Christianson Syndrome

Gene-Targeted Testing

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotypes of ID often overlap, most individuals with CS are diagnosed by either multigene panel or exome sequencing. Single-gene testing (sequence analysis of SLC9A6, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.

A multigene panel for intellectual disability, autism spectrum disorder, and/or epilepsy that includes SLC9A6 and other genes of interest (see Differential Diagnosis) may be used. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Of note, given the rarity of Christianson syndrome, panels for ID may not include SLC9A6. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Comprehensive Genomic Testing

Comprehensive genomic testing (when clinically available) typically includes exome sequencing and genome sequencing.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Affected Males

Common manifestations (from Pescosolido et al [2014] and additional references where indicated):

• Developmental delay and intellectual disability typically range from moderate to profound, although mild ID has been reported [Masurel-Paulet et al 2016].
  • Gross motor milestones are delayed. Independent ambulation is achieved approximately one to two years later than average.
  • Speech is generally absent. Very limited receptive language and use of a few single words may emerge in the first years of life; however, these words may subsequently be lost. To date, speech was unaffected in one adult male [Masurel-Paulet et al 2016].
  • IQ is generally well below 35-40.
• ASD or autistic behaviors. Notable findings include poor eye contact, lack of use of facial expressions to communicate, using bodies of others as a tool (e.g., to turn a doorknob), unusual sensory interests and preoccupations, and lack of reciprocal play / social interest [Garbern et al 2010, Mignot et al 2013, Pescosolido et al 2014, Coorg & Weisenberg 2015]. In one cohort, 43% of affected males were previously diagnosed with ASD by a clinician [Pescosolido et al 2014]. The authors caution that diagnosis of ASD – even with standardized assessments – in nonverbal individuals with cognitive impairments may be challenging.
• Hyperkinesis. Affected males are commonly described as having hyperkinesis (i.e., hyperactive and described by parents as "always on the go") [Gilfillan et al 2008, Fichou et al 2009, Schroer et al 2010, Takahashi et al 2011, Mignot et al 2013].
• Epilepsy. Seizure onset is typically before age three years and is consistent with generalized epilepsy, although focal-onset seizures have been reported. Specific seizure types include infantile spasms, tonic, tonic-clonic, myoclonic, drop (unknown whether tonic or atonic), and absence seizures. Seizure frequency can range from daily clusters to seizure-free periods longer than one year.
  EEG findings include abnormalities in both background (e.g., generalized slowing) and epileptiform activity (e.g., frequent generalized spike-wave complexes, irregular generalized spike-wave pattern, and multifocal independent and sometimes synchronous spikes). One individual had generalized discharges in more than 85% of slow-wave sleep recordings, a pattern associated with electrographic status epilepticus of sleep [Coorg & Weisenberg 2015].
  Clinical and EEG findings suggestive of Lennox-Gastaut syndrome, a syndromic epileptic encephalopathy, have been reported [Schroer et al 2010].
  Epileptic encephalopathy (childhood-onset epilepsies characterized by severe, intractable, multiform seizures associated with cognitive impairments) has been reported [Zanni et al 2014]. Some suggest that epileptic encephalopathy appears in up to 20% of affected individuals [Pescosolido et al 2014].
• Truncal ataxia, a nearly universal finding, is manifest in ambulatory males as an ataxic, unsteady gait. While ataxia is typically present with emergence of independent ambulation and is lifelong, late-onset worsening of ataxia at age 13 years [Mignot et al 2013] and in the 40s-50s [Garbern et al 2010] has been reported.
  In one family, an affected boy and his maternal uncle did not have ataxia [Masurel-Paulet et al 2016].
  Progressive cerebellar atrophy, particularly affecting the vermis, is one of the most common neuroimaging findings [Garbern et al 2010, Schroer et al 2010, Mignot et al 2013].
• Postnatal microcephaly. Head circumference is typically normal at birth. Microcephaly becomes evident over time.

Distinctive features seen in some affected males (from Christianson et al [1999], Gilfillan et al [2008], and Pescosolido et al [2014], and additional references where indicated):

• Abnormal eye movements, such as convergent strabismus and esotropia, are common [Garbern et al 2010, Schroer et al 2010, Takahashi et al 2011, Mignot et al 2013, Riess et al 2013, Masurel-Paulet et al 2016]. Abnormal horizontal eye movements or the inability to look laterally, presumably due to dysfunction of cranial nerve VI and/or lateral recti muscles, are common [Schroer et al 2010, Mignot et al 2013].
• Feeding difficulties. Open mouth and drooling are common [Gilfillan et al 2008]. Feeding difficulties can include sucking and swallowing problems in infancy as well as lack of coordination in chewing later in infancy. Gastroesophageal reflux disease may be present often requiring Nissen fundoplication surgery (see Management, Treatment of Manifestations).
• Poor weight gain occurs despite normal caloric intake. Low body mass index (BMI) becomes more pronounced with age. Older males have been described as appearing "emaciated."
  Of note, birth weight (when reported) was normal in the majority of affected males.
• Constipation can be significant.
• Regression, typically beginning between ages 15 months and 16 years, can include loss of previously acquired skills such as independent ambulation, use of words/sounds, independent feeding, establishing eye contact / facial expressions, and fine/gross motor skills [Garbern et al 2010, Schroer et al 2010, Takahashi et al 2011, Mignot et al 2013].
  Medical illness and/or severe or worsening seizure episodes usually precede regressions [Schroer et al 2010, Takahashi et al 2011].
  The risk for regression appears to increase after the first decade of life as regression has been reported in males in their 40s-50s [Garbern et al 2010].

Findings identified in a few affected males include the following:

• Sleep disturbances, including frequent nighttime waking, an inability to fall asleep, and, in two males, no discernable sleep pattern [Christianson et al 1999, Gilfillan et al 2008, Garbern et al 2010, Mignot et al 2013, Pescosolido et al 2014]
• Scoliosis and one individual with severe kyphoscoliosis [Gilfillan et al 2008, Schroer et al 2010, Riess et al 2013]
• High pain threshold resulting in serious injury [Pescosolido et al 2014]
• Osteoporosis observed in some cases [Pescosolido et al 2014]

Life expectancy. Data on life expectancy are limited. Death in the second to fifth decade has been reported in a few individuals [Gilfillan et al 2008]. Causes have included pyogenic bronchopneumonia superimposed on miliary tuberculosis [Christianson et al 1999] and epileptic seizures [Schroer et al 2010].

Pathology. Postmortem brain examination in two adult males with CS from the same family showed diffuse glial tau deposition in cerebellar, brain stem, and centrum semiovale white matter tracts [Garbern et al 2010]. In addition, tau-positive inclusions were found throughout the substantia nigra, locus coeruleus, pontine nuclei, basal ganglia, thalamus, and cranial nerve nuclei.

Heterozygous Females (i.e., Carriers)

To date, 43 heterozygous females in 17 families have been reported [Christianson et al 1999, Gilfillan et al 2008, Fichou et al 2009, Garbern et al 2010, Schroer et al 2010, Takahashi et al 2011, Riess et al 2013, Pescosolido et al 2014, Zanni et al 2014, Masurel-Paulet et al 2016, Sinajon et al 2016].

Manifestations range from no reported abnormal neurologic or psychological findings [Gilfillan et al 2008, Fichou et al 2009, Takahashi et al 2011, Riess et al 2013] to mild or (rarely) moderate ID, behavioral issues, and hyperactivity [Pescosolido et al 2014, Masurel-Paulet et al 2016].

The most common findings:

• Mild developmental delay (especially with speech/language) and/or mild intellectual disability [Christianson et al 1999, Schroer et al 2010, Pescosolido et al 2014, Zanni et al 2014, Sinajon et al 2016]
• In some, a notable discrepancy on neuropsychological testing between verbal and performance IQ, with verbal IQ being much lower [Masurel-Paulet et al 2016]
• Speech disorder/dysphasia [Schroer et al 2010, Masurel-Paulet et al 2016, Sinajon et al 2016]
• Dyslexia [Gilfillan et al 2008, Masurel-Paulet et al 2016]
• Behavior problems including aggression [Christianson et al 1999, Schroer et al 2010, Sinajon et al 2016]
• Hyperactivity/hyperkinesia [Schroer et al 2010, Pescosolido et al 2014, Sinajon et al 2016]

Developmental Delay / Intellectual Disability Management Issues

The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.

Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy. In the US, early intervention is a federally funded program available in all states.

Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies, and an individualized education plan (IEP) is developed.

Ages 5-21 years

• In the United States, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
• Discussion regarding transition plans and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.

All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies and to support parents in maximizing quality of life.

Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.

In the US:

• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.

Motor Dysfunction

Gross motor dysfunction

• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).

Fine motor dysfunction. Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive functions, such as feeding.

Oral motor dysfunction. Assuming that the individual is safe to eat by mouth, feeding therapy – typically from an occupational or speech therapist – is recommended for affected individuals who have difficulty feeding due to poor oral motor control.

Communication issues. Consider evaluation for alternative means of communication (e.g., Augmentative and Alternative Communication [AAC]) for individuals who have expressive language difficulties.

Social/Behavioral Concerns

Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one on one with a board-certified behavior analyst.

Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications when necessary.

Other

Seizures. Currently, no guidelines exist for seizure control in Christianson syndrome. A range of antiepileptic drugs has been used, including levetiracetam, valproic acid, clonazepam, clobazam, diazepam, lamotrigine, phenobarbital, oxcarbazepine, carbamazepine, zonisamide, and topiramate [Pescosolido et al 2014].

GI manifestations. Fundoplication has been pursued to treat gastroesophageal reflux disease in some individuals. In a minority, a gastrostomy tube has been placed to improve nutrition. A bowel regimen to prevent constipation is recommended as needed.

Post-hospitalization. Because hospitalization for complications such as pneumonia or epileptic seizures may be particularly high-risk for subsequent regression in psychomotor skills [Pescosolido et al 2014], physical therapy following such an illness may be warranted in some instances.