Genetics of NBIA
Here we have compiled the basics on genetic issues relating 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 diagnosed you with NBIA. The costs are usually covered by health insurance.
NBIA is genetically very diverse. More than 15 genes have been described in the specialist literature to date (see What is NBIA?). Further genetic causes are currently being researched. NBIA diseases that cannot (yet) be assigned to any of the known genes are called idiopathic NBIA.
Human genes are normally located on 46 chromosomes, 23 from the mother and 23 from the father. 22 of these chromosome pairs are called autosomes, 1 chromosome pair is called sex chromosomes (gonosomes, X/Y). Women therefore normally carry two functioning copies of all genes. As men only have one X chromosome in the sex chromosomes, they lack a backup copy for the genes coded there. The karyogram on the right shows all 23 pairs of chromosomes of a man.
If a person carries a mutated, i.e. defective, copy of a gene, he or she is a carrier of the mutation. In the case of recessive genes, a mutation in one of the two copies has no consequences for the carrier and the disease only breaks out if both copies of the gene have a mutation. This is referred to as autosomal recessive inheritance. This is how most NBIA diseases are inherited.
Only individual NBIA diseases are inherited in an autosomal dominant manner, i.e. one mutated gene copy is sufficient to cause the disease to break out.
Another exception is BPAN. In this case, the mutation almost always arises spontaneously in the child, usually shortly after fertilization or already in the germline. This is referred to as a new mutation or de novo mutation.
Inheritance of most NBIA diseases
If a copy of a recessive gene contains a change (mutation), the "carrier" of the mutation is healthy but can inherit the mutated gene. Recessive diseases only occur if both parents are carriers for the same condition and both pass on the mutated gene to their child. Statistically, there is a 1 in 4 (25%) chance that two carriers will have a child affected by NBIA, a 2 in 4 (50%) chance of having a child who is also a carrier, and a 1 in 4 (25%) chance of having a child to whom the gene mutation has not been passed on. Most NBIA diseases are inherited in this way, i.e. autosomal recessively.
In autosomal dominant inheritance, a mutated gene copy from a parent who is usually affected themselves is sufficient to cause the disease in their children. The probability of an affected person passing on the mutated gene to one of their children is 1:2 (50%).
As far as is known, this inheritance only plays a role in two NBIA diseases: Neuroferritinopathy is always inherited as an autosomal dominant trait and in MPANwhich is usually inherited in an autosomal recessive manner, this inheritance has also been proven in some cases. Please also read the article: "MPAN can also be inherited autosomal-dominantly"
New mutation with BPAN
De novo mutations are so-called new mutations, i.e. neither parent is a carrier or affected themselves, instead the mutation occurs spontaneously. The mutation can occur in the germ cells of the parents, sperm or egg, or in the early development of the fertilized egg in the womb. This is the case in almost all BPAN-affected people:
BPAN is associated with a dominant new mutation in the WDR45 gene in the X chromosome. Dominant also means here that a defective gene is sufficient to cause the disease to break out.
However, as there are many more female than male patients with BPAN, it can be assumed that the additional X chromosome helps girls to compensate somewhat better for the loss of function of the WDR45 gene, whereas in boys, who only have one X chromosome, it is assumed that they often do not survive the pregnancy.
There are also exceptions with BPAN: Individual cases of male BPAN patients are known in which the mutation is caused by X-linked recessive inheritance was transmitted from the mutation-carrying but healthy mother.
Patient-oriented Disease description from thehe 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
Illustration of the X-linked dominant De Novo mutation: Noah Rusch, compiled with Gimp and supplemented from two images (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