Enzyme Replacement Therapy in Fabry Disease
Enzyme Replacement Therapy in Fabry Disease
Fabry disease is an X-linked rare metabolic disease, caused by a deficient activity of the
 hydrolase α-Galactosidase A, and characterized by a progressive and systematic deposition of
 glycosphingolipids in many organs.

 The disease is most severe in affected males. In the classic form (where the enzyme activity
 is absent) the clinical findings are represented by pain and paresthesias in the extremities,
 vessel ectasia (called angiokeratoma) in skin and mucous membranes, and hypohidrosis (a
 reduced sweating) during childhood or adolescence. Corneal and lenticular opacities may be
 present. Proteinuria, renal impairment,cardiac and neurological lesions develop with time,
 together with hypertension. When end stage renal disease occurs, dialysis or renal
 transplantation may be necessary. In heterozygous females a residual enzymatic activity may
 be demonstrated and they usually have asymptomatic or later onset disease manifestations,
 although rarely they could develop a disease as severe as in males.

 A cardiac and a renal variant, where the heart and kidney are the only organs involved by the
 disease have been described too.

 The recombinant human α-galactosidase A is now available for patients. Infusions of the
 enzyme replacement treatment have been demonstrated to be safe and effective. This study
 wants to evaluate the long term efficacy of enzyme replacement therapy in patients with Fabry
 disease and renal involvement.

 Clinical period evaluations together with a genetic counselling will be offered to each
 patient.
INTRODUCTION Fabry disease is an X-linked error of glycosphingolipid catabolism caused by the
 deficient activity of the lysosomal hydrolase α-galactosidase A (α-gal A) in tissues and
 fluids of affected hemizygous males; most heterozygous females have an intermediate level of
 enzymatic activity. The enzymatic defect leads to a systemic deposition of
 glycosphingolipids, predominantly globotriaosylceramide (Gb3), in body fluids and in the
 lysosomes of endothelial, perithelial, and smooth-muscle cells of blood vessels. Deposition
 also occurs in ganglion cells.

 Clinical manifestations in classically affected hemizygotes (with absent α-gal A activity),
 include pain and paresthesias in the extremities, vessel ectasia (angiokeratoma) in skin and
 mucous membranes, and hypohidrosis during childhood or adolescence. Corneal and lenticular
 opacities are early findings. With increasing age, proteinuria and renal impairment lead to
 hypertension and uremia. Renal failure typically occurs in the third-fifth decades of life,
 and these patients need chronic hemodialysis and/or renal transplantation.

 Atypical hemizygotes with residual α-gal A activity may be asymptomatic or have late-onset,
 mild disease manifestations primarily limited to the heart (the "cardiac variant"). Recently
 a renal variant has been identified too. Heterozygous females may have an attenuated form of
 the disease.The most frequent clinical finding in females is the characteristic whorl-like
 corneal epithelial dystrophy. They usually are asymptomatic, although rarely can be severely
 affected as hemizygous males.

 In the kidney accumulation of glycosphingolipids appear in the sequence in endothelial and
 epithelial cells of the glomerulus and of Bowman's space, epithelium of the loops of Henle
 and in distal tubules till proximal tubules, interstitial histiocytes and fibrocytes.
 Lipid-laden distal tubular epithelial cells desquamate and may be detected in the urinary
 sediment.

 Renal blood vessels may be involved progressively and extensively. An early finding is
 arterial fibrinoid deposits. Other histologic renal findings are severe arteriolar sclerosis,
 glomerular atrophy and fibrosis, pseudotubular proliferation of residual glomerular
 epithelium, tubular atrophy and diffuse interstitial fibrosis. Preliminary studies of enzyme
 replacement therapy demonstrate that periodic infusions of recombinant human α-galactosidase
 A are safe and effective in patients with Fabry disease.

 The purpose of this study is to evaluate the long term efficacy of enzyme replacement therapy
 in patients with Fabry disease and renal involvement.

 AIM Primary

 -  To evaluate the effect of enzyme replacement therapy on the rate of decline in the
 glomerular filtration rate (GFR, measured by inulin clearance) in Fabry patients with
 renal involvement

 -  To evaluate the biological activity of recombinant human galactosidase in terms of
 clearance of plasma Gb3 (that is directly correlated with renal endothelial
 glycosphingolipid clearance) Secondary

 To evaluate the effect of enzyme replacement therapy on:

 -  24-hour urinary protein excretion

 -  renal plasma flow (PAH renal clearance)

 -  glomerular perm-selectivity (fractional dextran clearances)

 -  end stage renal failure, kidney transplantation or death

 -  systolic and diastolic blood pressure

 -  cardiac anomalies (left ventricular hypertrophy, arrhythmias, conduction anomalies)

 -  cutaneous anomalies

 -  ocular anomalies DESIGN Twenty patients (males and females) with Fabry disease, and
 renal involvement, referred to the SMIMAF - Studio Multicentrico Italiano sulla Malattia
 di Anderson-Fabry - will be enrolled in the study.
Inclusion Criteria:

 -  age ≥ 16 years and ≤ 65 years

 -  clinical diagnosis of Fabry disease, confirmed by α-galactosidase A assay and
 detection of mutation in α-GalA gene

 -  serum creatinine ≥ 1.4 mg/dl (females) and ≥ 1.6 mg/dl (males) and/or proteinuria ≥
 0.4 g/24h

 -  written informed consent

 Exclusion Criteria:

 -  any clinically relevant condition that may affect study participation and/or study
 results

 -  inability to fully understand the purpose and the risks of the study