COL4A1/2-related familial vascular leukoencephalopathy

[galyea123]

Hi! This condition is linked to OMIM 175780 (Brain small vessel disease with or without ocular anomalies). You list the following as synonyms:

• COL4A1-related brain small vessel disease with hemorrhage
• COL4A1-related retinal arteriolar tortuosity-infantile hemiparesis-autosomal dominant leukoencephalopathy syndrome

I see that in the Orphanet classification "COL4A1/2-related familial vascular leukoencephalopathy" is under "COL4A1 or COL4A2-related cerebral small vessel disease with hemorrhagic tendency" ORPHA:477765 which also includes:

• Familial isolated retinal arteriolar tortuosity ORPHA:75326
• Familial porencephaly ORPHA:99810
• Familial schizencephaly ORPHA:481986
• HANAC syndrome ORPHA:73229

The GR entitled COL4A1-Related Disorders includes:

• Porencephaly type 1
• Brain small-vessel disease with or without ocular anomalies
• HANAC (hereditary angiopathy with nephropathy, aneurysms, and muscle cramps) syndrome
• Tortuosity of retinal arteries
• Nonsyndromic autosomal dominant congenital cataract

In our NORD report, COL4A1/A2-Related Disorders, authored by Dr. Gould we include the following subtypes:

• HANAC: hereditary angiopathy, nephropathy and cramps syndrome ([OMIM #611773]
• POREN1: autosomal dominant type 1 porencephaly; porencephaly with infantile hemiplegia ([OMIM #175780]
• RATOR: retinal arterial tortuosity ([OMIM #180000]
• BSVD: brain small vessel disease with or without ocular anomalies ([OMIM # 175780])
• ICH: susceptibility to intracerebral hemorrhage ([OMIM #614519] - the only difference with Orphanet, but it is a susceptibility only and not a disease per se.
• schizencephaly: ([OMIM #269160]

I would like to suggest adding "Brain small vessel disease with or without ocular anomalies" as a synonym of "COL4A1/2-related familial vascular leukoencephalopathy" and adding "COL4A1/A2-Related Disorders" as a synonym of the group "COL4A1 or COL4A2-related cerebral small vessel disease with hemorrhagic tendency" as this is now recognized spectrum of diseases that includes all these phenotypes.

Thank you, Gioconda Alyea

[sagehrke]

Dear @galyea123
Thank you for reaching out to the Mondo Disease Ontology, part of the Monarch Initiative!

We have received your ticket and will review it as soon as possible.

If you have any additional information or updates relevant to your inquiry, please add them in a comment on this ticket. Your input is valuable in helping us understand and resolve the issue effectively.

Thank you for your patience and for your contributions to Mondo!

Sincerely,
The Mondo Team

[katiermullen]

@galyea123 Thank you for this request!

Please note that the grouping terms from Orphanet have been obsoleted in Mondo:
MONDO:0018790 'obsolete COL4A1 or COL4A2-related cerebral small vessel disease with hemorrhagic tendency'
MONDO:0018788 'obsolete COL4A1 or COL4A2-related cerebral small vessel disease'

Currently in Mondo we have three familial porencephy terms:

• MONDO:0008289 'brain small vessel disease 1 with or without ocular anomalies' has synonym 'COL4A1-related familial vascular leukoencephalopathy'
• MONDO:0013773 'porencephaly 2' (note: this term could be renamed to brain small vessel disease 2 for consistency)
• MONDO:0100105 'brain small vessel disease 3'

We do not have a grouping term for COL4A1/A2-Related Disorders, but do have:

Please let us know if this classification suits your needs. Thank you!

[katiermullen]

@galyea123 Thank you for this request!

Could you please clarify what you are asking for? We think you would like a grouping term for COL4A1/A2-Related Disorders. Is that correct?

We have been having a lot of discussions on how to represent spectrum disorders in Mondo (for example “disorders caused by variation in COL4A1 AND/OR COL4A2”). These spectrum disorders (“and/or”) are difficult to represent in the ontology, especially regarding classification.

Please be aware that we recognize the need for such terms though, and we will involve you in these discussions when we are fully ready to have them.

[galyea123]

Yes, you are absolutely correct. I was asking adding "COL4A1/A2-Related Disorders" (Gould syndrome) as a synonym of the group "COL4A1 or COL4A2-related cerebral small vessel disease with hemorrhagic tendency" but I see it was obsoleted. COL4A1/A2-Related Disorders is now recognized as a spectrum of diseases that includes many phenotypes. You may want to consider adding this term (note that one of the writers of our NORD report is Dr. Gould, who first found that COL4A1 variants caused brain small vessel diseases https://omim.org/entry/175780) -hence the name, Gould syndrome as a synonym of COL4A1/A2-related disorders).

As commented, you have the entry "brain small vessel disease 1 with or without ocular anomalies" which is linked to Orphanet "COL4A1/2-related familial vascular leukoencephalopathy" (even so, they are not exact synonyms as "Brain small vessel disease 1" is caused by COL4A1 variants and "Brain small vessel disease 2" is caused by COL4A2 variants).

COL4A1 or COL4A2-related cerebral small vessel disease ORPHA:477759 subdivided in hemorrhagic and ischemic tendency as showed below:

COL4A1 or COL4A2-related cerebral small vessel disease with hemorrhagic tendency ORPHA:477765 which includes:
COL4A1/2-related familial vascular leukoencephalopathy ORPHA:36383
Familial isolated retinal arteriolar tortuosity ORPHA:75326
Familial porencephaly ORPHA:99810
Familial schizencephaly ORPHA:481986
HANAC syndrome ORPHA:73229

COL4A1 or COL4A2-related cerebral small vessel disease with ischemic tendency ORPHA:477762 which only includes
Pontine autosomal dominant microangiopathy with leukoencephalopathy ORPHA:477749 (which is also now in the NORD report)

I look forward to your discussions.

Thank you, Gioconda Alyea