Importance of long-term follow-up in the prognosis of Mucopolysaccharidosis IV-A: A case report from southwestern of Colombia
Clinical Genetics and Therapeutics
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Primary Categories:
- Clinical Genetics
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Secondary Categories:
- Clinical Genetics
Introduction
Mucopolysaccharidosis IV-A (MPS IV-A) is an autosomal recessively lysosomal disease (LSD) caused by pathogenic variants in the GALNS gene, leading to enzymatic deficiency of N-acetylgalactosamine-6-sulfatase and subsequent accumulation of chondroitin-6-sulfate (C6S) and keratan sulfate (KS), which are primary components of proteoglycans in cartilage and bone. Genomic analysis of GALNS has reported more than 400 variants in affected patients, allowing genotype-phenotype correlation and contributing to the understanding of clinical variability.
Case Presentation
Female patient, 16 years 9 months, product of a second non-consanguineous pregnancy and with initial manifestation of short stature, lower limb dysmetry and genu valgum at 5 years of age. She presented cervical spinal cord compression and had undergone multiple lower limb interventions. On physical examination she had a puffy facies, short neck, carinatum thorax and multiple joint malformations such as claw hand and ligament hyperlaxity.
Diagnostic Workup
It is reported the study of GALNS enzymatic activity: 0.06 mmol/ml/hour that establishes a case of MPS IV-A and the confirmation to make a specific diagnosis was performed the complete sequencing of the GALNS gene by NGS technology, identifying the homozygous variant c.239C>T (p.Ser80Leu) associated with the disease. The bioinformatic and in-silico prediction study was performed, which allowed it to be classified as pathogenic.
Treatment and Management
Targeted treatment of the patient is based on enzyme replacement therapy (ERT) with the recombinant enzyme elosulfase alfa administered intravenously at a dose of 2 mg/kg/weekly.
Outcome and Follow-Up
Long-term follow-up of the patient shows good adherence to ERT and a notable decrease in the concentration of quantitative urinary GAGs, in addition to preserved cardiac, renal, hepatic and thyroid function. Positive findings include mild deformity of the lumbar bodies L1-L2, osteopenia and scoliosis of left convexity, shortening of 4 mm in the total length of the left lower limb and mild genu valgum, decreased bone density, adenoid hypertrophy and mixed component spirometry with greater restrictive compromise. Neurological development and academic training has been normal, with good performance.
Discussion
The cases of adolescent patients with MPS IV-A worldwide show that in their long-term development there are bone-predominant complications, including dysplasia in the carpal bones and in the femoroacetabular joint, dorsolumbar kyphosis, plastipondyly, spinal compression at C2-C3 level and Madelung deformity, which are findings similar to those described in this study. Also, the variant identified in the patient had been previously described and associated with severe phenotypes, which coincides with the case presented.
Conclusion
The continuous follow-up of patients with MPS IV-A is not only vital to monitor disease progression and response to treatment, but also provides important data for clinical research and understanding of the pathology in a broader context. The study of MPS IV-A cases from a multidisciplinary approach allows the genotype/phenotype correlation of affected patients, which may in the future mean specific pathways and consensus of each variant associated with the disease.
Mucopolysaccharidosis IV-A (MPS IV-A) is an autosomal recessively lysosomal disease (LSD) caused by pathogenic variants in the GALNS gene, leading to enzymatic deficiency of N-acetylgalactosamine-6-sulfatase and subsequent accumulation of chondroitin-6-sulfate (C6S) and keratan sulfate (KS), which are primary components of proteoglycans in cartilage and bone. Genomic analysis of GALNS has reported more than 400 variants in affected patients, allowing genotype-phenotype correlation and contributing to the understanding of clinical variability.
Case Presentation
Female patient, 16 years 9 months, product of a second non-consanguineous pregnancy and with initial manifestation of short stature, lower limb dysmetry and genu valgum at 5 years of age. She presented cervical spinal cord compression and had undergone multiple lower limb interventions. On physical examination she had a puffy facies, short neck, carinatum thorax and multiple joint malformations such as claw hand and ligament hyperlaxity.
Diagnostic Workup
It is reported the study of GALNS enzymatic activity: 0.06 mmol/ml/hour that establishes a case of MPS IV-A and the confirmation to make a specific diagnosis was performed the complete sequencing of the GALNS gene by NGS technology, identifying the homozygous variant c.239C>T (p.Ser80Leu) associated with the disease. The bioinformatic and in-silico prediction study was performed, which allowed it to be classified as pathogenic.
Treatment and Management
Targeted treatment of the patient is based on enzyme replacement therapy (ERT) with the recombinant enzyme elosulfase alfa administered intravenously at a dose of 2 mg/kg/weekly.
Outcome and Follow-Up
Long-term follow-up of the patient shows good adherence to ERT and a notable decrease in the concentration of quantitative urinary GAGs, in addition to preserved cardiac, renal, hepatic and thyroid function. Positive findings include mild deformity of the lumbar bodies L1-L2, osteopenia and scoliosis of left convexity, shortening of 4 mm in the total length of the left lower limb and mild genu valgum, decreased bone density, adenoid hypertrophy and mixed component spirometry with greater restrictive compromise. Neurological development and academic training has been normal, with good performance.
Discussion
The cases of adolescent patients with MPS IV-A worldwide show that in their long-term development there are bone-predominant complications, including dysplasia in the carpal bones and in the femoroacetabular joint, dorsolumbar kyphosis, plastipondyly, spinal compression at C2-C3 level and Madelung deformity, which are findings similar to those described in this study. Also, the variant identified in the patient had been previously described and associated with severe phenotypes, which coincides with the case presented.
Conclusion
The continuous follow-up of patients with MPS IV-A is not only vital to monitor disease progression and response to treatment, but also provides important data for clinical research and understanding of the pathology in a broader context. The study of MPS IV-A cases from a multidisciplinary approach allows the genotype/phenotype correlation of affected patients, which may in the future mean specific pathways and consensus of each variant associated with the disease.