Unusual Mucopolysaccharidoses cases. Tim Hutchin and Louise Allen Newborn Screening and Biochemical Genetics, Birmingham Children s Hospital

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1 Unusual Mucopolysaccharidoses cases Tim Hutchin and Louise Allen Newborn Screening and Biochemical Genetics, Birmingham Children s Hospital

2 A Brief MPS History Lesson.. In 1917 Hunter (type II) reported two brothers with coarse facial features, mental retardation and bone disorders. First detailed description of an MPS was Hurler (Type I) in In 1929 Morquio gave a precise description of MPS IV and 1963 Sanfilippo defined Type III. Why no MPS V? In 1962 Scheie and colleagues described a patient with corneal clouding and skeletal dysplasia initially referred to as MPS V until it was discovered that it was a milder form of Type I Dr Maroteaux and Dr Lamy (MPS VI) 1972 Dr William Sly (MPS VII) 1996 Natowicz (MPS IX) -Hyaluronidase deficiency (one case?)

3 Signs and symptoms of MPS can be difficult to identify as they may overlap with common childhood complaints. Early diagnosis is important as treatment options are available for some. Clinically heterogeneous but generally characterized by a period of normal growth and development, followed by progressive organomegaly, developmental delay, skeletal abnormalities, cardiac abnormalities, coarsening of facial features. Hearing loss, corneal clouding, joint stiffness and short stature may occur. Mental retardation occurs in some forms. Diagnosis is made by increased excretion of glycosaminoglycans (GAGs) in urine and then determination of the GAG(s) excreted by 1D and/or 2D electrophoresis. Confirmation by enzyme or DNA analysis.

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5 One Dimensional Cellulose Acetate Electrophoresis

6 Case 1- Difficulties making a diagnosis 2 year old boy Global developmental delay Mild dysmorphic features Plagiocephaly (flat head) Hepatomegaly and nephromegaly Dysplastic hips Unusual rocking behaviour Severe speech delay

7 1 st urine- raised DMB 61.8mg/mmol creatine (<37.6) 1D too faint organic acids unsatisfactory possibly due to interfering substance urine also dilute Pos QC 2 nd urine- raised DMB (47 mg/mmol) but 1D too faint again organic acids suggested presence of contaminating emollient/soap

8 3 rd urine- raised DMB mg/mmol 1D and 2D showed spots in position of heparan and heparin-like component organic acids did not show contaminating bands Heparan sulphate Chondroitin sulphate Pos QC Enzyme analysis confirmed MPS IIIA. No treatment currently available

9 Case 2 - Difficulties not making a diagnosis 3 year old girl Skull asymmetry Developmental delay Out of region patient with raised DMB

10 1 st urine- raised DMB 45.1mg/mmol creatine (<37.6) 2D showed a spot of unknown significance Unknown spot Chondroitin sulphate Heparan sulphate

11 2 nd & 3 rd urine- raised DMB 8.0 & 7.5 mg/mmol creatine (<37.6) 1D electrophoresis normal So not consistent with an MPS disorder

12 Case 3- Diagnosis via Media

13 Case 3- Diagnosis via Media 2 year old boy, previously seen for sepsis/ jaundice and persistent wheeze. In and out of hospital with persistent infections. Large head. Seen in outpatients where mother told doctor he has what that little boy on television has and asked Dr to take a sample to test for this. Channel 4 series Inside Birmingham Children s Hospital had recently featured brothers with MPS II (Hunters).

14 Urine showed increased DMB (94.5mg/mmol), heavy band of dermatan and subsequent enzyme analysis confirmed diagnosis of MPSII Pos QC Child is now 4 years old and on ERT. Attending nursery though has problems with delayed motor skills, can be aggressive, development is levelling off.

15 Confusion via Media The dad who thought his son s MPS3B had been caused by being bitten by a schipperke dog somewhere in the forests of Eastern Europe where the family originates from. Sugar consumption reduced as a potential treatment

16 Unclear/incomplete Request Forms Positive nitrite - patient actually had developmental delay (MPS3) Mosquito syndrome Technical problems Difficulties with Urine GAGs Urine too dilute or contaminated, e.g. heparin in patients on ITU or cardiac patients, emollients in nappy (or beauty) creams. No cellulose acetate!!! The Future MS/MS methods Newborn Screening for MPS