1. with homozygous p.Leu490Pro mutation
Haematopoietic stem cell transplantation in 3 Mucopolysaccharidosis I patients
with homozygous p.Leu490Pro mutation
Ghosh A1, Jones S1, Broomfield A1, Mercer J1, Wynn R2
1Willink Biochemical Genetics Unit, Manchester Centre for Genomic Medicine, 2Bone Marrow Transplantation Unit, Royal Manchester Children’s Hospital
Introduction
The p.Leu490Pro mutation is a missense mutation first described in an Indian patient and subsequently found in Pakistani patients. This genotype is associated with an attenuated MPS I phenotype. A previous report described a cohort of 14 UK patients with this mutation all of Pakistani/Kashmiri origin who were treated with ERT1. We describe three patients diagnosed shortly after birth who were treated with haematopoietic stem cell transplantation and their 5 siblings who were treated with ERT.
Aims
To describe the experience and outcomes of haematopoietic stem cell transplantation in 3 patients homozygous for the p.Leu490Pro mutation
known to be associated with an attenuated phenotype.
Methods
Retrospective review of case notes, reporting on survival, transplant outcome, disease progression, neurological outcome and biomarker response
Results
8 children from 3 families, all homozygous p.Leu490Pro genotype, all of Pakistani/Kashmiri origin living in the UK
All ERT treated patients (5) had attenuated (Hurler-Scheie) phenotype, 2 started ERT at < 6 months as were siblings of known patients
HSCT treated patients diagnosed early in life as siblings of known MPS I patients
HSCT treated patients (3): All HSCT from related donors, 2/3 bone marrow, 1/3 peripheral blood stem cells
All received ERT with laronidase (α-l-iduronidase) prior to HSCT at a dose of 0.58 U/kg weekly
All received full intensity busulfan based conditioning with pharmacokinetic monitoring
Table 1. HSCT treated patients
Patient number
Sex
Signs at diagnosis
Age at HSCT (months)
ERT doses
(pre-HSCT)
(post-HSCT
Age at last review (years)
Survival
& engraftment
Clinical status
Neurological outcome 1 F
Trace corneal haze
Vertebral beaking
5.8 22
3.0
Alive
Stable chimerism
(70-80% donor)
Mild corneal clouding
Spinal brace for gibbus
Borderline overnight
saturations (mean 94%)
Normal development 2 M
Borderline cardiac function
No organomegaly or
spinal deformity
3.9 10
1.9
Falling chimerism now stabilised
(25%) donor
Good cardiac function 2m
post transplant 3
Mild hepatomegaly
Normal spine
4.8 14
(92% donor)
Small PFO on echo
Table 2. ERT treated patients
Patient number
Sex
Signs at diagnosis
Age at starting
ERT(years)
Age at last review (years)
Survival
Clinical status
Neurological outcome 4 M
Hepatomegaly
0.6
12.2
Alive
Asthma (FVC 81%, FEV1 72%)
Thickened mitral valve
Mild corneal opacification
Full scale IQ 72 (borderline) 5 F
Kyphosis
Upper airway obstruction
2.4
10.6
Carpal tunnel syndrome
Glaucoma (iridotomies age 8y)
Moderate corneal clouding
Dysplastic mitral/aortic valve
Full scale IQ
‘extremely low’ range 6
Abnormal facial features
Umbilical hernia
Mild LVH, good function
2.8
12.1
Corneal clouding
No LV dilatation, good function
Snoring but sleep study good
Mild restriction hips and shoulders
FVC 59%, FEV1 67%
Full scale IQ 92
‘average’ range 7
Hepatosplenomegaly
Corneal haze
Frequent infections
6.1
15.4
Carpal tunnel release
Adenoidectomy
Restriction of hip movement
8-plate surgery for genu valgum
Mild mitral/aortic regurgitation
FVC 42%, FEV1 37% 8
Minimal
No hepatosplenomegaly
0.4
8.6
Trivial mitral regurgitation
Mild hearing impairment
FVC 85%, FEV1 86%
Language ability
Working memory
Figure 1. Total GAG reduction
Conclusions
Biochemical outcomes were equivalent for ERT and HSCT in this cohort though a previous report has shown better substrate reduction by HSCT than ERT2
Further follow up and experience is needed to fully assess clinical outcomes but age at therapy is likely to be an important determinant
Neurological outcome has the potential to be better with HSCT
References
Arora, R. S., J. Mercer, M. Thornley, K. Tylee and J. E. Wraith (2007). "Enzyme replacement therapy in 12 patients with MPS I-H/S with homozygous p.Leu490Pro mutation." J Inherit Metab Dis 30(5): 821
Wynn, R. F., J. E. Wraith, J. Mercer, A. O'Meara, K. Tylee, M. Thornley, H. J. Church and B. W. Bigger (2009). "Improved metabolic correction in patients with lysosomal storage disease treated with hematopoietic stem cell transplant compared with enzyme replacement therapy." J Pediatr 154(4):
Total GAG not significantly different at 6m, 12m post treatment for HSCT vs ERT (Mann-Whitney U)
GAG as % of ULN for age not significantly different at 6m, 12m, most recent for HSCT vs ERT (Mann-Whitney U) (data not shown)
Urinary DS:CS ratio not significantly different for 6m, 12m, most recent for HSCT vs ERT (Mann-Whitney U) (data not shown)