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• Fabry disease requires a multidisciplinary approach
  Konstantinos Koulousios, Anastasios E. Germenis
  Published on: 11 May 2018
• D313Y variant: Evidence in favour or against its pathogenicity in Fabry Disease?
  Theodoros Karapanayiotides, Nikolaos Grigoriadis
  Published on: 20 April 2018

• Published on: 11 May 2018

  Fabry disease requires a multidisciplinary approach

  • Konstantinos Koulousios, Nephrologist MD University of Thessaly, School of Medicine
  • Other Contributors:
    • Anastasios E. Germenis, Professor and Chairman

  We are delighted to read the misleadingly entitled letter by Karapanagiotidis and Grigoriadis, as it gives us the opportunity to present additional convincing evidence gathered after publication in favor of the pathogenicity of the D313Y GLA mutation. It might also be noted that Karapanagiotidis and Grigoriadis refer to only two of the reported cases, disregarding the strong supporting evidence provided by the study of the other cases. Obviously, their objections come from the fact that they were restricted to the neurological approach to Patient 4 (thus their mention in the Acknowledgements of our paper), underestimating her nephrological profile, which is not even mentioned in their letter. Taking into account that, one year after the last stroke, the patient presented with microalbuminuria that was duplicated after 3 months, as was mentioned in our paper, we proceeded to renal biopsy. On electron microscopy, typical signs of Fabry disease were detected, i.e. podocyte injury, significant cytoplasmic vacuolization of podocytes with a mild presence of sphingolipids and myelin bodies in podocytes and tubular cells. According to the current diagnostic criteria, these findings confirm the definite diagnosis of Fabry disease in patients with “genetic variants of uncertain significance and non-specific FD signs” (Biegstraaten et al, Orphanet J Rare Dis 2015). Additionally, in a recent ophthalmological assessment, this patient presented with signs of "cornea verticillata...

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  We are delighted to read the misleadingly entitled letter by Karapanagiotidis and Grigoriadis, as it gives us the opportunity to present additional convincing evidence gathered after publication in favor of the pathogenicity of the D313Y GLA mutation. It might also be noted that Karapanagiotidis and Grigoriadis refer to only two of the reported cases, disregarding the strong supporting evidence provided by the study of the other cases. Obviously, their objections come from the fact that they were restricted to the neurological approach to Patient 4 (thus their mention in the Acknowledgements of our paper), underestimating her nephrological profile, which is not even mentioned in their letter. Taking into account that, one year after the last stroke, the patient presented with microalbuminuria that was duplicated after 3 months, as was mentioned in our paper, we proceeded to renal biopsy. On electron microscopy, typical signs of Fabry disease were detected, i.e. podocyte injury, significant cytoplasmic vacuolization of podocytes with a mild presence of sphingolipids and myelin bodies in podocytes and tubular cells. According to the current diagnostic criteria, these findings confirm the definite diagnosis of Fabry disease in patients with “genetic variants of uncertain significance and non-specific FD signs” (Biegstraaten et al, Orphanet J Rare Dis 2015). Additionally, in a recent ophthalmological assessment, this patient presented with signs of "cornea verticillata" ophthalmopathy onset, a characteristic mark of the disease. Further, the mother of this patient (Patient 5), initially misdiagnosed as a multiple sclerosis patient, not only carries the same GLA mutation but also suffers multiple white matter lesions and pains in the extremities of undetermined etiology, and thus is also diagnosed with Fabry disease.

  Consequent to the above, the “misunderstandings” in our paper to which Karapanagiotidis and Grigoriadis refer in their letter, such as the supposed use of Gb3s or the use of genotype-phenotype correlations as diagnostic criteria, are not worthy of comment.

  We can only agree, however, with the implication of Karapanagiotidis and Grigoriadis’ ironically expressed conclusion, which is that a multidisciplinary approach is imperative for effective investigation and management of the uncertainties of Fabry disease.

  We have obtained written consent to publish the personal medical information contained in this letter from the relevant patients.

  References

  Biegstraaten M, Arngr.msson R, Barbey F, et al. Recommendations for initiation and cessation of enzyme replacement therapy in patients with Fabry disease: the European Fabry Working Group consensus document. Orphanet J Rare Dis 2015;10:36.

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  Conflict of Interest:
  None declared.

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• Published on: 20 April 2018

  D313Y variant: Evidence in favour or against its pathogenicity in Fabry Disease?

  • Theodoros Karapanayiotides, Assistant Professor of Neurology Aristotle University of Thessaloniki, 2nd Department of Neurology, AHEPA University Hospital, Thessaloniki, Greece
  • Other Contributors:
    • Nikolaos Grigoriadis, Professor of Neurology

  Dear Editor,

  We read with interest the article by Koulousios et al. The authors report five patients with a presumed “definite” diagnosis of Fabry Disease (FD) out of a group of 17 Greek individuals with the D313Y variant of the a-galactosidase A (GLA) gene. The authors claim that they provide “strong evidence that the D313Y mutation could be pathogenic”. Beyond the obvious contradiction of being certain about an uncertainty, the study contradicts to overwhelming evidence from the literature, mainly due to a mechanistic interpretation of incomplete patient data without (in the majority of cases) the appropriate counseling and expertise by the medical specialties responsible for the management of the patients’ principal clinical manifestations. In particular, the authors claim that the “vast majority of patients with the D313Y mutation presented with neurologic symptoms and signs”. Nevertheless, none of the authors is a neurologist and it is obvious that a neurological perspective is missing from the manuscript.
  For the past two years, we have been following in our department Patient 4 (table 1) and her mother (Patient 5). Patient 5 had a history of slowly progressing spastic tetraparesis over at least 20 years, initially diagnosed in another institution as primary progressive multiple sclerosis. After all relevant investigations, our diagnosis was that of an undetermined moderate leukoencephalopathy. Plasma Gb3 levels were 4.7 nmol/mL (reference: 0.8-4.52). I...

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  Dear Editor,

  We read with interest the article by Koulousios et al. The authors report five patients with a presumed “definite” diagnosis of Fabry Disease (FD) out of a group of 17 Greek individuals with the D313Y variant of the a-galactosidase A (GLA) gene. The authors claim that they provide “strong evidence that the D313Y mutation could be pathogenic”. Beyond the obvious contradiction of being certain about an uncertainty, the study contradicts to overwhelming evidence from the literature, mainly due to a mechanistic interpretation of incomplete patient data without (in the majority of cases) the appropriate counseling and expertise by the medical specialties responsible for the management of the patients’ principal clinical manifestations. In particular, the authors claim that the “vast majority of patients with the D313Y mutation presented with neurologic symptoms and signs”. Nevertheless, none of the authors is a neurologist and it is obvious that a neurological perspective is missing from the manuscript.
  For the past two years, we have been following in our department Patient 4 (table 1) and her mother (Patient 5). Patient 5 had a history of slowly progressing spastic tetraparesis over at least 20 years, initially diagnosed in another institution as primary progressive multiple sclerosis. After all relevant investigations, our diagnosis was that of an undetermined moderate leukoencephalopathy. Plasma Gb3 levels were 4.7 nmol/mL (reference: 0.8-4.52). In this patient with the totally atypical for FD clinical manifestations, the authors posed a diagnosis of definite FD on the premises of the D313Y variant and the “high” plasma Gb3 levels, according to “the recently published criteria of the disease” (reference 15, Biegstraaten et al, Orphanet J Rare Dis 2015). However, the cited paper pertains to the recommendations for enzyme replacement therapy (ERT) and adopts the criteria by Smid et al, a consensus recommendation paper on the diagnosis of FD in adults with left ventricular hypertrophy and genetic variants of unknown significance (GVUS). Smid et al. clearly state in their introduction that “subjects with a non-pathogenic GLA mutation, such as D313Y, have low or normal levels (of lyso-Gb3). While some still consider the D313Y mutation pathogenic, it has been shown that this mutation results in a pseudo-deficiency of AGAL-A in plasma…”. It is at least frustrating to acknowledge that Koulousios et al. do not share the opinion of the experts whose criteria apply in their study. Furthermore, although Smid et al. permit the use of Gb3 and lyso-Gb3 interchangeably, the literature is clearly in favor of the lyso-Gb3 use for the following reasons: 1) Plasma Gb3 has been found to poorly reflect Fabry disease manifestations and therapeutic outcome (Vedder et al); 2) The relative increase in the plasma lysoGb3 exceeds that of Gb3 by more than an order of magnitude. Also in symptomatic Fabry females, clearly increased levels of lysoGb3 occur while Gb3 concentrations are in the normal range (Aerts et al); 3) Plasma Gb3 concentration has not been found to be a useful surrogate marker and the use of sequential plasma Gb3 measurements for monitoring efficacy of enzyme replacement therapy is not recommended (Young et al). Most importantly, cutoff values for lyso-Gb3 have been proposed to identify clinically relevant GLA mutations leading to FD among several GVUS (such as D313Y) (Niemann et al) while cutoffs for Gb3 do not exist. The issue of lyso-Gb3 use over Gb3 may need to be addressed in future revisions of the proposed FD criteria.
  Patient 4 suffered two consecutive strokes within 15 days involving first the anterior and subsequently the posterior circulation. Excepting a history of poorly controlled hypertension, an extensive etiological work-up was unrevealing. We assumed a diagnosis of embolic strokes of undetermined etiology (ESUS) and started anticoagulant treatment without any further complications. During hospitalization at our department we organized examination of urine and plasma Gb3 and lyso-Gb3 (Tandem Labs, New Jersey-USA). Urine Gb3 was high (54.08, reference: 0-29.99 nmol/g) and plasma Gb3 and lyso-Gb3 were undetectable. Within 16 months we repeated all above measurement in the same laboratory and this time all biochemical markers were undetectable. Had the authors had a closer collaboration with the treating neurologists, they would not have missed this spontaneous total remission of urine Gb3 excretion. Additionally, the reported “acroparaesthesias” did not have any of the typical characters of FD-associated neuropathic pain and were intermittent. The diagnosis of definite FD in Patient 4 was based on the combination of D313Y presence and the presence of her mother suffering from “definite” FD and carrying the same mutation, despite a spectacularly different phenotype.
  It is noteworthy that lyso-Gb3, the most constant biochemical marker of FD, proposed by most international experts is not elevated in a single patient with the D313Y mutation that Koulousios et al. classify as definite FD. By contrast, all their patients with novel mutations in whom lyso-Gb3 was tested had pathologically high values. In our view, the “strong evidence” in favor of D313Y potential pathogenicity is in fact strong evidence against its potential pathogenicity. From a neurologic point of view, it seems that D313Y is implicated in brain white matter lesions (Lenders et al) and this is a field of research in which we would urge Koulousios et al. to engage under responsible guidance by the greek neurologic community.
  We have obtained written consent to publish the personal medical information contained in the letter from the relevant patients.
  References

  Aerts JM, Groener JE, Kuiper S, et al. Elevated globotriaosylsphingosine is a hallmark of Fabry disease. Proc.Natl Acad. Sci. USA 2008;105:2812–2817.

  Niemann M, Rolfs A, Störk S, et al. Gene Mutations Versus Clinically Relevant Phenotypes.
  Lyso-Gb3 Defines Fabry Disease. Circ Cardiovasc Genet 2014;7:8-16.

  Smid BE, van der Tol L, Cecchi F, et al. Uncertain diagnosis of Fabry disease: consensus recommendation on diagnosis in adults with left ventricular hypertrophy and genetic variants of unknown significance. Int J Cardiol 2014;177:400-408.

  Vedder AC, Linthorst GE, van Breemen MJ, et al. The Dutch Fabry cohort: diversity
  of clinical manifestations and Gb3 levels. J Inherit Metab Dis 2007;30:68–78.

  Young E, Mills K, Morris P, et al. Is globotriaosylceramide a useful biomarker in Fabry disease? Acta Paediatr. 2005;447(Suppl 94):51–54.

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  Conflict of Interest:
  None declared.

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