Last updated:
August 20, 2021
Years published: 2021
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.
Summary
Spondyloepiphyseal dysplasia, Kondo-Fu type (SEDKF) is a rare genetic skeletal disorder caused by changes (mutations) in a gene named membrane bound transcription factor peptidase, site 1 (MBTPS1). MBTPS1 contains the 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 demonstrating mutations 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 a few 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 a MBTPS1 gene mutation 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 seven patients with SEDFK have been identified in the US, Brazil and Germany.
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, dysmorphic face, early onset of cataracts, bilateral inguinal hernia and gastrointestinal problems. Please note that prior to 2021, only eight patients had been identified as having mutations in MBTPS1. Thus, the relative frequency of the described symptoms is based on a small number of patients.
Patients 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 face progress through childhood. Patients exhibit short stature with curvature of the spine, bulging of chest (pectus carinatum) and characteristic dysmorphic 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 cases, low muscle tone, patients 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 patients experience digestive system problems and have difficulties in nutrition absorption. They require feeding support for survival in early childhood and suffer from chronic constipation.
Patients usually have normal speech, hearing and intelligence. Some relatively rare symptoms include seizures, temporary vision loss caused by reduced blood flow in the eye (ocular migraines), ovarian cysts, mild bluish coloration of the whites of the eyes (blue sclerae), reduced sweating, dry skin, skin follicular papules, brittle hair and hair loss.
SEDKF is inherited as an autosomal recessive genetic disorder, which means that an affected individual, either male or female, receives one altered MBTPS1 gene from the mother and one from the father. Changes 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 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 the 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 exhibit non-skeletal symptoms, which could vary depending on which part of the MBTPS1 gene is changed. Correlation between the MBTPS1 mutations and the diverse symptoms are under investigation.
Skeletal dysplasia is a group of disorders comprised of more than 450 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 mutations 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
TTY: (866) 411-1010
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
Meyer R, et al. Patient with an autosomal-recessive MBTPS1-linked phenotype and clinical features of Silver-Russell syndrome. Am J Med Genet A 2020;182(11):2727-2730.
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.
NORD strives to open new assistance programs as funding allows. If we don’t have a program for you now, please continue to check back with us.
NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations.
Learn more https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/Ensuring that patients and caregivers are armed with the tools they need to live their best lives while managing their rare condition is a vital part of NORD’s mission.
Learn more https://rarediseases.org/patient-assistance-programs/rare-disease-educational-support/This first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder.
Learn more https://rarediseases.org/patient-assistance-programs/caregiver-respite/The information provided on this page is for informational purposes only. The National Organization for Rare Disorders (NORD) does not endorse the information presented. The content has been gathered in partnership with the MONDO Disease Ontology. Please consult with a healthcare professional for medical advice and treatment.
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.
View report