After Retta Beery noticed muscle spasms and movement problems in her fraternal twin children Alexis and Noah, she was told by pediatricians that they had cerebral palsy. The children would have several developmental delays. After doing independent research on cerebral palsy, Mrs. Beery was unsatisfied with the diagnosis. She sought a better explanation with movement disorder specialists. At the age of five, the children were given the diagnosis of dopamine responsive dystonia (DRD) based on clinical presentation. DRD, also known as Segawa’s disease, is a genetic movement disorder that is characterized by neurological symptoms that include muscle spasms, muscle rigidity, and hyperreflexia. In addition, patients often exhibit dystonia and parkinsonism. The disease results from low levels of the neurotransmitter dopamine. The children were treated with the dopamine precursor levodopa, and made significant improvements. At the time, Alexis was more severely affected by the disease and was having difficulty with walking. After starting levodopa, she was able to walk and has since gone on to participate in school athletics. In her teenage years, she developed a cough and shortness of breath that was thought to be due to laryngospasm caused by the disease. The cough was severe and the shortness of breath was debilitating. Mrs. Beery sought further answers regarding her daughter’s worsening clinical condition and wanted her children’s genome sequenced in an attempt to obtain an explanation. Researchers lead by Dr. Richard Gibbs, head of the Baylor College of Medicine Human Genome Sequencing Center, took on the project. The results were published in the June 15, 2011 issue of Science Translational Medicine. Mutations in several genes have been shown to cause the disorder. To the researchers surprise, the children did not have mutations in the two genes commonly known to cause DRD. Tyrosine hydroxylase, which uses tetrahydrobiopterin as a cofactor, synthesizes dopamine from tyrosine. Mutations in the gene for GTP cyclohydrolase I, which disrupts production of tetrahydrobiopterin, cause an autosomal dominant form of DRD. Additionally, mutations in tyrosine hydroxylase cause an autosomal recessive form of the disease. The researchers found that the children did not have either of these mutations. In an attempt to further elucidate the etiology of their medical condition, the researchers used whole genome sequencing on the children. It was found that they have compound heterozygous mutations in the gene for sepiapterin reductase, which causes an autosomal recessive form of DRD in only 3% of cases. This enzyme is involved in the biosynthesis of the neurotransmitters dopamine and serotonin. As a result of this finding, the children were also treated with a serotonin precursor called 5-hydroxytryptophan. This new treatment improved their symptoms within one to two weeks and they now have better attention in school, better motion and coordination, and reduced hand tremors. This case study exemplifies how whole genome sequencing can be applied to obtain more information about a patient’s medical condition. As a result, the information obtained can be used to tailor the medical treatment to that particular patient. The authors wrote, “Because genetic diagnosis using whole genome sequencing in individual families is becoming more accessible, the debate concerning the underlying value of the extensive information that is generated has intensified”. This is a very remarkable and intriguing case, and has sparked a discussion on how whole genome sequencing can become more routine for future clinical diagnosis.
Bainbridge, MN et al. “Whole Genome Sequencing for Optimized Patient Management” Sci Transl Med 15 June 2011: Vol. 3, Issue 87, p. 87re3
See the YouTube video on the Beery family below: