In 1976, Schorr, Legum, and Oshorn described two brothers with unusual skeletal development characterized by flattened vertebrae and cartilaginous regions within bones, which led to the term spondyloenchondrodysplasia (SPENCD). Over time, it became clear that SPENCD is not limited to bone involvement–patients may also experience spasticity, brain calcifications, and autoimmune disorders.
In 2011, it was discovered that SPENCD results from inherited loss-of-function mutations in ACP5, the gene encoding TRAP (tartrate-resistant acid phosphatase). This enzyme, produced in monocytic lineage cells, participates in breaking down various molecules and has been known for over 70 years as a marker of bone diseases, macrophage activation, and hairy cell leukemia, although its physiological role remains unclear.
ACP5 mutations inactivate TRAP, leading to excessive activation of the interferon signaling pathway. One early clue to this connection was a case of a man diagnosed with skeletal anomalies and systemic lupus erythematosus (SLE) at age 10 in 1958, with a precise molecular diagnosis of SPENCD confirmed only 50 years later.
TRAP mutations impair the ability of osteopontin to undergo dephosphorylation in plasmacytoid dendritic cells, resulting in heightened TLR9 receptor activation and persistent interferon signaling.
Researchers from the University of Edinburgh and Université Paris Cité, specializing in genetics, oncology, and neuroinflammation, analyzed the clinical manifestations and molecular mechanisms of SPENCD. They summarized existing data on the function of the TRAP enzyme and examined how the loss of its activity might disrupt the innate immune system’s functioning.
Clinical Features of SPENCD
Researchers analyzed clinical data from 26 patients with confirmed ACP5 mutations and reviewed 90 previously reported SPENCD cases.
SPENCD typically manifests in childhood, with nearly all patients requiring medical attention before age 15, although congenital anomalies are generally absent. Some cases present in infancy, such as growth retardation within the first year of life. In rare instances, SPENCD may lead to fatal outcomes due to severe autoimmune and other complications, including thrombocytopenia, severe hypertension, unexplained respiratory failure, and sepsis. Most patients reach adulthood, though disease severity can vary even within families.
Radiographically, SPENCD is characterized by:
- Flattened vertebral bodies with irregular end plates and nodular lesions, especially in the posterior vertebral body regions.
- Non-ossifying lesions extend from the growth plate into the metaphysis and diaphysis.
These changes may be seen only in long bones–typically in the distal knee, proximal fibula, distal radius, and ulna–or in other growth areas. Skeletal abnormalities may cause short stature, leg pain, and curvature, but can also be minimal or absent. In 46% of patients in the current analysis, skeletal issues were the sole reason for seeking medical care.
Many patients also present with neurological impairments, notably spasticity and brain calcifications in the basal ganglia and cerebellum, which can appear within the first months of life and may accompany intellectual disability.
Autoimmune disorders are the most common SPENCD manifestation, prompting the initial medical consultation in half of the cases, and are diagnosed in 85% overall. The most frequent are:
- Autoimmune thrombocytopenia – 46%
- Systemic lupus erythematosus – 36%
- Autoimmune hemolytic anemia – 27%
- Hypothyroidism – 19%
Other diagnoses included juvenile arthritis, Sjögren’s syndrome, polymyositis, celiac disease, vasculitis, and eczema.
The clinical resemblance to Aicardi-Goutières syndrome–including spasticity and brain calcifications–and the high incidence of SLE classify SPENCD as a type I interferonopathy. Studies have shown that most patients exhibit elevated expression of interferon-stimulated genes (ISGs) and increased IFN-α levels in their blood. These abnormalities may persist into adulthood but can diminish with therapy or in the absence of pronounced autoimmunity.
Some patients exhibit immunodeficiency, as evidenced by severe infections caused by bacteria and viruses. Variable immunoglobulin levels, accompanied by poor antibody responses to vaccines such as tetanus, polio, and pneumococcus, have been observed. However, distinguishing immune defects caused by SPENCD from those induced by treatments remains challenging. Notably, several untreated patients exhibited reduced lymphocytes and immunoglobulins.
ACP5 Mutations and TRAP Loss in SPENCD
In 2011, two research teams independently established that biallelic mutations in ACP5 cause SPENCD. These mutations disrupt TRAP synthesis or function.
There is no established correlation between specific mutations and disease severity. To date, no SPENCD patients without ACP5 mutations have been identified, indicating the genetic uniformity of the disorder.
ACP5 encodes TRAP, which is reduced or absent in the blood and dendritic cells of SPENCD patients. Most mutant TRAP forms completely lack enzymatic activity and fail to convert into the active form, confirming that SPENCD stems from a total loss of TRAP activity.
TRAP Functions From Bone Remodeling to Immune Regulation
TRAP is essential for immune cells, such as macrophages and dendritic cells, as well as for osteoclasts, which are responsible for bone resorption. TRAP breaks phosphate bonds and can generate reactive oxygen species (ROS) that aid phagocytes in degrading ingested material. Even mutant TRAP may partially retain its ability to produce ROS.
TRAP exists in two isoforms:
- Form 5a, secreted by macrophages and dendritic cells into the blood, serves as an inflammation marker.
- Form 5b, retained within cells, is mainly active in osteoclasts.
In humans, ACP5 is minimally expressed in neurons and microglia.
TRAP-deficient mice survive but develop limb and axial skeleton deformities due to impaired osteoclast function, disrupting bone growth zones and remodeling.
Macrophages lacking TRAP exhibit altered cytokine profiles and reduced bacterial clearance post-infection. TRAP-deficient dendritic cells show reduced MHC class II and CD80 expression but increased IL-10 after lipopolysaccharide stimulation. Th1 cell responses are also impaired, suggesting that TRAP regulates dendritic cell maturation and T-cell responses to antigens.
How TRAP Deficiency Leads to Autoimmunity in SPENCD
Although TRAP is vital for immune defense, TRAP-deficient mice do not develop the autoimmune or neurological symptoms typically associated with SPENCD in humans. The mechanism by which TRAP inactivity triggers autoimmunity and heightened IFN-I signaling remains unclear.
One study directly linked TRAP deficiency to interferon signaling, proposing that SPENCD autoimmunity arises from mutant TRAP’s inability to regulate osteopontin (OPN) activity in dendritic cells. Normally, TRAP dephosphorylates OPN, which is essential for osteoclast migration and intracellular immune responses to viruses and bacteria. Without TRAP, OPN remains hyperphosphorylated, which may drive excessive IFN-α production.
TRAP may also influence other signaling pathways, including TLR7 and TLR9 in dendritic cells, the STING protein in macrophages, and lysosomal enzymes – mutations in some of which are also linked to interferonopathies.
Conclusion
The high frequency of severe autoimmune manifestations in SPENCD, along with the potential role of ACP5 mutations in systemic lupus erythematosus, underscores the importance of further studying SPENCD mechanisms. TRAP regulates the OPN/TLR9/MyD88 complex in dendritic cells and is expressed in B cells. Most patients exhibit heightened type I interferon pathway activity, though it is unclear whether this is a cause or consequence of the disease.
JAK1/2 or JAK1/3 inhibitors have effectively alleviated autoimmune symptoms, though neurological improvements remain limited. Further research is needed to clarify SPENCD’s immunopathogenesis and develop more targeted therapies.
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