Guidelines on Hereditary Leukodystrophies
How are congenital cerebral leukodystrophies inherited?
Overview
The inheritance patterns of congenital cerebral leukodystrophies are classified into three types: autosomal dominant, autosomal recessive, and X-linked recessive. Thus, correctly identifying the proband is important for genetic counseling to assess the risk within the family.
Types
The inheritance patterns of congenital cerebral leukodystrophies are classified as follows.
| X-linked recessive inheritance | Locus | Causative gene |
|---|---|---|
| Pelizaeus-Merzbacher disease | Xq22 | PLP1 |
| MCT8 deficiency (AHDS) | Xq13.2 | SLC16A2 |
| Autosomal recessive inheritance | Locus | Causative gene |
|---|---|---|
| Pelizaeus-Merzbacher–like disease 1 | 1q42.13 | GJC2 |
| Hypomyelination with ataxia and hypodontia | 10q22.3 | POLR3A |
| Diffuse cerebral hypomyelination with cerebellar atrophy and hypoplasia of the corpus callosum | 12q23.3 | POLR3B |
| Hypomyelination with congenital cataract | 7p15.3 | FAM126A |
| Hsp60 chaperonopathy | 2q33.1 | HSPD1 |
| Salla disease | 6q13 | SLC17A5 |
| Autosomal dominant inheritance | Locus | Causative gene |
|---|---|---|
| Hypomyelination with atrophy of the basal ganglia and cerebellum | 19p13.3 | TUBB4A |
| Peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome, and Hirschsprung disease | 22q13 | SOX10 |
| Other | Locus | Causative gene |
|---|---|---|
| Chromosome 18q deletion syndrome | 18q22 | MBP |
X-linked recessive inheritance
The diseases exhibiting X-linked recessive inheritance basically only appear in males. In most cases, the mother is a carrier. One in two boys (50%) born to a carrier mother will develop the condition. One in two girls (50%) born to a carrier mother will also carry the gene. Males in the next generation following that of an affected male who inherit a Y chromosome will not inherit the disease, but 100% of females who inherit an X chromosome will be carriers.
If the proband is found to suffer from a disease with X-linked recessive inheritance, the mother must be screened to see if she is a carrier to assess the risk. Female siblings of the proband must also be screened. However, minor children should not be screened solely on the basis of their parents' consent; screening is not be performed until they reach maturity and decide for themselves whether to be tested to determine whether they carry the gene.
Autosomal recessive inheritance
Usually both parents are carriers. In a consanguineous marriage, homozygous mutations can be expected, but in most other cases, compound heterozygosity is present. Even if a mutation is identified in the proband, a definitive diagnosis cannot be reached unless it can be shown that it has been inherited from each parent. If both parents are carriers, one in four (25%) of their children will develop the condition.
Autosomal dominant inheritance
Generally, in autosomal dominant inheritance the symptoms are passed down from parents to children at a rate of 50%. However, the congenital cerebral leukodystrophies described here tend to cause serious symptoms, and it is unlikely that a symptomatic patient will pass the condition on to the next generation of children. Therefore, most cases are de novo mutations. TUBB4A mutations may be associated with inherited dystonia, but in this case, the disease is transmitted in a dominant fashion from parent to child along with the mutation.
Chromosome defects
Chromosome 18q deletion syndrome is caused by the loss of the terminal of the long arm of chromosome 18. Most cases are spontaneous mutations. However, if the deletion is the result of an unbalanced translocation caused by a balanced translocation on the long arm of chromosome 18 in the parental generation, it may be repeated in siblings. If chromosome 18q deletion syndrome is identified, it is recommended that the parents also be screened to confirm whether one of them is carrying a balanced translocation.
Genetic counseling
Genetic counseling is the process of deciding whether to undergo genetic screening to assess the risk of genetic disease and make life plans once provided with the appropriate information to obtain an accurate understanding of its advantages and disadvantages. Genetic screening to reach the correct diagnosis is important in genetic counseling for congenital cerebral leukodystrophies, but this may also reveal that blood relatives are also at genetic risk. Since the results will be the same at whatever point in an individual's life the testing is performed, it is important to have a full understanding of the advantages and disadvantages of genetic screening before making the decision.
If there is a risk that the same disorder will occur again within the family, prenatal diagnosis is also an option, but this entails ethical considerations. In Japan, the view is that it is only acceptable for diseases that have a major effect on the prognosis for survival, but as the prognosis for congenital cerebral leukodystrophies varies depending on the genetic mutation concerned, the decision must be made individually in each case.
References [1, 2]
(Unless otherwise noted at the end, all are evidence level 6.)
- Vanderver A, Tonduti D, Schiffmann R, Schmidt J, van der Knaap MS. Leukodystrophy overview. 1993; .
- Numata Y, Gotoh L, Iwaki A, Kurosawa K, Takanashi J, Deguchi K, et al. Epidemiological, clinical, and genetic landscapes of hypomyelinating leukodystrophies. J Neurol 2014; 261: 752-758.
Literature search of PubMed
- ("genetic counselling"[All Fields] OR "genetic counseling"[MeSH Terms] OR ("genetic"[All Fields] AND "counseling"[All Fields]) OR "genetic counseling"[All Fields]) AND (hypomyelinating[All Fields] AND leukodystrophies[All Fields]) 3 results
- ("prenatal diagnosis"[MeSH Terms] OR ("prenatal"[All Fields] AND "diagnosis"[All Fields]) OR "prenatal diagnosis"[All Fields]) AND (hypomyelinating[All Fields] AND leukodystrophies[All Fields]) 1 result
