Fabry Identified in Central Asian Family for First Time
Two cases of Fabry disease, diagnosed decades after symptom onset, were identified for the first time in a Central Asian family, a case study reported.
Further analysis revealed many affected family members, demonstrating the importance of examining the relatives of people diagnosed with Fabry, the researchers said.
The case study, “Case Report: First Two Identified Cases of Fabry Disease in Central Asia,” was published in the journal Frontiers in Genetics.
A deficiency in the alpha-galactosidase A (Gal A) enzyme, caused by mutations in the GLA gene, leads to the toxic buildup of a fatty molecule known as globotriaosylceramide (Gb3 or Gl-3). Gb3 accumulates in small blood vessels and most tissues and organs, causing damage.
Some GLA mutations lead to an enzyme without function or impaired function, which is associated with early onset, while other mutations leave some enzyme activity and are linked to onset at later ages.
As the GLA gene is found on the X chromosome, females can display a broad range of disease characteristics ranging from moderate to severe.
Many of the clinical features of Fabry are highly variable and can be non-specific, including episodes of severe pain, burning, and tingling sensations in the hands and feet, which may be triggered by fatigue, fever, stress, and exercise.
Other symptoms include ringing in the ear and hearing loss, generalized weakness and fatigue, and digestive problems. Fabry disease can also cause kidney and heart damage.
Because of the wide variety of symptoms, some patients report a delay in diagnosis of more than 10 years. Moreover, newborn screening programs show a higher prevalence compared to population studies, indicating that Fabry may be underdiagnosed.
Researchers in Cambodia and Kazakhstan now described, for the first time, two such cases in a family from Kazakhstan in Central Asia — where the prevalence of this disease is unknown — who were diagnosed many years after symptom onset.
The first case was a 56-year-old man referred for repeated episodes of dizziness, malaise, shortness of breath, and chest pain. His first symptom was dizziness, which occurred when he was 36. One of his brothers died suddenly at the age of 38.
More recently, the man was diagnosed with hypertrophic cardiomyopathy — when the heart muscle becomes abnormally thick, making it harder to pump blood.
A physical examination showed normal blood pressure, heart rate, oxygen saturation in the blood, and body temperature without shortness of breath at rest. Routine lab tests showed elevated protein levels in the urine, and mild anemia with a hemoglobin level of 12.7 grams per deciliter (g/dL), below the normal range of 13.5 to 17.5 g/dL.
Small raised, dark red skin lesions were clustered on the right side of his torso, and further blood tests reveal a markedly increased NT-ProBNP peptide, a marker of heart damage, of 2,928 picograms per mL (pg/mL) — significantly over normal range, which is under 450 pg/ml.
An electrocardiogram (ECG) showed signs of cardiac hypertrophy, which was supported by an echocardiogram and cardiac magnetic resonance. An ultrasound of the abdomen revealed multiple small cysts in both kidneys.
Due to the heart analyses and skin lesions, Gal A enzyme and genetic tests were ordered. These analyses showed deficient Gal A activity and a disease-causing mutation in the GLA gene — confirming the Fabry diagnosis.
The second patient was the man’s sister, age 65, who was referred due to the possibility of inherited hypertrophic cardiomyopathy. She recently experienced shortness of breath, chest pain upon physical activity, and had high blood pressure. She also had unexplained heart muscle thickness.
Blood tests revealed elevated NT-ProBNP peptide (721 pg/ml), and an abdominal ultrasound showed cysts in both kidneys. There was no evidence of abnormal heart rhythm. Although tests showed normal levels of Gal A activity, levels of Gb-3 were raised. Genetic analysis found the same GLA mutation seen in her brother.
These results prompted a complete genetic analysis of 115 family members across four generations, showing 31 females carrying one faulty GLA copy, along with 17 males. Of these people, 19 were tested, and 10 were affected.
Gal A activity was low in eight, with two males and eight females carrying the same mutation as the initial two patients. This mutation was previously associated with the classic type of Fabry disease. Two female family members with this mutation had normal levels of Gal A activity but elevated Gb-3.
Among affected individuals, one 34-year-old female had end-stage renal disease (kidney failure) and was on dialysis, another member had severe joint pain and kidney disease, one had an irregular heartbeat, while two were without symptoms. Notably, the patient with kidney failure had not been diagnosed with Fabry.
Further investigation of the family showed sudden death at a young age in three males and one female, as well as two cases of stroke in one female and one male.
“Our report is the first description of cases of Fabry disease in Central Asia and demonstrates the importance of constructing a detailed family pedigree and conducting biochemical and genetic analyses in relatives of patients diagnosed with the disease,” the investigators wrote.
“The screening of all family members is challenging; nevertheless, all efforts should be made to ensure that all at-risk groups of male and female relatives of an affected individual are timely screened to implement specific and symptomatic therapy before the disease progresses to its late stage,” they added.
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