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PAUL, A. L. (2000). Diastrophic Dysplasia: a Devastating Disease. National Undergraduate Research Clearinghouse, 3. Available online at http://www.webclearinghouse.net/volume/. Retrieved December 9, 2023 .

Diastrophic Dysplasia: a Devastating Disease

Sponsored by: TODD ECKDAHL (eckdahl@missouriwestern.edu)
Have you ever imagined what it would be like to wake up one morning, and go out to your car, only to find that your feet don`t reach the gas pedals? For hundreds of people in the world, this is a reality. These people have a disease called Diastrophic Dysplasia. Diastrophic Dysplasia is a genetic disease. The gene is located on the 5th chromosome and is called DTDST. The gene was mapped 5 years ago, and since then, much more research has been done. We have found the point mutations for the disease, and hope to use this information for better treatment and detection of Diastrophic Dysplasia. Although we currently have many treatments for this disease, there is simply not enough known to make gene therapy a possibility for individuals with the disease.

Lamy and Maroteaux first coined the clinical name Diastrophic Dysplasia in 1960. They borrowed the term diastrophic from geology. In geology it refers to the bending of the earth`s crust. (12) Many cases of Diastrophic Dysplasia have been misdiagnosed in the past. Patients with this disease were usually lumped together and diagnosed as Achondroplasia with clubfoot, or Arthrogryposis Multiplex Congenita. These patients were then classified as hopeless cases.

We know that there are two types of Diastrophic Dysplasia. One form is lethal, while the other is non-lethal. In the lethal form, there are usually abnormalities in the cartilage of the trachea, larynx, and bronchial tubes. Most patients that display the lethal form of Diastrophic Dysplasia are born at a lower birth weight and have congenital heart defects at birth. They also have radiographic differences, dislocation of the spine, and overlapping joints by age 6.

Diastrophic Dysplasia has many physical indications. The clinical phenotype of a patient is premature calcification of cartilage in the body, and scolioses. They usually have a clubbed foot and, in extreme cases, they may also have a cleft palate. However, the most obvious physical characteristic of this disease is the "Hitchhiker" thumb. This particular trait is due to a deformity in the bone of the finger. (4, 9, 13, 14, 17, 18, 19)

The average height for an adult male with this disease is 4`5". The average height for an adult female is 4`2". Growth failure in Diastrophic Dysplasia is progressive, and is usually caused by absence of a growth spurt in puberty.

Diastrophic Dysplasia can be diagnosed before birth. At 16 weeks, an ultrasound can tell if the limbs are abnormally short, and if the thumbs project outward. This is done using the values for bone length, and the Metacarpal Pattern Profile. (MCPP) However, sometimes the phenotype of the fetus is so mild that doctors are unable to render a definite diagnosis. (10, 12)

Other doctors are using DNA markers to predict the status of fetuses in the first trimester of pregnancy. This has been an extremely successful means of detecting Diastrophic Dysplasia. To date the correct prediction rate is over 99%.

Many of the deformities associated with Diastrophic Dysplasia can be corrected through surgery. The clubfoot and hitchhiker thumb that are associated with this disease are not nearly as resistant to treatment as they are in Diastrophic Dwarfism. The height factor can be treated by growth hormones, which have been showing a great deal of progress in this area. (3, 5, 12)

Diastrophic Dysplasia is a heritable osteochondrodysplasia. (1) It is inherited as an autosomal recessive disorder. (3, 5) Parents that conceive a child with Diastrophic Dysplasia have a 25% chance of having another child with the disorder. (3) The disease gene was mapped by a genetic metabolic study in 1994. By Hastbacka. (2) This study demonstrated a defect in the sulfate transport gene (DTDST) Hastbacka also used genetic linkage studies, in order to map the disease gene. (6)

The gene was isolated by these genetic linkage studies. Scientists then modified the formulas, by Luria and Delbruck, for estimating mutation rate in a rapidly growing bacteria culture. These equations were adapted to estimate the recombination rate between a disease locus and nearby marker in a rapidly growing human population. (6)



1 1014^ ^ ^ 1 2 3

1. 3` Splicer mutation. AG-AC. Disrupts Splicing.2. 575 AAG-AG. Eliminates 20% of the protein.3. 661 ACA-AC. Eliminates 10% of the protein. (7, 8)

There have been 3 specific deletions that have been studied in regard to this gene. Patients are heterozygous for a single base deletion in codon 575. This causes a frame shift with premature termination, and loss of 20% of the protein. They also have a deletion of one nucleotide in codon 661, causing a frame shift and premature termination with a loss of 10% of the protein. Finally there is a 3` splicer acceptor site mutation in a heterozygous state causing defective splicing. (6, 12)

The DTDST gene has a total of 2834 base pairs. There are 795 adenine, 576 cytosine, 596 guanine, and 865 thymine. (15)

The DTDST gene is widely distributed. This Sulfate-Chloride antiporter is located in the cell membrane. It is expressed specifically in many tissues. DTDST causes a defect in the structure and synthesis of type II collagen. (20) It also causes abnormal areas of tissue on the bone, causing calcium slats to be deposited, and ossification to occur. (11) It may also cause abnormalities in the Sodium and Sulfate concentrations of collagen IX. (12)

The Finnish founder mutation of the GT to GC transition in the splice donor site of the 5` untranslated exon of the DTDST gene. This mutation severely reduces the mRNA levels in the DTD patient. (12)

The Amino Acid Sequence for this Gene is as follows: (6) 1 msseskeqhn vsprdsaegn dsypsgihle lqresstdfk qfetndqcrp yhrilierqe 61 ksdtnfkefv ikklqkncqc spakaknmil gflpvlqwlp kydlkknilg dvmsglivgi 121 llvpqsiays llagqepvyg lytsffasii yfllgtsrhi svgifgvlcl migetvdrel 181 qkagydnahs apslgmvsng stllnhtsdr icdkscyaim vgstvtfiag vyqvamgffq 241 vgfvsvylsd allsgfvtga sftiltsqak yllglnlprt ngvgslittw ihvfrnihkt 301 nlcdlitsll cllvllptke lnehfksklk apipielvvv vaatlashfg klhenynssi 361 aghiptgfmp pkvpewnlip svavdaiais iigfaitvsl semfakkhgy tvkanqemya 421 igfcniipsf fhcfttsaal aktlvkestg chtqlsgvvt alvlllvllv iaplfyslqk 481 svlgvitivn lrgalrkfrd lpkmwsisrm dtviwfvtml ssallsteig llvgvcfsif 541 cvilrtqkpk ssllglvees evfesvsayk nlqtkpgiki frfvaplyyi nkecfksaly 601 kqtvnpilik vawkkaakrk ikekvvtlgg iqdemsvqls hdplelhtiv idcsaiqfld 661 tagihtlkev rrdyeaigiq vllaqcnptv rdsltngeyc kkeeenllfy svyeamafae 721 vsknqkgvcv pnglslssd

Because of the deletional mutations, Sulfate transport is extremely deficient in the fibroplasts of the DTD patient. (6)

There are very few differences in the structure of the DNA of normal vs. mutant characteristics. The differences between the two have been made bold. (15)CONTROL PATIENTGGTCGTCCCTTA CGGTCGTCCTTA

By having genetic information about Diastrophic Dysplasia, Superti-Furga, et al, described mutations in the DTDST gene in achondrogenesis. Hastbacka was able to take this genetic information and identify mutations in the DTDST gene in atelosteogenesis. Therefore, we now know that both of these disorders are allelic to Diastrophic Dysplasia.

Testing for Diastrophic Dysplasia can be done after the first trimester by ultrasonography. However, this delays the eventual question over abortion until midpregnancy, and raises ethical questions about mid to late term abortions. (7) DTD can also be determined by genetic tests, which leads to ethical questions over whether or not scientists should be "playing God." (16)

By knowing how this gene functions on the molecular level, we are able to understand and explore the best ways to treat this disease on the genetic level. Hopefully, this information will allow scientists to focus on gene therapy for a possible cure. However, for now most couples with a fetus carrying this disease opt for abortion.

1. Bailey, AJ, et al. Abnormal collagen cross-linking in the cartilage of a Diastrophic Dysplasia patient. British Journal of Rheumatology. 1995 June; 34(6): 512-515

2. Cetta, G, et al. Diastrophic Dysplasia sulfate transporter gene is not involved in Pseudodiastrophic Dysplasia. American Journal of Medical Genetics. 1997 Dec; 73(4): 493-494

3. Domer, Timothy P. Diastrophic Dysplasia. The Orthopedic Department; The Alfred Dupont Center. http://gait.aidi.udel.edu/res695/homepage/pd_ortho/orthhome.htm. Feb 1, 2000

4. Forese, LL, et al. Severe mid-cervical kyphosis with cord compression in Larsen`s syndrome and Diastrophic Dysplasia: unrelated syndromes with similar radiologic findings and neurosurgical implications. Pediatric Radiology. 1995; 25(2): 136-139

5. Greenberg Center for Skeletal Dysplasias. http://ww2.med.jhu.edu/Greenberg.Center/ diastrop.htm. Feb 1, 2000

6. Hastbacka, J, et al. The Diastrophic Dysplasia gene encodes a novel sulfate transporter: positional cloning by time structure linkage disequilibrium mapping. Cell. 1994 Sep; 78(6): 1073-1087

7. Hastbacka, J, et al. Prenatal diagnosis of Diastrophic Dysplasia with polymorphic DNA markers. Journal of Medical Genetics. 1993 April; 30(4): 265-268

8. Hastbacka, J, et al. A linkage map spanning the locus of Diastrophic Dysplasia. Genomics 1991 Dec;11(4):968-73

9. Makitie, O, et al. Growth in Diastrophic Dysplasia. Journal of Pediatrics. 1997 April; 130(4):641-646

10. Nishimura, G. A mild variant of Desbuquois Dysplasia. European Journal of Pediatrics. 1999 June; 158(6): 479-483

11. National Organization for Rare Diseases. Diastrophic Dysplasia. http://www.stepstn.com/ cgi-win/nord.exe?proc=GetDocument&rectype=0&recnum=482. March 20, 2000

12. OMIM . Online source for Diastrophic Dysplasia. http://www.ncbi.nlm.nih.gov/Omim/. Feb 1, 2000

13. Qureshi, F, et al. Histopathology of fetal Diastrophic Dysplasia. American Journal of Medical Genetics. 1995 April; 56(3): 300-303

14. Remes, Ville, et al. Cervical Kyphosis in Diastrophic Dysplasia. Spine. 1999 October; 24(19): 103-105

15. Rossi, A, et al. Phenotypic and Genotypic overlap between Atetoseogenesis type 2 and Diastrophic Dysplasia. Human Genet. 1996 Dec; 98(6): 657-661

16. Sachs, L. Knowledge of Genetic Risk. Acta Oncol. 1999 August; 38(6): 735-741

17. Scott, C.I., Jr. Dwarfism. Clinical Symp. 1988; 40: 2-32

18. Spranger, J., et al. The type II Collagenopathies: A spectrum of Chondrodysplasias. European Journal of Pediatrics. 1994; 153: 56-65

19. Superti-Furga, Andrea, et al. Recessively inherited multiple epiphyseal dysplasia with normal stature, clubfoot, and double-layered patella caused by a DTDST mutation. Journal of Medical Genetics. 1998 Aug; 36(8): 621-624

20. Wheeless, CR. Diastrophic Dysplasia http://www.medmedia.com/o14/92.htm 3/20/2000

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