Zaidi disorder, officially known as Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome, is a rare congenital condition impacting multiple body systems. As a neurodevelopmental disease with an onset in infancy, it affects the development of the nervous system. The disorder was first identified in 2016, and its recognition has grown with advanced genetic testing. The specific combination of features can differ among individuals.
Genetic Origins of Zaidi Disorder
The cause of Zaidi disorder is a mutation in the SON gene, located on chromosome 21. This gene provides instructions for making a protein that is a master regulator of RNA splicing, a process for the proper expression of many other genes. The SON protein is significant for normal brain development. A mutation in this gene can lead to a frameshift or a truncation of the gene product, which disrupts its function.
In nearly all documented cases, the mutation in the SON gene occurs as a de novo event. This means the genetic alteration happens spontaneously in the child and is not inherited from the parents. This type of mutation is a random event that occurs during the formation of reproductive cells or in early embryonic development.
The condition is caused by a heterozygous mutation, meaning one of the two copies of the SON gene is altered while the other is functional. This results in haploinsufficiency, where the single functioning copy cannot produce enough protein for the body to develop correctly. This protein deficiency leads to the variety of developmental issues seen in the disorder.
Physical and Developmental Characteristics
The effects of Zaidi disorder are wide-ranging, with intellectual and developmental delays being universal. All individuals experience some degree of intellectual disability, from mild to severe, and show delays in achieving developmental milestones. Speech and motor skill development are particularly affected, with many having delayed speech or being nonverbal and experiencing delays in learning to crawl or walk.
Neurological assessments reveal differences in brain structure, and seizures develop in about half of all individuals. Brain imaging, such as an MRI, may show abnormalities like abnormal gyral patterns, ventriculomegaly (enlarged ventricles), a thin corpus callosum, and cerebellar hypoplasia (an underdeveloped cerebellum).
Distinctive, though sometimes subtle, physical traits are present. Facial features can include a prominent forehead, deep-set eyes, a broad or depressed nasal bridge, and a short philtrum. Many individuals exhibit hypotonia (low muscle tone) from the neonatal period, which can contribute to poor feeding. Skeletal anomalies are also common, such as joint laxity, scoliosis, and limb contractures.
Other health concerns can involve various organ systems. Vision problems are frequent and can include strabismus (crossed eyes), hypermetropia (farsightedness), and nystagmus (involuntary eye movements), with some having structural issues like optic atrophy. Malformations can also occur in the heart, kidneys, and gastrointestinal tract.
The Diagnostic Process
The diagnostic process for Zaidi disorder often begins when an infant or young child shows developmental delays and physical characteristics of the condition. A pediatrician’s initial observations of signs like hypotonia or missed milestones usually lead to referrals to a team of specialists, including a neurologist and a geneticist, for a more in-depth assessment.
A neurologist may order a brain MRI to look for structural abnormalities associated with neurodevelopmental conditions. While these findings are not exclusive to Zaidi disorder, they provide evidence that points toward a genetic cause.
The definitive diagnosis is achieved through genetic testing. Whole exome sequencing (WES) or whole genome sequencing (WGS) is used to identify the specific heterozygous, loss-of-function mutation in the SON gene. Testing the parents’ DNA can confirm the mutation is de novo by showing they do not carry the same genetic change.
Management and Therapeutic Approaches
There is no cure for Zaidi disorder, so management focuses on comprehensive supportive care tailored to each individual’s symptoms. The goal is to address health and developmental challenges to improve quality of life. This requires a coordinated, multidisciplinary approach from medical specialists and therapists.
A combination of therapies is used to improve functional abilities. Physical therapy is used to address hypotonia and motor delays, helping with balance, strength, and mobility skills like walking. Occupational therapy helps individuals develop skills for daily living, from fine motor tasks to sensory processing. Speech therapy is another component, targeting communication challenges and assisting with feeding and swallowing difficulties.
Specialized educational support is necessary for addressing learning disabilities and ensuring access to an appropriate academic environment. Regular monitoring by specialists such as cardiologists, ophthalmologists, and nephrologists is also required. These routine check-ups help manage the specific health issues present and allow for early treatment of emerging concerns.