Keywords

Mucopolysaccharidosis, Hurler syndrome, Hurler scheie syndrome, attenuated hurler, glycosaminoglycan, L-iduronidase, aldurazyme, laronidase, dysostosis multiplex

About the Authors

Bharath Raj Kidambi, Kalpana Ramanathan, Srinivasagalu K

Junior Resident Institute of Internal Medicine Rajiv Gandhi Government General Hospital Chennai 03Assistant Professor Institute of Internal Medicine Rajiv Gandhi Government General Hospital Chennai 03Professor and Director of Institute of Internal Medicine Rajiv Gandhi Government General Hospital Chennai 03

Address For Correspondence

Dr. Bharath Raj Kidambi, No.5 Gokulam colony, No.2 Ramavaram Main road, Valasaravakkam, Chennai 600087

Introduction

Mucopolysaccharidosis type I, is a lysosomal storage disorder due to deficiency of enzyme alpha-L-iduronidase. Based on the recent clinical data and therapeutic outcomes, Mucopolysaccharidosis type I is classified into Hurler (severe phenotype), Hurler Scheie (intermediate phenotype) and Scheie (mild phenotype) syndromes [1].

The glycosaminoglycan, dermatan sulphate and heparan sulphate which provide structural support to the body is not degraded properly in this disorder. This leads to excessive accumulation within the lysosomes and lead to multiorgan damage. Diagnosis is done by identifying the deficient enzyme activity by a dried filter paper test. Treatment options and diagnostic testing are not available in most parts in India and the enzyme replacement therapy is quite costly. Uncertainty among primary physicians is due to rarity of the disease and the lack of well randomized trials and treatment guidelines [5, 6].

Case Report

13 year old male child, presented to our emergency department with swelling of both legs, gradual onset and progressive breathlessness (NYHA class IV at presentation) with history of orthopnoea and paroxysmal nocturnal dyspnoea. Family history revealed a similar history in the first born child who died due to suspected cardiac problem at 8 years. Developmental history suggested delay in development for all milestones. There was no history suggestive of congenital heart disease, or of any renal, liver or thyroid problem. On Examination, he appeared of short stature, had craniofacial disproportion, coarse facies (gargoyle), saddle shaped nose, thick lips, bilateral corneal clouding (see figure A-C). Auscultation showed a pan systolic murmur in the mitral area radiating to the axilla, distended abdomen with hepatosplenomegaly. Central nervous system showed a moderate mental retardation and a waddling gait.

Chest X-ray with PA and lateral view, showed cardiomegaly and spatula shaped ribs. X-ray of the wrist joint demonstrated irregularly shaped carpal bones and pointed (bullet shaped) metacarpals [4]. Collectively the X-Ray findings of Mucopolysaccharidosis are termed as dysostosis multiplex (see figure D-F). Special tests were done to diagnose the suspected mucopolysacharidosis. 24 hour Urinary heparin sulphate and urinary acid albumin was positive. Alpha iduronidase levels were only 0.2 micromole /L (deficient – less than 2 % of normal).

Echocardiography showed moderate mitral regurgitation with severe pulmonary hypertension and severe Tricuspid regurgitation. It also showed the right atrial and ventricular dilatation and bulging of interatrial septum into the Left atrium. Patient’s condition deteriorated rapidly and patient succumbed to refractory heart failure.

Discussion

Mucopolysaccharidosis type I is a rare disorder. It is inherited in an autosomal recessive manner. There are more than a 100 different mutations of IDUA gene [3]. Due to the varied phenotypic presentation, the natural history of the disease in not well known for intermediate and mild phenotype. However severe phenotype (Hurler Syndrome) is known to have an early involvement of the musculoskeletal and central nervous system involvement [1, 2]. It is usually progressive and leads to an early death within the first two decades. Death in severe phenotype is usually due to cardiorespiratory failure. Attenuated forms of Hurler syndrome (Hurler Scheie and Scheie) usually grow into adulthood. Life expectancy is good and CNS involvement is uncommon in intermediate and mild phenotype. Disease progression is much slower, and the disease has variable characteristics. Delineation between phenotypes is based on age of presentation, rate of progression and genotyping.

Recently Indian studies have been done for screening mucopolysaccharidosis type I and II with Heparin Co factor II as a biomarker. However its utility in differentiating subtypes and monitoring disease progression is limited [8, 9].

There are currently two treatment options for MPS type 1, Haematopoietic stem cell transplantation and Enzyme replacement therapy [7]. The indications, optimal dose, efficacy and safety profile are still being studied. Haematopoietic stem cell transplantation is the treatment of choice if patient is younger than 2.5 years. It is also indicated in patients with severe phenotype and CNS involvement. The procedure related mortality was initially high, but improved with better drug therapy. Using enzyme replacement as an adjunct before the stem cell transplantation improves the clinical condition.

All patients who are not candidates for haematopoietic stem cell transplantation, usually benefit from laronidase therapy. Laronidase is an intravenous enzyme replacement therapy. It cannot cross the blood brain barrier however and so is of limited use in treating central nervous system manifestations of MPS type 1.

Both the treatment options work better if started earlier in the course. The optimal dose of laronidase is approximately 100IU/week. However due to the rarity of this condition, much larger trials are needed before deciding on the dosage and safety. Life threatening anaphylaxis are reported after laronidase infusion. Finally treating MPS type 1 is a multimodal approach and team work is needed.

Disclosure Statement

None

References

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