A 9-Month-Old with Skeletal Abnormalities and a Consanguineous Sibling with Mucopolysaccharidosis IVA: The Role of Urinary Glycosaminoglycan Testing in Disease Diagnosis and Treatment Monitoring

Abstract

Mucopolysaccharidosis IVA (MPS IVA) is a rare autosomal recessive lysosomal storage disorder resulting from N-acetylgalactosamine-6-sulfatase (GALNS) deficiency that occurs in approximately 1 in 76 000 to 1 in 640 000 live births. Given that the diagnosis of MPS IVA relies heavily on the results of initial urine glycosaminoglycan (GAG) screening, cases that present with falsely normal urine GAG concentrations can delay the diagnosis and follow-up care for patients. This case study follows a patient diagnosed with MPS IVA at 9 months of age based on relation to a consanguineous 3-year-old sibling with MPS IVA and the use of direct enzyme activity analysis. Details regarding skeletal presentation and identification of genetic variants are presented along with data on follow-up urinary GAG monitoring during treatment with enzyme replacement therapy and treatment for a growth hormone disorder.

Keywords: Mucopolysaccharidosis IVA; N-acetylgalactosamine-6-sulfatase (GALNS); enzyme replacement therapy; glycosaminoglycan; growth hormone deficiency; keratan sulfate.

Figure 1.

Representative MRI and x-ray images demonstrating classical MPS IVA features. (A) Sagittal T2 fat-suppressed image obtained at 20 months of age demonstrating a classical cartilage cap (arrow) causing mild narrowing at the craniocervical junction. (B) Lateral spine radiograph obtained at 4 years of age demonstrating typical thoracolumbar spine changes including anterior vertebral body beaking (dashed arrows) and a short vertebral body/gibbus deformity (arrow) resulting in acute kyphosis. (C) Pelvis radiograph obtained at 4 years of age demonstrating the classic appearance of increased acetabular angles (arrowheads).

Figure 2.

Urine GAG measurements. Urinary GAG concentrations were measured using the DMB (A) and CPC (B) method. The younger sibling was receiving ERT at all times of measurement. Abbreviation: Cr, creatinine.

Figure 3.

Urinary creatinine-normalized GAG concentrations determined by an LC-MS/MS-based laboratory developed test using enzymatic digestion of GAGs. Creatinine concentrations were determined using an enzymatic method conducted on an automated chemistry analyzer. Dermatan Sulfate (DS), Heparan Sulfate (HS), Chondroitin-6-Sulfate (C6S), and Keratan Sulfate (KS) concentrations of different 24-hour urine specimens were measured by LC-MS/MS. Reference Ranges: DS (⩽1.00 mg/mmol Cr), HS (⩽0.25 mg/mmol Cr), C6S (⩽2.50 mg/mmol Cr), KS (⩽0.50 mg/mmol Cr). The patient was receiving ERT at all times of measurement. Cr, creatinine.

Figure 4.

MPS IVA female height (A, B) and weight (C, D) growth charts of the older and younger siblings. 50*, the thicker line in each chart represents the 50th percentile height (A, B) or weight (C, D) of healthy females without MPS IVA. Figure modified with permission from American Journal of Medical Genetics Part A.

Figure 5.

Growth hormone stimulation test results. Peak values < 10 ng/mL after administration of clonidine and after arginine indicate growth hormone deficiency. Abbreviation: GH, growth hormone.