A 29-year-old male patient, with no comorbidities or family history of heart disease, complained of tingling and burning in his legs as well as a spot in the abdominal region (angiokeratomas). He sought medical care due to atypical precordial pain (Table 1). The electrocardiogram (ECG) showed a short PR interval and signs of left ventricular overload (LVO) with T wave inversion in V3-V6 (Figure 1). The echocardiogram revealed asymmetric hypertrophy of the left ventricle (LV) in the apical region, with a maximum thickness of 17 mm and no obstruction in the LV outflow tract. The patient was initially diagnosed with non-obstructive hypertrophic cardiomyopathy (HCM), apical form. Cardiac magnetic resonance imaging (CMRI) showed circumferential hypertrophy in the middle and apical segments, with a thickness of 21 mm and multifocal myocardial late enhancement of a non-ischemic pattern (Figure 1). Genetic investigation revealed a pathogenic variant in the GLA gene (Table 2), and the alpha-galactosidase enzyme dosage showed a reduced value, confirming the diagnosis of FD. Family screening was performed and the same variant was found in the patient’s mother.

Table 1

	Case #1	Case #2	Case #3	Case #4	Case #5	Case #6
Age, years	29	57	52	40	68	64
Gender	Male	Female	Female	Male	Female	Male
Phenotype	Apical HCM	Cardiac amyloidosis	Atrial fibrillation	Asymptomatic	(Heart Failure with Preserved Ejection Fraction) HFpEF	(Heart Failure with Reduced Ejection Fraction) HFrEF
Clinical Presentation	Cardiovascular symptoms – Chest pain	Hypohidrosis, acroparesthesia, and palpitations	Palpitations, acroparesthesia, and vertigo	Anhidrosis and heat intolerance	Cardiovascular symptoms – Dyspnea	Cardiovascular symptoms – Dyspnea
Short PR interval	Yes	*	Yes	Yes	Yes	*
LVEF, %	Preserved	Preserved	Preserved	Preserved	Preserved	Reduced
Maximum thickness, mm	21	15	21	12	19	17
α-galactosidase dosage	Reduced	Reduced	-	Reduced	-	Reduced
Lyso-gb3 dosage (range: up to 0.8 ng/ml)	3.1	15.71	-	71.7	23.1	-
Renal impairment	No	No	Yes	Yes	No	Yes

* Non-sinus heart rhythm. Source: The authors.

Figure 1

Table 2

	Case #1	Case #2	Case #3	Case #4	Case #5	Case #6
Genetic Testing	Panel	Sanger	Sanger	Sanger	Sanger	Panel
Reference sequence	NM_000169.3	NM_000169.3	NM_00169.3	NM_00169.3	NM_00169.3	NM_00169.3
Chromosome Coordinate (GRCh37)	chrX-100653021	chrX-100662818	chrX-100656700	chrX-100655733-100655734	chrX-100655733-100655734	chrX: 100653930
c.DNA variant	c.1066C>T	c.73delG	c.467C>A	c.559_560del	c.559_560del	c.644A>G
Protein Variant	p.Arg356Trp	p.Asp25Thf*96	p.Ala156Asp	p.Met187ValfsTer6	p.Met187ValfsTer6	p.Asn215Ser
Zygosity	Hemizygosity	Heterozygosity	Heterozygosity	Hemizygosity	Heterozygosity	Hemizygosity
ACMG Classification	Pathogenic	Probably Pathogenic	Probably Pathogenic	Pathogenic	Pathogenic	Pathogenic

Source: The authors.

A 57-year-old female patient, reported long-standing hearing loss and tinnitus, as well as hypohidrosis and pain in the lower limbs exacerbated by cold weather during childhood (Table 1). Previously diagnosed with permanent atrial fibrillation (AF) and recurrent palpitations, she had undergone five unsuccessful ablation procedures. Her family history was poor for diseases of genetic origin. The echocardiogram showed moderate concentric LV hypertrophy, with a 114 g/m² mass index and preserved ejection fraction. The global longitudinal strain (GLS) of the LV was reduced, mainly in the basal segments of the anterior and lateral walls. CMRI revealed asymmetric LV hypertrophy, predominating in the inferolateral region, with a thickness of 15 mm, heterogeneous late enhancement of a non-ischemic pattern, and reduced myocardial native T1 (852 ms, reference ~1000 ms) (Figure 1). Genetic testing identified a pathogenic variant in the GLA gene (Table 2). The measured alpha-galactosidase enzyme activity was reduced, confirming the diagnosis of FD. The patient had two daughters and one son. The son tested positive for the same variant in family screening.

A 52-year-old female patient, on hemodialysis due to hypertensive chronic kidney disease was referred for cardiological evaluation after an episode of AF, reversed with amiodarone, during one of the hemodialysis sessions. She had always reported neuropathic pain in the extremities that worsened with cold and hot weather, as well as frequent episodes of vertigo (Table 1). Her ECG showed sinus rhythm and short PR interval as well as right bundle branch block (Figure 1). An echocardiogram was requested, which showed the interventricular septum was 21 mm thick and the lateral wall was 14 mm thick, with preserved ejection fraction and no obstruction in the LV outflow tract.

The patient reported a significant family history, including the death of her mother from chronic kidney disease, two brothers on hemodialysis, and a sister with non-dialysis chronic kidney disease. Given the family history associated with kidney and heart problems, a genetic analysis was performed which revealed a pathogenic variant in the GLA gene (Table 2), also found in her brother, confirming the diagnosis of FD in the family.

A 40-year-old male patient, reported heat intolerance and absence of sweating since childhood (Table 1). He said that his mother had been diagnosed with cardiac arrhythmia. His ECG showed sinus rhythm with a short PR interval and signs of LVO. On echocardiogram, the left ventricular mass index was 142 g/m², with septal thickness of 10 mm, lateral wall thickness of 12 mm, and hypertrophy of the papillary muscles (Figure 2). Biochemical tests revealed impaired renal function and proteinuria of 1.55 g/24h. Given these findings, FD was suspected. The alpha-galactosidase enzyme activity dosage was reduced (Table 1) and the genetic test (Sanger) revealed a pathogenic variant in the GLA gene (Table 2), also identified in his mother.

Figure 2

A 68-year-old female patient, complained of dyspnea on exertion, which significantly limited her daily activities. She reported episodes of atypical precordial pain, unrelated to the effort, (Table 1) with no other complaints. When asked about her family history, she said that her father had died at the age of 45 from an undetermined cause. The ECG showed a short PR interval, intraventricular conduction disturbance, and diffuse alterations in ventricular repolarization. The echocardiogram showed concentric ventricular hypertrophy of the LV, as well as increased thickness of the interventricular septum and lateral wall of 19 mm and 18 mm, respectively. The calculated LV-indexed mass was 320 g/m². The GLS was calculated and showed reduced values in the inferno-later-basal region (Figure 2). A genetic panel for evaluation of HCM genocopies showed the presence of a pathogenic variant in the GLA gene, confirming FD (Table 2). Two of the patient’s children underwent a family screening and the variant was identified in one of them.

A 64-year-old male patient, with a history of HCM diagnosed 30 years ago, without other systemic symptoms (Table 1), was admitted due to decompensated heart failure, profile C. Family history included a brother also diagnosed with HCM. Despite optimized treatment and cardiac resynchronization therapy performed three years earlier, the echocardiogram revealed an LV ejection fraction of 29% and ventricular hypertrophy with septal and lateral wall thicknesses of 17 mm (Figure 2). Due to being refractory to inotropic withdrawal, the patient was considered to be in the terminal phase of the disease and underwent a successful heart transplant.

Histopathological analysis of the explanted specimen (Figure 2) and a genetic panel (Table 2) revealed a pathogenic variant in the GLA gene, with reduced levels of alpha-galactosidase enzyme activity. His brother was also sequenced for the same gene, and the same variant was found, of maternal origin.