Rare Autosomal Recessive Cardiac Valvular Form of Ehlers-Danlos

August 3, 2004

I got this information from 2 different sites - 1 that was posted by

another member. Hope this is helpful to all. Love Lana

---------------------------------------------------------------------

Rare Autosomal Recessive Cardiac Valvular Form of Ehlers-Danlos

Syndrome Results from Mutations in the COL1A2 Gene That Activate the

Nonsense-Mediated RNA Decay Pathway

Ulrike Schwarze,1 Ryu-Ichiro Hata,3 Victor A. McKusick,4 Hiroshi

Shinkai,5 H. Eugene Hoyme,6 E. Pyeritz,7 and H. Byers1,2

Departments of 1Pathology and 2Medicine, University of Washington,

Seattle; 3Department of Biochemistry and Molecular Biology and

Research Center of Advanced Technology for Craniomandibular Function,

Kanagawa Dental College, Yokosuka, Japan; 4McKusick-s Institute

of Genetic Medicine, Baltimore; 5Department of Dermatology, Chiba

University School of Medicine, Chiba, Japan; 6Department of

Pediatrics, Stanford University School of Medicine, Stanford; and

7Department of Medicine, University of Pennsylvania, Philadelphia

Received December 19, 2003; accepted for publication February 25,

2004; electronically published April 9, 2004.

Splice site mutations in the COL1A2 gene of type I collagen can give

rise to forms of Ehlers-Danlos syndrome (EDS) because of partial or

complete skipping of exon 6, as well as to mild, moderate, or lethal

forms of osteogenesis imperfecta as a consequence of skipping of

other exons. We identified three unrelated individuals with a rare

recessively inherited form of EDS (characterized by joint

hypermobility, skin hyperextensibility, and cardiac valvular

defects); in two of them, COL1A2 messenger RNA (mRNA) instability

results from compound heterozygosity for splice site mutations in the

COL1A2 gene, and, in the third, it results from homozygosity for a

nonsense codon. The splice site mutations led to use of cryptic

splice donor sites, creation of a downstream premature termination

codon, and extremely unstable mRNA. In the wild-type allele, the two

introns (IVS11 and IVS24) in which these mutations occurred were

usually spliced slowly in relation to their respective immediate

upstream introns. In the mutant alleles, the upstream intron was

removed, so that exon skipping could not occur. In the context of the

mutation in IVS24, computer-generated folding of a short stretch of

mRNA surrounding the mutation site demonstrated realignment of the

relationships between the donor and acceptor sites that could

facilitate use of a cryptic donor site. These findings suggest that

the order of intron removal is an important variable in prediction of

mutation outcome at splice sites and that folding of the nascent mRNA

could be one element that contributes to determination of order of

splicing. The complete absence of pro 2(I) chains has the surprising

effect of producing cardiac valvular disease without bone involvement.

----------------------------------------------------------------------

Background: Ehlers-Danlos syndrome (EDS) is the name given to a group

of more than 10 different inherited disorders; all involve a genetic

defect in collagen and connective tissue synthesis and structure.

EDS can affect the skin, joints, and blood vessels. This syndrome is

heterogeneous from a clinical point of view; the underlying collagen

abnormality is different for each type. Clinical recognition of the

types of EDS is important. One type, type IV, is associated with

arterial rupture and visceral perforation, with possible life-

threatening consequences.

Pathophysiology: EDS is a heterogeneous group of inherited connective

tissue disorders characterized by joint hypermobility, cutaneous

fragility, and hyperextensibility. The collagen defect has been

identified in only 6 of the 11 types of EDS. Type IV is characterized

by a decreased amount of type III collagen. Types V and VI are

characterized by deficiencies in hydroxylase and lysyl oxidase, an

important posttranslational modifying enzyme in collagen

biosynthesis. Type VII has an amino-terminal procollagen peptidase

deficiency. Type IX has abnormal copper metabolism. Type X has

nonfunctioning plasma fibronectin.

In EDS types I and II, the classic variety, identifying the molecular

structure in most individuals who are affected is difficult.

Causative mutations may involve the COL5A1, COL5A2, and tenascin-X

genes and are implied to be in the COL1A2 gene. Nonetheless, in most

families with autosomal dominant EDS, the disease appears to be

linked to loci that contain the COL5A1 or COL5A2 genes. Although one

half of the mutations that cause EDS types I and II are likely to

affect the COL5A1 gene, a significant portion of the mutations result

in low levels of messenger RNA (mRNA) from the mutant allele as a

consequence of nonsense-mediated mRNA decay (Schwarze, 2000).

Bouma et al evaluated 3 generations in a family with EDS type II. The

genomic defect was an A(-2)®G substitution at the exon 14 splice

acceptor site. Transmission electron micrographs of type I collagen

fibrils in a proband dermal biopsy specimen demonstrated

heterogeneity in fibril diameter that was greater than that of a

matched control sample. The proband was found to have a greater

proportion of both larger and smaller fibrils, and occasional fibrils

with a cauliflower configuration were observed.

Wenstrup and associates identified haploinsufficiency of the COL5A1

gene that encodes the proalpha1(V) chain of type V collagen in the

classic form of EDS. Eight of 28 probands with classic EDS who were

heterozygous for expressed polymorphisms in COL5A1 had complete or

nearly complete loss of expression of one COL5A1 allele. One third of

individuals with classic EDS were estimated to have mutations of

COL5A1 that result in haploinsufficiency. These findings suggest that

the normal formation of the heterotypic collagen fibrils that contain

types I, III, and V collagen requires the expression of both COL5A1

alleles.

Autosomal recessive–type VI EDS, also known as the kyphoscoliotic

type, is characterized by neonatal kyphoscoliosis, generalized joint

laxity, skin fragility, and severe muscle hypotonia at birth.

Biochemically, this type is attributed to a deficiency in lysyl

hydroxylase (LH), the enzyme that hydroxylates specific lysine

residues in the collagen molecule to form hydroxylysines with 2

important functions. The residues are attachment sites for galactose

and glucosylgalactose, and they act as precursors of the cross-

linking process that gives collagen its tensile strength.

More than 20 mutations are identified in the LH1 gene that

contributes to LH deficiency and clinical EDS type VI. Yeowell and

identified 2 of these mutations in 5 or more unrelated

patients: (1) a large duplication of exons 10-16, which arise from a

homologous recombination of intronic Alu sequences, and (2) a

nonsense mutation, Y511X, in exon 14 of the LH1 gene. Both mutations

seem to originate from a single ancestral gene.

Tenascin-X is a large extracellular matrix protein, a deficiency of

which causes a clinically distinct recessive form of this syndrome

(Schalkwijk, 2001). Thus, factors other than collagens or collagen-

processing enzymes may cause this syndrome. This newly described form

may be associated with additional anomalies.

Frequency:

· In the US: In America, the incidence is approximately 1 case

in 400,000 people.

· Internationally: The incidence of EDS is reported to be 1

case in about 400,000 people, but mild or incomplete forms appear to

be underdiagnosed and more common than other forms.

Mortality/Morbidity:

· Type IV EDS is a severe form. Patients often have a shortened

lifespan because of the spontaneous rupture of a large artery (eg,

splenic artery, aorta) or the perforation of internal organs. Surgery

can pose life-threatening risks in these patients.

· The other types are usually not as dangerous, and affected

individuals can live a healthy if somewhat restricted life.

· Type VI is also somewhat dangerous, although it is rare.

Race: No racial predominance seems to exist; however, some believe

that whites probably are affected more than others.

Sex: The sex-related incidences are almost equal.

Age: The disease has clinical features (eg, joint mobility, skin

extendibility, scarring tendency) that are easily recognizable

beginning in early childhood.

· The other clinical manifestations require more time to become

evident.

· EDS is usually diagnosed in young adults.

Cutis Laxa (Elastolysis)

Pseudoxanthoma Elasticum

Other Problems to be Considered:

syndrome

Cartilage-hair hypoplasia syndrome

Imaging Studies:

· Calcification of small, deep, palpable, and movable nodules

(often present in the subcutaneous tissue) can lead to opacity on

radiographs.

Other Tests:

· For type IV, a prenatal diagnosis by means of polymorphic

restriction genetic studies is possible.

· For type VI, measurements of LH in the amniotic fluid can be

used to predict the outcome of pregnancy.

Histologic Findings: Histologic findings in skin biopsy specimens are

variable and sometimes normal. Dermal collagen fibers are disorderly

arranged, with a whorled appearance. Elastic fibers show

irregularities in size and orientation.

Electron microscopy reveals defects in the striations of the collagen

fibers, with large or small fibrils.

TREATMENT Section 6 of 11

Author Information Introduction Clinical Differentials Workup

Treatment Medication Follow-up Miscellaneous Pictures Bibliography

Medical Care:

· Treatment is unsatisfactory.

· One isolated report showed that patients with type VI disease

benefited from oral vitamin C, 4 g daily. Scars and bleeding time

seemed to improve with this treatment.

Surgical Care:

· Extreme caution is mandatory in any surgical maneuver.

· Plastic re-excision of scars sometimes provides acceptable

cosmetic results.

Activity:

· Patients with EDS types IV or VI should avoid participating

in dangerous contact sports.

· Some authors mention risks with activities that can increase

intracranial pressure as a result of the Valsalva effect. An example

of one such activity is playing the trumpet.

MEDICATION Section 7 of 11

Author Information Introduction Clinical Differentials Workup

Treatment Medication Follow-up Miscellaneous Pictures Bibliography

The goals of pharmacotherapy are to prevent complications and reduce

morbidity.

Drug Category: Vitamins -- Vitamin C may improve morbidity. It is a

critical cofactor for collagen fibril synthesis.

Drug Name Ascorbic acid (Cecon, Cevalin, Cevi-Bid) -- For

collagen synthesis and tissue repair.

Adult Dose 100-250 mg PO qd/bid for at least 2 wk

Pediatric Dose 100-300 mg PO in divided doses for at least 2 wk

Contraindications Pregnancy if large doses given

Interactions Decreases effects of warfarin and fluphenazine;

increases aspirin levels

Pregnancy A - Safe in pregnancy

Precautions Prolonged high doses may cause renal calculi,

especially in diabetes

FOLLOW-UP Section 8 of 11

Author Information Introduction Clinical Differentials Workup

Treatment Medication Follow-up Miscellaneous Pictures Bibliography

Further Inpatient Care:

· Type IV EDS should be carefully monitored because they are at

high risk for spontaneous rupture of a large artery (eg, splenic

artery, aorta) or the perforation of internal organs. These patients

should be educated that surgery can pose life-threatening risks.

Deterrence/Prevention:

· Patients should avoid trauma and participation in contact

sports.

· Pregnancy is dangerous for some patients.

· Bleeding risk should be considered in surgical operations.

Prognosis:

· EDS type IV is a severe form, and patients with this disease

often have a shortened lifespan.

o Arterial aneurysms, valvular prolapse, and spontaneous

pneumothorax are common complications.

o The prognosis with this type is poor.

o Sudden death can occur after visceral perforation or after

the rupture of a large vessel, most commonly an abdominal and splenic

vessel.

· The other types usually are not as dangerous, and affected

individuals can live healthy if somewhat restricted lives.

MISCELLANEOUS Section 9 of 11

Author Information Introduction Clinical Differentials Workup

Treatment Medication Follow-up Miscellaneous Pictures Bibliography

Medical/Legal Pitfalls:

· This diagnosis can be important, especially with regard to

the severe form, type IV, in which skin also is fragile but not

extensible.

Special Concerns:

· Pregnancy is dangerous for some patients.

PICTURES Section 10 of 11

Author Information Introduction Clinical Differentials Workup

Treatment Medication Follow-up Miscellaneous Pictures Bibliography

Caption: Picture 1. Patient with Ehlers-Danlos syndrome. Note the

abnormal ability to elevate the right toe. Courtesy of Enrico

Ceccolini, MD.

View Full Size Image