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Betegségjelentés · Metabolic

Fabry Disease

Whole genome sequencing identifies all GLA variants (including the variants of uncertain significance that represent the Fabry diagnostic challenge), providing the complete genotype to guide enzyme replacement therapy initiation.

A betegségjelentés olyan ritka variánsokat keres, amelyekről ismert, hogy okozzák az általa lefedett betegségeket.

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A(z) condition ismertetése

An inherited lysosomal storage disorder caused by variants in the GLA gene, in which a fatty substance (Gb3) builds up in the body's cells. It can cause pain, kidney disease, heart problems and stroke, and affects both males and females.

Fabry disease (Anderson-Fabry disease) is an X-linked lysosomal storage disorder caused by pathogenic variants in the GLA gene on chromosome Xq22.1, which encodes alpha-galactosidase A (alpha-Gal A). Deficiency of alpha-Gal A leads to progressive accumulation of globotriaosylceramide (Gb3) and its deacylated form lyso-Gb3 in the endothelial and smooth muscle cells of blood vessels, kidney tubular cells, cardiomyocytes, dorsal root ganglia neurons, and other cell types. Fabry disease is one of the most common lysosomal storage disorders, with classic (hemizygous male) disease estimated at 1 in 40,000-60,000, though newborn screening studies suggest the actual prevalence (including atypical late-onset forms) may be substantially higher.

Classic (severe) Fabry disease in hemizygous males presents in childhood with episodes of acroparesthesias (neuropathic pain crises in the extremities triggered by fever, exercise, or temperature change), heat intolerance, angiokeratoma (small red skin lesions), hypohidrosis (reduced sweating), and corneal verticillata on slit-lamp examination. Multi-organ damage accumulates over time: progressive nephropathy leads to end-stage renal disease typically by the fourth to fifth decade; left ventricular hypertrophy and cardiomyopathy develop in virtually all patients; and cerebrovascular disease causes stroke at a mean age of 37. Heterozygous females have variable expression: some are nearly asymptomatic carriers, while others develop symptoms comparable in severity to hemizygous males, particularly cardiac and neurological involvement.

Enzyme replacement therapy (ERT) with agalsidase alfa (Replagal) or agalsidase beta (Fabrazyme) has been available since 2001-2003 and substantially slows disease progression, particularly when initiated before irreversible organ fibrosis occurs. Migalastat (Galafold), an oral pharmacological chaperone, provides an alternative therapy for patients with amenable GLA variants, approximately 35-50% of all GLA pathogenic variants. The urgency of molecular diagnosis lies in the evidence that ERT benefits are greatest when started early; patients who initiate therapy after significant renal or cardiac fibrosis has developed have attenuated treatment response. Despite this, the average diagnosis delay remains 13-16 years; most patients have symptoms for over a decade before the correct diagnosis is established.

Late-onset cardiac and renal Fabry variants (particularly p.Asn215Ser in males) produce isolated organ involvement without classic childhood features and are frequently missed. GLA variants of uncertain significance require careful functional assessment.

A vizsgált betegség

X-kromoszómához kötött recesszív

Fabry disease (FD) is a progressive, inherited, multisystemic lysosomal storage disease characterized by specific neurological, cutaneous, renal, cardiovascular, cochleo-vestibular and cerebrovascular manifestations.

Mit változtat a diagnózis

Enzyme replacement therapy (agalsidase alfa or agalsidase beta); migalastat (Galafold) for amenable GLA variants; pain management (carbamazepine, gabapentin); ACE inhibitor/ARB nephroprotection; cardiac device management for arrhythmias

Vizsgált gének

Más néven

Alpha-galactosidase A deficiency; Anderson-Fabry disease; angiokeratoma corporis diffusum; diffuse angiokeratoma; Fabry's disease; FD

MONDO:0010526OMIM 301500Orphanet 324MedGen 8083

Miért a teljes genom szekvenálás

Standard enzyme assays in females give normal or borderline results due to X-inactivation skewing, making GLA molecular genotyping essential. Rare GLA variants outside standard hotspot panels require complete gene sequencing.

Alpha-Gal A enzyme assays are unreliable in heterozygous females; molecular diagnosis is the gold standard

In hemizygous males, alpha-galactosidase A enzyme activity in leukocytes is a reliable diagnostic marker: activity is severely reduced (<1% of normal in classic Fabry disease). In heterozygous females, however, X-inactivation skewing produces a wide range of enzyme activities, from near-normal to severely reduced, making enzyme assay unreliable for female diagnosis. A female with a GLA pathogenic variant whose X inactivation mostly silences the X chromosome carrying the variant may have enzyme activity in the normal reference range and be incorrectly excluded from the diagnosis. Molecular GLA genotyping is the definitive diagnostic approach in females, and whole genome sequencing provides complete GLA sequence analysis for all variant types.

Variant amenability to migalastat determines whether a patient can use the oral therapy, and requires precise variant identification

Migalastat is an oral pharmacological chaperone that stabilizes certain mutant alpha-Gal A conformations, allowing correct protein folding and lysosomal trafficking. Migalastat is approved only for GLA variants classified as 'amenable' in regulatory databases, determined by functional in vitro assays. Approximately 35-50% of GLA pathogenic variants are amenable. This amenability classification is specific to the individual variant: the same variant must be in the migalastat database. For a patient to access migalastat therapy rather than intravenous ERT, their exact GLA variant must be precisely identified. A variant-level report from complete GLA sequencing enables this determination; an enzyme assay without variant identification cannot.

További metabolic conditions

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Egy csomag, házhoz szállítva. Az egész genomját a diagnosztikai döntésekhez használt klinikai színvonalon szekvenáljuk. Orvos számára is használható jelentéseit 6–8 héten belül küldjük el a Genome Manager-be. Ezek tartósan érvényesek, és a tudomány fejlődésével frissülnek.

449 $-tól

Ingyenes szállítás · Eredmények 6–8 hét alatt

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