Genetics of NBIA
Here we have compiled basics on genetic issues related to NBIA.
The information provided here can only offer a rough guide and does not cover every individual case, which is why we strongly recommend that all affected families seek genetic counseling. Please contact the genetics laboratory that also made the NBIA diagnosis. The costs are usually covered by the health insurance.
NBIA is genetically very diverse. More than 10 genetic variants have been described in the literature so far (see NBIA variants). Further genetic causes are currently being researched. NBIA disorders that cannot (yet) be assigned to any of the known genes are called idiopathic NBIA.
Human genes are normally located on 46 chromosomes, 23 each from the mother and the father. 22 of these chromosome pairs are called autosomes, 1 chromosome pair is called sex chromosomes (gonosomes, X/Y). Normally, we carry two working copies of each gene, one from the mother, one from the father. The karyogram on the right shows sorted all 23 pairs of chromosomes of a man.
Inheritance of most forms of NBIA
Exceptions
In autosomal dominant inheritance, a mutated gene copy from a parent who is usually affected is sufficient to cause the disease in the children as well. The probability that an affected person will pass on the mutated gene to one of his or her children is 1:2 (50%).
As far as is known, this mode of inheritance only plays a role in two forms of NBIA: Neuroferritinopathy is always inherited in an autosomal-dominant manner and in MPANwhich is usually inherited in an autosomal recessive manner, this mode of inheritance has also been demonstrated in some cases. Please also read the article: "MPAN can also be inherited in an autosomal dominant manner"
New mutation in BPAN
De novo mutations are so-called new mutations, i.e. no parent is a carrier or affected itself, instead the change occurs spontaneously. The mutation may be new in the germ cells of the parents, sperm or egg, or in the early development of the fertilized egg in the womb. This is common in almost all BPAN-This is the case for all those affected:
BPAN is associated with a dominant new mutation in the WDR45 gene in the X chromosome. Dominant also means here that one defective gene is sufficient to cause the disease to break out. Since there are many more female than male patients with BPAN, it can be assumed that the additional X chromosome helps the girls to compensate for the loss of function of the WDR45 gene somewhat better, while in boys, who have only one X chromosome, it is suspected that they often do not survive the pregnancy.
There are also exceptions in BPAN: There are individual cases of male BPAN sufferers in whom the mutation is caused by X-linked recessive inheritance was transferred from the mutation-bearing but healthy mother.
Sources:
Patient-oriented Disease description from dem ACHSE network (German)
The karyogram is in the public domain and was taken from Wikipedia: https://de.wikipedia.org/wiki/Karyogramm#/media/File:DNA_human_male_chromosomes.gif
Illustrations of autosomal recessive and autosomal dominant inheritance: Kuebi = Armin Kübelbeck - own work, people taken from Image: Autorecessive.svg made by en:User:Cburnett, made with InkScape. PNG file derived from SVG master, CC BY-SA 3.0, https://commons.wikimedia.org/wiki/File:Autodominant_01.png, https://commons.wikimedia.org/wiki/File:Autodominant_01.png#/media/File:Autorecessive_01.png
Figure for the X-linked dominant De Novo mutation: Noah Rusch, compiled with Gimp and supplemented from two figures (https://commons.wikimedia.org/w/index.php?curid=3755086#/media/File:X-chromosomal-dominant-Vater.png and https://commons.wikimedia.org/w/index.php?curid=3755086#/media/File:X-chromosomal-dominant-Mutter.png) from Kuebi = Armin Kübelbeck, CC BY-SA 3.0
