Delivery of anesthesia for children with Mucopolysaccharidosis Type III (Sanfilippo syndrome): a review of 86 anesthetics.

BACKGROUND: Sanfilippo syndrome (MPS III) is rare, with 97 cases in the United Kingdom between 1988 and 1998. Mucopolysaccharide infiltration of tissues in mucopolysaccharidosis (MPS) causes multi-systemic pathology including difficult airways and cardiac disease. Published anesthesia case reviews of Sanfilippo syndrome have included limited numbers of patients to date. AIM: To identify the perioperative management and complications of anesthesia in children with mucopolysaccharidosis Type III at Great Ormond Street Hospital. METHODS: A retrospective case note review of all children with MPS III in our institution was undertaken. All medical notes and anesthetic charts were analyzed, and conduct of anesthesia, airway management, perioperative complications, and associated comorbidities were identified. RESULTS: There were 43 patients with MPS III, of which 34 required anesthesia, on 86 occasions for 156 procedures between 1993 and 2015. Dental extraction was the likeliest indication for anesthesia (34%) (general surgery [30%]; ear, nose, and throat [26%]; other [10%]). Thirteen of 34 patients had cardiac pathology (valvular [n = 6], functional [n = 6], electrophysiological [n = 1]). Ten of 34 patients had evidence of clotting abnormality (mild prolonged clotting time [n = 5], low von Willebrand factor [n = 2], thrombocytopenia [n = 3]). The majority of intubations were Cormack-Lehane Grade 1 (n = 47) (Grade 2 [n = 14], Grade 3 [n = 1], Grade 4 [n = 1]). In 86 anesthetics, there were 0 cases of difficulty with mask ventilation. There was 1 case of failed intubation. They were subsequently anesthetized by a different operator uneventfully at a later date. Two perioperative complications occurred: a failed intubation and bleeding during adenoidectomy. CONCLUSION: We demonstrate a difficult airway is unlikely when anesthetizing an MPS III patient although a risk does remain. A significant proportion of MPS III have cardiac involvement although no perioperative complications were described. With associated coagulation issues, bleeding tendency, while uncommon, can occur in this group.

Mucopolysaccharidosis III (Sanfilippo Syndrome)- disease presentation and experimental therapies.

Sanfilippo Syndrome or Mucopolysaccharidosis Ill (MPS Ill) is a group of lysosomal storage diseases resulting from a deficiency of one of four lysosomal enzymes: Type A - heparan N-sulfatase (SGSH), Type B - a-N-acetylglucosaminidase (NAGLU), Type C - acetyl CoA a-glucosaminide acetyltransferase (HGSNAT) and Type D - N-acetylglucosamine-6-sulfatase (GNS). Each of these enzymes is necessary for degradation of heparan sulfate. Deficiency of any of these enzymes manifests as a neurodegenerative disorder with accompanying somatic manifestations. Typically this presents early in life with developmental delays followed by developmental regression and usually results in death sometime during the second decade of life, though several less severe cases have been described living into late adulthood (30's to 60's). Often there is a delay of several years from time of symptom onset to diagnosis. Currently treatment is limited to supportive care. We will briefly discuss the typical natural history and presumed pathophysiology of the disease. We will also discuss current experimental therapies being pursued for treatment of this devastating disease. These include enzyme replacement, gene therapy, stem cell therapy, and substrate reduction approaches.

Unexpected coronary artery findings in mucopolysaccharidosis. Report of four cases and literature review.

INTRODUCTION: The mucopolysaccharidosis syndromes are a group of lethal inherited disorders affecting multiple organ systems by the progressive deposition of glycosaminoglycan. Advances in treatment such as enzyme replacement and hematopoietic stem cell transplantation have significantly improved the outcome of these disorders. An in-depth understanding of the pathophysiology of heart disease in these disorders is essential since death from cardiac causes continues to be common. Epicardial coronary artery luminal narrowing from myointimal proliferation and glycosaminoglycan deposition is well described in severe mucopolysaccharidosis type I [Hurler syndrome, mucopolysaccharide IH] but poorly understood in other "non-Hurler" phenotypes of these disorders. Given the rarity of these conditions, autopsy specimens are uncommon. METHODS: Tissue from epicardial coronary arteries from autopsies of four patients with non-Hurler mucopolysaccharidosis (attenuated type I, type IIIA, type IIIC, and type VI) who had died after hematopoietic cell transplantation (within 1 month in three cases; after 5 years in the fourth) was examined by light microscopy. RESULTS: Unexpectedly, near-normal coronary arteries were observed in the patient with attenuated mucopolysaccharidosis type I, while the coronaries from patients with type IIIA, IIIC, and VI demonstrated classic histologic features of glycosaminoglycan deposition. The most severe findings were found in the MPS IIIC patient who had 5 years of full donor engraftment after transplantation. CONCLUSIONS: Our current understanding of the cardiac manifestations of the mucopolysaccharidoses fails to explain why near-normal coronary arteries may be observed when abnormalities would be most likely to be expected and, conversely, why significant histopathology is present when it would be least expected. Identification of downstream effects of glycosaminoglycan deposition may identify other metabolites or metabolic pathways that are important in the clinicopathologic manifestations of these diseases. SUMMARY: The mucopolysaccharidosis diseases are a group of inherited disorders affecting multiple organ systems by the progressive deposition of glycosaminoglycan. Severe coronary artery disease is well recognized in severe type I mucopolysaccharidosis (Hurler syndrome), but unexpected coronary artery disease occurs in other, "non-Hurler" mucopolysaccharidoses. Factors responsible for the development of coronary pathology in the mucopolysaccharidoses remain elusive.

Cerebrospinal fluid shunts in the management of behavioural problems in Sanfilippo syndrome (MPS III).

UNLABELLED: Severe behavioural disturbance is a very common feature of Sanfilippo syndrome (mucopolysaccharidosis III, MPSIII), and one of the more difficult aspects of the disease to treat. We describe a series of six patients with MPS III who had cerebrospinal shunts inserted in an attempt to ameliorate behaviour that had proved refractory to conventional treatment. Symptoms improved significantly in all six but removal of the shunt was necessitated in one patient due to shunt blockage and infection. CONCLUSION: Our experience suggests cerebrospinal fluid shunting should be formally evaluated as an adjunct to conventional forms of treatment of extreme behavioural disturbance in MPS III.

Ocular abnormalities in the mucopolysaccharidoses after bone marrow transplantation. Longer follow-up.

OBJECTIVE: The purpose of the study was to provide longer follow-up of ocular findings in patients with mucopolysaccharidoses (MPS) after bone marrow transplantation (BMT). DESIGN: The study design was a retrospective 6-year cohort evaluation. PARTICIPANTS: Twenty-three patients with MPS (19 with MPS type I-H, 3 with MPS type III, 1 with MPS type VI) were studied. INTERVENTION: Bone marrow transplantation was performed. MAIN OUTCOME MEASURES: The following outcome measures were considered: vision, slit-lamp biomicroscopic and funduscopic examinations, intraocular pressure, electroretinography (ERG), and retinoscopy. RESULTS: Thirteen (81%) of 16 patients showed ERG improvement in the first year. However, all patients showed slowly progressive decline of the ERG over longer follow-up. Other ocular findings included optic atrophy (n = 7 patients), disc edema (n = 6 patients), strabismus (n = 6 patients), nystagmus (n = 6 patients), cataract (n = 3 eyes), keratoconjunctivitis sicca (n = 4 eyes), ocular hypertension (n = 2 eyes), and glaucoma (n = 2 eyes). CONCLUSIONS: The MPS are rare and heterogeneous disorders characterized by progressive retinal degeneration and blindness. Ocular abnormalities can occur as a result of the disease or as a consequence of BMT. Successful BMT has been shown to improve systemic health, but this may not reflect continuing ocular status and retinal function. Despite early improvement in ERG function, longer follow-up suggests progressive retinal decline.

Usefulness of frequency analysis of cytotoxic T-lymphocytes precursors (CTL-p) for selection of HLA matched unrelated marrow donors.

A child with Sanfilippo syndrome and 5 potential unrelated marrow donors were typed serologically, tested in mixed lymphocyte reaction and typed by restriction fragment length polymorphism analysis in attempt to find a suitable donor. All donors were found to be identical with the recipient, however, these studies were not conclusive in identifying the best match donor. Therefore, recipient-donor pairs were examined by HLA-DR oligotyping. In addition we have studied the potential of cytotoxic T-lymphocytes precursors (CTL-p) analysis as a means of selection for matched unrelated donors. Low frequencies (1/10(5)) of pretransplant CTL-p correlated with oligotyping identity in all donor-recipient pairs evaluated. In one case oligotyping disclosed a previously unrecognized HLA-DRB1 disparity. This resulted in high frequencies of CTL-p (1/35,000). Based on this experience we can argue that CTL-p analysis may be used as an additional tool for selection of compatible unrelated marrow donors.

Sanfilippo disease type B. A case report and review of the literature on recent advances in bone marrow transplantation.

A patient with enzymatically proven Sanfilippo disease type B is presented. This type of mucopolysaccharidosis results from deficient o-N-acetylglucosaminidase activity leading to defective degradation of heparan sulphate. As this disease is associated with high morbidity and mortality, different therapeutic approaches are under investigation. Bone marrow transplantation is among these new choices of management. The value of bone marrow transplantation in the mucopolysaccharidoses, especially in MPS IIIB, is discussed with a wide review of the literature.

Severe mitral insufficiency in mucopolysaccharidosis type III-B (Sanfilippo syndrome).

A 6-year-old girl with mucopolysaccharidosis (MPS) III-B (Sanfilippo syndrome) who developed severe mitral regurgitation and congestive heart failure requiring surgery (valvuloplasty) is reported. One year after surgery the patient remains well, with marked improvement in her physical activity, and without signs of heart failure. This is only the second report of severe mitral regurgitation in MPS III, and is the first report of a successful repair (valvuloplasty) of a dysplastic mitral valve in the MPS. Mitral valvuloplasty should be considered instead of valve replacement in any MPS patient with mitral valve regurgitation requiring surgery.

Bone marrow transplantation for Sanfilippo disease type B.

Allogeneic bone marrow transplantation was performed on twins with Sanfilippo B disease. They were the first two patients with this disorder to undergo the procedure. There was definite evidence of engraftment as shown by conversion to donor blood group antigen and tissue type, and increased leukocyte alpha-glucosaminidase activity. Nine years post transplant, neither twin is as handicapped as her untreated brothers were at the same age, although in one twin hyperactivity and behavioural problems, characteristic of the disorder, are present. Details of the twins' intellectual development and growth, their alpha-glucosaminidase activity and urinary glycosaminoglycan excretion are reported.