A 26-year-old man was admitted to our Department of Nephrology for a headache and newly ascertained advanced renal insufficiency (serum creatinine level 606 μmol/L, urea nitrogen 21 mmol/L, creatinine clearance 0.29 mL/s) with blended urinalysis (proteinuria 5.6 g/day, microhematuria – 25/ μl). Any serious diseases were noted at the time of admission to the hospital in February 2001. When he was sixteen he was hospitalized for a headache and uncertain abnormality of urinalysis but after this incident the patient was not examined and followed by the doctors. The patient did not take any regular treatment or addictive drugs, he abstained from alcohol and was a nonsmoker. There was an interesting statement in his family history about his 4-year older brother, who was hemodialysed for four years due to end stage renal disease probably evoked by addictive drugs (without verification by a renal biopsy) and he died at the age of 29 years. His five brothers and two sisters had no symptoms for renal or other diseases. The patient’s father died of prostate cancer at the age of 35 and he had no cardiovascular or renal disease, the patient’s mother suffered from a heart attack and epilepsy.
Physical examination of the patient revealed arterial hypertension (blood pressure was 150/100 mmHg, pulse was 70 beats/min), body temperature was 36.1°C, BMI 25, and no other abnormalities were found by clinical examination.
The levels of renal parameters at the time of admission to the hospital are mentioned above. Ultrasound of abdomen detected bilateral smaller kidney (length 98 mm with an unclear structure). Laboratory results showed serum level of potassium 5.3 mmol/L, hyperphosphataemia 2.1 mmol/L, total protein 67 g/L, albumin 43 g/L, metabolic acidosis (pH 7.2, HCO3 16.8 mmol/L, BE – 6.8 mmol/L), mild anaemia (the level of hemoglobin 125 g/L), mild hyperuricaemia (the level of uric acid 448 mmol/L), dyslipoproteinaemia with an elevation of LDL cholesterol (total cholesterol 7.5 mmol/L, LDL cholesterol 4.8 mmol/L, triglycerides 3.11 mmol/L), results of liver function tests were negative, urinalysis showed a pH 6, microhematuria – 25/ μl, the 24-h protein excretion was 5.6 g/d). Immunology tests were normal (immunoglobulin A, immunoglobulin M, immunoglobulin G, C3 and C4 complement, antinuclear antibodies, antibodies to extractable nuclear antigens, anti-neutrophil cytoplasmic antibodies, immune complexes). The electrocardiogram revealed the signs of left ventricle hypertrophy.
The patient underwent renal biopsy. In a renal biopsy sample, immunofluorescence and light microscopy [Figure ,] showed an advanced form of mesangioproliferative IgAN with marked scarring and epithelial crescents (in two glomeruli of the 12, the remaining 10 glomeruli were completely sclerotic) and vascular changes as a part of hypertension (electron microscopy was not performed because only sclerotic glomerulus was present in the sample). FD was not identified at that time. Blood pressure was well regulated by means of antihypertensive treatment (angiotensin-converting enzyme inhibitors, beta-blockers, diuretics). The regimen with corticosteroids (Prednisone 0.5 mg/kg) was initiated because of the age of the patient and suspected signs of the disease activity in the renal biopsy sample even though the possible influence of hypertension played a role in the occurrance of epithelial crescents. Subsequently, because of his progressive renal insufficiency the patient started to be hemodialysed in August 2001 (six months after renal biopsy) and corticosteroids were discontinued.
Figure 1 a. Immunofluorescence with IgA positive staining in the mesangium, which is diagnostic for IgAN. b. Advanced lesion with diffuse interstitial fibrosis and sclerotic glomerulus. IgAN was confirmed by immunofluorescence. No swollen podocytes indicative (more ...)
By means of the screening method in dried blood spots in 2003 [4
] a diagnosis of FD was suspected. Extensive tests for FD were implemented. Deficient activity of alpha-galactosidase A in the patient’s plasma (patient 0,47 nmol.ml-1
, normal range 2.4 - 11.3 nmol.ml-1
) and leukocytes (patient 0.23 nmol.mg-1
, normal range 30–77 nmol.mg-1
) confirmed the diagnosis of FD. After the patient’s informed consent was obtained mutation analysis (Sanger sequencing and RFLP method) was performed. We identified a missense mutation c.950 T>C (p.Ile317Thr) in exon 6. This mutation was previously found in an unrelated FD patient [5
]. With this knowledge we performed additional electron microscopy from archive paraffin embedded kidney tissue [Figure and additionally showed dense deposits in paramesangial areas as a part of IgAN, and podocytes with inclusions of so-called zebra bodies and myelin figures characteristic of FD. The enzyme replacement therapy started in July 2004 and still continues. The patient underwent kidney transplantation in November 2005. Currently, the actual serum creatinine level is 250 μmol/L without the necessity of dialysis.
Other organ damages included hypertrophic cardiomyopathy. After the diagnosis of the coincidence of FD and IgAN was assessed we asked the patient about the possible clinical symptoms in his history related to FD and we found two typical signs such as febrile crisis and neuropathic pain in the extremities. Typical symptoms of FD – angiokeratomas and corneal changes – were not observed in this patient. Nevertheless, other findings (febrile and painful crisis, neuropathy, hypertrophic cardiomyopathy and Fabry nephropathy) supported the diagnosis of FD. On enzyme replacement therapy myocardial hypertrophy has stabilised, febrile crisis and neuropathic pain in the extremities have disappeared. To date, no other progression of the disease has been noted. After the informed consent was obtained, mutation analysis of the GLA gene was performed in 12 relatives, using the direct sequencing. Other 8 relatives were newly diagnosed with FD [3 hemizygous and 5 heterozygous, Figure ].
Pedigree of the family of the first patient.
The second, a 30-year-old woman, suffered from long-term hematuria with a good renal function. Due to increasing proteinuria (2.6 g/day) appeared and a renal biopsy was performed. Histopathology showed IgAN with remarkably enlarged podocytes. IgAN and a high suspicion of a combination with FD was diagnosed by evaluation using immunofluorescence and light microscopy [Figure , . Electron microscopy [Figure , semithin section] revealed dense deposits in paramesangial areas typical of IgAN and podocytes with inclusive zebra bodies and myelin-like bodies characteristic of FD. The activity of alpha-galactosidase A in plasma was within the range of control values (3.3 nmol.ml-1
, normal range 2.4 - 11.3 nmol.ml-1
) and was decreased in leukocytes (26 nmol.mg-1
, normal range 30–77 nmol.mg-1
). The diagnosis of FD was confirmed by the identification of the GLA
gene mutation c.1085C>T (p.Pro362Leu). This mutation was previously described in an unrelated FD patient [5
]. Mutation analysis was performed after the informed consent was obtained. The mutation analysis also revealed the diagnosis of FD in the patient’s mother and sister (both heterozygous) with the same mutation [Figure . Subsequent examination of our patient showed corneal changes (cornea verticillata). Other organ defects were not proved. Enzyme treatment was initiated recently, but we still can not assess the effect of enzyme replacement treatment (the short duration of enzyme treatment – only one month).
Figure 3 a. Positive mesangial IgA staining in immunofluorescence (high power field). b. Light microscopy - glomerulus with remarkably enlarged podocytes with many vacuoles in their cytoplasm. Swollen lacy cytoplasm of podocytes is indicative of FD (Jones methenamine (more ...)
Pedigree of the family of the second patient (the relatives of the proband’s mother refused the genetic analysis).