What enzyme is deficient in Fabry disease, and what builds up?

Fabry disease is caused by deficiency of the lysosomal enzyme alpha-galactosidase A, encoded by the GLA gene on the X chromosome. Normally the enzyme removes the terminal galactose from globotriaosylceramide (Gb3, also called ceramide trihexoside), turning it into lactosylceramide. Without enough enzyme, Gb3 and its deacylated form, lyso-Gb3, build up in the lining of blood vessels and in kidney, heart and nerve cells, which explains the pain, skin, kidney, heart and stroke problems.

What are the classic symptoms of Fabry disease?

In the classic form, symptoms start in childhood: episodes of burning pain in the hands and feet (acroparesthesias) triggered by exercise, heat, fever, fatigue or stress; clusters of dark red angiokeratomas in the bathing-trunk area; reduced sweating with heat intolerance; whorled corneal opacities that do not affect vision; abdominal pain and diarrhea; and tinnitus. In adulthood, proteinuria progresses to kidney failure, the heart develops hypertrophy and arrhythmias, and strokes can occur at a young age.

Is Fabry disease X-linked recessive, and can women have it?

Fabry disease is X-linked. Many review books list it as X-linked recessive, but MedlinePlus Genetics and NORD simply call it X-linked, and MedlinePlus notes that it causes significant problems in many heterozygous women. Random X-inactivation means a woman's symptoms can range from none to as severe as in affected men; whorled corneal opacities and burning pain are common, and about 10 percent reach kidney failure. An affected man passes the variant to all of his daughters and none of his sons.

How is Fabry disease diagnosed?

In males, low alpha-galactosidase A activity in plasma or white blood cells establishes the diagnosis, and GLA gene testing confirms the variant; classic disease shows less than 1 percent of normal activity. In females, enzyme activity is unreliable because some heterozygotes have levels in the normal range, so GLA genetic testing is required. Plasma lyso-Gb3 supports the diagnosis. Organ involvement is then assessed with urine protein and kidney function, ECG and cardiac imaging, brain MRI, and hearing and eye examinations.

How is Fabry disease treated?

US options include enzyme replacement with intravenous agalsidase beta (Fabrazyme), labeled for patients 2 years and older, or pegunigalsidase alfa (Elfabrio), labeled for adults, each given every 2 weeks and both carrying boxed warnings for anaphylaxis. Adults with an amenable GLA variant can instead take migalastat (Galafold), an oral pharmacologic chaperone that stabilizes their own misfolded enzyme. Supportive care includes an ACE inhibitor or ARB for proteinuria, carbamazepine or gabapentin for pain, and dialysis or kidney transplantation for kidney failure.

How do you tell Fabry disease from Gaucher, Tay-Sachs and Niemann-Pick disease?

Fabry disease is the only X-linked sphingolipidosis and the only one defined by pain crises, angiokeratomas, reduced sweating and kidney, heart and stroke complications. Gaucher disease (glucocerebrosidase) causes hepatosplenomegaly, cytopenias and bone crises. Tay-Sachs disease (hexosaminidase A) causes infant regression with a cherry-red spot and an exaggerated startle but no organ enlargement. Niemann-Pick types A and B (sphingomyelinase) cause hepatosplenomegaly with foam cells, and type A adds neurodegeneration and a cherry-red spot. All three are autosomal recessive.

Fabry Disease: Enzyme, Pathway, Signs & USMLE Question

Fabry disease is an X-linked lysosomal storage disease: variants in the GLA gene leave too little alpha-galactosidase A, so globotriaosylceramide (Gb3, also called ceramide trihexoside) builds up in blood vessel walls and in kidney, heart and nerve cells. In the classic form, boys develop burning pain in the hands and feet (acroparesthesias), angiokeratomas, reduced sweating (hypohidrosis) and whorled corneal opacities (cornea verticillata) in childhood, then proteinuria and chronic kidney disease, left ventricular hypertrophy (LVH) and arrhythmias, and early stroke as adults. Heterozygous women are often affected too. Men are diagnosed by low enzyme activity and women by GLA genetic testing; treatment is enzyme replacement (agalsidase beta or pegunigalsidase alfa) or, for amenable variants, the oral chaperone migalastat.

The Q-bank vignette

A 17-year-old boy has episodes of burning pain in his hands and feet brought on by exercise and hot weather. He sweats very little and feels unwell in the heat. Examination shows clusters of small, dark red-purple papules over his lower trunk and groin, and slit-lamp examination shows faint whorl-like corneal opacities; his vision is normal. Urinalysis shows proteinuria. His maternal uncle developed kidney failure in his 40s.

Deficiency of which enzyme most directly causes this condition?

A. Alpha-galactosidase A
B. Beta-glucocerebrosidase
C. Hexosaminidase A
D. Sphingomyelinase
E. Acid alpha-glucosidase (acid maltase)
F. Glucose-6-phosphatase

Answer: A, alpha-galactosidase A (Fabry disease). Every clue maps to Gb3 storage:

Clue in the stem	Why it points to Fabry
Burning hand and foot pain with exercise and heat	Acroparesthesias from small-fiber neuropathy; crises last minutes to days and are triggered by exercise, fatigue, emotional stress or rapid changes in temperature and humidity
Dark red papules on the lower trunk and groin	Angiokeratomas in the "bathing trunk" area (lower abdomen, groin, genitals, hips and thighs)
Little sweating, heat intolerance	Hypohidrosis, an early and nearly constant finding
Whorled corneal streaks, normal vision	Cornea verticillata, which does not affect vision
Proteinuria in a teenager	Gb3 storage in the kidney; proteinuria and a urine-concentrating defect come first
Maternal uncle with kidney failure	X-linked: affected men are related through their mothers

Why every other answer choice is wrong

B. Beta-glucocerebrosidase (Gaucher disease): glucocerebroside fills macrophages, giving hepatosplenomegaly, cytopenias with bruising, bone pain crises, Erlenmeyer flask femurs and "wrinkled tissue-paper" Gaucher cells. It is autosomal recessive and causes no angiokeratomas or hypohidrosis. Sketch it with the Gaucher disease draw-it-out guide.
C. Hexosaminidase A (Tay-Sachs disease): GM2 ganglioside accumulates in neurons. Infants develop normally until 3-6 months, then regress, with an exaggerated startle, a cherry-red spot and seizures, but no hepatosplenomegaly; children usually live only into early childhood. A teenager with pain crises does not fit. Review the Tay-Sachs 5-second rule.
D. Sphingomyelinase (Niemann-Pick disease types A and B): sphingomyelin-laden foam cells cause hepatosplenomegaly; type A adds rapid neurodegeneration, a cherry-red spot and death by age 2-3, while type B patients often reach adulthood. Type C is a cholesterol-transport defect, not a sphingomyelinase deficiency. See the Niemann-Pick mnemonic.
E. Acid alpha-glucosidase (Pompe disease, glycogen storage disease type II): glycogen accumulates in lysosomes of muscle. The infantile form brings cardiomyopathy with heart failure, severe hypotonia and macroglossia; later forms cause skeletal and respiratory muscle weakness. There is no rash, sweating problem or neuropathic pain. More in the Pompe disease mnemonic.
F. Glucose-6-phosphatase (von Gierke disease, type Ia): not lysosomal. Onset before age 1 with severe fasting hypoglycemia, lactic acidosis, hepatomegaly, hyperuricemia and hypertriglyceridemia; the kidneys enlarge. Treatment is frequent feeds and uncooked cornstarch.

The Fabry pathway: where alpha-galactosidase A acts

Gb3 is ceramide carrying three sugars (galactose-galactose-glucose). In the lysosome, alpha-galactosidase A removes the terminal alpha-linked galactose, turning Gb3 into lactosylceramide; later steps strip the remaining sugars, the last one by glucocerebrosidase (the Gaucher enzyme), to leave ceramide.

Enzyme missing: Gb3 and its deacylated form, lyso-Gb3, pile up in blood vessel linings and in kidney, heart and nervous system cells.
Result: painful small-fiber neuropathy and poor sweating, plus progressive disease of small blood vessels, the heart and the kidneys.
Exam rule: every sphingolipidosis is autosomal recessive except Fabry. Hunter syndrome is also X-linked, but it is a mucopolysaccharidosis, not a sphingolipidosis.

Disease	Deficient enzyme	Stored lipid	Inheritance	Telltale clues
Fabry	Alpha-galactosidase A	Gb3 (ceramide trihexoside)	X-linked	Pain crises, angiokeratomas, hypohidrosis, cornea verticillata, CKD, LVH, stroke
Gaucher	Glucocerebrosidase	Glucocerebroside	AR	Hepatosplenomegaly, cytopenias, bone crises, Erlenmeyer flask, tissue-paper macrophages
Niemann-Pick A/B	Sphingomyelinase	Sphingomyelin	AR	Hepatosplenomegaly, foam cells; type A: cherry-red spot, neurodegeneration
Tay-Sachs	Hexosaminidase A	GM2 ganglioside	AR	Regression from 3-6 months, exaggerated startle, cherry-red spot, no organomegaly
Krabbe	Galactocerebrosidase	Galactocerebroside, psychosine	AR	Infant irritability, stiffness, unexplained fevers, vision loss; globoid cells
Metachromatic leukodystrophy	Arylsulfatase A	Sulfatides	AR	Central and peripheral demyelination: motor and cognitive decline, neuropathy

For the full degradation map, use the sphingolipid metabolism table.

Clinical features from childhood to adulthood

Organ	Classic Fabry (mostly hemizygous males)
Nerves	Acroparesthesias and pain crises from childhood (reported as early as 2-8 years in boys)
Skin	Angiokeratomas; hypohidrosis or anhidrosis with heat and exercise intolerance
Eyes	Cornea verticillata (whorled streaks radiating from a central vortex), lens opacities
Gut	Episodic diarrhea, nausea, vomiting, bloating and cramping pain, especially after a large meal
Ears	Tinnitus, high-frequency hearing loss, vertigo
Kidney	Proteinuria and isosthenuria first, then progressive CKD; kidney failure usually in the third to fifth decade; Maltese crosses in urine, zebra bodies on electron microscopy
Heart	LVH that can mimic hypertrophic cardiomyopathy, short PR interval, conduction disease, supraventricular tachycardias, fibrosis, heart failure
Brain	Stroke or TIA in about 13% of patients, white matter lesions, an enlarged and elongated basilar artery

Later-onset variants (residual enzyme activity, onset usually after 25) skip the childhood signs and present with disease of the heart, kidneys or brain vessels. They are far more common than the classic form: MedlinePlus estimates all forms at 1 in 1,000 to 9,000 people, whereas GeneReviews puts classic disease at 1 in 50,000 to 117,000 males.
Prognosis: GeneReviews cites a life expectancy of about 58 years for men and 75 years for women with Fabry disease (vs about 75 and 80 years in the general population); cardiovascular disease is the most common cause of death.

Women with Fabry disease are not just carriers

Each heterozygous woman is a mosaic: random X-inactivation (lyonization) leaves some cells using the normal GLA copy and others using the variant. Severity therefore ranges from no symptoms to disease as severe as in classic males.

GeneReviews figures for heterozygous women: cornea verticillata 70-90%, acroparesthesias 50-90%, angiokeratomas 10-50%, and about 10% reach kidney failure needing dialysis or a transplant.
Exam framing: many review books file Fabry under X-linked recessive, but MedlinePlus and NORD simply call it X-linked, and MedlinePlus notes that, unlike most X-linked disorders, it causes significant problems in many heterozygous women. A woman with whorled corneas and proteinuria can still have Fabry.
Pedigree: an affected man passes the variant to all of his daughters and none of his sons; a heterozygous woman passes it to half of her children. Practice the patterns in the X-linked disorders flowchart.

Diagnosis

Males: measure alpha-galactosidase A activity in plasma or leukocytes; classic disease shows less than 1% of normal, later-onset variants more. Confirm the hemizygous GLA variant.
Females: enzyme activity ranges from markedly low to normal, so molecular GLA testing is the diagnostic test.
Biomarker: plasma lyso-Gb3 supports the diagnosis; GeneReviews notes that levels track disease severity and organ involvement and help separate classic from later-onset disease.
Stage the organs: urine protein or albumin and eGFR; ECG, echocardiography or cardiac MRI; brain MRI; hearing and slit-lamp examinations.
Biopsy is not usually needed (GeneReviews does not recommend it as a diagnostic test), but kidney electron microscopy shows lamellated zebra bodies; hydroxychloroquine can cause look-alike inclusions.
Family: test relatives once a variant is known; prenatal diagnosis by chorionic villus sampling or amniocentesis is possible.

Treatment: current US labels

Drug	Type and dosing	Labeled for	Key points
Agalsidase beta (Fabrazyme)	Enzyme replacement, IV 1 mg/kg every 2 weeks	Adults and children 2 years and older with confirmed Fabry disease	Boxed warning for hypersensitivity, including anaphylaxis; infusion reactions are common
Pegunigalsidase alfa (Elfabrio)	PEGylated enzyme made in plant cells, IV 1 mg/kg every 2 weeks	Adults with confirmed Fabry disease	Boxed warning for hypersensitivity, including anaphylaxis
Migalastat (Galafold)	Oral pharmacologic chaperone, 123 mg every other day on an empty stomach	*Adults with an amenable GLA* variant** (in vitro assay)	Binds and stabilizes the patient's own misfolded enzyme so it reaches the lysosome; no effect without an amenable variant; not recommended in severe renal impairment or dialysis; accelerated approval
Agalsidase alfa (Replagal)	Enzyme replacement, IV 0.2 mg/kg every 2 weeks	Not FDA-approved	Used in Europe and other regions

Start early. Enzyme replacement slows or prevents the decline in kidney function, especially when started early (NORD); GeneReviews advises starting it as early as possible in males and in women with clinical manifestations.
Supportive care: an ACE inhibitor or ARB for proteinuria; carbamazepine, gabapentin or phenytoin for neuropathic pain, plus avoiding triggers; aspirin, lipid lowering and blood pressure control for vascular risk; no smoking; dialysis or kidney transplantation for kidney failure.

How USMLE tests Fabry disease

The cluster: a boy with pain crises + angiokeratomas + hypohidrosis, later proteinuria, LVH or stroke. Any two should make you think of Fabry.
The adult stem: unexplained LVH (an HCM phenocopy), a stroke in a young adult, or proteinuric CKD with an X-linked family history.
The woman twist: heterozygous women can be symptomatic; diagnose them with GLA testing, not enzyme activity.
Eye contrast: cornea verticillata (Fabry, vision spared) vs corneal clouding (Hurler); Hunter syndrome has no corneal clouding.
Buzzwords: ceramide trihexoside, zebra bodies, Maltese crosses.
Drug matching: IV enzyme replacement works whatever the GLA variant; oral migalastat only for amenable variants; eliglustat is a Gaucher drug.

Key takeaways

Fabry = X-linked alpha-galactosidase A deficiency → Gb3 (ceramide trihexoside) accumulation; alpha-galactosidase A turns Gb3 into lactosylceramide.
Childhood: acroparesthesias, angiokeratomas, hypohidrosis, cornea verticillata, GI upset, tinnitus.
Adulthood: proteinuria → CKD, LVH and arrhythmias, stroke; cardiovascular disease is the main cause of death.
Heterozygous women are often affected because of random X-inactivation.
Diagnose men by enzyme activity, women by GLA genetic testing; lyso-Gb3 supports both.
Treat with agalsidase beta (age 2 and up) or pegunigalsidase alfa (adults), or migalastat for amenable variants, plus ACE inhibitor or ARB and pain control.
It is the only X-linked sphingolipidosis; the rest are autosomal recessive.