PMC9822754_01
Sanger sequencing of exon 6 of the GLA gene. (a) Normal control showing wild-type (WT) sequence. (b) Patient sequence with GLA variant c.809T >C p.(Ile207Thr) in heterozygosity. The arrow indicates the nucleotide position with the sequence variant.
CRIG2022-3208810.001.jpg
PMC9822754_03_CRIG2022-3208810.001.jpg
fig1
Genetic testing demonstrated the presence of a pathogenic sequence variant in the GLA gene: c.809T >C p.(Ile270Thr), the same as the previous case although not a relative (Figure 1).
PMC9822754_02
Pedigrees. The proband is indicated with an arrow. Striped boxes represent males with Fabry disease; striped circles represent females with Fabry disease; slash indicates deceased.
CRIG2022-3208810.002.jpg
PMC9822754_03_CRIG2022-3208810.002.jpg
fig2
Regarding her family history, although her mother had a hypertrophic cardiomyopathy and her father and brother had ischaemic heart disease and sensorineural hearing loss, genetic testing was negative for FD (Figure 2).
Medical history and occurrence of events over time in two female patients treated at different stages of FD. aAT1001-011 (NCT00925301), bAT1001-041 (NCT01458119), and cAT1001-042 (NCT02194985). AV, atrioventricular; ECG, echocardiogram; eGFR, estimated glomerular filtration rate, normal: >90 and >60 for omen >50 years15; FD, Fabry disease; GI, gastrointestinal; IBD, irritable bowel syndrome; LVEF, left ventricular ejection fraction; LVH, left ventricular hypertrophy; OLE, open-label extension.
CRIG2022-3208810.003.jpg
PMC9822754_03_CRIG2022-3208810.003.jpg
fig3
At that time, typical FD manifestations (severe sensorineural hypoacusis, cornea verticillata, and angiokeratomas) were also detected (Figure 3). FD. Fabry-specific therapy was immediately initiated with enzyme replacement therapy (ERT) (agalsidase beta) (Figure 3). During follow-up, the patient experienced unexplained syncopes and conduction disturbances (first-degree auriculoventricular blockade with right ventricle bundle branch block and left anterior hemiblock), which were confirmed by a pathological electrophysiological study showing a prolonged Hiss-Ventricular (HV) interval, and the patient was fitted with a permanent dual chamber pacemaker in 2019 (Figure 3).
Changes in (a) Metabolism. (b) Renal. (c) Cardiac Parameters with treatment at different stages in two cases of FD. alpha-Gal A is expressed as a percentage of normal (% normal). Normal white blood cell activity: 22 nmol free 4 MU released/mg protein/h7 (patient 1); normal laboratory reference activity on dried blood spots samples: 4.7-18.8 mumol/L/h (patient 2); normal Lyso-Gb3: <=0.6 nm/L; normal urine GL-3: <33.8 ng/mL; normal protein excretion rate: <150 mg/24 hours; normal eGFR: >90 mL/min/1.73 m2; normal UACR: <3 mg/mmol; normal LVMI: 43-95 g/m2; normal LVPWT: 6-10 mm; normal IVSD: 6-9 mm. Dotted lines define the end of study (case 1) or treatment switch (case 2). In the cardiac parameters graph of case 1, gaps indicate a different method of measurement. Case 1: urine GL-3 and GL-3 inclusions were measured up to month 12 of the FACETS study; LVMI and LVM not measured at 8, 9, and 10 months; LVPWT measured upto 12 months of the FACETS study; case 2: UACR and LVPWT not measured at years 3 and 4. aNCT00925301, bAT1001-041; cAT1001-042. alpha-Gal A, alpha-galactosidase A; eGFR, estimated glomerular filtration rate; FD, Fabry disease; GL-3, globotriaosylceramide; IVSD, interventricular septal thickness at end diastole; LVMI, left ventricular mass index; LVPWT, left ventricular posterior wall thickness; Lyso-Gb3, globotriaosylsphingosine; OLE, open-label extension; UACR, urine albumin-to-creatinine ratio.
CRIG2022-3208810.004.jpg
PMC9822754_03_CRIG2022-3208810.004.jpg
fig4
Plasma alpha-Gal A activity was decreased (less than 30%) (Figure 4(a)).
PMC9822754_03
Sanger sequencing of exon 6 of the GLA gene. (a) Normal control showing wild-type (WT) sequence. (b) Patient sequence with GLA variant c.809T >C p.(Ile207Thr) in heterozygosity. The arrow indicates the nucleotide position with the sequence variant.
CRIG2022-3208810.001.jpg
PMC9822754_03_CRIG2022-3208810.001.jpg
fig1
Genetic testing demonstrated the presence of a pathogenic sequence variant in the GLA gene: c.809T >C p.(Ile270Thr), the same as the previous case although not a relative (Figure 1).
Pedigrees. The proband is indicated with an arrow. Striped boxes represent males with Fabry disease; striped circles represent females with Fabry disease; slash indicates deceased.
CRIG2022-3208810.002.jpg
PMC9822754_03_CRIG2022-3208810.002.jpg
fig2
Regarding her family history, although her mother had a hypertrophic cardiomyopathy and her father and brother had ischaemic heart disease and sensorineural hearing loss, genetic testing was negative for FD (Figure 2).
Medical history and occurrence of events over time in two female patients treated at different stages of FD. aAT1001-011 (NCT00925301), bAT1001-041 (NCT01458119), and cAT1001-042 (NCT02194985). AV, atrioventricular; ECG, echocardiogram; eGFR, estimated glomerular filtration rate, normal: >90 and >60 for omen >50 years15; FD, Fabry disease; GI, gastrointestinal; IBD, irritable bowel syndrome; LVEF, left ventricular ejection fraction; LVH, left ventricular hypertrophy; OLE, open-label extension.
CRIG2022-3208810.003.jpg
PMC9822754_03_CRIG2022-3208810.003.jpg
fig3
At that time, typical FD manifestations (severe sensorineural hypoacusis, cornea verticillata, and angiokeratomas) were also detected (Figure 3). FD. Fabry-specific therapy was immediately initiated with enzyme replacement therapy (ERT) (agalsidase beta) (Figure 3). During follow-up, the patient experienced unexplained syncopes and conduction disturbances (first-degree auriculoventricular blockade with right ventricle bundle branch block and left anterior hemiblock), which were confirmed by a pathological electrophysiological study showing a prolonged Hiss-Ventricular (HV) interval, and the patient was fitted with a permanent dual chamber pacemaker in 2019 (Figure 3).
Changes in (a) Metabolism. (b) Renal. (c) Cardiac Parameters with treatment at different stages in two cases of FD. alpha-Gal A is expressed as a percentage of normal (% normal). Normal white blood cell activity: 22 nmol free 4 MU released/mg protein/h7 (patient 1); normal laboratory reference activity on dried blood spots samples: 4.7-18.8 mumol/L/h (patient 2); normal Lyso-Gb3: <=0.6 nm/L; normal urine GL-3: <33.8 ng/mL; normal protein excretion rate: <150 mg/24 hours; normal eGFR: >90 mL/min/1.73 m2; normal UACR: <3 mg/mmol; normal LVMI: 43-95 g/m2; normal LVPWT: 6-10 mm; normal IVSD: 6-9 mm. Dotted lines define the end of study (case 1) or treatment switch (case 2). In the cardiac parameters graph of case 1, gaps indicate a different method of measurement. Case 1: urine GL-3 and GL-3 inclusions were measured up to month 12 of the FACETS study; LVMI and LVM not measured at 8, 9, and 10 months; LVPWT measured upto 12 months of the FACETS study; case 2: UACR and LVPWT not measured at years 3 and 4. aNCT00925301, bAT1001-041; cAT1001-042. alpha-Gal A, alpha-galactosidase A; eGFR, estimated glomerular filtration rate; FD, Fabry disease; GL-3, globotriaosylceramide; IVSD, interventricular septal thickness at end diastole; LVMI, left ventricular mass index; LVPWT, left ventricular posterior wall thickness; Lyso-Gb3, globotriaosylsphingosine; OLE, open-label extension; UACR, urine albumin-to-creatinine ratio.
CRIG2022-3208810.004.jpg
PMC9822754_03_CRIG2022-3208810.004.jpg
fig4
Plasma alpha-Gal A activity was decreased (less than 30%) (Figure 4(a)).