Introduction
Materials and methods
Patient diagnosis
Blood sample collection
Measurement of heparin cofactor II-thrombin (HCII-T) complex
Measurement of urinary glycosaminoglycans (GAGs)
Delivery of KS to mice and serum sampling
Statistical analysis
Ethical approval
Results
Serum HCII-T is elevated in MPSI, II, III and VI patients
Serum [HCII-T] (nM) | Blood spot [HCII-T] (pM) | |||||
---|---|---|---|---|---|---|
Mean ± SD | Mean age (years) (range) |
n
| Mean ± SD | Mean age (years) (range) |
n
| |
Unaffected | 8.0 ± 2.1 | 8.8 (1.0–19.5) | 8 | 71 ± 33 | 7.2 (1.9–12.0) | 6 |
MPSI post-HSCT | 16.7 ± 10.3 | 7.6 (2.3–16.4) | 20 | 78 ± 37 | 5.3 (1.0–10.6) | 6 |
MPSI | 176.2 ± 81.1 | 2.1 (0.3–10.9) | 9 | 667 ± 470 | 3.2 (0.4–10.9) | 4 |
MPSII | 212.0 ± 49.5 | 2.4 (1.5–4.1) | 3 | |||
MPSIII | 32.1 ± 22.1 | 12.6 (2.7–35.0) | 17 | 107 ± 83 | 8.3 (6.9–9.7) | 2 |
MPSIV | 14.8 | 2.5 | 1 | 132 | 2.5 | 1 |
MPSVI | 189.8 ± 57.3 | 0.6 (0.61–0.64) | 2 |
DS affects HCII-T complex formation much more than HS or KS
HCII-T deteriorates in improperly stored dried blood spots
Dried blood spot HCII-T is significantly elevated in MPSI patients
HCII-T and DS:CS ratio both respond to treatment and correlate with clinical outcomes
Patient | Diagnosis | Age of presentation | Presenting symptoms | Treatment | Clinical outcomes |
---|---|---|---|---|---|
A | MPSIH | 8 months | Hernia, hearing loss, hepatosplenomegaly, spinal gibbus | 11 weeks ERT (Laronidase) | Improvements in hearing, speech and language |
Matched (6/6) unrelated cord transplant (accepted) | Developed the ability to walk unaided | ||||
Worsening thoracolumbar kyphosis | |||||
B | MPSIH | 5 months | Coarse facial features, spinal gibbus, hepatosplenomegaly, respiratory symptoms, soft systolic heart murmur | 11 weeks ERT (Laronidase) | No mitral regurgitation |
Matched (6/6) unrelated cord transplant (rejected) | Respiratory symptoms improving but recurrent chest infections possibly due to GVHD in the lungs | ||||
Autologous rescue 3 months after failed transplant | Progressive bone and joint disorders, severe scoliosis, but no cord compression | ||||
13 weeks ERT (Laronidase) | |||||
Matched (10/10) unrelated marrow transplant (accepted) | |||||
C | MPSIH | 7 years | Joint stiffness, hepatosplenomegaly, facial dysmorphia, corneal haze, sleep apnoea, kyphosis, scoliosis (at first consultation in Manchester aged 10 years) | ERT from first consultation in Manchester (Laronidase) | Normal cardiac function, with mild mitral regurgitation |
Hepatosplenomegaly drastically reduced | |||||
Improvements in breathing and mobility | |||||
D | MPSIH | 3 months | Severe cardiomyopathy, severe metabolic acidosis, hepatosplenomegaly | ERT from diagnosis (Laronidase) to be followed by HSCT | Cardiomyopathy improved -fractional shortening increased from 11 to 25% |
E | MPSII | 4 years | Large head, coarse facial features, moderate developmental delay, history of upper airway obstruction and sleep apnoea | ERT from diagnosis (Elaprase) | Increased energy levels, alertness and ease of movement |
Improved hearing, motor development | |||||
Lack of sleep apnoea | |||||
Mild mitral regurgitation | |||||
Physiotherapy scores improved from moderate to mild range | |||||
F | MPSII | 18 months | Chest deformity, coarse facial features, spinal gibbus, hepatosplenomegaly, no speech development, history of recurrent respiratory tract infections | ERT from diagnosis (Elaprase) | Improvements in speech and language |
Increased mobility and exercise tolerance | |||||
Lack of hepatosplenomegaly and joint stiffness | |||||
G | MPSVI | 6 months | Curvature of the spine, cardiac systolic murmur, club foot, respiratory tract infections, scoliosis, dysmorphic face, hepatomegaly | ERT from diagnosis (Naglazyme) | Desaturation in sleep study, nasal obstruction and large tonsils |
Mitral valve regurgitation progressed from mild–moderate to moderate–severe | |||||
Improved posture and walking ability | |||||
H | MPS VI | 7 months | Gibbus and pectus excavatum deformities, reduced hearing on one side, noisy breathing and recurrent respiratory infections, soft systolic heart murmur | ERT from diagnosis (Naglazyme) | Normal cardiac function, no heart murmur |
Stopped snoring, tonsils smaller and nose clear | |||||
Hearing appears normal |