Last updated:
2/14/2025
Years published: 2021, 2025
NORD gratefully acknowledges Wei Jing, PhD, Study Coordinator, MBTPS1-related Disorders Research Group and Lijun Xia, MD, PhD, Member and Chair, Cardiovascular Biology Research Program, Merrick Foundation Chair in Medical Research, Oklahoma Medical Research Foundation, for the preparation of this report.
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Summary
Spondyloepiphyseal dysplasia, Kondo-Fu type (SEDKF) is a rare genetic skeletal disorder caused by changes (variants) in a gene named membrane bound transcription factor peptidase, site 1 (MBTPS1). MBTPS1 contains information for the body to make a protein called site-1 protease (S1P), which is considered a master regulator of various cellular functions. Affected individuals have low birth weight and their growth milestones are delayed. Abnormal bone development progresses through childhood which results in short stature, curvature of the spine and characteristic facial features. Common non-skeletal symptoms include early onset of cataracts, inguinal hernia and feeding difficulties in early childhood. The skeletal abnormalities of SEDKF overlap with some other rare bone diseases. Normal intelligence and an increased level of lysosomal enzymes in the blood can differentiate SEDKF from similar bone diseases. However, the final diagnosis should be based on genetic testing that shows variants in the MBTPS1 gene. There are currently no therapies that target the cause of SEDKF. Patients can be managed with symptomatic and supportive treatment.
Please note that SEDKF was only recently discovered and only thirteen patients have been identified so far. Thus, the symptoms described here are based on limited information, and understanding of this disease is still evolving.
Introduction
The first child with MBTPS1 gene variants was reported in 2018 by a group of doctors and scientists in Oklahoma, US. This patient showed signs of spondyloepiphyseal dysplasia (SED), conditions that primarily affect the development of bones in the spine and the ends of long bones in legs and arms. Thus, the disease was named SED, Kondo-Fu type, after Drs. Yuji Kondo and Jianxin Fu, two scientists who authored the published report. Since then, a total of thirteen patients with SEDFK have been identified worldwide.
The specific symptoms and severity of SEDKF can vary from one person to another, possibly depending on where the change happens in the MBTPS1 gene. In addition, affected individuals may not have all possible symptoms discussed here. Some common manifestations are delayed growth, short stature, curvature of the spine, facial differences, early onset of cataracts, bilateral inguinal hernia and feeding difficulties. Because of the rarity of the disease, the relative frequency of the symptoms described is only based on a small number of people.
Affected children can be born at full term but with relatively low birth weight. Delayed growth and gross motor milestones are noticeable soon after birth, and deformity of spine and facial differences progress through childhood. Affected individuals have short stature with curvature of the spine, bulging of chest (pectus carinatum) and characteristic facial features including prominent forehead, prominent cheekbones, small lower jaw which is set further back than the upper jaw (retromicrognathia) and large ears. Due to weak bones and, in some people, low muscle tone, people may complain of back pain and fatigue and display waddling gait. Some uncommon musculoskeletal changes have been recorded including funnel chest, outward turning of the heel or inversion of the foot (pes valgus), expanded gap between the great toe and the rest of the toes (sandal grooves), joint hypermobility and hip joint inflammation.
Some people have digestive system problems and have difficulties in nutrition absorption. They require feeding support for survival in early childhood and suffer from chronic constipation.
Most affected people have normal speech, hearing and intelligence. A few suffer from speech delay and/or mild intellectual disability.
SEDKF is caused by changes (variants) in the MBTPS1 gene. Variants in the MBTPS1 gene result in an abnormal level or dysfunction of S1P, which is required for various functions in the body, and, of those, the three primary ones are: intracellular transportation of large molecules such as collagen II (major component of cartilage); lipid metabolism such as cholesterol production and uptake; and targeting lysosomal enzymes to lysosomes, an organelle inside the cell where the enzymes digest complex molecules. Defects in S1P cause problems in the three functions and for most SEDKF patients, these are more so in bone development and less so in the other two.
Cartilage is a connective tissue found in areas such as joints between bones, ends of the ribs and between the vertebrae in the spine. In babies, cartilage is more widespread and is gradually replaced with bones during normal development. Collagen II is the major component of cartilage, which is made and released to cartilage by chondrocytes, the major cells in cartilage. Collagen II is a very large molecule, and defects in S1P hinder its transportation inside the cells. When collagen II is abnormally accumulated in chondrocytes, cartilage lacks collagen, and sick chondrocytes die, leading to abnormal bone development and delayed body growth.
S1P is involved in the regulation of a protein that adds a unique tag, mannose-6-phosphate (M6P), to lysosomal enzymes so that these enzymes can be recognized and delivered to the lysosomes. Without this tag, some of these enzymes will end up outside of the cells. Therefore, a higher-than-normal level of lysosomal enzymes is detected in the blood of SEDKF patients. Extracellular lysosomal enzymes in cartilage further weaken the bone by breaking down bone material.
Because S1P affects many proteins that play various roles not just in chondrocytes, SEDKF patients also have non-skeletal symptoms, which could vary depending on which part of the MBTPS1 gene is changed. Correlation between the MBTPS1 gene variants and the diverse symptoms is being studied.
SEDKF is inherited as an autosomal recessive genetic disorder. Recessive genetic disorders occur when an individual inherits a disease-causing gene variant from each parent. If an individual receives one normal gene and one disease-causing gene variant, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the gene variant and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
Other syndromic conditions associated with MBTPS1 variants
To date, three patients with likely pathogenic MBTPS1 variants have not shown severe skeletal abnormalities. Rather, except for cataract, they have obvious abnormalities in skin, hair, oral mucosa and have other ocular symptoms such as sensitivity to light (photophobia). The correlation between the MBTPS1 variants and the syndrome categories has yet to be established.
Genetic skeletal dysplasia is a group of disorders comprised of more than 700 types characterized by abnormal growth or development of cartilage and bone. Among those are SED disorders sharing many overlapping symptoms with one another. The diagnosis of SEDKF should be based on characteristic symptoms, patient history, clinical evaluation and laboratory tests and confirmed by whole-genome sequencing.
X-ray, magnetic resonance imaging (MRI) and computed tomography (CT) can be used to examine the bone system and to identify characteristic spondylo-epiphyseal abnormalities. Laboratory tests should demonstrate normal blood cell count, generally normal organ functions and elevated plasma lysosomal enzymes. Detection of variatns in the MBTPS1 gene via genomic sequencing confirms the diagnosis.
Treatment
There are currently no therapies that target the cause of SEDKF. Patients can be managed with symptomatic/supportive treatment.
Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/ All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government website.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
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Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
https://www.centerwatch.com/
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
JOURNAL ARTICLES
Chen F, et al. S1P defects cause a new entity of cataract, alopecia, oral mucosal disorder, and psoriasis-like syndrome. EMBO Mol Med. 2022;14(5):e14904.
Kondo Y, et al. Site-1 protease deficiency causes human skeletal dysplasia due to defective inter-organelle protein trafficking. JCI Insight 2018;3(14).
Shao W, Machamer CE, and Espenshade PJ. Fatostatin blocks ER exit of SCAP but inhibits cell growth in a SCAP-independent manner. J Lipid Res. 2016;57(8):1564-73.
Ye J, et al. ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs. Mol Cell 2000;6(6):1355-64.
DeBose-Boyd RA, et al. Transport-dependent proteolysis of SREBP: relocation of site-1 protease from Golgi to ER obviates the need for SREBP transport to Golgi. Cell 1999; 99(7):703-12.
INTERNET
Wang H, Wierenga A, Prabhu S, et al. MBTPS1-Related Spondyloepimetaphyseal Dysplasia with Elevated Lysosomal Enzymes. 2023 Nov 30. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK597768/ Accessed Jan 30, 2025.
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Online Mendelian Inheritance In Man (OMIM) has a summary of published research about this condition and includes references from the medical literature. The summary contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. OMIM is authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.
View reportGeneReviews has an article on this condition covering diagnosis, management, and inheritance. Each article is written by one or more experts on the specific disease and is reviewed by other specialists. The article contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. The GeneReviews database is managed by the University of Washington.
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