Ehlers-Danlos has 2 enzyme deficiencies?

[Jonari]

UWorld says its due to procollagen peptidase, which leads to EDS type 7, whereas Kaplan says it's due to lysyl hydroxylase which leads to EDS type 6.

Anybody ever get a question that doesn't give the classification, but gives both enzymes as an answer choice? What's the correct answer in this case?

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[Myxedema]

Classification of EDS into numerical types is the old classification. In the new classification, there are 6 types, with 3 of them being common: (a) Classical, (b) Kyphoscoliotic, and (c) Vascular. Classical EDS is associated with mutations in type V collagen, kyphoscoliotic EDS is associated with lysyl hydroxylase deficiency in type I and III collagens, and vascular EDS is associated with mutations in type III collagen.

 

[Jonari]

Classification of EDS into numerical types is the old classification. In the new classification, there are 6 types, with 3 of them being common: (a) Classical, (b) Kyphoscoliotic, and (c) Vascular. Classical EDS is associated with mutations in type V collagen, kyphoscoliotic EDS is associated with lysyl hydroxylase deficiency in type I and III collagens, and vascular EDS is associated with mutations in type III collagen.

confusing...so which variant has procollagen peptidase missing?

 

[esrever]

I think you are stuck in the weeds a bit. There are several variants of Ehlers-Danlos, just know that, yes there are several types with varying modes of inheritance and several enzyme deficiencies that can lead to varying types of Ehlers-Danlos but the most clinically relevant (therefore most likely tested) is the vascular (type III collagen variant) as this will make you prone to aneurysms (berry) and organ rupture. And this is an issue with cross-linking of collagen. Don't worry about specific enzymes for this disorder (IMO), World and Kaplan may test you on these just as learning points (which is great), but Step 1 is more likely to make you determine if the patient has ehlers-danlos or marfan's.

 

[Jonari]

I think you are stuck in the weeds a bit. There are several variants of Ehlers-Danlos, just know that, yes there are several types with varying modes of inheritance and several enzyme deficiencies that can lead to varying types of Ehlers-Danlos but the most clinically relevant (therefore most likely tested) is the vascular (type III collagen variant) as this will make you prone to aneurysms (berry) and organ rupture. And this is an issue with cross-linking of collagen. Don't worry about specific enzymes for this disorder (IMO), World and Kaplan may test you on these just as learning points (which is great), but Step 1 is more likely to make you determine if the patient has ehlers-danlos or marfan's.

Thanks for the write-up. Just to clarify for differential btwn the two:

EDS - collagen problem, hypermobile joints, joint dislocations, aortic dissection & berry aneurysm

Marfans - Fibrillin gene defect. Long arms/legs, dislocated lens (I forgot the direction of this, because I know some other disease also causes dislocated lens, and the differential is in the direction of the lens).

anything else excluding their genetic differences? figured you may know something else that i could potentially pick up on.

 

[esrever]

Predominantly yeah thats the point. However, just keep in mind the different collagen and associated syndromes.

Type I is going to be your Osteogenesis Imperfecta (this is a glycosylation issue at the ER). Also Vitamin C deficiency is involved as well (hyrdoxylation of lysine and proline)
Type III - Ehlers Danlos
Type IV - Alport (this is BM so you also have your BM autoimmune issues Goodpasture, etc)

Marfan, fibrillin as you said and there are a lot of similarities with Ehlers Danlos. But just think skeletal, cardio and eyes. Pectus excavatum, same joint mobility as you might see in ehlers danlos. Likely to be a tall skinny individual w/ arachnodactly (difference here). but yeah they can have issues with berry aneurysms as well and aortic dissections (thoracic) and I think both ED and marfan associated with cystic medial necrosis. Marfan also floppy mitral valve and aortic incompetence (Cystic medial necrosis). Marfan also ascending aortic aneurysm (vs tertiary syphilis which is the arch and related to vasa vasorum destruction). etc etc. Now I am confused too. but that just compares a few details that you tend to see tested. Where is the aneurysm? What is that pathology of it. cystic medial necrosis vs. vasa vasorum destruction for example.

 

[Jonari]

Predominantly yeah thats the point. However, just keep in mind the different collagen and associated syndromes.

Type I is going to be your Osteogenesis Imperfecta (this is a glycosylation issue at the ER). Also Vitamin C deficiency is involved as well (hyrdoxylation of lysine and proline)
Type III - Ehlers Danlos
Type IV - Alport (this is BM so you also have your BM autoimmune issues Goodpasture, etc)

Marfan, fibrillin as you said and there are a lot of similarities with Ehlers Danlos. But just think skeletal, cardio and eyes. Pectus excavatum, same joint mobility as you might see in ehlers danlos. Likely to be a tall skinny individual w/ arachnodactly (difference here). but yeah they can have issues with berry aneurysms as well and aortic dissections (thoracic) and I think both ED and marfan associated with cystic medial necrosis. Marfan also floppy mitral valve and aortic incompetence (Cystic medial necrosis). Marfan also ascending aortic aneurysm (vs tertiary syphilis which is the arch and related to vasa vasorum destruction). etc etc. Now I am confused too. but that just compares a few details that you tend to see tested. Where is the aneurysm? What is that pathology of it. cystic medial necrosis vs. vasa vasorum destruction for example.

Oh wow, learned something new about the cystic medial degeneration. Didn't realize that the degeneration is via necrosis of the elastic tissue. Didn't know that...I just know that it "fragments in the t. media" according to rapid review.

 

[Phloston]

Two enzymes affected in Ehlers-Danlos you need to know:

1) procollagen peptidase

2) lysyl oxidase

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For Ehlers-Danlos, for all intents and purposes, it is PROCOLLAGEN PEPTIDASE DEFICIENCY. You've gotta know that when the collagen is extruded from the cell, it still has its non-helical N- and C-terminal regions (heavy in S-S bonds) attached. When procollagen peptidase cleaves off these regions, the collagen becomes MUCH LESS water soluble. Without procollagen peptidase, the collagen is weaker.

For Menkes syndrome (Ehlers-Danlos type-IX), you've gotta know that there's defective COPPER UPTAKE from the intestines. Copper is a co-factor for lysyl oxidase, so in Menkes, active lysyl oxidase is deficient.

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I had encountered two questions on Menkes syndrome during my prep year. I wish it had showed up on my exam bc I was ready for it. It presents similar to vitamin C deficiency bc you get "kinky" or "wiry" hair + bruising.

 

[Jonari]

Two enzymes affected in Ehlers-Danlos you need to know:

1) procollagen peptidase

2) lysyl oxidase

--------

For Ehlers-Danlos, for all intents and purposes, it is PROCOLLAGEN PEPTIDASE DEFICIENCY. You've gotta know that when the collagen is extruded from the cell, it still has its non-helical N- and C-terminal regions (heavy in S-S bonds) attached. When procollagen peptidase cleaves off these regions, the collagen becomes MUCH LESS water soluble. Without procollagen peptidase, the collagen is weaker.

For Menkes syndrome (Ehlers-Danlos type-IX), you've gotta know that there's defective COPPER UPTAKE from the intestines. Copper is a co-factor for lysyl oxidase, so in Menkes, active lysyl oxidase is deficient.

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I had encountered two questions on Menkes syndrome during my prep year. I wish it had showed up on my exam bc I was ready for it. It presents similar to vitamin C deficiency bc you get "kinky" or "wiry" hair + bruising.

Yeah, I think the location for where Menkes affects and Wilsons is what differentiates the two...

Menkes problem of uptake from intestines to blood
Wilsons problem of uptake from the liver to blood

It was interesting that kayser-fleisher rings are not pathognomonic for wilsons...

 

[MDMikeRyan]

This is Non-Important for all examination purposes.

Lysyl Hydroxylase deficiency it is cause by a mutation in PLOD1 Gene and its manifestations it is why its called Kyphoscoliosis type (Type VI AR ED) with common hip dislocations.
Procollagen Peptidase Deficiency it is cause by a mutation in ADAMTS2 Gene and its manifestations is why its given the name dermatosparaxis type ( Type VIIC ED) ( breaking of skin, sagging of skin).

What is important for examination?

Examinations will test probably Classical, Hypemobile, Vascular type
What you need to learn is type of collagens?

Type 1: Bone, tendon, skin involvement, Cornea
Type 2: Cartilage (Cartwolage)
Type 3: Blood Vessels, Smooth Muscle (Uterus, Heart)
Type 4: Basement Mebrane ( Renal Glomerulopathies (Alport Syndrome))
Type 5: Same as Type 1 ( Bone, Skin, Cornea) and it usually always found with Type 1 Collagen

The other thing you need to learn is what type collagen is involved in the types that are important

Classical type(Type I, Type II): has deficiency in type 5 collagen alpha chain 1 and alpha chain 2, so you know the mutation in gene COL5A1, COL5A2
Hypermobile Type (Type III): deficiency in Tesnacin X protein ( function is to properly organized collagen in joints ligaments and tendons)
Vascular Type (Type IV): Deficiency in Collagen type 3 alpha chain 1, so mutation is in gene COL3A1

If you know the type of collagen and the 3 types I mention above you will know which type of collagen is involved.

The most commonly tested type of Ehler Danlos type is type IV because of vessel weakness and rupture of smooth muscle organs ( Pregnant woman with ruptured uterus, a kid with spleen hemorrhage, a Berry aneurysm, an Aortic Dissection)

The other question that may appear are comparisons with Marfan's syndrome, Scurvy ( Vitamin C is needed for Lysyl Hydroxylation).

What is unique for Marfan?: (long thin limbs, super Tall for age with arachnodactyly and lens displacement (ectopia lens)/ retinal dettachment, big testicles, pectus excavatum, pectus carinatum, flat foot, big organs)
What is unique for EDS? :( Hyperextensible skin, sagging of skin, acrogeria( older appearance), cigar shaped scars,keloid formation)

Mitral Prolapse and Aortic Regurgitation cannot be ruled out in EDS vascular type
Corneal Displacement cannot be ruled out in Marfans
Dural Ectasia cannot be ruled out in EDS
Arthralgia and Scoliosis cannot be ruled out in Marfans
Stretch Marks cannot be ruled out in EDS
Aneurysm and Aortic Dissection are equally common in both
Deformities of fingers cannot be ruled out in both
Hypermobility of joints cannot be ruled out in both

Rare: Marfans may present with mental disability

Hope this helps!!!!