An overview of the multi-pronged approach in the diagnosis of Alport syndrome for 22 children in Northeast China

Zhang, Li; Sun, Bai-chao; Zhao, Bing-gang; Ma, Qingshan

doi:10.1186/s12882-020-01962-y

Cited by 8 publications

(6 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A review of all reported digenic COL4A5 variants in 16 men with a median age of 16 years (5–55) found that the COL4A5 change was severe in five (31%) and that the additional variant was severe in only two (13%) (16,21,30–32) (Table 1). Digenic disease was associated with proteinuria in 12 (12 of 13; 92%) and kidney failure in five (five of 15; 33%), which developed at a median age of 27 (range, 23–47), as well as hearing loss (six of ten; 60%) and ocular abnormalities (three of six; 50%).…”

Section: Pathogenic Variants In Col4a5 Plus Col4a3 or Col4a4 In Men O...mentioning

confidence: 99%

Digenic Alport Syndrome

Savige

Renieri

Ars

et al. 2022

CJASN

View full text Add to dashboard Cite

Digenic Alport syndrome refers to the inheritance of pathogenic variants in COL4A5 plus COL4A3 or COL4A4 or in COL4A3 plus COL4A4. Where digenic Alport syndrome includes a pathogenic COL4A5 variant, the consequences depend on the sex of the affected individual, COL4A5 variant “severity,” and the nature of the COL4A3 or COL4A4 change. A man with a pathogenic COL4A5 variant has all his collagen IV α3α4α5-heterotrimers affected, and an additional COL4A3 or COL4A4 variant may not worsen disease. A woman with a pathogenic COL4A5 variant has on average 50% of her heterotrimers affected, which is increased to 75% with a further COL4A3 or COL4A4 variant and associated with a higher risk of proteinuria. In digenic Alport syndrome with pathogenic COL4A3 and COL4A4 variants, 75% of the heterotrimers are affected. The COL4A3 and COL4A4 genes occur head-to-head on chromosome 2, and inheritance is autosomal dominant when both variants affect the same chromosome (in cis) or recessive when they affect different chromosomes (in trans). This form of digenic disease results in increased proteinuria and a median age of kidney failure intermediate between autosomal dominant and autosomal recessive Alport syndrome. Previous guidelines have suggested that all pathogenic or likely pathogenic digenic variants should be identified and reported. Affected family members should be identified, treated, and discouraged from kidney donation. Inheritance within a family is easier to predict if the two variants are considered independently and if COL4A3 and COL4A4 variants are known to be inherited on the same or different chromosomes.

show abstract

Section: Pathogenic Variants In Col4a5 Plus Col4a3 or Col4a4 In Men O...mentioning

confidence: 99%

Digenic Alport Syndrome

Savige

Renieri

Ars

et al. 2022

CJASN

View full text Add to dashboard Cite

show abstract

“…In the present case, a genetic analysis was performed to investigate the origin of the vulnerability of the GBM and a heterozygous variant was identified at c.4793 T > G (p.L1598R) in the COL4A3 gene. A previous report showed that a patient with c.4793 T > G in COL4A3 and c.448G > C in COL4A5 had irregular thinning of the GBM while his father with c.4793 T > G in COL4A3 did not show hematuria [ 14 ]. Another previous report analyzed 24 patients with autosomal recessive Alport syndrome, 17 of which had mutations in COL4A3 [ 15 ].…”

Section: Discussionmentioning

confidence: 99%

“…Of the 17 patients, 13 had compound heterozygous mutations in COL4A3 , 5 of which had c.4793 T > G in COL4A3 . Among the parents of the 5 patients, only one mother with c.4793 T > G in COL4A3 had hematuria; the other parents seemed normal [ 14 ]. As the thinness of the GBM in the present case was not obvious and hematuria had not been pointed out previously, c.4793 T > G in COL4A3 might not have affected the synthesis of the triple helical molecule of the type IV collagen α3/4/5 chains.…”

Section: Discussionmentioning

confidence: 99%

Disruption of the glomerular basement membrane associated with nutcracker syndrome and double inferior vena cava in Noonan syndrome: a case report

et al. 2022

View full text Add to dashboard Cite

Background Nutcracker syndrome (NCS) is characterized by compression of the left renal vein (LRV) between the aorta and the superior mesenteric artery. While rare, NCS was reported to be accompanied by double inferior vena cava (IVC). We herein report a case of Noonan syndrome (NS) with double IVC who presented with macrohematuria and proteinuria. Case presentation The patient was a 23-year-old man, who had been diagnosed with NS due to RIT1 mutation, after showing foamy macrohematuria 3 weeks previously. A physical examination revealed low-set ears and a webbed neck. A urinalysis showed hematuria and proteinuria, and urinary sediments showed more than 100 isomorphic red blood cells per high-power field. His proteinuria and albuminuria concentrations were 7.1 and 4.5 g/g⋅Cr, respectively. Three-dimensional contrast-enhanced computed tomography (CT) showed double IVC and narrowing of the LRV after interflow of the left IVC. The aortomesenteric angle on a sagittal reconstruction of the CT image was 14.7°. Cystoscopy revealed a flow of macrohematuria from the left ureteral opening. On Doppler ultrasonography, there was scant evidence to raise the suspicion of the nutcracker phenomenon. Since severe albuminuria continued, a left kidney biopsy was performed. Light microscopy showed red blood cells in Bowman’s space and the tubular lumen. Electron microscopy revealed disruption of the glomerular basement membrane (GBM). Vulnerability of the GBM was suspected and a genetic analysis revealed a heterozygous mutation at c.4793 T > G (p.L1598R) in the COL4A3 gene. Screening for coagulation disorders revealed the factor VIII and von Willebrand factor (vWF) values were low, at 47.6 and 23%, respectively. A multimer analysis of vWF showed a normal multimer pattern and he was diagnosed with von Willebrand disease type 1. As the bleeding tendency was mild, replacement of factor VIII was not performed. His macrohematuria and proteinuria improved gradually without treatment, and his urinalysis results have been normal for more than 6 months. Conclusions The present case showed macrohematuria and proteinuria due to NCS in NS with double IVC and von Willebrand disease type 1. The macrohematuria and proteinuria originated from glomerular hemorrhage because of vulnerability of the GBM due to COL4A3 mutation.

show abstract

“…In our community, previous studies reported Alport syndrome to be the most common cause of hematuria in Egyptian children and Alport syndrome represents > 16% of the original kidney disease in transplanted children [ 13 , 32 ]. Alport syndrome mostly presents with hematuria, but it may present with nephrotic syndrome even in the absence of hematuria [ 33 , 34 ].…”

Section: Discussionmentioning

confidence: 99%

Role of detached podocytes in differentiating between minimal change disease and early focal segmental glomerulosclerosis, can we rely on routine light microscopy?

et al. 2022

View full text Add to dashboard Cite

Background Detachment of podocytes represents a turning point in the development of glomerular sclerosis and consequently, of CKD progression. Furthermore, detachment may differentiate minimal change disease (MCD) cases—which have only podocyte effacement—from early focal segmental glomerulosclerosis (FSGS) in which effacement and detachment are observed by electron microscopy. Noteworthy, it is not uncommon for early FSGS to present with clinical presentation and light microscopy (LM) pictures identical to MCD. In our routine practice, we often find cells that lie freely in Bowman’s space by LM. In this study, we try to determine whether these cells are detached podocytes that are worth reporting or just an artifact that can be ignored. Methods To the best of our knowledge, no study has discussed the accuracy of LM in detecting detached podocytes by the routinely used stains. We retrospectively selected 118 cases that were diagnosed as MCD by LM, and searched for detached cells in Bowman’s space in their archived, routinely stained LM slides. After that, we tried to find any correlation between the clinical course, detached cells in LM picture and the EM reports. Results LM can significantly detect detached podocytes with a positive predictive value of 93%, specificity of 85%, and sensitivity of 46%. Significant correlations were found between detached cells and degree of proteinuria and late steroid resistance. Conclusion Detecting detached podocytes by LM is a specific finding that must be reported whenever detected, as it predicts response to steroids and may be able to differentiate MCD from early FSGS by identifying patients who could have podocytopenia.

show abstract

An overview of the multi-pronged approach in the diagnosis of Alport syndrome for 22 children in Northeast China

Cited by 8 publications

References 34 publications

Digenic Alport Syndrome

Digenic Alport Syndrome

Disruption of the glomerular basement membrane associated with nutcracker syndrome and double inferior vena cava in Noonan syndrome: a case report

Role of detached podocytes in differentiating between minimal change disease and early focal segmental glomerulosclerosis, can we rely on routine light microscopy?

Contact Info

Product

Resources

About