Q J Med 2004; 97: 205-209
QJM vol. 97 no. 4 (c) Association of Physicians 2004; all rights reserved.
Secondary skeletal involvement in Sanfilippo syndrome
From the Departments of 1Pediatric Sciences and 2Internal Medicine, Università Cattolica Sacro Cuore, Rome, Italy
Received 17 October 2003 and in revised form 19 January 2004
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Background: Sanfilippo syndrome, or mucopolysaccharidosis (MPS) type III, is a rare lysosomal storage disease, resulting from errors in the catabolism of heparan sulphate.
Aim: To evaluate bone turnover and bone mineral density (BMD) in MPS type III patients.
Design: Clinical and observational study.
Methods: We evaluated serum markers of bone formation or resorption, and measured BMD using dual-energy X-ray absorptiometry (DEXA), in three patients with MPS type III.
Results: Serum vitamin D were low, and BMDs greatly reduced at lumbar and femoral sites, indicating the possibility of osteoporosis and osteomalacia.
Discussion: These skeletal effects probably result from nutritional deficiencies and inability to walk, rather than from the genetic defect itself. Secondary skeletal involvement in patients with MPS type III may represent a considerable cause of morbidity, and requires interventions to reduce the risk of pathological fractures.
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Sanfilippo syndrome, or mucopolysaccharidosis (MPS) type III, comprises a group of lysosomal storage diseases caused by the deficiency of one of four of the lysosomal hydrolases involved in heparan sulphate catabolism. Heparan sulphate is a complex molecule, consisting of repeating disaccharides of glucuronic acid and L-iduronic acid, some of which are sulphated with
-linked glucosamine residues. MPS type III is due to accumulation of heparan sulphate and other complex molecules in the central nervous system and is the commonest form of glycosaminoglycan storage disease in Italy. The four enzyme defects are expected to cause an identical clinical phenotype, which may be recognized in childhood by developmental retardation, slowly progressing to behavioural disturbances, severe dementia and a vegetative state by the second decade. Each of the four enzymic deficiencies constitutes a specific subtype of MPS III (named A, B, C and D), inherited as autosomal recessive disease.1 Symptoms, severity and rate of progression can vary widely among patients with MPS type III, but mental retardation is generally profound: children do not develop social or communicative skills in the preschool years, with a tendency toward the flattening of motor development during childhood, and death in the second or third decade.2,3 Despite its frequency, MPS type III is the most difficult type of MPS to manage, and only supportive care can be offered to patients and their families. There is little evidence of bone tissue involvement in MPS type III, since the process of heparan sulphate accumulation is mostly limited to the central nervous system, in contrast to other forms of MPS. Unfortunately, data about fracture risk and bone mineral density (BMD) in MPS type III are lacking, and there are few reports in the medical literature regarding animal models of MPS. We have studied three patients with MPS type III, to better comprehend the mechanisms responsible for their skeletal pathology. |
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Case histories
Patient 1, female, came to physicians’ observation because of her coarse face and speech delay at 3 years of age. Diagnosis of Sanfilippo A syndrome became clear on large urinary excretion of heparan sulphate and dosage of fibroblast heparan-sulphaminidase. At the age of 8 years, she showed marked neurological deterioration with disorganized sleep, characterized by confabulation, tears and frequent awakenings. She had lost the ability to walk at the age of 9 years, and had been fed through a percutaneous gastrostomy since the age of 13 years. At the time of our evaluation, the patient was 15 years old, and no fracture demonstrated on X-ray films had been reported in her history.
Patient 2, male, had a normal history excepted for irritability and walking disability: he was diagnosed with Sanfilippo B syndrome at the age of 6 years on urinary heparan sulphate checking. He had reported sleeplessness since the age of 15 years, and had been using a wheelchair since 16, having lost the ability to walk independently at the age of 10 years. He underwent a percutaneous gastrostomy, as a consequence of severe failure to thrive at 19 years. At the time of our evaluation, the patient was 24 years old, and no fracture had been observed on X-ray films.
Patient 3, male, without dysmorphic features, began to complain of great restlessness at the age of 5 years. Diagnosis of Sanfilippo B syndrome was established by heparan sulphate urinanalysis, and he was referred to our hospital for neurological follow-up. He walked without support until the age of 10 years, and only in recent times he has encountered progressive difficulties in standing upright. Sleep disturbance began at an early age, and still produces problems for the family. At the time of our evaluation, the patient was 11 years old and no atraumatic fracture had been demonstrated on X-ray films in his history.
Investigations
These three patients with MPS type III, diagnosed by the combination of urinary tests and enzymic dosages in skin fibroblast cultures, strictly home-living and with very limited sun exposure, were briefly admitted to our department. Heights were measured to the nearest 0.5 cm and weights to the nearest 0.1 kg; body mass index was calculated as weight divided by height squared for each patient. We investigated bone turnover by evaluating biochemical parameters related to bone formation/resorption and checked cortical and trabecular BMD through dual-energy X-ray absorptiometry (DEXA) in the same patients. We measured 25OH-vitamin D (cut-off for vitamin D insufficiency: 20 ng/ml), osteocalcin (N 3.4–11.7 ng/ml), alkaline phosphatase (N < 279 UI/l in adults, < 525 UI/l in adolescents), parathyroid hormone (N 10–40 pg/ml), serum CrossLaps (a biochemical marker of bone resorption, N 0.2–1.2 ng/ml in females, 0.2–0.7 ng/ml in males), calcium (N 8.5–10.5 mg/dl), phosphorus (N 2.5–4.5 mg/dl) and urinary calcium and phosphorus output over 24 h (respectively N 75–200 mg/l and N 220–740 mg/l). The Hologic QDR-2000 densitometer was used for BMD assessments: no anaesthesia was required, and the maximum time required for each evaluation was about 20 min. BMDs for each patient were expressed in g/cm2, both from lumbar vertebrae L2–L4 and femoral neck; results were expressed as Z-score, the standard deviation (SD) from normal mean BMD for an age- and sex-matched Italian paediatric population. Z-scores have the advantage of clearly indicating not only how likely/unlikely a certain result is to occur within a normal population, but how far the result is from that predicted.4 An abnormal DEXA result is defined as more than 1 SD below the normal mean, expressed as a Z-score > - 1. Osteopenia is defined as Z-score > - 1, osteoporosis as Z-score > - 2. A Z-score > - 1 indicates approximately a two-fold higher risk for fractures, a Z-score > - 2.5, more than four-fold risk for fractures.
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The features of the patients studied are shown in Table 1.
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Discussion |
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Osteopenia and osteoporosis are defined by variable degrees of reduced BMD, associated with microarchitectural deterioration of the skeleton, leading to enhanced bone fragility and subsequent increased fracture risk; osteomalacia is otherwise characterized by defective mineralization of the osteoid in mature bones.5 Our knowledge of genetic mechanisms involved in bone formation and resorption is rapidly and progressively expanding. Bone pathology is a further challenge to the management of patients with MPS: osteoporosis and osteomalacia may be observed at different times, depending on the stage of the disease, and derive from impaired maintenance of the mineralizing matrix at the level of bone formation. Spine radiographs are not highly sensitive for quantitative bone mass assessment, although demineralization can be suspected in the spine when trabeculae appear radiographically indistinct or fuzzy.6 In our experience, the occurrence of vertebral collapse and long bone fracture is a likely outcome of osteoporosis/osteomalacia in older patients with MPS type III who were not extensively studied with modern devices. Bone derangements in MPS may be explained by many contributing factors: low body weight, nutritional deficiencies, lack of sun exposure, absence of pubertal events, sex hormone deficiencies, relative inactivity and lower limb disuse, spasticity, and treatment with antiepileptic drugs, as well as the accumulation of undegraded glycosaminoglycans in bone tissue for some types of MPS.
The importance of environmental factors on bone mass acquisition is often underestimated, compared to that of genetic determinants, and this is particularly true for MPS type III, where heparan sulphate deposition is almost exclusively neurological (and not skeletal). Deficiency of vitamin D causes growth retardation, with rickets in children and osteomalacia in adults through deficient bone mineralization. The basic abnormalities are delay in the skeleton mineralization rate and failure of 1,25(OH)2-vitamin-D-dependent mechanisms in the osteoblasts. Vitamin D plays an important role in osteoblast differentiation in vivo, and enhances the in vitro expression of alkaline phosphatase, osteopontin and osteocalcin pivotal genes.7 In addition, reduced supplies of calcium/phosphorus due to malabsorption with secondary hyperparathyroidism may lead to unbalanced bone turnover and osteopenia. Bone densitometry is becoming widely used, because of its rapidity, safety and accuracy in measuring BMD and in defining fracture risk.8 DEXA has been used in animal models of MPS, but not in human MPS, to measure BMD and elucidate the pathophysiology of skeletal involvement.9–11
Our three patients with MPS type III, two males aged 11 and 24 years, respectively, and one female aged 15 years, were evaluated for serum parameters related to bone health and underwent BMD assessment at the lumbar spine and femoral neck. We found vitamin D insufficiency with mild secondary hyperparathyroidism, high serum levels of osteocalcin, alkaline phosphatase and CrossLaps, resulting in high-turnover osteoporosis.
For the definition of BMD, the Z-scores were generated from Italian paediatric population reference values. Comparison of BMD values in our patients shows relevant differences: patients 1 and 2 had significant degrees of osteoporosis, with low BMD, in contrast to patient 3, who was younger, able to maintain a standing position with aid and showed no densitometric signs of skeletal disease. Differences among these patients can be found in type of feeding (gastrostomy in the first two) with subsequent inadequacy of nutritional support, inability or preservation of walking, and use of antiepileptic drugs. Clearly, immobilization even for a short period is deleterious with respect to skeletal health, while weight-bearing activity such as walking (even with aid) is greatly beneficial. In a previous study, related to children with myelomeningocele who might present serious locomotor disabilities, the ability to walk was a highly significant determinant of normal BMD and bone mass acquisition, along with the development of appropriate muscle mass.12 The absence of pubertal events is another co-factor in compromised bone acquisition, but we currently know very little about how hormone roles during puberty interact with nutrition and exercise to affect bone tissue. In patients with MPS type III, the effect of physical activity on bone mass acquisition seems more pronounced than that of sex hormones. Anti-epileptic drugs may also influence bone loss, and vitamin D supplementation should be recommended in every patient with epileptogenic MPS. Prolonged artificial nutrition combined with immobilization appears to worsen the possibility of bone acquisition: mineral or vitamin intakes in patients with neurodegenerative disease rarely meet the recommended dietary allowance, and a few studies suggest differences in BMD related to different levels of neurological deterioration.13 Calcium and vitamin D replacement therapy could be a simple inexpensive approach to mitigate osteopenia and improve quality of life in patients with advanced MPS, tailoring dosage to the individual patient, ensuring compliance, and carefully monitoring hypercalcaemia/hypercalciuria. In our patients, we have suggested the oral daily supplementation of dietary calcium and vitamin D to ameliorate bone mass and structure, but this ideally needs to be applied before peak bone density is achieved, i.e. when it is easier to influence bone mineral acquisition. When BMD is found to be lower than expected in MPS type III, great efforts to enhance bone formation and to gain weight should be encouraged to attain an acceptable bone status and thus a better quality of life (free from fracture and bone pain).
In conclusion, patients with MPS type III are at high risk for osteoporosis or osteomalacia, because of prolonged artificial nutrition (with the possibility of nutritional deficiencies), reduced intake or biogenesis of vitamin D, unavoidable vitamin D insufficiency and the inability to walk. Fracture rate risk increases substantially with the rate of bone turnover, as assessed by markers of bone formation (osteocalcin, alkaline phosphatase) and resorption (serum CrossLaps) and with progressive failure in ambulation. Checks on vitamin D metabolism and DEXA scans represent simple and reproducible means to monitor nutritional supply and assess bone loss in patients with MPS type III, although adequate interventions to correct BMD and improve skeletal health in the long term are still needed.
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Acknowledgments |
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We are indebted to Professor G. Segni for his constant guidance in the clinical management of these patients, and we owe special thanks to the laboratory of Metabolic Diseases in the Department of Pediatric Sciences for their contribution to the diagnostic path of our patients with mucopolysaccharidoses.
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Footnotes |
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Address correspondence to Dr D. Rigante, Department of Pediatric Sciences, Università Cattolica Sacro Cuore, Policlinico Universitario ‘A. Gemelli’, Largo Gemelli n. 8 I-00168, Rome, Italy. e-mail: drigante{at}libero.it
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