Maroteaux-Lamy Syndrome

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Disease Entity

Mucopolysaccharidoses (MPSs) are a group of disorders caused by inherited defects in lysosomal enzymes resulting in widespread intra- and extra-cellular accumulation of glycosaminoglycans (GAGs)[1]. Mucopolysaccharidosis VI (MPS VI), or Maroteaux-Lamy syndrome, is a very rare disorder with incidence estimates ranging from 0.36 to 1.30 per 100,000 [2].  Maroteaux-Lamy syndrome causes a variety of clinical manifestations that progressively worsen with age.

Etiology

It is an autosomal recessive disorder caused by deficient activity of the enzyme N-acetylgalactosamine 4-sulfatase, or arylsulfatase B, in the ARSB gene, which is involved in the degradation of the GAGs dermatan sulfate and chondroitin 4-sulfate [3]. This enzyme deficiency leads to lysosomal accumulation of partially degraded GAGs in tissues and organs[3].

Pathophysiology

The mechanisms causing clinical manisfestations of Maroteaux-Lamy are poorly understood, but the GAGs are implicated in signal transduction, sequestration of extracellular factors, and cell to cell communication[4]. Partially degraded GAGs can accumulate in soft tissues and cause joint contracture and carpel tunnel syndrome[4].

Diagnosis

Characteristic signs and symptoms, family history, and clinical evaluation can guide the physician towards diagnosis. Clinical workup includes testing for elevated dermatan sulfate, decreased arylsulfatase B activity, and molecular genetic testing[5].

Signs and Symptoms

Early signs of the disease include umbilical and inguinal hernias, followed by abnormal structural development. Facial signs include enlarged tongue, prominent eyes, a flat nasal bridge, as well as macrocephaly. The accumulation of substrate results in abnormal cartilage development and increased mucosal thickness resulting in recurrent lung infections and sleep apnea. Cardiac manifestations include valvular disease, cardiomyopathy, and arrhythmias. The reduction of exercise tolerance is attributed mainly to pulmonary and cardiac complications, in addition to increased joint stiffness. Affected patients are usually intellectually typical[2][6]. Rapidly progressive disease shows signs before 3 years of age, whereas slowly progressive disease is most often diagnosed in the 2nd or 3rd decade[5].

Ocular manifestations include corneal clouding, ptosis, acute and chronic angle-closure and open-angle glaucoma, optic nerve atrophy, and papilledema[3]. Progressive corneal opacification affects all layers of the cornea and is one the primary contributors to low visual acuity in these patients. Retinal changes are not usually associated with MPS VI[6][7][4].

There is only a 1972 postmortem study describing glycosaminoglycan deposits at the scleral level[8]. The absence of cases described may be due to two reasons. On the one hand, the fact that these scleral deposits may not be effectively common. On the other hand, these deposits may be present in most patients, but given the high prevalence of corneal opacity in MPS VI, these deposits become difficult to see and may go unnoticed. However, with the advent of new diagnostic technologies, namely the OCT, this paradigm may change. Similarly, retinal changes, although not commonly associated with this syndrome, may actually be present in some patients but go unnoticed, largely because of the highly common corneal opacity.

Management

The treatment of these patients is mainly directed to the control of factors that contribute to a low visual acuity. The main cause of visual impairment in these patients is, as noted above, the deposition of glycosaminoglycans at the cornea and subsequent hypo-transparency[7]. The ocular hypertension can be controlled medically or, if necessary, through filtering surgery. Despite being particularly challenging patients with numerous systemic comorbidities, efforts should be directed to maximize the visual acuity of these patients, allowing them to have the best quality of life possible.

Treatment

Maroteaux-Lamy syndrome can be effectively treated with corneal transplant and medical management. Both penetrating keratoplasty (PKP) and deep anterior keratoplasty (DALK) have been shown to be effective, but DALK may have fewer complications[3]. Human recombinant enzyme replacement therapy and bone marrow transplants have also been shown to be a safe and effective therapies to reduce symptoms of excess lysosomal storage[2][9].

Prognosis

Prognosis individually varies depending on the severity of symptoms and the organs involved[5].

Additional Resources

References

  1. Ashworth JL, Biswas S, Wraith E, Lloyd IC. Mucopolysaccharidoses and the eye. Surv Ophthalmol. 2006;51(1):1-17. doi:10.1016/j.survophthal.2005.11.007
  2. 2.0 2.1 2.2 Harmatz P. Mucopolysaccharidosis VI pathophysiology diagnosis and treatment. Front Biosci. 2017;22(3):385-406. doi:10.2741/4490
  3. 3.0 3.1 3.2 3.3 Rahmati-Kamel M, Javadi M, Shojaei A, Eslani M, Karimian F. Deep Anterior Lamellar Keratoplasty for Maroteaux-Lamy Syndrome. Cornea. 2010;29(12):1459-1461. doi:10.1097/ico.0b013e3181d927d6.
  4. 4.0 4.1 4.2 Fenzl C, Teramoto K, Moshirfar M. Ocular manifestations and management recommendations of lysosomal storage disorders I: mucopolysaccharidoses. Clinical Ophthalmology. 2015:1633. doi:10.2147/opth.s78368.
  5. 5.0 5.1 5.2 Giugliani R. Maroteaux Lamy Syndrome. NORD (National Organization for Rare Disorders). https://rarediseases.org/rare-diseases/maroteaux-lamy-syndrome/. Accessed October 1, 2019.
  6. 6.0 6.1 Pitz S, Ogun O, Arash L, Miebach E, Beck M. Does enzyme replacement therapy influence the ocular changes in type VI mucopolysaccharidosis? Graefes Arch Clin Exp Ophthalmol. 2009;247(7):975-980. doi:10.1007/s00417-008-1030-1
  7. 7.0 7.1 Sornalingam K, Javed A, Aslam T, et al. Variability in the ocular phenotype in mucopolysaccharidosis. Br J Ophthalmol. 2019;103(4):504-510. doi:10.1136/bjophthalmol-2017-311749
  8. Kenyon KR, Topping TM, Green WR, Maumenee AE. Ocular pathology of the Maroteaux-Lamy syndrome (systemic mucopolysaccharidosis type VI). Histologic and ultrastructural report of two cases. Am J Ophthalmol. 1972;73(5):718-741.
  9. Krivit W, Pierpont ME, Ayaz K, et al. Bone-Marrow Transplantation in the Maroteaux–Lamy Syndrome (Mucopolysaccharidosis Type VI). New England Journal of Medicine. 1984;311(25):1606-1611. doi:10.1056/nejm198412203112504.