SCIENTIFIC BACKGROUND

AEBP1, TNXB

Scientific Background

In the current EDS classification of 2017, the autosomal recessively inherited EDS due to tenascin-X deficiency is designated as classical-like Ehlers-Danlos syndrome (clEDS). The minimum requirement for a clinical diagnosis of clEDS is the presence of all three major criteria: velvety hyperextensible skin without atrophic scarring, generalized joint hypermobility without dislocations, and increased skin fragility with spontaneous ecchymosis. Thus, with respect to joint and skin involvement, there is clinical overlap with classical EDS (cEDS), but without cigarette-paper-like scarring, and to hypermobile EDS (hEDS), which in turn does not show increased skin fragility.

 

Classical-Like EDS Type 1 due to Tenascin Deficiency

EDS due to tenascin-X deficiency (EDSCLL1) was genetically identified in a patient with adrenogenital syndrome and 21-hydroxylase deficiency who also had clinical symptoms of classical EDS. The cause was a 30 kb deletion on chromosome 6p21.3 that included both the CYP21A2 gene and the partially overlapping TNXB gene, thus representing a contiguous gene syndrome. Molecular causes of tenascin-X deficiency are homozygous or combined heterozygous variants in the TNXB gene. To date, the Human Gene Mutation Database and the Ehlers-Danlos Syndrome Variant Database (LOVD) include only six pathogenic missense variants, six nonsense variants, five small frameshift variants, two splice variants, and two large genomic rearrangements in the TNXB gene. Homozygosity and combined heterozygosity of variants leading to premature translational arrest resulting in complete absence of the tenascin-X gene product at the RNA and protein levels. In patients, tenascin-X is no longer detectable in serum. Tenascin-X is a glycoprotein synthesized in the extracellular matrix of skin, tendons, muscles and blood vessels. Some patients with tenascin-X deficiency have myopathic symptoms that are characteristic for Bethlem myopathy or Ullrich muscular dystrophy. The absence of tenascin-X in serum causes decreased expression of type VI collagen expression.

The absence of tenascin-X in serum supports the clinical diagnosis of EDS due to tenascin-X deficiency.

 

Classical-Like EDS Type 2

In 2018, another autosomal recessively inherited form of the classical-like EDS subtype was described: classical-like EDS type 2 (EDSCLL2). It is characterized by massive skin and musculoskeletal involvement with phenotypic variability and clinical overlap with other EDS subtypes. Skin manifestations include hyperextensible, loose, fragile skin, which may be translucent, with delayed wound healing and atrophic scarring. In addition to generalized joint hypermobility, joint dislocations and subluxations, early onset osteoporosis or osteopenia is typical. In addition, cardiovascular complications have been described. Skin biopsy in the patients studied to date showed an ultrastructure of irregular cross-sections of collagen fibrils and frayed collagen fibers.

The molecular causes are homozygous or combined heterozygous loss-of-function variants in the AEBP1 gene. AEBP1 encodes the aortic carboxypeptidase-like protein ACLP, which is associated with collagen within the extracellular matrix and is involved in the proliferation of fibroblasts and mesenchymal stem cells into collagen-producing cells. One hypothesis for the pathophysiology of ACLP deficiency is abnormal collagen fibril assembly and impaired wound healing due to reduced TGFβ receptor signaling.

 

References

Syx et al. 2019, Hum Mol Genet 28:1853 / Ritelli et al. 2019, Genes (Basel) 10, pii:E135 / Blackburn et al. 2018, Am J Hum Genet 102:696 / Malfait et al. 2017, Am J Med Genet C 175:8 / Brady et al. 2017, Am J Med Genet C 175:70 / Demirdas et al. 2017, Clin Genet 91:411 / Chen et al. 2016, Hum Mutat 37(9):893 / Morissette et al. 2015, J Clin Endocrinol Metab 100:E1143 / Pénisson-Besnier et al. 2013, Neuromuscul Disord 23:664 / Merke et al. 2013, J Clin Endocrinol Metab 98:E379 / Schalkwijk et al. 2001, N Engl J Med 345:1167

GENES
AEBP1, TNXB
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