CDKL5-related Autism

A 3 year old girl was evaluated for autistic features, repetitive hand movements and developmental delay.Her birth and gestation were unremarkable. At 3 months of age she developed mixed seizures that were poorly controlled until 6 months of age, after which primarily absence seizures remained. When evaluated at 1 year of age, her motor and mental abilities were delayed, with some evidence of regression, by parental accounts. Her examination at 1 year of age was otherwise normal.

On examination at 3 years of age:

• General exam: normal, including a normal head circumference of 47 cm (15 %ile).

•  Neurological exam:

  • Mental status: notable for her speaking in one or two word sentences, typically while looking away from others, and referring to herself using her name. According to the parents she often spends hours at a time shuffling around toy dishes.

  • Cranial nerves: normal, with normal pupillary responses and following objects in her visual fields, though she avoids eye contact. Her eye movements are normal. She is able to drink juice and eat a cookie without apparent difficulty.

  • Motor exam: strength, reflexes and tone appear normal, but assessment is difficult due to lack of cooperation. There are no tremors or tics. She is able to walk with some unsteadiness and feed herself using a spoon, but has prominent repetitive hand movements.

  • Reflexes: normal.

The autistic features and stereotypies (repetitive hand movements) led to suspicion of the atypical form of Rett syndrome, atypical because of the earliness of the seizures. However, MECP2 gene testing was normal. There had been some suspicion of Angelman syndrome, but the emergence of the stereotypies and the lack of visual and oculomotor abnormalities made that diagnosis seem unlikely. Based on the Rett-like phenotype and the prominent early seizures, the CDKL5 gene was tested, revealing a 525A->T mutation (arginine -> serine) in the gene on one X chromosome, making the diagnosis of CDKL5-related autism / epileptic encephalopathy.

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Using only the clinical findings as described above, one could have determined that the most useful test to order was CDKL5 gene testing.  This is illustrated using the SimulConsult Neurological Syndromes decision support program.  Access to the software is free with registration, which is not needed if you work at a hospital with institutional access.  Videos describing how to use the software are online.  Then:

1. Click here to launch the software with the findings from this case already entered, illustrating that CDKL5-related autism / epileptic encephalopathy is by far the leading diagnosis (clicking the "Patient's findings" tab shows the pertinent positives and pertinent negatives used).
2. Click the "Add findings" tab to see a list of useful clinical findings, and uncheck the "Clinical > labs" checkbox to see a list of useful lab tests, in which the CDKL5 test is listed #1.
3. Click the CDKL5 button to see the link in the yellow box at the bottom of the screen leading to details of how to order the test.