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Published in final edited form as:
J Paediatr Child Health. 2010 June ; 46(6): 316–322. doi:10.1111/j.1440-1754.2010.01715.x.

The Natural History and Osteodystrophy of Mucolipidosis Types
II and III
Grace David-Vizcarra1, Julie Briody3, Jenny Ault4, Michael Fietz5, Janice Fletcher5, Ravi
Savarirayan6, Meredith Wilson1, Jim McGill7, Matthew Edwards8, Craig Munns9, Melanie
Alcausin1, Sarah Cathey, and David Sillence1,2
1Department of Clinical Genetics, The Children’s Hospital at Westmead, NSW
2Discipline of Genetic Medicine, University of Sydney, Camperdown, NSW
3Bone Densitometry, Department of Nuclear Medicine, The Children’s Hospital at estmead, NSW
4Department of Rehabilitation, The Children’s Hospital at Westmead, NSW

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5Division of Genetic Medicine, Women’s and Children’s Hospital, North Adelaide, SA
6Genetic Health Victoria, Royal Children’s Hospital, Parkville, Victoria
7Department of Metabolism, Royal Children’s Hospital, Brisbane, Qld
8Hunter Genetics, Newcastle, NSW
9Department of Endocrinology, The Children’s Hospital at Westmead, NSW

Abstract
Aim—To assess the natural history and impact of the secondary bone disease observed in patientswith Mucolipidosis II and III.

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Methods—Affected children and adults were ascertained from clinical genetics units around
Australia and New Zealand and the National Lysosomal Diseases Research Unit in Adelaide. The
study encompassed all patients ascertained between 1975 and 2005. Data focussing on
biochemical parameters at diagnosis, and longitudinal radiographic findings were sought for eachpatient. Where feasible, patients underwent clinical review and examination. Examinations
included skeletal survey, bone densitometry, and measurement of serum and urine markers ofbone metabolism. Functional assessment was performed using the Pediatric Evaluation andDisability Inventory (PEDI).
Results—25 patients with ML II and III were ascertained over a 30-year period. Serum calcium(median 2.35 mmol/L range 2.16–2.64) and phosphate (median 1.51 mmol/L range 1.17–1.72)
were normal but five patients had mild elevation of alkaline phosphatase. Serum osteocalcin andurine deoxypyridinoline/creatinine were elevated. Two radiological patterns were observed (i)transient neonatal hyperparathyroidism in infants with ML II and (ii) progressive osteodystrophy
in patients with ML II/III and ML III. Molecular Genetic analysis of mutations in the αβsubunit ofCorresponding Author: Professor David Sillence, Academic Department of Medical Genetics, The Children’s Hospital at Westmead,
Locked Bag 4001, Westmead, NSW AUSTRALIA 2145, Tel: +61-2-9845 0000, Fax: +61-2-9845 3204, davids@chw.edu.au.

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Page 2the UDP-N-acetylglucosamine:lysosomal enzyme N-acetylglucosaminyl-1-phosphotransferase
gene in 9 subjects correlated with the phenotypic severity.

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Conclusion—ML is characterised by a progressive bone and mineral disorder which we
describe as the Osteodystrophy of Mucolipidosis. The clinical and radiographic features of thisosteodystrophy are consistent with a syndrome of “Pseudohyperparathyroidism”. Much of the
progressive skeletal and joint pathology is attributable to this bone disorder.
Keywords
Mucolipidosis; hyperparathyroidism; pseudohyperparathyroidism; osteoporosis

Introduction

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Mucolipidosis II and III (I-cell disease and pseudo-Hurler polydystrophy, respectively) are
rare genetically related inherited metabolic disorders of lysosomal metabolism with a
combined frequency of 1:422,0001. These are characterised by disordered processing ofmultiple lysosomal degradative enzymes caused by the deficiency or abnormal function of
UDP-N-acetylglucosamine:lysosomal enzyme N-acetylglucosaminyl-1-phosphotransferase(phosphotransferase)2. The underlying defects result in deficient post-translational
modification of numerous enzymes, which depend on mannose phosphorylation for uptake
and localisation by cells where substrate degradation occurs3. This in turn results in global
deficiencies of lysosomal degradative enzymes with concomitant intracellular accumulationof both partly degraded glycosaminoglycans and sphingolipids.
ML II has symptoms and signs similar to those encountered in patients withmucopolysaccharidoses and to a lesser extent gangliosidoses. It is characterised by coarse
facial features, short stature, hyperplastic gums, organomegaly, and retarded psychomotor
development4, 5. ML III is a milder disorder with attenuated characteristics and survival toadult life6, 7. Intermediate forms of ML II and III have been previously described8, 9. The
presence of clinical heterogeneity is explained by the presence of at least threecomplementation groups26–28. This is consistent with the finding that the phosphotransferase
is a complex enzyme consisting of three subunits that are product of two genes30, 31. Most
affected individuals with ML II and ML III have mutations in the alpha/beta subunit32.

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Previous radiographic studies of mucolipidosis types II and III have focussed mainly on
those bone changes collectively called “dysostosis multiplex”, although a few authors havedrawn attention to bone changes in infants with ML II which are similar to infantile
hyperparathyroidism and rickets. In this study, we describe a progressive bone and mineraldisorder, its biochemical characteristics and skeletal radiographic findings in patients with
Mucolipidosis II and III. In addition, we assess the impact of the secondary bone disease
observed in patients on spine and hip morbidity, and assess the frequency and morbidity
arising from non-osseous complications of mucolipidosis.

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Materials and Methods
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Patients were ascertained through Clinical Genetics Units around Australia and New
Zealand, the Kazimierz Kozlowski Skeletal Dysplasia Library and the Connective Tissue
Dysplasia clinic at the Children’s Hospital at Westmead. Patients registered with those units
between 1975 and 2005 were included. All diagnoses were enzymatically confirmed by the
National Lysosomal Diseases Research Unit in Adelaide. Ethics committee approval for the
study was obtained from the ethics committee of the Children’s Hospital at Westmead.
Information was sought from collaborating clinical geneticists on diagnosis, radiographic
findings, and previous biochemical investigation of mineral metabolism in the patientsmanaged by them. Where feasible, living patients underwent clinical review andinvestigations. Investigations included skeletal survey, bone densitometry, measurement ofbone markers (serum calcium, alkaline phosphatase, parathyroid hormone, parathyroid
hormone related protein, serum osteocalcin, and urine deoxypyridinoline crosslinks).
Functional assessment was performed using the Pediatric Evaluation and Disability
Inventory (PEDI)10. This standardised scaling tool measures the domains of life skills,
mobility, and social function. DNA molecular genetic diagnosis was undertaken in a subsetof patients10.

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Results
Clinical Data
A total of 25 affected (ML II = 15; ML III = 5; Intermediate MLII/ML III = 5) from 16
families were ascertained. The female to male ratio was 1.8 (16F:9M).
Morbidity

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Ten surviving patients were available for clinical review. Five patients had ML type II/III, 1
had ML type II and 4 had ML type III. All of the 8 subjects in whom height data wereavailable were very short, height SDS = −8.25±3.4. Chronic otitis media was present in 7/10
patients. Cardiovascular complications such as mild dilatation of the heart and valvular
thickening and incompetence were present in 9/10. Sleep disordered breathing requiringcontinuous or bi-level positive airway pressures (CPAP or BiPAP) at the level of 8 to 10 cm
water was recorded in 6/10. Four young adults developed upper limb paraesthesia with MRI
evidence of thickening of the extradural tissues at the level of C1-2. One patient required
cervical fusion for C1-C2 instability at 8 years of age and a 20 year old progressed toinoperable occipitocervical dislocation. Five patients had chronic constipation requiringalmost daily laxatives and occasional bowel evacuation.
Nine patients had psychomotor retardation. One patient with ML III who was evaluated at
40 years of age had normal intelligence. All patients had progressive joint stiffness. The
patient with ML type II had significant joint stiffness at 5 years of age such that she could
only sit and stand with support. She moved around with her small wheelchair for less than
90 minutes a day. She cried when being held and picked up, implying that she hadsignificant pain, probably bone in origin. The other 9 patients suffered from significant backand joint pains, mainly in the hips by age 3 years. They became confined in their wheelchair

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Page 4by the time they reach 10 years of age. One patient had bilateral hip replacements at 36
years.

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Biochemical findings
Eight patients underwent biochemical evaluation, Table 3. All had normal serum calcium(median 2.35 mmol/L range 2.16–2.64), phosphate (median 1.51 mmol/L range 1.17–1.72),
and parathyroid hormone (median 2.9 pmol/L range 1.8–5.0). Parathyroid receptor protein
concentrations were available in six patients and all were within normal levels (median <0.6
range <0.6–1.4). Alkaline phosphatase was elevated in only 1 out of the 8 (median 155 u/Lrange 102–495). Seven had osteocalcin levels and were elevated in 6 (median 3.8 nmol/L
range 0.8–7.5). Levels of urine deoxypyridinoline/creatinine were elevated in all patients(median 26.7 nM/mM range 14.2–45.5).
Lysosomal Enzyme Biochemistry

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Diagnosis of all patients, with one exception, was confirmed enzymatically by measurementof markedly elevated plasma lysosomal hydrolases and the demonstration of markedly
deficient white cell enzymes in cultured skin fibroblast. In one patient, diagnosis was
accomplished by review of radiographs after her siblings had been confirmed to havemucolipidosis on enzymology testing. This particular subject was stillborn and was also
found to have 45, X on chromosome analysis.
Molecular DNA Analysis
Mutations in αβsubunit of the UDP-N-acetylglucosamine:lysosomal enzyme Nacetylglucosaminyl-1-phosphotransferase gene were detected in 9 patients and aresummarized in table 2.
Radiographic findings
Skeletal radiographs showed distinctive patterns in patients at different ages. These weregrouped as evidence of:i.

neonatal hyperparathyroidism

ii. osteodystrophy (similar to chronic osteitis fibrosis cystica)

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The radiographic findings of neonatal hyperparathyroidism were seen in all babies with ML
type II. These changes included generalised bone demineralisation, subperiosteal bone
resorption around the shafts of the long bones or periosteal cloaking, and fractures of longbones and ribs (Figure 1). In addition, there were features of rickets with metaphyseal
cupping or fraying. Three patients had punctate calcifications in the region of the coccyx,
pubis and tarsals at birth.
In subjects over 4 months, radiographs show features of an osteodystrophy with features
reminiscent of “osteitis fibrosa cystica”. There were marked progressive changes in bone
texture and density with areas of cystic lucency. Erosive changes especially in the hands andhips were progressive over time (Fig 3 and 4). The proximal phalanges became broad and

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under modelled. The proximal metacarpals showed a mixture of features of osteodystrophyand dysostosis multiplex becoming extremely eroded and narrowed to a point. The carpal
bones became extremely osteopenic and hypoplastic, consistent with severe carpal
osteolysis. Similarly there was severe osteolysis of the femoral heads and femoral necks.
There was also over modelling of the long bones and bowing of the proximal end of thehumerus and femur leading to coxa valga or “shepherd’s crook deformity” (Figure 2). The
lower third of the ilia became progressively hypoplastic and resorbed (Figure 4). In addition,
there was progressive osteopenia of the spine. The spine showed thoracolumbar kyphosis,
beaking of the vertebrae, and subluxation typical of lysosomal storage disorders withskeletal involvement.
In all patients surviving the first year of life, skeletal radiographs showed a mixture ofosteodystrophic bone changes and atypical changes of dysostosis multiplex. These included
proximal pointing of metacarpals in the wrist, dysplastic changes in the lower third of theilia, marked broadening of the ribs becoming oar-shaped, and beaking of the lower thoracic
and lumbar vertebrae.
Bone Densitometry

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The results are reported in a supplementary paper detailing the baseline parameters andeffect of treatment with Cyclic Intravenous Pamidronate.
Functional assessment (PEDI)
Except for Assistance to Caregiver Skills in the Social Function Domain, the five subjects
who were assessed had scores below the level of their age normative functional capability
and performance in all domains. Almost all of the scaled scores in all subjects were below
70. However the subjects understood requests and instructions and they were able to provide
information about their own activities and needs indicating that comprehension was muchhigher than might be concluded from their severe physical disability.

Discussion

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Many lysosomal storage disorders, particularly the mucopolysaccharidoses are characterisedby “dysostosis multiplex”. The combination of radiographic features includes “J” shaped
sella turcica, oar shaped ribs, anterior inferior beaking of lower thoracic to upper lumbar
vertebral bodies, flared iliac wings, constricted iliac bodies, dysplastic femoral heads,“bullet-shaped” proximal phalanges and central pointing of proximal metacarpals12. In thisstudy, dysostosis multiplex developed with age but was not the characteristic feature ofnewborns.
In addition to dysostosis multiplex, the skeleton in Mucolipidosis types II and III ischaracterised by an osteodystrophy. In ML II, the osteodystrophy has clinical andradiographic features of congenital hyperparathyroidism. In some neonatal subjects,
chemical hyperparathyroidism was also demonstrated.
Features of congenital hyperparathyroidism have been reported in Mucolipidosis type II as
early as 19 weeks of gestation13. Osteoporosis, fractures, periosteal new bone formation

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NIH-PA Author Manuscript(“cloaking”) and cupped epiphyses have been described in neonates14–21. Histologic
examination has confirmed the presence of hyperparathyroidism22–24. Pazzaglia et al23–25
described spontaneous evolution of hyperparathyroidism to dysostosis multiplex in threepatients, and they noted resolution of high bone turnover and defective calcification in theolder child. In this study we have observed that in ML II/III and ML III there are progressive
radiographic features which overlap with juvenile hyperparathyroidism or chronic
hyperparathyroidism or “osteitis fibrosa cystica”.
In this study, we have confirmed that ML II cell disease is not associated with a disturbanceof serum levels of calcium and phosphorus. In our one patient with ML II serum parathyroid
hormone was normal but may have been elevated previously as the diagnosis was not madeuntil 4 months of age. Similarly bone and mineral investigations have been delayed in other
patients in this series. However all subjects had persisting high bone turnover as measured
by deoxypyridinoline/creatinine ratio and progressive osteopenia. Since features of thisosteodystrophy are not present in the other lysosomal storage disorders except for
Galactosialidosis, we hypothesize that the osteodystrophy is related to the underlying
biochemical disorder.

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The possible pathogenesis for the osteodystrophy needs to explain the observation oftransient hyperparathyroidism of the newborn and the progressive “osteitis fibrosa cystica”
which develops from 3–6 months of age. Transient neonatal hyperparathyroidism is also
reported where a fetus has inherited a mutation in the calcium-ion sensing receptor36
mutation from the father, and has an unaffected mother. The clinical disorder in the father ismanifest as familial hypercalcaemic hypocalciuria. The fetal parathyroid in this situation has
a higher “set point” than normal for serum calcium and registers that the mother’s serum
calcium is too low35. The fetal parathyroid responds with excessive secretion ofparathormone at the expense of the skeletal integrity with resultant demineralisation, rickets,
resorption, and cystic changes with periosteal cloaking. Characteristically, the secondary
hyperparathyroidism resolves spontaneously by 3–4 months of age. In ML a possible
mechanism for the biochemical/radiologic changes might be that one of the components ofsignal transduction from the PTH receptor requires mannose-6-phosphate targeting and thisinduces the PTH receptor signalling.

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Following birth we have confirmed that chemical hyperparathyroidism in ML II resolves but
a progressive osteodystrophy appears to develop further and progress. We also confirmedthat circulating levels of parathyroid related protein were normal. Postnatally, theradiographic features could be consistent with an increased sensitivity of skeletal tissue tonormal circulating levels of parathormone.
In a previous report of the treatment of the osteodystrophy with cyclic intravenous
pamidronate in two teenagers with ML III, attention was drawn to the bone
histomorphometric finding of increased osteoclastic activity25. Our biochemical findings
support high bone turnover with elevated osteocalcin and deoxypyridinoline. One possibility
is that there is defective targeting of lysosomal enzymes to the osteoclast with abnormal
biofeedback and induction of PTH receptor transduction, with focal areas of increased
resorbtion. Another possibility is that mannose-6-phosphate targeting is important for other

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proteins involved in signal transduction of PTH effects on bone formation and remodelling.
The radiographic findings show a remarkable similarity to Osteitis Fibrosa Cystica. We
hypothesize that the pathology is best explained as “Pseudohyperparathyroidism” i.e. tissue
sensitivity to circulating PTH.
There is a need for further studies regarding the pathophysiology of the osteodystrophy in
ML II and ML III. Answers to these questions will be obtained from the early andsystematic study of the osteodystrophy of subjects with Mucolipidoses who should be
investigated from birth or time of diagnosis. Furthermore study of the cat model33, 34 of
Mucolipidosis might give additional answers to this perplexing problem.
The osteodystrophy of the Mucolipidoses contributes significantly to the skeletal and joint
symptoms and progressive and destructive bone disease which place a significant additionalburden of weakness, pain and disability over that encountered in mucopolysaccharide
storage disorders. A better understanding of the pathogenesis is important to improve thequality of life of those affected. Treatment with Cyclic Intravenous Pamidronate is apromising adjunctive therapy which is presently being evaluated for those affected with the
Mucolipidoses25.

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Acknowledgments
Dr David-Vizcarra was the ConnecTeD and Jameson Read Fellow during this research. The authors acknowledge
the helpful discussion and insights with Dr Sheila Unger, Clinical Geneticist, into the potential mechanisms
particularly the mechanisms resulting in neonatal hyperparathyroidism.
We are indebted to the other clinical geneticists who contributed information about patients reviewed in the study.
Drs Martin Delatycki, David Amor from Genetic Health Victoria,
We also express our gratitude to Mrs Jenny Noble, secretary Lysosomal Diseases New Zealand, who provided
much encouragement and support.

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Fig 1.

Radiograph of pelvis and femurs in a neonate with Mucolipidosis Type II – showing
features of neonatal hyperparathyroidism including periosteal cloaking and destructive bonelesions,

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Fig 2.

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Radiograph of pelvis and femurs in a 3 year old with Mucolipidosis type II showing overmodelling of the proximal end of the femur leading to coxa valga or “shepherd’s crook
deformity”. The lower third of the ilia have become progressively hypoplastic and resorbed.

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Fig. 3.

Radiograph of hands and wrists in four affected with ML II/III aged (a) 4 yrs., (b) 16 yrs.,(c) 18 yrs., (d) 19 yrs. showing progressive osteolysis of carpal centres, proximal
metacarpals and distal forearm bones.

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Fig. 4.

Radiograph of pelvis and proximal femurs in four affected with ML II/III aged (a) 4 yrs., (b)16 yrs., (c) 18 yrs., (d) 19 yrs. showing progressive dysplasia/resorbtion of the low third of
the ilia femoral heads and femoral necks.

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Table 1

NIH-PA Author Manuscript

Clinical Features at Diagnosis
Clinical Features at Diagnosis
Coarse facial features

ML II
N=15

ML II/III
N=5

ML III
N=5

14

5

4

Corneal clouding

1

3

1

Chest deformity

5

0

1

Umbilical hernia

3

3

0

Inguinal hernia

5

1

0

Hepatomegaly

3

0

0

Splenomegaly

3

0

0

Joint contractures

8

5

2

Congenital hip dislocation

6

2

0

Evidence of hyperparathyroidism

15

5

NK

5

5

Progressive Osteodystrophy

NIH-PA Author Manuscript

NK = not known

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Table 2

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Mutations in the “Clinical” cohort of mucolipidosis (n = 9)
Mutations in the AB subunit in a subgroup of patients
Mutation 1

Mutation 2

Mucolipidosis II (1)c.2591insG

c.3503ΔTC

Mucolipidosis II/III (5)c.10A>Cc.1399ΔG

Mucolipidosis III (1)c.1399ΔG

c.3335+6T>G

Mucolipidosis III (2)c.3565C>T

IVS17+6T>G

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Table 3

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Baseline Biochemical Findings (n=8)
Biochemistry and markers

MedianRange

Normal Values

Calcium

2.35

2.16–2.64

2.10–2.65 mmol/L

Phosphorus

1.51

1.17–1.72

1.00–1.80 mmol/L

ALP

155

102–495

80–355 U/L

Osteocalcin

3.8

0.8–7.5

0.5–2.3 nmol/L

PTH

2.9

1.8–5.0

1.0–7.0 pmol/L

PTHrP

<0.6

<0.6–1.4<1.3 pmol/L

Deoxypyridinoline/Creatinine

26.7

14.2–45.5

Variable ranges

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NIH-PA Author Manuscript
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