X-linked inheritance and its implication in the diagnosis and management of female patients in Fabry disease

Germain, Dominique P.; Bénistan, Karelle; Angelova, L.

doi:10.1016/s0248-8663(10)70013-8

Cited by 17 publications

(15 citation statements)

References 40 publications

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“…Contrary to the misconception that females will be marginally affected given the X-chromosome linked inheritance pattern, many heterozygotes will develop early symptoms and, later on, vital organ involvement [ 24 , 26 , 182 ]. The use of the term X-linked 'recessive' is therefore misleading and should be discontinued and FD described as following X-linked inheritance [ 177 , 208 ].…”

Section: Reviewmentioning

confidence: 99%

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Fabry disease

Germain

2010

Orphanet J Rare Dis

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1,230

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Fabry disease (FD) is a progressive, X-linked inherited disorder of glycosphingolipid metabolism due to deficient or absent lysosomal α-galactosidase A activity. FD is pan-ethnic and the reported annual incidence of 1 in 100,000 may underestimate the true prevalence of the disease. Classically affected hemizygous males, with no residual α-galactosidase A activity may display all the characteristic neurological (pain), cutaneous (angiokeratoma), renal (proteinuria, kidney failure), cardiovascular (cardiomyopathy, arrhythmia), cochleo-vestibular and cerebrovascular (transient ischemic attacks, strokes) signs of the disease while heterozygous females have symptoms ranging from very mild to severe. Deficient activity of lysosomal α-galactosidase A results in progressive accumulation of globotriaosylceramide within lysosomes, believed to trigger a cascade of cellular events. Demonstration of marked α-galactosidase A deficiency is the definitive method for the diagnosis of hemizygous males. Enzyme analysis may occasionnally help to detect heterozygotes but is often inconclusive due to random X-chromosomal inactivation so that molecular testing (genotyping) of females is mandatory. In childhood, other possible causes of pain such as rheumatoid arthritis and 'growing pains' must be ruled out. In adulthood, multiple sclerosis is sometimes considered. Prenatal diagnosis, available by determination of enzyme activity or DNA testing in chorionic villi or cultured amniotic cells is, for ethical reasons, only considered in male fetuses. Pre-implantation diagnosis is possible. The existence of atypical variants and the availability of a specific therapy singularly complicate genetic counseling. A disease-specific therapeutic option - enzyme replacement therapy using recombinant human α-galactosidase A - has been recently introduced and its long term outcome is currently still being investigated. Conventional management consists of pain relief with analgesic drugs, nephroprotection (angiotensin converting enzyme inhibitors and angiotensin receptors blockers) and antiarrhythmic agents, whereas dialysis or renal transplantation are available for patients experiencing end-stage renal failure. With age, progressive damage to vital organ systems develops and at some point, organs may start to fail in functioning. End-stage renal disease and life-threatening cardiovascular or cerebrovascular complications limit life-expectancy of untreated males and females with reductions of 20 and 10 years, respectively, as compared to the general population. While there is increasing evidence that long-term enzyme therapy can halt disease progression, the importance of adjunctive therapies should be emphasized and the possibility of developing an oral therapy drives research forward into active site specific chaperones.

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Section: Reviewmentioning

confidence: 99%

“…In contrast, affected girls and adult females may have their enzyme activity falling within the normal range [ 250 ]. Therefore, all females should have their status determined by genotyping (analysis of the GLA gene mutation) [ 208 ].…”

Section: Reviewmentioning

confidence: 99%

Fabry disease

Germain

2010

Orphanet J Rare Dis

1,008

1,230

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“…Die Diagnose kann bei komplettem Fehlen bei allen Männern und wenigen Frauen durch Messung der α-GalaktosidaseEnzymaktivität im Blut oder der Abbauprodukte Globotriaosylceramid (GB3) im Blut/Urin gestellt werden. Aufgrund der oben genannten Restaktivität des Galaktosidase-Gens in vielen Zellen bei den weiblichen Patienten ist die Diagnosesicherung bei Frauen meistens erst über eine humangenetische Abklärung mög-lich [7].…”

Section: Diskussionunclassified

Vorderabschnittbefund mit weitreichenden Folgen

2016

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“…However, clear genotype-phenotype correlation does not exist [9]. Moreover, this is especially true in women who may be asymptomatic, oligo symptomatic, or present the classic form of the disease due to skewed X inactivation [10]. In men, the diagnosis of FD can be established with the identification of deficient α-GAL activity in leukocytes, plasma, or cultured cells.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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Background: Genetic changes in the LIM homeobox transcription factor 1 beta (LMX1B) have been associated with focal segmental glomerulosclerosis (FSGS) without the extra-renal or ultrastructural manifestations of Nail-patella syndrome (NPS) known as Nail-patella-like renal disease (NPLRD). Fabry disease (FD) is an X-linked lysosomal disease caused by the deficiency of alpha-galactosidase A. The classic form of the disease is characterized by acroparesthesia, angiokeratomas, cornea verticillata, hypertrophic cardiomyopathy, strokes, and chronic kidney disease. Podocyte myelin bodies on ultrastructural examination of kidney tissue are very characteristic of FD; however some medications and other conditions may mimic this finding. Case presentation: Here, we report on a female patient with chronic kidney disease (CKD), positive family history for kidney disease and kidney biopsy showing a FSGS lesion and presence of focal myelin figures within podocytes concerning for FD. However, genetic testing for FD was negative. After comprehensive clinical, biochemical, and genetic evaluation, including whole exome and RNA sequencing, she was ultimately diagnosed with NPLRD. Conclusions: This case illustrates the difficulties of diagnosing atypical forms of rare Mendelian kidney diseases and the role of a multidisciplinary team in an individualized medicine clinic setting in combination with state-of-the-art sequencing technologies to reach a definitive diagnosis.

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X-linked inheritance and its implication in the diagnosis and management of female patients in Fabry disease

Cited by 17 publications

References 40 publications

Fabry disease

Fabry disease

Vorderabschnittbefund mit weitreichenden Folgen

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

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