Christianson Syndrome - Clinical Features, Cause, Diagnosis, and Treatment

Introduction

Christianson syndrome also called Angelman-like syndrome is a type of disorder that affects the nerves. This condition affects mostly males. Individuals with this syndrome lose their ability to walk in childhood even after learning it. Children have happy demeanor (frequent laughing and smiling). Infants who suffer from oropharyngeal dysphagia (difficulty in swallowing) and hypotonia (poor muscle tone) have slow physical development. Individuals with Christianson syndrome live up to a second or fifth decade of life and lose life because of complications such as epileptic seizures and severe miliary tuberculosis (a life-threatening form of tuberculosis in which there is the presence of a large number of bacteria in the bloodstream).

What Is Christianson Syndrome?

Christianson syndrome is a rare disorder that affects the nervous system and occurs due to a mutation in the SLC9A6 (solute carrier family 9 member A6) gene. The main features of the affected individuals include delay in development, hyperkinesis, intellectual disability, and regression in which the acquired skills are lost. There is no cure for this syndrome but involves the management of any pain or discomfort, physical therapies, occupational therapies, and treatment of seizures.

What Are the Clinical Features of Christianson Syndrome?

The clinical features of Christianson syndrome in males are:

• Developmental delay.

• Intellectual disability.

• Inability to speak.

• Hyperkinesis (abnormal movements).

• Ataxia (lack of coordination and balance).

• Difficulty in walking or standing.

• Feeding difficulties.

• Constipation.

• Poor weight gain.

• Regression starts between 15 months and 16 years of age where the previously acquired skills are lost such as independent feeding, motor skills, and language.

• Epilepsy can occur before the age of three years. It is the abnormal brain electrical activity that causes abnormal emotions, behavior, and movements and can involve different types which are:

  • Infantile spasms are the sudden stiffening of muscles in infants who are between three to eight months of age

  • Tonic seizures, which are characterized by stiff muscles

  • Tonic-clonic seizures are characterized by stiffening and then jerking of extremities

  • Myoclonic seizures are characterized by nonrepetitive contractions involving the upper extremity commonly

  • Atonic seizures are characterized by the absence of muscle movements.

• Microcephaly (small head).

• Narrow long face with prominent jaw, nose, and ears.

• Open mouth along with uncontrolled drooling.

• Abnormal eye movements.

• Behavioral disorders in which autism spectrum and hyperactivity are frequently seen.

• Sleep disturbances.

• frequent nighttime waking.

• Osteoporosis rarely.

The clinical features of Christianson syndrome in carrier females are:

• Mild developmental delay and intellectual disability.

• Low verbal intelligence quotient (IQ).

• Speech disorder.

• Behavioral problems such as aggression.

• Hyperkinesia.

• Dyslexia (learning difficulty).

What Is the Cause of Christianson Syndrome?

Christianson syndrome is caused due to mutation in the SLC9A6 gene. This mutation is inherited in an X-linked recessive pattern, where the gene is located on X-chromosome. Males who carry one X-chromosome and the presence of the altered gene in that chromosome is enough to be affected by this condition. Females with two X-chromosomes and alteration in one chromosome do not likely cause any problem but are considered carriers who can pass down the mutated gene. If alterations are present in two chromosomes then, females are affected by this condition. But a characteristic feature of the X-linked recessive pattern is that X-linked traits are not passed down from father to son. The features of this gene include:

• The SLC9A6 gene is located in the X-chromosome.

• This gene provides information in producing a protein called sodium/hydrogen exchanger 6 (NHE6 or Na+/H+ exchanger 6).

• These sodium/hydrogen exchangers are found in the compartments of the cells (endosomes) and membranes of the cells.

• These sodium/hydrogen exchanges protein act as a channel and helps in the exchange of positively charged NA+ ions (sodium ions) into the cell with the removal of positively charged H+ ions (hydrogen ions or protons) from the cell compartment.

• Therefore removal of hydrogen ions helps in maintaining the PH (potential of hydrogen) which is the relative acidity of the cell.

• NHE6 proteins which are found in endosomes help in recycling proteins and in maintaining the PH of these endosomes.

• NHE6 also helps with protein trafficking (movement of proteins).

A mutation in the SLC9A6 gene can lead to the formation of an abnormal NHE6 protein which is short, nonfunctional, and breaks down quickly in the cell. Therefore, the PH inside the endosomes is not maintained, causing neurological problems, and also affecting protein trafficking. Some studies have shown that protein trafficking is important for memory and learning.

What Is the Diagnosis of Christianson Syndrome?

The diagnosis of Christianson syndrome involves:

• Christianson syndrome can be diagnosed by clinical manifestations such as developmental delay, impairment in language, epilepsy, hyperkinesis, and facial features like microcephaly, long face, and abnormal eye movements.

• Prenatal testing (genetic tests, blood tests, and ultrasound tests which are done to the fetus during pregnancy) and preimplantation genetic testing (genetic tests done to the embryos that are formed through in-vitro fertilization) can be done which shows mutated genes.

• Molecular genetic testing shows a mutation in the SLC9A6 gene which is found on X-chromosome. In males, there is the presence of a hemizygous pathogenic variant (presence of one copy of the mutated gene) in the X-chromosome. In females, there is the presence of a heterozygous pathogenic variant (presence of two copies of mutated gene each on two chromosomes).

What Is the Treatment for Christianson Syndrome?

The treatment for Christianson syndrome involves the management of manifestations such as feeding difficulties, neurodevelopmental disorders, and seizures. Evaluations are done to provide a proper treatment which includes:

• Physical therapy and Occupational therapy to assess gross and fine motor skills.

• Speech and language assessment.

• Assessment of nutrition and feeding

• Ophthalmologic assessment for abnormalities in eye movements.

Treatment includes:

• Early intervention programs such as speech, feeding, and physical and occupational therapy

• Individualized educational plan.

• Assistance from the developmental pediatrician.

• Use of anti-seizure medications such as Levetiracetam, Clonazepam, Diazepam, Valproic acid, and Phenobarbital.

• Use of Fundoplication treatment (a surgical treatment to treat stomach acid reflux) in case of gastroesophageal reflux disease.

• Applied behavior analysis (ABA) therapy is used in the case of autism spectrum disorder which improves social, behavioral, and adaptive skills.

• Enrollment in the developmental disabilities administration (DDA) which is a public agency that provides support and services to the affected individuals.

Conclusion

Christianson syndrome is a rare genetic disorder for which there is no cure. Individuals with Christianson syndrome along with family members should receive genetic counseling as it is inherited in an X-linked recessive pattern and the carrier females have a 50 percent of chance to pass down the mutated gene in each pregnancy. Males who inherit this mutated gene are affected by this syndrome but females who inherit this mutated gene show mild behavioral issues and intellectual disability.