Nail-patella-like renal disease masquerading as Fabry disease on kidney biopsy: a case report

Vairo, Filippo Pinto e; Pichurin, Pavel N.; Fervenza, Fernando C.; Nasr, Samih H.; Mills, Kevin; Schmitz, Christopher T.; Klee, Eric W.; Herrmann, Sandra M.

doi:10.1186/s12882-020-02012-3

Cited by 7 publications

(10 citation statements)

References 24 publications

(26 reference statements)

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“…After their report, Pinoto e Vairo et al described a similar case with the same mutation [4]. In general, highly electron-dense multilamellar inclusions of glycosphingolipids (myelin figures and zebra bodies) on EM is a key diagnostic feature of Fabry disease, which is an X-linked inherited lysosomal storage disorder caused by a deficiency of α-galactosidase A [13].…”

Section: Discussionmentioning

confidence: 97%

“…Lei et al recently reported two families with LMX1Bassociated nephropathy (LAN) who showed focal segmental glomerulosclerosis on light microscopy and myelin figures and zebra bodies on EM along with NM_002316.3:c.737G > A:p.(Arg246Gln) mutation, and they proposed that LAN should be included in the differential diagnosis when myelin figures or zebra bodies are observed by EM without extrarenal manifestation [3]. After their report, Pinoto e Vairo et al described a similar case with the same mutation [4]. Herein we present the case of a patient with LAN who showed the histological findings of focal segmental glomerulosclerosis with podocyte myelin figures and missense mutation NM_002316.3:c.746G > A:p. (Arg249Gln) in LMX1B gene.…”

Section: Introductionmentioning

confidence: 99%

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LMX1B-associated nephropathy that showed myelin figures on electron microscopy

et al. 2021

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The mutation of LIM homeodomain transcription factor LMX1B gene leads to nail-patella syndrome (NPS), which is characterized by dysplastic nails, hypoplastic patellae, iliac horns and nephropathy. The characteristic renal histological finding of NPS nephropathy is irregular thickening of the glomerular basement membrane with patchy lucent areas, including deposits of bundles of type III collagen fibrils revealed by electron microscopy (EM). Fabry disease is a lysosomal storage disorder caused by a deficiency of α-galactosidase A activity, and the characteristic EM finding is a lamellated membrane structure (myelin figures). We present the case of a male with LMX1B-associated nephropathy (LAN) who showed focal segmental glomerulosclerosis (FSGS) on light microscopy, and myelin figures and slight deposits of collagen fibrils on EM, without findings of glomerular basement membrane abnormality suggestive for NPS. A 21-year-old Japanese-Brazilian man was admitted to hospital for an investigation of the cause of proteinuria and decreased renal function. A renal biopsy was performed to investigate the cause of renal damage. Fabry disease was initially considered, based on the presence of myelin figures on EM, but since he had normal α-galactosidase A activity, this initial diagnosis was denied, and the patient was subsequently diagnosed with FSGS. At 22 years after that renal biopsy, the patient was incidentally diagnosed with LAN when NM_002316:3c.746G > A:p.(Arg249Gln) LMX1B variant was identified in his older brother by a pre-transplantation examination, and the same mutation was confirmed in the patient. Myelin figures revealed by EM might become one of the clues for the diagnosis of LAN.

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

LMX1B-associated nephropathy that showed myelin figures on electron microscopy

et al. 2021

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“…[8,9] In recent years, NPLRD without extrarenal manifestations caused by LMX1B gene mutation has aroused the interest of workers. [10][11][12][13][14][15][16][17][18][19][20] NPLRD caused by LMX1B mutations lacks extra-renal manifestations, it is often misdiagnosed due to nonspecific symptoms and renal pathology. This study presents a comprehensive analysis of a large three-generation Chinese family exhibiting an autosomal dominant pattern of chronic kidney disease.…”

Section: Discussionmentioning

confidence: 99%

“…There is a significant difference in the severity of renal involvement in both classic NPS and NPLRD patients, and this characteristic has been described in relevant literature. [2,10,21] The specific factors that influence the progression of renal function are still unknown and the clinical course of the nephropathy cannot be predicted. For example, Olivia Boyer et al reported in 2013 on a kidney disease family involving 10 members.…”

Section: Discussionmentioning

confidence: 99%

Case report: A novel R246L mutation in the LMX1B homeodomain causes isolated nephropathy in a large Chinese family

Li,

Fan,

et al. 2024

Medicine

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Background: Genetic factors contribute to chronic kidney disease (CKD) and end-stage renal disease (ESRD). Advances in genetic testing have enabled the identification of hereditary kidney diseases, including those caused by LMX1B mutations. LMX1B mutations can lead to nail-patella syndrome (NPS) or nail-patella-like renal disease (NPLRD) with only renal manifestations. Case presentation: The proband was a 13-year-old female who was diagnosed with nephrotic syndrome at the age of 6. Then she began intermittent hormone and drug therapy. When she was 13 years old, she was admitted to our hospital due to sudden chest tightness, which progressed to end-stage kidney disease (ESRD), requiring kidney replacement therapy. Whole-Exome Sequencing (WES) results suggest the presence of LMX1B gene mutation, c.737G > T, p.Arg246Leu. Tracing her family history, we found that her father, grandmother, uncle and 2 cousins all had hematuria, or proteinuria. In addition to the grandmother, a total of 9 members of the family performed WES. The members with kidney involved all carry the mutated gene. Healthy members did not have the mutated gene. It is characterized by co-segregation of genotype and phenotype. We followed the family for 9 year, the father developed ESRD at the age of 50 and started hemodialysis treatment. The rest patients had normal renal function. No extra-renal manifestations associated with NPS were found in any member of the family. Conclusions: This study has successfully identified missense mutation, c.737G > T (p.Arg246Leu) in the homeodomain, which appears to be responsible for isolated nephropathy in the studied family. The arginine to leucine change at codon 246 likely disrupts the DNA-binding homeodomain of LMX1B. Previous research has documented 2 types of mutations at codon R246, namely R246Q and R246P, which are known to cause NPLRD. The newly discovered mutation, R246L, is likely to be another novel mutation associated with NPLRD, thus expanding the range of mutations at the crucial renal-critical codon 246 that contribute to the development of NPLRD. Furthermore, our findings suggest that any missense mutation occurring at the 246th amino acid position within the homeodomain of the LMX1B gene has the potential to lead to NPLRD.

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“…We predicted random XCI in the individual with 2.5% (2/77 SNPs with > 10 reads) of variants observed to be skewed. This finding triggered a more comprehensive genetic evaluation of the ES data which detected a pathogenic variant in the LMX1B gene, ultimately providing the patient with a diagnosis [ 24 ]. Based on our approach, GLA was deemed not related to the patient’s phenotype.…”

Section: Discussionmentioning

confidence: 99%

Identification of skewed X chromosome inactivation using exome and transcriptome sequencing in patients with suspected rare genetic disease

Fadra,

Schultz-Rogers,

Chanana

et al. 2024

BMC Genomics

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Background X-chromosome inactivation (XCI) is an epigenetic process that occurs during early development in mammalian females by randomly silencing one of two copies of the X chromosome in each cell. The preferential inactivation of either the maternal or paternal copy of the X chromosome in a majority of cells results in a skewed or non-random pattern of X inactivation and is observed in over 25% of adult females. Identifying skewed X inactivation is of clinical significance in patients with suspected rare genetic diseases due to the possibility of biased expression of disease-causing genes present on the active X chromosome. The current clinical test for the detection of skewed XCI relies on the methylation status of the methylation-sensitive restriction enzyme (Hpall) binding site present in proximity of short tandem polymorphic repeats on the androgen receptor (AR) gene. This approach using one locus results in uninformative or inconclusive data for 10–20% of tests. Further, recent studies have shown inconsistency between methylation of the AR locus and the state of inactivation of the X chromosome. Herein, we develop a method for estimating X inactivation status, using exome and transcriptome sequencing data derived from blood in 227 female samples. We built a reference model for evaluation of XCI in 135 females from the GTEx consortium. We tested and validated the model on 11 female individuals with different types of undiagnosed rare genetic disorders who were clinically tested for X-skew using the AR gene assay and compared results to our outlier-based analysis technique. Results In comparison to the AR clinical test for identification of X inactivation, our method was concordant with the AR method in 9 samples, discordant in 1, and provided a measure of X inactivation in 1 sample with uninformative clinical results. We applied this method on an additional 81 females presenting to the clinic with phenotypes consistent with different hereditary disorders without a known genetic diagnosis. Conclusions This study presents the use of transcriptome and exome sequencing data to provide an accurate and complete estimation of X-inactivation and skew status in a cohort of female patients with different types of suspected rare genetic disease.

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Nail-patella-like renal disease masquerading as Fabry disease on kidney biopsy: a case report

Cited by 7 publications

References 24 publications

LMX1B-associated nephropathy that showed myelin figures on electron microscopy

LMX1B-associated nephropathy that showed myelin figures on electron microscopy

Case report: A novel R246L mutation in the LMX1B homeodomain causes isolated nephropathy in a large Chinese family

Identification of skewed X chromosome inactivation using exome and transcriptome sequencing in patients with suspected rare genetic disease

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