Practical Pearls: Recognition and Treatment For Fabry’s Disease and Morquio A Syndrome

Fabry’s Disease and Morquio A syndrome are two rare genetic diseases that lead to a diverse series of problems including cardiovascular.(1,30) Until recently, treatment options have been limited to treat these conditions. Now that there are available therapies to help improve quality and quantity of life, (20,46) it is important to be able to recognize these conditions in clinical practice to help initiate treatment earlier. The goal of this “Practical Pearl” is to help identify these conditions earlier to help improve patient outcomes.

Mucopolysaccharidoses (MPA) type IV A, also known as Morquio A syndrome, is an autosomal recessive inherited deficiency of the lysosomal enzyme N-acetylegalactosamine-6-sulphate sulphatase (GALNS). The syndrome is characterized by the accumulation of keratan sulphate and chondroitin-6-sulphate.(1,2) The presentation ranges from mild to severe phenotypes due to over 220 mutations linked to the GALNS gene on chromosome 16q24.3.(3-5) Given its rarity, it is common for diagnosis to be delayed or missed with reported incidence ranging from 1 in 76,000 to 1 in 640,000 live births.(6-8) 

Infants usually appear normal at birth and develop signs and symptoms over time due to the accumulation of glycosaminoglycans in organs. The condition is characterized by skeletal dysplasia. Findings include
a short stature, odontoid hypoplasia, cervical spinal cord compression, pectus carinatum, abnormal gait, hypermobile joints, genu valga, platyspondyly, kyphoscoliosis, thickened heart valves and preserved intellect.(9-14) Left ventricular hypertrophy is associated with a decrease in stroke volume and compensatory higher resting heart rates, which should be allowed to remain elevated to help preserve cardiac output.(15) Spinal cord injury and respiratory failure result in significant mortality with patients often becoming wheelchair dependent in the second decade and not surviving past the third decade of life.(16,17) Given the progressive nature of the disease, early referral to a genetic center for definitive diagnosis is crucial in optimizing patient outcomes. Enzyme activity testing in dried blood and urinary glycosaminoglycan testing may serve as screening tools but definitive diagnosis is by demonstration of reduced GALNS activity in fibroblasts or leukocytes. In cases with strong clinical suspicion for the disease but inconclusive enzyme results, molecular analysis clinches the diagnosis.(15,18)

Until recently, treatment for Morquio A syndrome was supportive and symptom-driven. However, the approval of enzyme replacement therapy with elosulfase alpha, a recombinant human GALNS administered as weekly infusions, has proven to be effective with a favorable safety profile. Treatment should be implemented as soon as diagnosis is confirmed.(15,19-21)  Valve replacement surgery may be considered per standard guidelines.(22,23) Anesthesia for surgery should be carried out by an anesthesiologist familiar with the disease as deposition of mucopolysaccharides in the oro-pharynx complicates intubation and atlanto-axial instability raises the risk of subluxation and quadriparesis.(24)

Fabry’s disease is an X-linked lysosomal storage disorder caused by the deposition of globotriaosylceramide (ceramide trihexoside), a lipid material, throughout the body. This is due to deficiency of the enzyme alpha-galactosidase.(25,26) Males are more commonly and severely affected than females who usually manifest at a later age.(27) Carrier females may remain asymptomatic or manifest as full-blown disease.(28) The incidence of the classic manifestation of Fabry’s disease is reported to be 1:22,000 to 1:40,000 in males.(29-31) Glycosphingolipid accumulation in vascular endothelium results in ischemia and infarction (systemic, but uniquely effects the renal vasculature) culminating in early death.

Signs and symptoms may appear in childhood or adolescence and include acroparesthesias (pain in the extremities), “Fabry’s crises” of episodic acute pain, characteristic angiokeratomas on the skin with hypohydrosis, intolerance to extremes of temperature and proteinuria.(32-34) These patients develop left ventricular hypertrophy, valvular and coronary artery disease, arrhythmias, ascending aortic aneurysms and heart failure.(35-37) Progressive renal ischemia and dysfunction lead to dialysis dependence by the fifth decade of life.(38)

Given the spectrum of manifestations, diagnosis is often delayed. Clues to diagnosis include renal failure, cardiomyopathy with left ventricular hypertrophy, arrhythmias, heat intolerance, corneal opacities, obstructive pulmonary disease and hearing loss.(39) Initial testing includes obtaining a a-Gal A enzyme level, which if markedly deficient or absent in a male patient is diagnostic. Female carriers may have a normal a-Gal A assay and thus should undergo molecular testing.(40) Once diagnosis is established, referral to a genetic counselor should be made to educate the patient on the course of the disease, its inheritance and treatment options including enzyme replacement therapy. Prenatal testing for a-Gal A activity can be performed on cultured amniocytes or chorionic villi.(41)

“Before the development of enzyme replacement therapy (ERT), the management of Fabry’s disease was supportive and symptom-driven.”

Before the development of enzyme replacement therapy (ERT), the management of Fabry’s disease was supportive and symptom-driven. Blood pressure control is essential to reduce cardiovascular, renal and cerebrovascular disease. Given there is evidence to support this is a prothrombotic state, anti-platelet agents can be considered.(42) Pain is usually the earliest manifestation and is refractory to non-steroidal anti-inflammatory agents, which may conversely hasten renal dysfunction.(43,44) Renal failure is the most common cause of death in classic Fabry’s disease and dialysis or renal transplant can prolong life. Transplanted kidneys do not develop the disease.(45) 

Enzyme replacement therapy in Fabry’s disease is an area of active research. Therapy should be initiated as soon as the diagnosis has been established. Two preparations of human a-Gal A are available – gene-activated human a-Gal
A (Replagal) and recombinant human a-Gal A (Fabrazyme). Both proteins have been found to be similar in structure, tolerability and activity.(46) The goal of treatment with ERT is to halt progression of the disease. Early trial data has been encouraging and clinical experience with Gaucher’s disease supports this.(47,48) The availability of ERT has put a new focus on the prompt recognition and diagnosis of Fabry’s disease.

In summary, these are two rare conditions related to abnormal accumulation of material related to enzyme deficiencies.  We should be aware of these conditions and the features that can prompt an earlier diagnosis.  We now have treatments beyond supportive care that show promise in treating these conditions, which makes earlier diagnosis and intervention even more important. 

Disclosure statement: Dr. Shetty has no financial disclosures to report. Dr. Davidson has received honoraria from Amgen, Sanofi, Regeneron, Akcea, and Esperion.

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