진단이 지연된 Fabry 병 환자에서 효소대체요법을 통한 사지 말단 동통의 호전을 보인 1례

양아람,김진섭,조성윤,진동규,Yang, Aram,Kim, Jinsup,Cho, Sung Yoon,Jin, Dong-Kyu 대한유전성대사질환학회 2017 대한유전성대사질환학회지 Vol.17 No.3

Fabry 병은 성염색체 연관 유전성 리소좀 대사 질환으로 ${\alpha}$-galactosidase A 를 코딩하는 GLA 유전자의 변이로 인한 ${\alpha}$-galactosidase A 효소의 결핍에 의해 발생한다. 이 질환은 globotriaosylceramide (GL-3) 및 관련된 글리코스핑고리피드(glycophospholipids)가 신장 사구체, 심근, 후근 신경절 및 자율 신경계, 혈관 내피 세포 및 평활근 등에 축적되어 사지 말단 동통, 신부전, 심부전 등의 다양한 임상양상을 보이게 된다. 대증적 요법으로만 치료하던 Fabry 병은 효소대체요법의 발전으로 신부전을 포함하여, 심각한 합병증의 예방 및 호전과 함께 질환의 예후를 향상시키고 있다. 또한 사지 말단 동통은 Fabry 병 환자들의 삶의 질을 특히 떨어뜨리며, 적절한 효소대체요법에 효과가 있는 것으로 알려져 있다. 저자들은 40대 후반에 Fabry 병을 진단받고 효소대체요법을 시작하여 사지 말단 동통이 호전된 중국인 남자 환자에 대해 보고하는 바이다. Fabry disease (FD) is an X-linked lysosomal storage disorder caused by an ${\alpha}$-galactosidase A (GLA, MIM 300644) enzyme deficiency due to pathogenic variants in the ${\alpha}$-galactosidase A gene (GLA). The disease leads to accumulation of globotriaosylceramide (Gb3) and related glycophospholipids affecting nearly all major organ systems, with the primary sites damaged by Gb3 including renal glomeruli, myocardium, neurons of the dorsal ganglion and autonomic nervous system, and vascular endothelial and smooth muscle. Progressive deposition in these organ systems present with various clinical manifestations including acroparesthesia, renal failure and heart failure. Here, we report a Chinese male diagnosed with Fabry disease in his late $4^{th}$ decades showing improvement of acroparesthesia during enzyme replacement therapy (ERT). A 48-year-old Chinese man who presented with chronic recurrent severe burning pain in his fingers and toes since the age of 10, with worse involvement of the former visited to our clinic for further evaluation. His medical history included a transient ischemic attack aged 40 and diagnosed with stage 4-5 chronic kidney disease aged 47. In the family history, the patient's brother was found to be have Fabry disease 1 month before his visit. Except for his brother, all other members of the family are healthy. Based on his medical history and family history, he was strongly suspicious for Fabry disease. He was found to have a galactose-alpha-1,3-galactose level 4.96 (Reference range, 42.5-67.9) suggestive of Fabry disease. The followed sequencing of GLA coding region in our patient revealed hemizyosity for the mutation c.988C>T (Q330X) in Exon 7. Since ERT start, he showed significant improvement in his symptoms of burning sensation of fingers and toes. On the contrary, due to deteriorating kidney function even with ERT, he is considered for kidney transplantation. Despite of diagnostic delay until late 4th decades, ERT showed a potential improvement of acroparesthesia in our patient. However, late start of ERT can lead to poor outcome in multiorgan function. Therefore, early diagnosis with high index of suspicion followed by continuous ERT with regular monitoring have an impact on quality of life in Fabry disease.

Serum Globotriaosylceramide Assay as a Screening Test for Fabry Disease in Patients with ESRD on Maintenance Dialysis in Korea

( Jeong-Yup Kim ),( Young-Youl Hyun ),( Ji-Eun Lee ),( Hye-Ran Yoon ),( Gu-Hwan Kim ),( Han-Wook Yoo ),( Seong-Tae Cho ),( No-Won Chun ),( Byoung-Chunn Jeoung ),( Hwa-Jung Kim ),( Keong-Wook Kim ),( S 대한내과학회 2010 The Korean Journal of Internal Medicine Vol.25 No.4

Background/Aims: Fabry disease is an X-linked recessive and progressive disease caused by α-galactosidase A (α-GaL A) deficiency. We sought to assess the prevalence of unrecognized Fabry disease in dialysis-dependent patients and the efficacy of serum globotriaosylceramide (GL3) screening. Methods: A total of 480 patients of 1,230 patients among 17 clinics were enrolled. Serum GL3 levels were measured by tandem mass spectrometry. Additionally, we studied the association between increased GL3 levels and cardiovascular disease, cerebrovascular disease, or left ventricular hypertrophy. Results: Twenty-nine patients had elevated serum GL3 levels. The α-GaL A activity was determined for the 26 patients with high GL3 levels. The mean α-GaL A activity was 64.6 nmol/hr/mg (reference range, 45 to 85), and no patient was identified with decreased α-GaL A activity. Among the group with high GL3 levels, 15 women had a α-GaL A genetics analysis. No point mutations were discovered among the women with high GL3 levels. No correlation was observed between serum GL3 levels and α-GaL A activity; the Pearson correlation coefficient was 0.01352 (p = 0.9478). No significant correlation was observed between increased GL3 levels and the frequency of cardiovascular disease or cerebrovascular disease. Conclusions: Fabry disease is very rare disease in patients with end-stage renal disease. Serum GL3 measurements as a screening method for Fabry disease showed a high false-positive rate. Thus, serum GL3 levels determined by tandem mass spectrometry may not be useful as a screening method for Fabry disease in patients with end stage renal disease. (Korean J Intern Med 2010;25:415-421)

Fabry disease exacerbates renal interstitial fibrosis after unilateral ureteral obstruction via impaired autophagy and enhanced apoptosis

( Sungjin Chung ),( Mina Son ),( Yura Chae ),( Songhee Oh ),( Eun Sil Koh ),( Yong Kyun Kim ),( Seok Joon Shin ),( Cheol Whee Park ),( Sung-chul Jung ),( Ho-shik Kim ) 대한신장학회 2021 Kidney Research and Clinical Practice Vol.40 No.2

Background: Fabry disease is a rare X-linked genetic lysosomal disorder caused by mutations in the GLA gene encoding alpha-galactosidase A. Despite some data showing that profibrotic and proinflammatory cytokines and oxidative stress could be involved in Fabry disease-related renal injury, the pathogenic link between metabolic derangement within cells and renal injury remains unclear. Methods: Renal fibrosis was triggered by unilateral ureteral obstruction (UUO) in mice with Fabry disease to investigate the pathogenic mechanism leading to fibrosis in diseased kidneys. Results: Compared to kidneys of wild-type mice, lamellar inclusion bodies were recognized in proximal tubules of mice with Fabry disease. Sirius red and trichrome staining revealed significantly increased fibrosis in all UUO kidneys, though it was more prominent in obstructed Fabry kidneys. Renal messenger RNA levels of inflammatory cytokines and profibrotic factors were increased in all UUO kidneys compared to sham-operated kidneys but were not significantly different between UUO control and UUO Fabry mice. Protein levels of Nox2, Nox4, NQO1, catalase, SOD1, SOD2, and Nrf2 were not significantly different between UUO control and UUO Fabry kidneys, while the protein contents of LC3-II and LC3-I and expression of Beclin1 were significantly decreased in UUO kidneys of Fabry disease mouse models compared with wild-type mice. Notably, TUNEL-positive cells were elevated in obstructed kidneys of Fabry disease mice compared to wild-type control and UUO mice. Conclusion: These findings suggest that impaired autophagy and enhanced apoptosis are probable mechanisms involved in enhanced renal fibrosis under the stimulus of UUO in Fabry disease.

Fabry nephropathy before and after enzyme replacement therapy: important role of renal biopsy in patients with Fabry disease

( Il Young Kim ),( Hyun Jung Lee ),( Chong Kun Cheon ) 대한신장학회 2021 Kidney Research and Clinical Practice Vol.40 No.4

Background: In Fabry disease, the presence of globotriaosylceramide (GL3) deposits in various kidney cells leads to progressive renal dysfunction. However, kidney biopsy studies in patients with Fabry disease are limited. In the present study, the pathologic findings of patients with Fabry nephropathy receiving enzyme replacement therapy (ERT) and untreated patients without albuminuria were investigated. Methods: The present study included 15 patients with Fabry disease who underwent renal biopsy while receiving ERT (group 1: n = 9, age 19-58 years, two males and seven females) or before ERT initiation (group 2: n = 6, age 11-66 years, one male and five females). All patients in group 2 were normoalbuminuric. Results: Group 1 showed improved clinical symptoms, such as acroparesthesia. The ERT duration was 1.2 to 8 years and seven of the nine patients showed GL3 deposits in various kidney cells and segmental foot process effacement (FPE) of podocytes. GL3 deposits and FPE were not observed in the two remaining patients in group 1. Group 2 showed segmental FPE and podocyte GL3 deposits. Most patients in group 2 also showed GL3 deposits in the mesangium, endothelium, or tubular epithelium. Conclusion: The study results showed that segmental FPE and GL3 deposits can persist in Fabry nephropathy despite ERT. In addition, segmental FPE and GL3 deposits were observed in various kidney cells in normoalbuminuric patients with Fabry disease. These findings indicated that kidney biopsies at baseline and follow-up evaluation of Fabry nephropathy are essential for timely ERT initiation and ERT response assessment.

파브리병에서 효소대치요법의 장기적 효과

김자혜,조자향,최진호,이범희,유한욱,Kim, Ja Hye,Cho, Ja Hyang,Choi, Jin-Ho,Lee, Beom Hee,Yoo, Han-Wook 대한유전성대사질환학회 2014 대한유전성대사질환학회지 Vol.14 No.1

Fabry disease is an X-linked disease caused by deficiency of the lysosomal enzyme alpha-galactosidase A. Affected males present anhydrosis, acroparesthesia and angiokeratoma, and subsequently cardiac, cerebral and renal complications are followed. Females and atypical variants show heterogeneous clinical symptoms. In 2001, two recombinant enzymes were approved for Fabry disease: agalsidase alpha and agalsidase beta. Since the introduction of enzyme replacement therapy (ERT), the number of long-term follow-up studies has been reported. Long-term ERT showed effectiveness on renal function in patients with chronic kidney disease, decrease or stabilization of left ventricular mass, and improvement of pain and quality of life. However, there were limited effects on cerebrovascular events and their mortality. Current literatures on the clinical effect of ERT have reported limited datain adult patients who have already advanced disease. Therefore, further study for pre-symptomatic patients and atypical variants is needed to verify the impact of ERT. This review summarized recent progresses in ERT and limitations of long-term effect of ERT in patients with Fabry disease.

A 10-year-old Boy with Microscopic Hematuria and Renal Biopsy Findings Mimicking Fabry Disease

Chung, Woo Yeong,Kang, Mi Seon Korean Society of Pediatric Nephrology 2016 Childhood kidney diseases Vol.20 No.2

Fabry disease is an X-linked lysosomal storage disorder caused by a deficiency of the enzyme ${\alpha}-galactosidase$ A, resulting in the accumulation of glycosphingolipids within the lysosomes of various cell types. It has a wide spectrum of clinical phenotypes, and renal failure is a serious complication. Fabry disease is confirmed either by measurement of ${\alpha}-galactosidase$ A activity or by genetic testing for GLA mutations. Renal biopsy findings on light microscopy, specifically enlarged podocytes with foamy cytoplasm, and osmiophilic inclusion bodies in the cytoplasm in all types of renal cells on electron microscopy, are characteristic of this disease. The predominant differential diagnosis is iatrogenic phospholipidosis in association with certain drugs that can cause cellular injuries indistinguishable from Fabry disease. Here, we report the case of a 10-year-old boy with microscopic hematuria who underwent a renal biopsy that showed morphological findings consistent with Fabry disease, although the patient had neither a GLA mutation nor a history of drug consumption. Six years later, spontaneous regression of this renal pathology was observed in a second renal biopsy examination.

파브리병에서의 심장 자기공명영상의 역할

홍유진,김영진 대한영상의학회 2020 대한영상의학회지 Vol.81 No.2

Fabry disease is a rare X-linked metabolic disorder that is characterized by the accumulation of glycosphingolipids in various organs, resulting from the deficiency of alpha-galactosidase A. Cardiac involvement is relatively common; myocardial inflammation, left ventricular hypertrophy, and myocardial fibrosis secondary to abnormal lipid deposition in myocytes are often observed. Hence, the diagnosis of cardiac involvement is crucial for evaluating patient prognosis. Cardiac MRI is the standard technique for measuring the function, volume, and mass of the ventricles. It is also useful for myocardial tissue characterizations. The evaluation of native myocardial T1 values can facilitate early diagnosis of cardiac involvement, while measurements of left ventricular myocardial mass can be used to monitor treatment outcomes, in patients with Fabry disease. Consequently, cardiac MRI can provide useful information for diagnosing, monitoring, and treating patients with Fabry disease. 파브리병(Fabry disease)은 매우 드문 X-연관 유전 대사 질환으로 알파 갈락토시다아제(alpha galactosidase A)의 결핍으로 인하여 다양한 세포 및 기관에 글리코스핑고지질(glycosphingolipid) 의 축적을 초래하는 질환이다. 심장 침범이 비교적 흔하며 비정상적인 지질침착으로 인한 심근 염증, 좌심실 비대 및 심근 섬유증을 일으킨다. 심장 침범은 환자 예후를 결정하는 중요한 요인이므로 이를 진단하는 것은 매우 중요하다. 심장 자기공명영상은 심실의기능, 부피 측정을 위한 표준기법으로 알려져 있으며 심근의 조직 변화를 볼 수 있는 유용한기법이다. 특히 최근 많이 쓰이는 T1 지도화 기법을 통한 심근 조영 전 T1 수치를 이용하여파브리병의 심장 침범을 조기 진단할 수 있으며 자기공명영상을 이용한 심근 질량 측정으로치료 모니터링을 할 수 있다. 심장 자기공명영상은 파브리병 환자에서 다양한 역할을 할 수있을 것으로 생각되며 이에 대해 정리해보고자 한다.

Substrate-specific gene expression profiles in different kidney cell types are associated with Fabry disease

SHIN, YOUN-JEONG,JEON, YEO JIN,JUNG, NAMHEE,PARK, JOO-WON,PARK, HAE-YOUNG,JUNG, SUNG-CHUL SPANDIDOS PUBLICATIONS 2015 MOLECULAR MEDICINE REPORTS Vol.12 No.4

<P>Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the gene encoding the α-galactosidase A (α-Gal A) lysosomal enzyme, which results in globotriaosylceramide (Gb3) storage in vascular endothelial cells and different cell types throughout the body. Involvement of the of Fabry disease. An increased concentration of deacylated Gb3 (lyso-Gb3) in the plasma of symptomatic patients has also been suggested as a causative molecular event. To elucidate the molecular mechanisms involved in renal fibrosis in Fabry disease, the present analyzed the changes in global gene expression prior to and following Gb3 or lyso-Gb3 treatment in two types of kidney cell lines, human proximal renal tubular epithelial (HK-2) and mouse renal glomerular mesangial (SV40 MES 13) cells. Gb3 and lyso-Gb3 treatment regulated the expression of 199 and 328 genes in each cell type, demonstrating a >2.0-fold change. The majority of the biological functions of the regulated genes were associated with fibrogenesis or epithelial-mesenchymal transition (EMT). The gene expression patterns of sphingolipid-treated HK-2 cells were distinguishable from the patterns in the SV40 MES 13 cells. Several genes associated with the EMT were selected and evaluated further in kidney cells and in Fabry mouse kidney tissues. In the SV40 MES 13 cells, the <I>DLL1</I>, <I>F8</I>, and <I>HOXA11</I> genes were downregulated, and <I>FOXP2</I> was upregulated by treatment with Gb3 or lyso-Gb3. In the HK-2 cells, the <I>ADAMTS6</I>, <I>BEST1</I>, <I>IL4</I>, and <I>MYH11</I> genes were upregulated. Upregulation of the <I>FOXP2</I>, <I>COL15A1</I>, <I>IL4</I>, and <I>MYH11</I> genes was also observed in the Fabry mouse kidney tissues. The gene expression profiles in kidney cells following the addition of Gb3 or lyso-Gb3 revealed substrate-specific and cell-specific patterns. These findings suggested that Gb3 and lyso-Gb3 lead to renal fibrosis in Fabry disease through different biochemical modulations.</P>

신장 조직검사를 통해 진단된 Fabry Disease

옥재욱 ( Og Jae Ug ),최기현 ( Choe Gi Hyeon ),오재인 ( O Jae In ),권건호 ( Kwon Geon Ho ),양동호 ( Yang Dong Ho ),김경수 ( Kim Gyeong Su ),이용희 ( Lee Yong Hui ) 대한신장학회 2001 Kidney Research and Clinical Practice Vol.20 No.6

Fabry disease, angiokeratoma corporis diffusum, is a rare X-linked inborn error of glycosphingolipid metabolism due to the lack of the lysosomal enzyme, α-galactosidase A, resulting in a progressive deposition of specific neutral glycosphingolipids within the lysosomes of endothelial and smooth muscle cells of the cardiovascular and renal systems predominantly. We reported a case of Fabry disease, following renal biopsy for the investigation of proteinuria(Creatinine clearance 87.28 mL/min/1.73, serum creatinine 1.1 mg/dL, 24-hour urine protein 1,125 mg, 24-hour urine creatinine 1,382 mg). The patient was 46 year old male. He had experienced anterior chest pain regarded as angina pectoris for a few years. A 12- lead electrocardiogram was abnormal(T-wave inversion in II, III, AVF, and V3-V6), but echocardiography and coronary angiography revealed no abnormal. Kidney biopsy findings showed lamella inclusion bodies on electron microscopy, which are typical finding of Fabry disease. The patient is followed at O.P.D without any significant complaints for 18 months after diagnosis of Fabry disease.

A Fast Determination of Globotriaosylsphingosine in Plasma for Screening Fabry Disease Using UPLC-ESI-MS/MS

( Hye Ran Yoon ) 한국질량분석학회 2015 Mass spectrometry letters Vol.6 No.4

Globotriaosylsphingosine (lyso-Gb3) is considered as one of the biological marker for Fabry disease. To date, a reliable biomarker that reflects disease severity and progression has not been discovered to guide the management of Fabry disease. A new method included a simple protein precipitation with acetonitrile in 100 μL of plasma following analyte separation on an Phenomenex Kintex- C18 column using a gradient elution (0.1% formic acid in 5-90% acetonitrile). Total run time was within 12 min including sample preparation and MS/MS analysis. The limit of detection and limit of quantitation were 1 ng/mL and 2 ng/mL, respectively. The calibration curve was linear over the concentration range of 2.0-200.0 ng/mL (r2 = 0.9999). Inter-day accuracy and precision at 7 level were 93.4-100.7% with RSD of 0.55-5.97%. Absolute recovery was 97.6-98.6%. The method was applied to human and mice plasma, proved the suitability for quantification of lyso-Gb3 for screening, diagnosis and therapeutic monitoring of Fabry disease patients.