Ausführliche Publikation mit Schwerpunkt der genetischen Diagnostik.
Verlauf und Ausprägung unterschiedlich bei allen Betroffenen und in keinerlei nachweisbarer Korrelation zur Mutation.
Zur Publikation als PDF
Wir haben den persönlichen Kontakt mit einer Familie gefunden,
welche einen Sohn im Alter von 5 Jahren hat.
Dieser ist molekulargenetisch gesichert an HJMD erkrankt.
Die Familie lebt in Florida und wir freuen uns auf regen Austausch zukünftig,
im Wissen das es doch immer mehr bekannte Fälle gibt.
Wieder mal etwas neues gefunden bzw. von 2009/2010,
aber bis dato noch nicht hier gelistet unter Publikationen.
Splice Site Mutations in the P-Cadherin Gene Underlie Hypotrichosis with Juvenile Macular Dystrophy
Der Fall eines damals 4 jährigen Mädchens aus Portugal ist nun publiziert.
Das Mädchen und deren Mutter sind persönlich bekannt und es besteht regelmäßiger Austausch.
Wie in einer Publikation vom Oktober 2018
in einem brasilianischen Ophthalmologie-Fachmagazin beschrieben wurde, gab es in einer Familie 3 Fälle.
3 Geschwisterkinder, alles Mädchen, wobei eine aus unbekannten Gründen bereits verstorben ist, diese zeigte aber die üblichen Merkmale.
1x Mädchen mit 9 Jahren und einem Visus von
Dezimal L 0,20 R 0,25 Logmar 0,6 / 0,7
1x Mädchen mit 15 Jahren und einem Visus von
Dezimal L 0,20 R 0,13 Logmar 0,6 / 0,9
Auffallend auch hier der deutlich schlechtere Wert der jüngeren Schwester im Vergleich zum Alter der größeren Schwester.
Eine Angabe der Genmutation fehlt.
Zur Publikation als PDF Download:
Untenstehende Fragen wurden bei der Konsultation am 18.Oktober 2018
detailliert und sehr aufschlussreich beantwortet.
(1) patient registries
Does England have its own patient registry for retinal patients,
such as the American >My Retina Tracker< ?
The German self-help association Pro Retina has implemented one
for its members.
This registry will facilitate access to clinical trials for patients and help researchers recruit patients.
I have already suggested that <My Retina Tracker> and the German Registry should discuss whether it would not be useful for researchers if such a Registry included mutations such as missense or nonsense. Therefore, it would be easier to reach suitable patients with nonsensical mutations, especially in one of their research areas. How do you see this?
(2) changes during pregnancy and puberty
The affected siblings from Germany report that during puberty both had improved structural hair growth.
During pregnancy, Mrs. XXX once again experienced a noticeable positive change.
To what extent are factors known that could lead to these noticeable
changes during pregnancy?
It is known that chemical processes are increased during puberty or pregnancy.
Are you aware of any results in these cases which, for example, explain the epigenetic factors in retinal diseases?
I have the following further question on this subject.
Is it conceivable that during this phase of physical change,
where the growth behaviour of the hair changes,
there is also a slowed rate of decay of the photoreceptors ?
In the case of known patients, among others in the UK,
it would be desirable to observe this point in time more closely with regard to this thesis.
Are you aware of any changes in other retinal diseases during puberty and pregnancy?
(3) progression forms
I have compiled an overview table of all publications on HJMD available to me which contained information on visual acuity.
I have attached this table as an attachment.
(The values consist of 2 points: 1x visual acuity at diagnosis and 1x visual acuity at last examination.In some cases there are many years in between.Unfortunately there are not 2 points for all patients.
All values have been converted to decimal values.)
Here it can be deduced that in the vast majority of cases there is a slow deterioration in vision.
Nevertheless, there are some conspicuous features.
It seems that those with good vision at a younger age tend to retain it even at an advanced age, in correlation with the other processes.
More data will certainly be needed to provide a more accurate prognosis of the progression. In the meantime I learned that a representation in decimal values is not correct and above all should not be represented linearly graphically. I will next convert the results of the patients presented to you into LogMar values and create a new overview.
In this context, the following question arises: XXX and XXX, the siblings who have identical mutations in the CDH3 gene, have so different visual acuity values. XXX is much older, but also has a much better visual acuity.
What are the underlying factors why there is such a variety of progressions, even with identical mutations?
Do you have an explanation why the EEM syndrome,
which is based on the same genetic defect, is accompanied by pronounced ectodermal malformations?
After studying the publications on the syndrome,I put forward the thesis that HJMD and EEM syndrome are the same disease, but HJMD is a milder form.
Also with the HJMD there is the occurrence of ectodermal changes.
Do you know if he already gives antibodies for the detection of the CDH3 gene? These antibodies are, as far as I understand it, used for testing e.g. TRIDs to detect the missing expression.
(6) hair phenotype
The hair phenotype in HJMD patients is an essential feature,
the hair growth cycle can normally be detected optically over a few weeks,
so that the HJMD would be ideal for testing the efficacy in nonsense mutations, or ?
The proof of photoreceptors seems to me to be more tedious here.
Do you have knowledge of investigations in the field of hereditary hair growth disorders based on this genetic basis.
With Mrs. Doctor XXX from Wolfrum Lab,Mainz I have already talked personally about her work on USH2 several times.
Meanwhile a Usher pig was drilled there.
Is there actually an international exchange among you as researching doctors ?
In patients with various genetic mutations, do you usually also take skin samples known as fibroblasts for the purpose of demonstrating efficacy ?
PTC124 and several other designers aminoglycoside are meanwhile very familiar to me. I'm following the clinical study >Study of Ataluren in Patients With Aniridia (STAR)< with excitement.
Are you already aware of the first interim results, about the efficacy ? Is it correct that in this study PTC124 is taken exclusively orally?
Orally administered, the active substance should probably fail at the blood retina barrier, or ?
I therefore do not necessarily understand the point of this study if the active ingredient is administered orally rather than not by drop.
At clinical trials the administration of the study is clearly described orally.
https://clinicaltrials.gov/ct2/show/NCT02647359?cond=aniridia&rank=1thBut other sources report that the active substances are administered with drops. http://ffb.ca/scientists-are-developing-an-eye-drop-to-treat-inherited-blinding-eye-diseases/
This is confusing.
(8) blood retina barrier
Various publications report on possible parmakological therapy approaches in connection with liposomes. It is intended to facilitate administration into the retina.
How do you assess the state of affairs here?
(9) eye drops
The administration of eye drops, which would certainly have to be taken daily, would be a great option here.
Is it possible that active substances diffuse through the dermis and choroid?
There are 3 stop codons.
Ataluren does not react immediately to these three codons.
You get the best results with the code UGA.
Then follow the UAG and the UAA. Another important effect that affects effectiveness is seen in the first letter of the following codon.
If the following codon starts with the letter C,
this is the best prerequisite for the effectiveness of atalures.
Have I understood this so far?
Do you already have experience values such as such deviations show up in their effectiveness? Is it the same for other aminoglycosides?
I think my son XXX has a UGA nonsense, is that right?
c.1086G>A / pTrp362*
Which active substances do you evaluate with regard to their suitability for the most promising and do you already have practical knowledge about ELX-02 ?