NORD gratefully acknowledges Prof Annick Toutain from the Service de Genetique Hopital Bretonneau in France for the updates to this report.
Wieacker syndrome is a rare, slowly progressive, genetic disorder present at birth and characterized by deformities of the joints of the feet (contracture), muscle degeneration (atrophy), mild intellectual disability and an impaired ability to move certain muscles of the eyes, face and tongue. Wieacker syndrome is inherited as an X-linked recessive trait.
Symptoms of Wieacker syndrome include stiffening of the muscles and joints of the feet (contracture), slowly progressive atrophy of certain muscles of the legs and arms, and mild intellectual disability. Other symptoms are impairment or inability to move the eyes despite the wish to do so, and impairment in the use of face and tongue muscles. In some cases, affected individuals may have droopy eyelids (ptosis), crossed eyes (strabismus), and farsightedness (hyperopia). Abnormal curvature of the spine may also occur (kyphoscoliosis).
Wieacker syndrome is inherited as an X-linked recessive trait. It is caused by a defect in the ZC4H2 gene, located on a particular site of the X chromosome (Xq13-q21). The ZC4H2 gene is expressed in the synapses of the nervous system and plays an important role during embryonic development of the central and peripheral nervous system.
Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome Xq13-q21″ refers to a region on the long arm of the X chromosome between bands 13 and 21. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
X-linked recessive genetic disorders, such as Wieacker syndrome, are conditions caused by an abnormal gene on the X chromosome. Females have two X chromosomes, but one of the X chromosomes is “turned off” and all of the genes on that chromosome are inactivated. Females who have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms of the disorder because it is usually the X chromosome with the abnormal gene that is “turned off”. A male has one X chromosome and if he inherits an X chromosome that contains a disease gene, he will develop the disease. Males with X-linked disorders pass the disease gene to all of their daughters, who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease, and a 25% chance to have an unaffected son.
The prevalence of Wieacker syndrome is not known. Wieacker syndrome usually affects males, but some carrier females show mild manifestations of the disorder. As of 2015, the syndrome has been reported in 5 families. ZC4H2 gene mutations have also been identified in 3 sporadic patients who presented more or less severe intellectual disability and congenital contractures of multiple joints, at least equinovarus of the feet, associated with neurological symptoms such as muscle weakness, spasticity, seizures and ptosis. In one of the families, those affected had neonatal respiratory distress responsible for early death. Wieacker syndrome is therefore now considered to be part of a wider phenotype consisting of arthrogryposis multiplex congenita (congenital multiple joint contractures) and intellectual disability, caused by ZC4H2 gene mutations.
In some instances in the history of the family in which the syndrome was first described, the syndrome was present at birth.
Treatment is symptomatic and supportive. The syndrome is little understood at this time.
Physical therapy, surgery, speech therapy, and special education can be of benefit, especially if started as early as possible. Genetic counseling may be of benefit for the families of children with Wieacker syndrome.
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