Maternal Grandparents

Teresa & Howard

*
(Carrier)

(4 Daughters)
Linda Gail Shirley Paula
25%/75 25%/75 25%/75 75%/25

A.L.D
1 Son 1 Son 1 Son 2 Sons
Jason Curtis R.J. Mitch & Matt

Genetic Testing Results

•Genetic Testing of the (4) daughters
revealed: ALL 4 are Carriers

•Linda: 25/75 Gail: 25/75 Shirley: 25/75

Paula: 75/25

•Male sons of the 4 sisters: Are not carriers

 Understanding Sex Chromosomes and
Sex-linked Inheritance
Sex Determination and Sex-linked
Inheritance
1. How is the genetic determination of sex established in humans?
In the diploid genome of human beings there are 46 chromosomes, 44 of them
are autosomes and 2 are sex chromosomes. The individual inherits one of these
chromosomes from each parent.

The human sex chromosomes are called X chromosome and Y chromosome.

Individuals having two X chromosomes (44 + XX) are female. Individuals having
one X chromosome and one Y chromosome (44 + XY) are male. (Individuals 44 +
YY do not exist since the chromosome Y is exclusively from paternal lineage.)

Understanding Genetic Inheritance

To analyze the X DNA of a mother (assuming no access to her own
material) it is more indicated to study the genetic material of her sons since
all X chromosomes of males come from the mother while the daughters
have X chromosomes from the mother and from the father. By researching
the material of the sons it is ensured that the studied X chromosome is from
the mother.
1-Human karyotype with color added to distinguish chromosome pairs.(color pic)
2-Human cells normally contain 23 pairs of chromosomes, for a total of 46 chromosomes
in each cell.

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A particularly important category of genetic linkage has to do with the X and Y
sex chromosomes. These chromosomes not only carry the genes that
determine male and female traits, but also those for some other characteristics
as well. Genes that are carried by either sex chromosome are said to be sex
linked. Men normally have an X and a Y combination of sex chromosomes,
whereas women have two X's. Because only men inherit Y chromosomes, they
are the only ones to inherit Y-linked traits. Both men and women can have X-
linked traits because both inherit X chromosomes.
X-linked traits not related to feminine body characteristics are primarily
expressed in the phenotype of men. This is because men have only one X
chromosome. Subsequently, genes on that chromosome that do not code for
gender are expressed in the male phenotype, even if they are recessive. In
women, a recessive allele on one X chromosome is often masked in their
phenotype by a dominant normal allele on the other. This explains why
women are frequently carriers of X-linked traits but more rarely have them
expressed in their own phenotypes. In humans, at least 320 genes are X-
linked. These include the genes for hemophilia, red–green color blindness,
and congenital night blindness. There are at least a dozen Y-linked genes, in
addition to those that code for masculine physical traits

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Valproic acid stimulates ABCD2 gene
expression:
A novel potential therapy for X-
adrenoleukodystrophy
"the killer of children"
"I read of a study in a European genetics journal where
treatment mechanisms for the X-linked neuro-degenerative,
demyelinating childhood disorder of X-ALD, are sought and
derived by studying the very source of the genetic disorder: The
mutated (ABCD1) gene, which will eventually trigger a disease
state in at least 50% of the boys who carry this genetic mutation.
The particular study that was conducted, focused on "stabilizing"
the mutated gene that codes for a specific ALD phenotype. By
studying the similar mechanisms of both (ABCD1) and (ABCD2)
gene mutations, where each act similarly as peroxisomal
transporters, it was concluded that stimulation of the ABCD2
gene expression using valproic acid, leads to the stabilization of
"over-expression", which is currently used to prevent "late onset
ALD" in the older males those who are aware through genetic
testing, they carry the gene for the disorder...So, at the
conclusion of this European study, it was theorized that due to
the homologous nature of these genes, (both ABCD1 & ABCD2)
there may also be a possible connection between the
"stabilization" of "over-expression" in these mutated genes. So,
the hope being that, by the use of valproic acid to treat the
ABCD1 mutation, it may react similarly in the body, as it does in
ABCD2, resulting in a delayed onset, OR, possibly even,
PREVENTION of the onset of the disorder completely. This would
truly be "miracle by medicine", by prevention of the onset of
such a vile childhood disease by the use of modern day drug
therapy.
With the use of valproic acid, there may be a glimmer of hope in
the treatment of the children who must endure such a horrible,
slowly degenerative, yet rapidly progressive, life-taking disorder:
Childhood Cerebral X-linked adrenoleukodystrophy"... Lynn D

Article: Published in the European Journal of

Genetics

Valproic acid stimulates ABCD2 gene expression:

Our ultimate goal is to develop new therapies for X-linked
adrenoleukodystrophy (X-ALD), the most frequent inherited,
yet most lethal demyelinating disease. X-ALD leads to death in
boys due to cerebral demyelination aka (Childhoold Cerebral
ALD) or (CCALD)

The mutated gene in the disease (ABCD1), is a peroxisomal

transporter of very-long-chain-fatty acids-(VLCFA), whose
accumulation is the hallmark of the disease.
We have generated and characterized mouse models for X-ALD
by inactivation of ABCD1 and activation of a close homolog, the
ABCD2 peroxisomal transporter.
Recently, we have conducted studies showing that stable
overexpression of ABCD2 is able to prevent the late-onset
ALD phenotype as presented by ABCD1 knock-out mice.
This study constitutes an in vivo evidence of the overlapping
functions
of both transporters, ABCD1 & ABCD2 in the mouse.
We investigated the effect of "valproic acid" and found that VPA
stimulates ABCD2 expression in vitro and ex vivo in mouse and
human.
When given to X-ALD patients, a 2 to 4 fold upregulation of
ABCD2 in peripheral mononuclear cells in 50% of the patients is
reached.

Thus, our findings open encouraging perspectives for the

therapy of this devastating disease.

REFERENCE: THE EUROPEAN JOURNAL OF HUMAN GENETICS/VOL 14

A. Pujol1, S. Fourcade1, L. Brichta2, E. Hahnen2, P. Aubourg3, B. Wirth2, J.Mandel4;
1IRO/IDIBELL, Barcelona, Spain, 2Institute of Human Genetics, Cologne, Germany, 3INSERM
U561, Université Paris V, Paris, France, 4IGBMC, Illkirch, Strasbourg, France