Diagnostic journey and impact of enzyme replacement therapy for mucopolysaccharidosis IVA: a sibling control study

Abstract

Background: Mucopolysaccharidosis (MPS) IVA, also known as Morquio A syndrome, is a rare autosomal recessive lysosomal storage disorder caused by a deficiency in the enzyme N-acetylgalactosamine-6-sulfatase. Early recognition, diagnosis, and treatment of this progressive, multisystem disease by enzyme replacement therapy (ERT) can lead to improved outcomes and reduced mortality.

Methods: This report documents the diagnostic journey and treatment with ERT of three siblings with MPS IVA. Clinical outcome measures included growth, endurance, imaging, cardiac, respiratory, ophthalmology, and laboratory evaluations.

Results: Three siblings, diagnosed at 14.7, 10.1, and 3.2 years of age, demonstrated clinical improvement with weekly infusions of 2.0 mg/kg elosulfase alfa (Vimizim^®, BioMarin Pharmaceutical, Novato, CA, USA). Patient 1 (oldest sibling) and Patient 2 (middle sibling) experienced a diagnostic delay of 8 years 7 months and 4 years after symptom onset, respectively. All three patients demonstrated improvements in growth, 6-min walk distance, joint range of motion, and respiratory function after 30 months of ERT. The treatment was well tolerated without any adverse events.

Conclusions: This case series highlights the importance of early recognition of the clinical and imaging findings that are initially subtle in MPS IVA. Early treatment with ERT is necessary to slow irreversible disease progression and improve patient outcomes. The oldest sibling experienced improvements in mobility despite severe symptoms resulting from a late diagnosis. When evaluating patients with skeletal anomalies, imaging multiple body regions is recommended. When findings such as anterior beaking of vertebrae or bilateral femoral head dysplasia are present, MPS IVA should be included in the differential diagnosis. Newborn screening must be considered for early detection, accurate diagnosis, and initiation of treatment to reduce morbidity.

Keywords: Anterior beaking; Diagnosis; Enzyme replacement therapy; Mucopolysaccharidosis IVA; Platyspondyly; Treatment.

Fig. 1

Anteroposterior radiograph of hips and pelvis in Patient 1 at 6 years of age shows bilateral sclerotic, fragmented, and flattened proximal femoral epiphyses (asterisks), irregular acetabula (arrowheads), and coxa valga deformities. The patient was initially diagnosed with Legg–Calve–Perthes disease; in retrospect, acetabular irregularities and coxa valga would not be typical in this condition

Fig. 2

Representative serial radiographs of the proximal right femur of Patient 1 over time show progressive flattening of the epiphysis, concomitant widening of the proximal metaphyses, and increased irregularity of the acetabula resulting in compensatory pseudarthrosis-like formation

Fig. 3

Lateral radiographs and MRIs of the thoracic spine in the three siblings. a In Patient 1, lateral thoracic spine radiograph (left) at 10 years of age shows relatively moderate vertebral body height loss (platyspondyly) and anterior vertebral body beaking, most prominent in the mid-to-lower thoracic spine (arrowheads). Sagittal T2-weighted MRI of the thoracic spine (right) shows moderate platyspondyly with prominent anterior beaking of multiple thoracic and upper lumbar vertebral bodies (arrowheads). The patient was initially diagnosed with spondyloepiphyseal dysplasia on the basis of clinical presentation, platyspondyly, and femoral epiphyseal abnormalities on imaging, although anterior beaking in the middle third of the spine is highly suggestive of MPS IVA, and vertebral flattening is not as prominent as would be expected in spondyloepiphyseal dysplasia. b In Patient 2, lateral thoracic spine radiograph at 6 years of age (left) shows anterior beaking of multiple thoracic vertebral bodies (arrowheads). Sagittal T2-weighted MRI of the thoracic spine at 10 years of age (right) shows anterior vertebral body beaking (arrowheads) with mild vertebral height loss without platyspondyly. Presence of anterior vertebral body beaking in this case is strongly suggestive of MPS IVA. c In Patient 3, lateral thoracic spine radiograph at 3 years of age (left) shows anterior beaking of multiple thoracic vertebral bodies without significant vertebral body height loss. Sagittal T2-weighted MRI of the thoracic spine at 5 years of age (right) highlights anterior vertebral body beaking. As with this patient’s siblings, anterior vertebral body beaking supported the diagnosis of MPS IVA

Fig. 4

Sagittal T2-weighted TSE MRI of the cervical spine of Patient 1 at 10 years of age shows dysplastic odontoid process of C2, with irregular sclerosis and posterior migration of the tip of the dens (asterisk)

Fig. 5

Radiographic features of the hand in the three siblings supportive of MPS IVA. a Patient 1 at 6 years of age showed prominent shortening of the fourth and fifth metacarpals (asterisks) with proximal pointing of the fifth metacarpal (arrowhead) and widening of the first metacarpal. b Patient 2 at 6 years of age showed proximal pointing of the fifth metacarpal (arrowhead) and irregular carpal bones (asterisk). Notably, this patient’s metacarpal abnormalities were much less conspicuous compared with those of his older brother (Patient 1) at the same age. c Patient 3 at 3 years of age showed proximally shortened, widened metacarpals with proximal pointing of the second and fifth metacarpals (arrowheads)

Fig. 6

Physical examination of the siblings. Patient 1 at 14 years of age, Patient 2 at 9 years of age, and Patient 3 at 3 years of age. Lordotic posture can be noted in all three patients. Prior to starting ERT, all three siblings showed skeletal abnormalities and walking impairment, which were more advanced in the oldest sibling (Patient 1)