The Mucolipidoses in Australia - The Role of Secondary

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The Mucolipidoses in Australia - The Role of
Secondary Metabolic Bone Disease

• Dr Grace David
• Professor David Sillence

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MUCOLIPIDOSES

• biochemically-related disorders of lysosomal
  enzyme processing
• characterised by facial appearance, psychomotor
  retardation, and severe skeletal abnormalities
• deficiency of phosphorylating enzyme (uridine
  diphosphate N-acetyl-glucosaminelysosomal enzyme
  precursor N-acetylglucosaminylphosphotransferase)

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PATHOPHYSIOLOGY
ROUGH ENDOPLASMIC RETICULUM
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PATHOPHYSIOLOGY
ROUGH ENDOPLASMIC RETICULUM
GOLGI BODY (transport system)
MANNOSE-6-PHOSPHATE MARKER
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PATHOPHYSIOLOGY
ROUGH ENDOPLASMIC RETICULUM
GOLGI BODY (transport system)
MANNOSE-6-PHOSPHATE MARKER
LYSOSOME
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PATHOPHYSIOLOGY
ROUGH ENDOPLASMIC RETICULUM
GOLGI BODY (transport system)
LYSOSOME
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METABOLIC BONE DISEASE IN MUCOLIPIDOSES

• Sillence (1978) noted skeletal features
  characteristic of neonatal hyperparathyroidism
• Patriqin et al (1977) described 2 cases of
  neonatal ML II with subperiosteal new bone
  formation and resorption, and irregular
  metaphyses suggestive of systemic bone disease
• Pazzaglia et al (1989) demonstrated ricket-like
  lesion of bones and hyperparathyroidism in
  neonatal ML II
• hyperparathyroidism commences prenatally in ML II
  but measurements of serum parathyroid hormone
  normalises by 3 months of age

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POTENTIAL TREATMENT FOR THE SECONDARY METABOLIC
BONE DISEASE

• Treatment of bone disorder in 2 patients with ML
  III has produced promising results (Paul Hoffman
  - personal communication 2001)
• cyclic intravenous pamidronate 15mg/M2 monthly
• rapid reduction in bone pain
• increased joint mobility
• biochemical evidence of remission of metabolic
  bone disease

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BONE REMODELING Normal vs Osteoporosis
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BISPHOSPHONATES Effect on Bones
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ASCERTAINMENT

• Skeletal Dysplasia Register, Western Sydney
  Genetics Program
• Connective Tissue Dysplasia Clinic, The
  Childrens Hospital At Westmead
• Clinical Genetics Units around Australia
• National Lysosomal Diseases Research Unit,
  Womens and Childrens Hospital, North Adelaide

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PRELIMINARY RESULTS

• 6 ML type II
• 5 ML type II/III
• 5 ML type III
• all confirmed by enzymology testing
• 11 living subjects
• 5 deceased
• 7 ascertained for cyclic intravenous pamidronate
  therapy

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METABOLIC BONE DISORDER INVESTIGATION

• Serum calcium, phosphorus and ALP - normal
• Serum osteocalcin - all elevated
• Deoxypyridinoline/creatinine ratio - elevated
• Spine bone densities low

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CONCLUSION

• ML is characterised by progressive secondary
  Metabolic Bone Disease
• some symptoms are attributable to this bone
  disorder
• joint pathology particularly hip and back
  complications are aggravated by this bone
  disorder
• there is a need for further studies regarding
  the pathophysiology of the metabolic bone disease
• the role of bisphosphonates in treatment needs to
  be investigated

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ACKNOWLEDGEMENTS

• Families who have assisted us with the studies
• Clinical geneticists who have contributed
  patients known to them
• ConnecTeD committee for their support
• MPS Australia