EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Key words : Anderson-Fabry disease, Chaperone therapy, D313Y, Renal transplantation

Fabry disease (FD) is an X-linked inherited disorder of glycosphingolipid metabolism. Fabry disease is characterized by a deficiency or complete absence of lysosomal α-galactosidase A (α-GALA) activity, leading to the intracellular accumulation of glycosp-hingolipids,predominantly globotriaosylceramide (Gb3), within vascular endothelial cells, neurons, and various organs. This pathological accumulation contributes to the distinctive clinical features of FD, such as cornea verticillata, clusters of angiokeratomas, neuropathic pain, hypohidrosis, hearing impairment, vertigo, and tinnitus. Progressive multiorgan dysfunction, including renal failure, cardiovascular disease, cerebrovascular events, and peripheral neuropathy, may arise. However, FD is characterized by great phenotypic variability. The classic form of the disease primarily affects male patients and is characterized by an absence or minimal residual activity of α-GALA. Individuals with partially retained enzymatic function exhibit the nonclassical, late-onset phenotype FD. In female patients, the onset and severity of symptoms are largely influenced by the stochastic inactivation pattern of 1 of the 2 X chro-mosomes. Thus, female patients often exhibit a more heterogeneous phenotype, ranging from asympto-matic carriers to late-onset disease presentations.¹

Fortunately, effective intravenous enzyme repla-cement therapy (ERT) for FD has been available from 2001.2 Since 2016, an oral treatment for FD has been available. Migalastat reversibly binds to the active site of specific amenable enzyme variants. This interaction stabilizes the enzyme’s molecular conformation, facilitating its proper trafficking to the lysosome. Migalastat (Galafold, Amicus Therapeutics Europe Ltd, Dublin, Ireland) serves as an effective therapeutic option for approximately 35% to 50% of FD patients who possess amenable GLA gene variants.^3,4

Although migalastat is considered as effective as ERT, data on its use in kidney transplant recipients with FD remain limited. To our knowledge, only a single case report has been published, which described a male kidney transplant recipient who transitioned from ERT to migalastat for a 12-month period.⁵ Here, we present the case of a female kidney transplant recipient who was diagnosed with FD posttransplant and who underwent migalastat therapy for a duration of 33 months.

All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional review board and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Written informed consent for submitting this case report was obtained from the patient.

We present a 57-year-old female patient who had initiated hemodialysis because of end-stage renal disease (ESRD) of undetermined etiology. Because the patient had no prior medical follow-up and her kidneys were already small at the time of hemo-dialysis initiation, a kidney biopsy was not performed. She underwent hemodialysis for approximately 4 years before she received a deceased donor kidney transplant, which proceeded without perioperative complications. After transplant, her renal function remained stable, and she maintained good physical health, aside from experiencing symptoms of depression, for which she was prescribed a serotonin reuptake inhibitor. In addition, she reported episodes of vertigo, tinnitus, headaches, and upper limb finger paresthesia. Despite comprehensive otolaryngology and neurology evaluation, no definitive cause for these symptoms was identified. The patient also had a history of hypertension, which was well controlled with antihypertensive medications, maintaining blood pressure below 130/70 mm Hg, both during the hemodialysis period and after kidney transplant. The patient’s immunosuppressive regimen consisted of tacrolimus, mycophenolate, and methylprednisolone.

Approximately 5 years after transplant, as part of a screening program for FD in kidney transplant recipients with ESRD of unknown etiology, a dried blood spot test from the patient was sent for analysis. At that time, the patient had a serum creatinine level of 1.0 mg/dL and a urine protein-to-creatinine ratio of 205 mg/g. Echocardiographic evaluation revealed left ventricular hypertrophy (LVH), with an interventricular septum thickness of 11.7 mm (normal range, 6-11 mm), a posterior wall thickness of 11.8 mm (normal range, 6-11 mm), and a left ventricular ejection fraction of 65%. Laboratory analysis showed that lyso-Gb3 levels, measured by liquid chromatography-mass spectro-metry, were at the lower limit of normal (1.8 ng/mL). Genetic testing with next-generation sequencing (Illumina platform) identified the patient as a hete-rozygous carrier of the GLA gene variant c.937G>T (D313Y). Notably, subsequent genetic screening of her descendants revealed that her 42-year-old son also carried the same mutation.

Despite positive reports about the pathogenicity of D313Y variant,6-19 this variant has been now characterized as possibly benign with a potential correlation to neurological symptoms,²⁰ and a kidney biopsy was not performed. The patient’s LVH could be attributed to her history of hypertension, and a neurological consultation was requested. Brain magnetic resonance imaging (MRI) revealed ischemic microangiopathic changes in the periventricular and deep white matter of both cerebral hemispheres, along with focal old hemosiderin deposition in the right insular region, para-sagittally in the left pons, and in the right thalamus (Figure 1). These findings could be associated with FD.¹⁶

After the patient’s neurological consultation and with consideration of the patient’s clinical symptoms and diagnostic findings, the initiation of treatment for FD was determined. Given that the D313Y variant is classified as amenable, therapy with migalastat tablets was started at a standard dosage of 123 mg every other day.^3,4

After 33 months of migalastat treatment, no adverse effects were observed, and the patient did not require a modification of type or dosage of immunosuppressive medications. The patient reported symptomatic improvement, specifically a reduction in vertigo, tinnitus, and paresthesia in the fingers of the upper limbs. Renal function remained stable, with a serum creatinine level of 1.03 mg/dL and a urine protein-to-creatinine ratio of 176 mg/g. A follow-up echocardiogram demonstrated the resolu-tion of LVH, with an interventricular septum thickness of 10.2 mm, a posterior wall thickness of 9.6 mm, and a left ventricular ejection fraction of 64%. In addition, a repeat brain MRI revealed no progression of white matter lesions.

Fabry disease is an X-linked disorder affecting glycosphingolipid metabolism, caused by a deficiency or absence of lysosomal α-GALA activity. This presentation results in the intracellular accumulation of glycosphingolipids, leading to multiorgan dysfunction, including renal failure, cardiovascular disease, cerebrovascular events, and peripheral neuropathy. Key clinical features include cornea verticillata, angiokeratoma clusters, neuropathic pain, hypohidrosis, hearing impairment, vertigo, and tinnitus. Fabry disease exhibits substantial phenotypic variability, with male patients typically presenting the classic form because of absent or minimal α-GALA activity, whereas those with partial enzyme activity develop a nonclassical, late-onset phenotype. Female patients display a heterogeneous spectrum, ranging from asymptomatic carriers to late-onset disease manifestations.¹

Our patient was a female transplant recipient with ESRD of unknown origin. She reported vertigo, tinnitus, headaches, upper limb finger paresthesia, and depression. In addition, she had LVH and a brain MRI revealed ischemic microangiopathic changes. Genetic testing identified the patient as a hete-rozygous carrier of the GLA gene variant D313Y. Lyso-Gb3 levels were at the lower limit of normal, a common finding in carriers of the above mutation.²⁰

The GLA gene D313Y variant is the most common variant associated with FD,²¹ with evidence sup-porting its pathogenic role.^6-19 However, analyses of cohorts have currently classified this mutation as possibly benign, except for potential neurological involvement.²⁰ In our patient, a native kidney biopsy was not performed to confirm FD-related ESRD, and LVH could be attributed to a history of hypertension. Because of the progressive nature of this rare disease, diagnosis often occurs at advanced stages, when renal impairment is severe and the kidneys have greatly decreased in size. Consequently, in many reported cases, kidney biopsy is not feasible.^6,7,9 In a cohort of patients with FD, a retrospective reevaluation of a previously available kidney biopsy (originally diagnosed as focal segmental glomeru-losclerosis in a carrier of the D313Y variant) revealed cytoplasmic microvacuolization of podocytes, a finding suggestive of FD.⁶

In another study, kidney biopsies were retros-pectively analyzed from a cohort of 35 consecutively biopsied patients among 64 individuals with a confirmed genetic diagnosis of FD. The biopsies were systematically evaluated using the International Study Group of Fabry Nephropathy Scoring System. Four of these patients were carriers of the “benign variant” D313Y. In the early stages of their clinical course, individuals with normal or mild albuminuria exhibited vacuolization and inclusions within podocytes, tubular cells, and peritubular capillaries. In addition, signs of chronic renal injury, including glomerulosclerosis, interstitial fibrosis, and tubular atrophy, were observed.¹⁵

A recent case report described a patient with hypertension and chronic lower limb pain who experienced his first ischemic stroke at the age of 35 years. Genetic analysis identified the D313Y variant; however, initial plasma enzyme activity was within the normal range, precluding therapy initiation. Subsequently, the patient had 2 additional ischemic strokes, progressive renal dysfunction, acute coronary syndrome, and LVH. Enzymatic activity assessment in leukocytes revealed reduced activity, leading to the initiation of ERT. The authors suggested that patients carrying the D313Y variant who exhibit significant organ involvement should be considered for early therapeutic intervention.²² Our patient, in addition to kidney failure, also presented with LVH; it is important to mention that our patient records indicated well-controlled blood pressure, with consistent readings below 130/70 mm Hg, both during the hemodialysis period and after kidney transplant.

Subsequently, a neurological evaluation was conducted, and brain MRI revealed white matter ischemic microangiopathic changes. Such lesions have been observed in carriers of the D313Y variant; are correlated with cognitive and neurobehavioral deficits, gait and balance disturbances, epileptic seizures, or depression; and may be associated with FD.¹⁶ Another study identified a potential association between the D313Y variant and Parkinson disease,¹³ whereas an increased prevalence of this mutation has been observed in young patients with stroke.^8,10,11,18 Regarding the peripheral nervous system, small fiber neuropathy was diagnosed in 7 of 9 female patients carrying the nonclassical D313Y variant.¹⁷ In addition, another study reported that patients with this GLA gene variant exhibited distinctly enlarged dorsal root ganglia.¹² Our patient experienced depression along with symptoms associated with the peripheral nervous system. Because patient with the D313Y variant are responsive to migalastat treatment,⁴ the patient was initiated on migalastat therapy. No adverse effects were observed, and no modifications to the immunosuppressive regimen (including methylprednisolone, mycophenolate mofetil, and tacrolimus) were necessary. Tacrolimus levels remained stable, as migalastat is not metabolized via the cytochrome P450 system.⁴ Notably, approximately 20% of the drug is excreted in feces, whereas 77% is eliminated via the kidneys. Therefore, migalastat administration is not recommended in patients with a glomerular filtration rate of <30 mL/min/1.73 m2.4 Interestingly, the patient’s blood pressure remained well controlled at <130/70 mm Hg without the need for adjustments in antihypertensive therapy.

After 33 months of migalastat treatment, the patient reported a reduction in vertigo, tinnitus, headaches, and upper limb digital paresthesia. In addition, LVH had also resolved, and follow-up brain MRI findings indicated no progression of white matter lesions. Notably, renal function has remained stable. It is important to highlight that, with the initiation of ERT, both allograft and patient survival outcomes in FD are comparable to those observed in other renal pathologies. However, FD demonstrates a recurrence rate of 11% over a follow-up period extending to 11.5 years.²³

Considering the discussion on the role of the D313Y variant in FD,^6-20 a limitation of our study is the absence of histopathological confirmation of FD. Unfortunately, as already noted, the diagnosis of FD was established 5 years after transplant. In addition, the patient initiated hemodialysis because of ESRD of undetermined etiology. Given the absence of prior medical follow-up and the presence of small kidneys at the time of hemodialysis initiation, a kidney biopsy was not performed, preventing any retrospective evaluation of previous biopsies. This scenario is frequently observed in reported cases of FD.^6,7,9 However, our patient exhibited characteristic FD symptoms, along with involvement of the kidneys, heart, and brain. To the best of our knowledge, this represents the second published case report on the use of migalastat in a kidney transplant recipient with FD.⁵ Notably, it is the first case in which migalastat was initiated as the primary therapy rather than after a switch from ERT. Finally, the reported case includes a follow-up period extending to 33 months. The sustained absence of adverse events related to migalastat, along with the absence of interaction between migalastat and the standard antirejection immunosuppressive regimen, provides additional evidence supporting the safety of migalastat administration in kidney transplant recipients with FD.

This case highlights that migalastat is a safe and effective therapeutic option for FD in kidney transplant recipients with amenable GLA gene mutations.

Volume: 23 Issue: 5 May 2025

FULL TEXT