CB is a 16-year-old girl whose first developmental concerns arose at four to five months of age. At that time, she was not visually fixing on faces. She did not smile responsively or laugh. She remained extremely quiet through her first year of life, with only minimal babbling. Language did not develop until approximately three years of age. Rather than go through a period of babbling, she exhibited echolalia. She was able to pronounce words clearly, but did not use them in an appropriate context.
CB engaged only in solitary play until she was approximately three years old, when she began to interact with her older sister. It was not much later that she began to interact with her parents. She did not exhibit joint attention until nine years of age. Even after she began interacting, her play was repetitive. She was very rigid in her behaviors and craved structure. CB had poor attention. She developed simple motor tics including throat clearing. She displayed features of sensory integration disorder; she did not allow anyone to touch her hands and there were certain textures of food that upset her greatly. Over time, CB displayed severe obsessive compulsive symptoms. She has never had any seizures.
The family history was limited since the patient was adopted, but her biological mother was known to have cognitive delays and social impairments. The patient has a half sister by the same mother who has a seizure disorder, cognitive delays, and social impairments.
The physical examination was notable for short stature and almond-shaped eyes. She was otherwise non-dysmorphic. The neurological examination was notable for pressured, perseverative speech involving a limited array of topics. She repetitively asked the same questions and dictated the topics of conversation. CB exhibited poor attention, motor tics, and obsessive compulsive behaviors. She insisted that the examiner use the same stethoscope that had been used during previous visits and that the order of the examination not deviate from previous visits. The remainder of the general and neurological examinations was normal.
To evaluate CB’s developmental concerns, she underwent fluorescent in-situ hybridization (FISH) of the 15q11-13 region. This revealed a duplication within 15q12.
The 15q11-13 locus is highly unstable and subject to genomic imprinting. Of 58 CNVs observed in this locus, 45 are associated with disorders, including Prader Willi Syndrome, Angelman Syndrome, autism, intellectual disability, and schizophrenia.18
A number of genes within this locus, such as UBE3A
and members of the GABA receptor gene family, are expressed throughout the central nervous system and have been associated with autism or other neuropsychiatric disorders.19
Variations at the 15q11-13 locus are observed in up to one percent of autistic individuals, and the majority of the numerous observed variations are maternally-inherited duplications.14
Many of CB’s symptoms are in accordance with those described in other patients harboring 15q11-13 duplications, including developmental delay, echolalia, lack of major facial dysmorphisms, and short stature.20
As expected, many of CB’s symptoms overlap with ASD symptoms, including delayed development of language, abnormal social interaction, solitary and repetitive play, sensory integration differences, and strong desire for structure. Based on the family history, it is likely that both CB and her half-sister inherited the duplication from their mother.
Of note, a recent physician advisory (http://www.idic15.org/PhysicianAdvisory_Feb2009.pdf
) warns that medications that target the GABA-A receptor—including benzodiazepines, phenobarbital, and ethanol derivatives—may increase the risk of sudden death in individuals with 15q11-13 duplications. Further research is necessary to definitively establish a link between these medications and sudden death in these individuals; however, the fact that the 15q11-13 locus includes several GABA receptor genes provides biological plausibility for this clinical concern.
In summary, CB now has a diagnosis of “autism associated with 15q11-13 duplication.” This molecular subtype of autism provides a biological explanation, has relevance to recurrence risk, may have significant implications for treatment (e.g. caution in prescribing benzodiazepine, phenobarbital, or ethanol derivatives) and may help predict the clinical course.