High Performance Liquid Chromatography (HPLC)
- Initial test to diagnose or rule out EDS VIA (kyphoscoliotic type)
- Not recommended to screen for other types of EDS
Polymerase Chain Reaction/Sequencing
- Preferred test to confirm a diagnosis of EDS, type VI, when urine Dpyr:Pyr is elevated
- Not recommended to rule out other types of EDS
Ehlers-Danlos syndrome type VI (EDS VI) is an autosomal recessive generalized connective tissue disease caused by variants in the PLOD1 gene. EDS VI is characterized by hypotonia, early-onset progressive kyphoscoliosis, osteopenia, generalized joint hypermobility, skin fragility, artery rupture, and ocular abnormalities (eg, eye globe rupture). Life expectancy and quality of life may be affected by the risk of artery rupture and an increased risk for complications due to restrictive lung disease, recurrent pneumonia, and cardiac failure in adults with severe kyphoscoliosis.
Disease Overview
Prevalence
- Carrier frequency 1/150
Nomenclature
- Sometimes described as EDS VIA to differentiate from EDS VIB
- EDS VIB individuals have normal lysyl hydroxylase activity
Symptoms
- Kyphoscoliosis at birth or within first year of life
- Leads to respiratory compromise
- Severe neonatal hypotonia
- Thin, hyperextensible, bruisable skin
- Atrophic scarring
- Joint hypermobility
- Scleral fragility
- Increased risk of globe rupture
Diagnostic criteria
- Increased urinary Dpyr:Pyr
- Identification of two pathogenic PLOD1 gene variants
- Decreased lysyl hydroxylase activity (<25% of normal in fibroblasts)
Physiology
Lysyl hydroxylase is involved in formation of collagen cross-links
Genetics
Gene
PLOD1
Inheritance
Autosomal recessive
Structure/Function
Common 8.3 kb duplication of exons 10-16 is responsible for 20% of pathogenic variants
Test Interpretation
Sensitivity/Specificity
- Clinical sensitivity
- Sequencing: 67%
- Deletion/duplication: 33%
- Analytical sensitivity/specificity: 99%
Results
- Detection of two pathogenic PLOD1 pathogenic variants on opposite chromosomes predicts EDS VI
- When one or no PLOD1 pathogenic variants are detected in a clinically affected individual, individual may have PLOD1 variants undetectable by this test
- Variants of uncertain clinical significance may be detected
Limitations
- Diagnostic errors can occur due to rare sequence variations
- Not determined or evaluated:
- Regulatory region variants
- Deep intronic variants
- Breakpoints of large deletions/duplications
- Large deletions/duplications of exon 9
- Large deletions/duplications of exons 1 and 5 may not be detected based on breakpoints of the rearrangement
References
-
23056730
Kariminejad A, Bozorgmehr B, Khatami A, et al. Ehlers-Danlos syndrome type VI in a 17-year-old Iranian boy with severe muscular weakness - a diagnostic challenge? Iran J Pediatr. 2010;20(3):358-362.
PubMed
28306225
Brady AF, Demirdas S, Fournel-Gigleux S, et al. The Ehlers-Danlos syndromes, rare types. Am J Med Genet C Semin Med Genet. 2017;175(1):70‐115.
15979919
Giunta C, Randolph A, Steinmann B. Mutation analysis of the PLOD1 gene: an efficient multistep approach to the molecular diagnosis of the kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VIA). Mol Genet Metab. 2005;86(1-2):269‐276.
GeneReviews - PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome
Yeowell HN, Steinmann B. PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al, editors. GeneReviews, University of Washington; 1993-2020. [Last update: Oct 2018; Accessed: May 2020]