndrome; the different genotype-phenotype correlations for autosomal dominant and X-linked disease; and the novel treatments that are available including SGLT2 inhibitors for persistent albuminuria despite renin-angiotensin-aldosterone blockade, as well as early studies of gene-modifying agents.

Novel genetic markers for chronic kidney disease in a geographically isolated population of Indigenous Australians: Individual and multiple phenotype genome-wide association study.

Background: Chronic kidney disease (CKD) is highly prevalent among Indigenous Australians, especially those in remote regions. The Tiwi population has been isolated from mainland Australia for millennia and exhibits unique genetic characteristics that distinguish them from other Indigenous and non-Indigenous populations. Notably, the rate of end-stage renal disease is up to 20 times greater in this population compared to non-Indigenous populations.

Retinal small vessel narrowing in women with gestational diabetes, pregnancy-associated hypertension, or small-for-gestational age babies.

Background: Gestational diabetes, pregnancy-associated hypertension and small-for-gestational age babies are all associated with impaired placental vascularisation. This study compared the effects of these conditions the systemic small vessel calibre that was examined in the retina.

Methods: This was a cross-sectional observational study of consecutive pregnant women recruited from an antenatal clinic.

Genetic Modifiers of Mendelian Monogenic Collagen IV Nephropathies in Humans and Mice.

Familial hematuria is a clinical sign of a genetically heterogeneous group of conditions, accompanied by broad inter- and intrafamilial variable expressivity. The most frequent condition is caused by pathogenic (or likely pathogenic) variants in the collagen-IV genes, . Pathogenic variants in are responsible for the severe X-linked glomerulopathy, Alport syndrome (AS), while homozygous or compound heterozygous variants in the or the gene cause autosomal recessive AS.

Drusen and Other Retinal Findings in People With IgA Glomerulonephritis.

Purpose: Retinal drusen have been described in people with IgA nephropathy. We examined the frequency of drusen in IgA nephropathy and compared their location and composition with those for drusen in age-related macular degeneration.

Design: Immunohistological case series of eyes of patients with IgA nephropathy, and a comparison eye with age-related macular degeneration.

Ocular manifestations of the genetic renal tubulopathies.

Background: The genetic tubulopathies are rare and heterogenous disorders that are often difficult to identify. This study examined the tubulopathy-causing genes for ocular associations that suggested their genetic basis and, in some cases, the affected gene.

Methods: Sixty-seven genes from the Genomics England renal tubulopathy panel were reviewed for ocular features, and for retinal expression in the Human Protein Atlas and an ocular phenotype in mouse models in the Mouse Genome Informatics database.

Ocular manifestations of renal ciliopathies.

Renal ciliopathies are a common cause of kidney failure in children and adults, and this study reviewed their ocular associations. Genes affected in renal ciliopathies were identified from the Genomics England Panels. Ocular associations were identified from Medline and OMIM, and the genes additionally examined for expression in the human retina ( https://www.

Ocular manifestations of the genetic causes of focal and segmental glomerulosclerosis.

Genetic forms of focal and segmental glomerulosclerosis (FSGS) often have extra-renal manifestations. This study examined FSGS-associated genes from the Genomics England Renal proteinuria panel for reported and likely ocular features. Thirty-two of the 55 genes (58%) were associated with ocular abnormalities in human disease, and a further 12 (22%) were expressed in the retina or had an eye phenotype in mouse models.

A comparison of the ocular features in Pierson and Alport syndrome: a case report and literature review.

Background: Pierson syndrome and X-linked Alport syndrome result from pathogenic variants in and , respectively, and both affect basement membranes in the kidney and the eye. This study describes the ocular features in an individual with a homozygous pathogenic variant and compares the reported abnormalities in Pierson syndrome with those in Alport syndrome.

Methods: A 28-year-old man who developed kidney failure 10 years previously and subsequently had an atrial septal defect repair was suspected of having genetic kidney disease on the basis of his likely diagnosis of Focal and Segmental Glomerulosclerosis (FSGS), his young age at presentation, and his cardiac anomaly.

Population Frequency of Undiagnosed Fabry Disease in the General Population.

Introduction: Fabry disease is an X-linked disorder that results from pathogenic variants and can now be treated. Most studies of its population frequency have examined only males or attendees at kidney failure or cardiac clinics. This study determined the prevalence of undiagnosed Fabry disease from predicted pathogenic variants in the general population.

What patients want to know about genetic testing for kidney disease.

Previously, genetic kidney disease was often recognised when family members shared clinical features. Now, many genetic kidney diseases are diagnosed when testing demonstrates a pathogenic variant in a gene associated with the disease. Detection of a genetic variant also identifies the mode of inheritance, and suggests family members at risk.

Delayed-Onset olanzapine-induced rhabdomyolysis.

Olanzapine is a commonly used and effective second-generation antipsychotic agent used for the control of paranoia and agitation in schizophrenia and bipolar disorder as well as in the behavioural and psychological symptoms of dementia. Serious side effects of treatment are uncommon but spontaneous rhabdomyolysis represents a rare complication. We describe here a patient treated with a stable dose of olanzapine for more than 8 years who developed acute severe rhabdomyolysis without an identifiable trigger and without features suggestive of neuroleptic malignant syndrome.

A founder pathogenic variant resulting in autosomal recessive Alport syndrome accounts for most genetic kidney failure in Romani people.

Introduction: Romani people have a high prevalence of kidney failure. This study examined a Romani cohort for pathogenic variants in the , and genes that are affected in Alport syndrome (AS), a common cause of genetic kidney disease, characterized by hematuria, proteinuria, end-stage kidney failure, hearing loss, and eye anomalies.

Materials And Methods: The study included 57 Romani from different families with clinical features that suggested AS who underwent next-generation sequencing (NGS) of the genes, and 83 family members.

and Scalp-Ear-Nipple ('Finlay-Marks') syndrome may be associated with myopia and Thin basement membrane nephropathy through an effect on the collagen IV α3 and α4 chains.

Introduction: Scalp-Ear-Nipple syndrome is caused by pathogenic KCTD1 variants and characterised by a scalp defect, prominent ears, and rudimentary breasts. We describe here further clinical associations in the eye and kidney.

Methods: Fifteen affected members from two unrelated families with p.

A Systematic Review of Pathogenic Variants and Proteinuria in Women and Girls With X-linked Alport Syndrome.

Introduction: Women and girls with X-linked Alport syndrome have a risk of disease progression that is difficult to predict. This systematic review examined whether proteinuria correlated with genotype and disease severity in this population.

Methods: PubMed and Scopus were searched for manuscripts from the past 20 years with "," "female," "proteinuria" and related terms.

Increased retinal drusen in IgA glomerulonephritis are further evidence for complement activation in disease pathogenesis.

Drusen are retinal deposits comprising cell debris, immune material and complement that are characteristic of macular degeneration but also found in glomerulonephritis. This was a pilot cross-sectional study to determine how often drusen occurred in IgA glomerulonephritis and their clinical significance. Study participants underwent non-mydriatic retinal photography, and their deidentified retinal images were examined for drusen by two trained graders, who compared central drusen counts, counts ≥ 10 and drusen size with those of matched controls.

Heterozygous Pathogenic and Variants (Autosomal Dominant Alport Syndrome) Are Common, and Not Typically Associated With End-Stage Kidney Failure, Hearing Loss, or Ocular Abnormalities.

The term "autosomal dominant (AD) Alport syndrome" is often used to describe the condition associated with heterozygous pathogenic or variants and has largely replaced "thin basement membrane nephropathy (TBMN)." AD Alport syndrome implies that affected individuals develop end-stage kidney failure (ESKF) as well as the typical Alport hearing loss and ocular abnormalities, but these features have been considered rare with TBMN. Recent studies suggest that ESKF occurs in 14% to 30% of those with heterozygous pathogenic or variants but confirm that the hearing loss and ocular defects occur uncommonly if at all.

Obstructive sleep apnea, chronic obstructive pulmonary disease and hypertensive microvascular disease: a cross-sectional observational cohort study.

Hypertensive microvascular disease is associated with an increased risk of diastolic heart failure, vascular dementia and progressive renal impairment. This study examined whether individuals with obstructive sleep apnoea (OSA) had more retinal hypertensive microvascular disease than those with chronic obstructive pulmonary disease (COPD) and hospital controls. This was a single-centre, cross-sectional, observational study of participants recruited consecutively from a general respiratory clinic and a general medical clinic.