Fabry Disease

About Fabry Disease

Fabry disease is a progressive disorder of glycosphingolipid metabolism caused by a deficiency or absence of lysosomal α-galactosidase A activity due to mutations in the GLA gene, located on the x-chromosome.

Lack of sufficient α-galactosidase A activity leads to progressive accumulation of the glycosphingolipids globotriaosylceramide (denoted Gl3 or Gb3) and globotriaosylsphingosine (lyso-Gl3 or lyso-Gb3) within lysosomes in a variety of cells types, including vascular endothelium, podocytes, arterial smooth muscle cells, and cardiomyocytes.1,2 Fabry patients are typically classified as Classic or Late-onset (Non-classic) where classic males primarily present in childhood/adolescence with neuropathic pain, angiokeratomas, corneal opacities, hypohidrosis and GI disturbances that progresses to kidney failure, cardiomyopathy, cardiovascular disease, arrhythmias, and stroke/TIA.

Late-onset patients present with variable age of onset and manifestations, and may not have multiple organ involvement. Female Fabry patients have a wide spectrum of disease manifestations from asymptomatic to a severe phenotype similar to classic.7

Males typically exhibit symptoms earlier than females but all patients typically experience a diagnostic delay due to the non-specific disease symptoms that overlap with other diseases7.

Disease presentation is heterogeneous, but the following symptoms may prompt further examination: pain, gastrointestinal symptoms (postprandial abdominal pain, diarrhea, nausea, vomiting), hypohidrosis or anhidrosis, angiokeratomas on the skin, corneal changes, chronic fatigue, and difficulty gaining weight.1

Diagnosis of Fabry disease involves assay of α-galactosidase A activity in males, followed by GLA sequencing. For females, GLA sequencing is the appropriate first test as enzyme activity can be normal. In addition, current evidence suggests globotriaosylsphingosine (denoted Lyso-Gl3 or Lyso-Gb3) can be useful in the diagnostic process. Lyso-Gl3 is significantly increased in classic male and classic female Fabry patients; elevated but less so in non-classic males and may be mildly elevated or normal in non-classic female Fabry patients.6

Incidence

The reported incidence of Fabry disease has been estimated at 1 in 117,0001; United States incidence estimates based on newborn screening vary from 1 in 1500 males (Missouri) to 1 in 7800 males (Washington state).2

Inheritance

Fabry Disease follows an X-linked inheritance pattern, but 80% of heterozygous females manifest symptoms of varying degrees.1

Program Eligibility

The Lantern Project consists of α-galactosidase A enzyme assay with reflex to GLA sequencing if deficient in males, GLA sequencing in females, and quantitation of lyso-Gl3 for both males and females. This program is for individual patients suspected of having Fabry disease via:

  1. Symptoms consistent with Fabry disease
  2. Presumptive positive newborn screen for Fabry disease
  3. Family history of Fabry disease or individuals with symptoms consistent with Fabry disease

About the Test

Testing Algorithm:

  • Males: α-galactosidase A enzyme activity assay, if deficient, will reflex to GLA sequencing and lyso-Gl3.
  • Females:  GLA gene sequencing; samples demonstrating one pathogenic or likely-pathogenic variant, or one variant of uncertain significance will reflex to lyso-Gl3.
  • *LysoGl3 testing via the Lantern Project is for diagnostic purposes only – for ongoing monitoring please click here.

α-galactosidase A Enzyme Assay, Lyso-GB3

  • Dried blood spots are preferred, but whole blood is also acceptable.

GLA Gene Sequencing

  • Dried blood spots (DBS) are preferred, but whole blood is also acceptable. A saliva sample can be used if only gene sequencing is being ordered.

Bundled Testing (Enzyme assay with reflex to sequencing and biomarker)

  • Dried blood spots (DBS) are preferred, but whole blood is also acceptable. A saliva sample cannot be used for enzyme assay or biomarker measurement.

Click Here for detailed sample instructions and required quantities.

Enzyme Assay

  • α-galactosidase A activity is measured on dried blood spots (DBS) via Flow Injection Tandem Mass Spectrometry (FIA/MS/MS).

Biomarker Assay

  • Lyso-ceramide trihexoside (Lyso-GB3) is measured on dried blood spots (DBS) via Liquid Chromatography Tandem Mass Spectrometry (LC/MS/MS)

Gene Sequencing Assay

  • GLA sequencing is performed using NGS and analysis of all coding exons and 10bp of flanking intronic regions. This assay cannot detect variants in regions of the exome that are not covered, such as deep intronic, promoter, and enhancer regions, or areas containing large numbers of tandem repeats. Copy number variation (CNV) of three exons or more is reported. Single exon CNVs can also be predicted, but reported after follow-up confirmation is performed.

α-galactosidase A Enzyme Assay: 3 days

GLA Gene Sequencing: 3 weeks

Ordering Instructions

Select the correct test for your patient, and fill out The Lantern Project Requisition Form.

  1. Obtain a sample for testing from the patient using one of the provided PerkinElmer Genomics test packs. If you do not have a kit available in your office, please contact us here and we can have one sent out to your office.
    • Ensure that the patient sample is labeled with the patient name and date of birth.
    • Please note that all biochemical assays require a dried blood spot sample or whole blood. Step-by-step instructions for collecting a DBS sample can be found here.
    • Samples may be submitted without a collection kit by following the guidelines for specimen requirements and completing the requisition form.
  2. Package the patient sample, informed consent form, and test requisition form back into the test kit, and utilize the included pre-paid shipping label to return the kit to PerkinElmer Genomics for processing.
    • As a patient’s clinical presentation is an essential part of fully interpreting genetic test results, we ask that you kindly include any applicable medical records or clinical notes with the sample at the time of test submission.

Once PerkinElmer receives the sample, you will receive phone call to report abnormal findings, with a written report to follow within the established turnaround time for the ordered test. Bundled tests will be reported together in one comprehensive result.

Other Conditions in the Lantern Project

  • To learn more about The Lantern Project, Click Here
  • To learn more about Pompe disease, Click Here
  • To learn more about Gaucher disease and Niemann-Pick Type A/B (ASMD), Click Here
  • To learn more about Mucopolysaccharidosis I (MPS I) and Other MPS Disorders, Click Here
  • To learn more about Limb Girdle Muscular Dystrophy (LGMD) and Overlapping Myopathies, Click Here

References

  1. Germain DP. Fabry disease. Orphanet J Rare Dis. 2010;5(30):1-49.
  2. Schiffmann R, Hughes DA, Linthorst GE, et al. Screening, diagnosis, and management of patients with Fabry disease: conclusions from “Kidney Disease: Improving Global Outcomes” (KDIGO) Controversies Conference. Kidney Int. 2017;91:284-293.
  3. Eng CM, Germain DP, Banikazemi M, et al. Fabry disease: guidelines for the evaluation and management of multi-organ system involvement. Genet Med. 2006;8(9):539-548.
  4. Ortiz A et al. Fabrydisease revisited: Management and treatment recommendations for adult patients. Mol Genet Metab. 2018 Apr;123(4):416-427. doi: 10.1016/j.ymgme.2018.02.014. Epub 2018 Feb 28. Review. PMID: 29530533
  5. Matern, D. Gavrilov, D. Oglesbee, K. Raymond, P. Rinaldo, S. Tortorelli, Newborn screening for lysosomal storage disorders, Semin. Perinatol. 39 (2015) 206–216.
  6. Smid BE, et al. Plasma globotriaosylsphingosine in relation to phenotypes of Fabry disease J Med Genet 2015;52:262–268
  7. Wilcox W et al Females with Fabry disease frequently have major organ involvement: Lessons from the Fabry Registry Molecular Genetics and Metabolism 93 (2008) 112–128.