Autosomal Dominant Leukodystrophy

Autosomal dominant leukodystrophy - ADLD - is a neurodegenerative disorder that leads to symptoms of ataxia, . ADLD is caused by duplications of the LMNB1 gene located on chromosome 5q3.2. Symptoms usually onset between age 40-50, and then the disorder is fatal within 10-15 years. Since it is an autosomal dominant disorder, a person only needs to inherit one copy of the mutation to develop the disorder (Nahhas, 2016).

Figure 1. Evidence of autosomal dominant inheritance pattern from affected families.

Leukodystrophies are a class of demyelination disorders, meaning that the disorders lead to a a loss of white matter in the brain. Specifically, ADLD has been linked to lipid synthesis dysregulation in oligodendrocytes, which are the glial cells that normally surround the axons of neurons (Roylan et al., 2015).

Figure 2. A visual showing normal myelination of neurons by oligodendrocytes (Aubourg, 2007).

The LMNB1 duplication causes an over-expression of the lamin B1 protein, which is found in the nuclear lamina in cells (Padiath et al., 2006.

Figure 3. Location of LMNB1 gene in humans (Gene Cards).

Mouse models have been helpful in determining the mechanisms that cause symptoms in ADLD - hindered lipid synthesis in oligodendrocytes has been reported as a possible mechanism. Currently, there is no treatment for ADLD, only management strategies for the symptoms as they appear.

Figure 4. 13 month old wild type mouse compared to transgenic mouse mouse with
LMBN1 duplication, in which the transgenic mouse has clear symptoms of ADLD (Roylan et al., 2015).   

Now that the gene for ADLD has been found, people can be tested for it as early as prenatally. However, since there is currently no treatment for the disorder, it could be very difficult for someone to hear that they will definitely develop symptoms for an untreatable disorder. The main benefit of genetic testing for ADLD is that it can now be diagnosed properly, whereas people with ADLD were often diagnosed with multiple sclerosis before the mutation was found (Padiath, 2016).

References:

Aubourg, P. 2007. Axons need glial peroxisomes. Nat. Genet. 39(8): 936-938.

GeneCards. n.d. LMNBI Gene. <http://www.genecards.org/cgi-bin/carddisp.pl?gene=LMNB1>.

Nahhas, N., Rasekh, P. S., Vanderver, A., Padiath, Q. S. 2016. Autosomal Dominant Leukodystrophy with Autonomic Disease. GeneReviews. <http://www.ncbi.nlm.nih.gov/books/NBK338165/>.

Padiath, Q. S. 2016. Presentation.

Padiath, Q. S., Saigoh, K., Schiffman, R., Asahara, H., Yamada, T., Koeppen, A., Hogan, K., Ptacek, L. J., Fu, Y. 2006. Lamin B1 duplications cause autosomal dominant leukodystrophy. Nat. Genet. 38(10): 1114-1123.

Rolyan, H., Tyurina, Y. Y., Hernandez, M., Amoscato, A. A., Sparvero, L. J., Nmezi, B. C., Lu, Y., Estecio, M. R. H, Lin, K., Chen, J., He, R., Gong, P., Rigatti, L. H., Dupree, J., Bayir, H., Kagan, V. E., Casaccia, P., Padiath, Q. S. 2015. Defects of Lipid Synthesis Are Linked to the Age-Dependent Demyelination Caused By Lamin B1 Overexpression. J. Neurosci. 35(34): 12002-12017.