Fabry symptoms vary widely in family members with same gene mutation
Case series: Manifestations ranged from recurrent strokes to nerve pain
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Four family members with Fabry disease carrying the same GLA mutation showed markedly different neurological manifestations, ranging from recurrent strokes to nerve pain and hearing loss, according to a case series.
Brain small-vessel disease was detected in three evaluated adults, while the youngest family member, an 18-year-old girl, had eye and heart changes but no neurological issues, highlighting the variable effects of the mutation even within the same family.
The cases were described in “Neurological phenotype in Fabry disease: case series with GLA missense variant c.749 A > C (p.Gln250Pro),” published in The Egyptian Journal of Neurology, Psychiatry and Neurosurgery.
All four family members carried same GLA mutation
Fabry disease is caused by mutations in the GLA gene, leading to the toxic accumulation of fatty substances, mainly globotriaosylceramide (Gb3), in cells and tissues. This may lead to symptoms affecting the skin, kidneys, heart, and nervous system. The GLA gene contains instructions for producing an enzyme called alpha-galactosidase A (alpha-Gal A).
Neurological manifestations of Fabry disease may present suddenly or progressively, spanning from pain due to nerve damage to severe cerebrovascular events, and may significantly reduce patients’ quality of life.
In this report, researchers described the case of four family members with Fabry disease carrying a missense GLA mutation called c.749 A>C (p.Gln250Pro), a disease-causing variant reported in Fabry patients in the U.S, Europe, and Japan. A missense mutation causes one amino acid, or protein building block, to be replaced by another, which may alter a protein’s function or stability.
The researchers identified the variant during the evaluation of a 53-year-old man who had been diagnosed with severe chronic kidney disease at age 49. He had also experienced a stroke that caused temporary weakness on his right side and had a history of high blood pressure and small, dark-red skin lesions.
Neurologically, the man also reported intermittent pain, numbness, or tingling in his hands and feet, particularly when exposed to high temperatures. He also reported frequent headaches, hearing impairment, and tinnitus, or perception of noises in the ears when no external sound is present.
Testing showed markedly reduced alpha-Gal A activity and elevated levels of lyso-Gb3, a fatty substance derived from Gb3 that circulates in the blood. Genetic testing identified the disease-causing GLA variant, confirming a Fabry diagnosis.
Brothers’ strokes related to cerebral small-vessel disease
The same variant was subsequently identified in the man’s mother, brother, and niece, showing he inherited the mutation from his mother.
The patient’s 49-year-old brother had the most severe neurological involvement, with recurrent strokes causing temporary weakness and walking problems. He also developed hearing loss and tinnitus, as well as protein in the urine, a sign of kidney damage, and cornea verticillata, a Fabry-related change in the eye.
Brain MRI showed areas of stroke-related damage and areas of brain tissue loss. Despite these findings, nerve conduction testing was normal.
Researchers believed that the strokes in the two brothers were related to cerebral small-vessel disease (SVD), a condition in which damage to the brain’s tiny blood vessels can reduce blood flow and cause small areas of brain damage. These findings “reinforce current recommendations that patients with [Fabry] undergo brain MRI every 3-5 years to detect cerebrovascular abnormalities,” the researchers wrote.
We emphasise the importance of early and comprehensive neurological exploration — including brain MRI and neurophysiological studies — of all patients and carriers with Fabry disease, even when they are asymptomatic.
The 73-year-old mother had a much milder disease. She had slightly reduced alpha-Gal A activity and elevated lyso-Gb3 levels but normal kidney function. She reported mild episodes of pain or tingling in her feet over the previous decade and had developed hearing impairment in one ear.
Brain imaging showed small areas of stroke-related damage, although she had no history of stroke, and nerve testing suggested mild slowing of nerve conduction. The researchers noted that this pattern is unusual in Fabry disease, and additional tests would be needed to determine its significance.
The youngest family member had cornea verticillata and a shortened PR interval, a change in the heart’s electrical activity, but neurological examination and nerve testing were normal. She had mildly reduced alpha-Gal A activity and elevated lyso-Gb3 levels. The girl had refused a brain MRI.
Overall, brain SVD was detected in all clinically evaluated adults, while small-fiber neuropathy was present in two family members.
“Thus, we emphasise the importance of early and comprehensive neurological exploration — including brain MRI and neurophysiological studies — of all patients and carriers with Fabry disease, even when they are asymptomatic,” the researchers concluded.
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