2q37.2 chromosomal deletion and psychiatric manifestations

Sufian Agwani, M.D. and Theodor Rais, M.D.

Case Report

Miss B. is a 17 Years old Caucasian female with an extensive psychiatric history. She was admitted because of increasing aggressive behavior in school. According to the mother patient “lashes out”. Miss B. had two incidences at school that involved unprovoked screaming at the teacher and mother, kicking her mother, making herself throw up in class and hitting the wall. This kind of behavior alienated her from her class peer and was an obstacle in building relationships.


Miss B had significant developmental delay. She was slow in learning to sit up unassisted. She was over 1 year old before learning to talk and did not walk until she was 2 years old. ADHD was the first diagnosis to be given to her at age of 5. By age of 10, she exhibited features of anxiety, oppositional behaviors and anger outbursts. She started swearing, pulling hair, and hitting other individuals and herself, leading to gain a different image from other peers. By age 14, she had begun to bite and scratch herself when she was nervous. Her polyphagia also began at that time as her weight increased to 220 lbs. following this, she started binge eating and has learned to purge on command. At the same time, she had a habit of being extremely nervous, irritable, and tearful.


She also got very impulsive and would throw any thing when angry endangering others. Prior to her admission, she repeatedly used voluntary emesis to gain attention at school. She had past history of suicide and homicide attempts. There was no history of Conduct disorder, psychosis or prior psychiatric admissions. Her past medications included Risperdal, Trileptal, Phenergan (for nausea) and multivitamins. She had no history of substance use.

 
Miss B reported that her parents were divorced because of constant marital conflicts. She was living with her mother and younger brother and denied any history of emotional, sexual or physical abuse. She was born with a chromosomal deletion at 2q37.2 (7/99), ASD that was surgically corrected and had minor limb deformities. Her family history included anxiety disorder in mother, Alzheimer’s in paternal grand mother and some history of Diabetes type 2 in distant family.

On mental status examination, Miss B was  a 17 year old Caucasian female who was overweight. She was cooperative during interview but reported a tense mood and exhibited a restricted affect. Speech was age appropriate. Thought content and process were intact. She denied hallucinations there was no evidence of gross delusions. Immediate, recent and remote memory and concentrations were impaired. She was awake and oriented to time, place and person. She had below average intelligence and showed moderately impaired judgment and severely impaired insight. She denied suicidal or homicidal ideations, plan or intent at that time.

Diagnosis


Axis I: ADHD, ODD, Anxiety NOS R/O social phobias, bipolar Disorder NOS R/O Bipolar type 1, Eating Disorder NOS R/O Bulimia nervosa
Axis II: Mild Mental Retardation
Axis III: Chromosome 2q37.2 deletion, ASD (repaired), polycystic ovarian syndrome.

Axis IV: peer problems, Educational and economic problems
Axis V: GAF 35

Miss B was willing to be compliant with medications and treatment regimen as well as her mother who agreed with the plan. She was started on seroquel and dose was increased to 300mg at bed time. Multivitamins were restarted after being checked by her PCP who was following her for her medical problems. Cognitive behavioral therapy was considered to address violent behavior and develop stress reducing techniques. Referral was made for placement in special education programs and other programs that cater to children with special needs to build communication and social skills. She tolerated the medications very well and showed no significant side effects. She was stabilized and discharged to follow up with an out patient Child and adolescent psychiatrist and therapist.

Discussion


Our patient, Miss B, was found to have a deletion of the long arm of chromosome 2q37.2 in her medical history. There are many clinical scenarios associated with this particular deletion that are important to recognize while encompassing a complete pharmacological and psychological treatment for our patient. It is also important to assess her future prognosis and clinical progression.

A study compared 70 patients with the deletion of 2q37 chromosome in recent years. It was loosely noted that there are many physical associations with a breakpoint at 2q37.
The physical phenotype associated with terminal 2q37 deletion show macroencephaly, frontal bossing, depressed nasal bridge and cardiac anomalies. A 5 month old girl with a deletion of 2q37 was reported to have widely spaced nipples, redundant nuchal skin, coarctation of the aorta, anal atresia with distal fistula, postnatal growth retardation, hypotonia, and sparse scalp hair. Dysmorphic ears, small hands and feet with bilater brachymetaphalangism, proximal implantation of the thumbs and short toenails features are also repeatedly seen. Other facial characteristics seen in a patient with a small terminal deletion include long eyelashes and micrognathia. Horseshoe kidney and Wilms’ tumor were limited to patients with a breakpoint of 2q37.1 and structural brain anomalies and tracheal anomalies were reported only in patients with breakpoints at or proximal to 2q37.1. Cleft palate was reported in patients with the most proximal breakpoints. The facial characteristics of 2q37 deletion are not uniform but developmental delay is a consistent finding.

Development delay, mental retardation, autistic like behavior and hypotonia were typical in this patient population but did not stratify in severity according to the breaking point. Rocking back and forth, hand flapping, feeding problems, and repetitive behavior are also seen during different times of development of many children with this deletion. Terminal deletion of the long arm of chromosome should be considered in the infants with marked hypotonia, poor feeding, gastroesophageal reflux, and growth delay.

Several chromosome abnormalities have been described in the occurrence of autism, a distinct subtype of autism that has been proposed with a comparison of two cases of the long arm of 2q37. Increased awareness of the dysmophic features associated with 2q37 deletions may aid in the molecular genetic analysis of the chromosome anomaly and can help clarify its relationship with autism. Many patients also depict rigid restricted range or interests consistent with this diagnosis. Diverse range of social and communication deficits are also observed in many of these patients and may also be linked to the position of the breakpoint in the chromosome.

Many cases of chromosome 2q37 deletion have been reported with a large range of physical features that vary throughout the population. However, hypotonia, psychomotor retardation and developmental delay were the only manifestation common to all cases. In general, the larger the deletion the more severe the phenotype is. Autistic patients with characteristic feature should be assessed for chromosome deletion of 2q37. The deletion of this gene can be a susceptibility factor creating a predisposition to autism.

It is exciting to consider the possibilities that can be obtained with the use of gene therapy as a treatment modality. The future seems hopeful for not only improving – but CURING – physical diseases that are caused by genetic mutations, like cystic fibrosis. Does this hope remain for the treatment of neuropsychatric illnesses as well? What about the case of autism, a developmental disorder with prominent psychiatric symptoms? If a genetic mutation or mutations were identified as the cause for the disorder, would gene therapy be able to cure autism? Although only the few will hold the answer, doubt remains to the cure of autism, given the multifactorial issues regarding the etiology of autism and the difficulty of implementing changes to the dynamic brain.

Although in theory autism could be caused solely by a genetic mutation, the multifactorial nature of the etiology of autism cannot be forgotten. Autistic symptoms are present in congenital rubella, phenylketorunia, tuberous sclerosis, and Rett’s disorder. Autism has also been linked to obstetrical complications and immunological factors. ( ) These different neurological disease-stages speak against a single genetic mutation as the cause for autism. However, it must be noted that in twin studies the concordance rate for autism is 36% for monozygotic twins. Perhaps autism disorder is in reality a spectrum of disease-states leading to a common syndrome.

Setting arguments aside, let’s say that there is one genetic mutation governing the production of autistic disorder. Would gene therapy be realistic? The first stumbling block for gene therapy would be how to get a vector into the brain. The blood-brain barrier is a difficult physiologic protection to penetrate. Even with direct inoculation of the brain through surgery, how can the specificity of the vector be assured? Neurons are dynamic cells of the brain that have different functions depending on the brain pathway in which they are present. It is anticipated that psychoactive drugs will cross-react in unintended brain pathways because of the use of the same neurotransmitters across different pathways, resulting in different psychological, physical, or cognitive effects. How can gene therapy be specified to the correct neurologic target to avoid unintended adverse side effects?

Additionally, one must consider the importance of neurological remodeling in disease states. It is known that covering a child’s eyes at birth will lead to blindness and permanent remodeling of the visual cortex to interpret other nonvisual senses. Likewise, neurological remodeling appears to be present in autism. Studies of autistic children have revealed neurological changes including hypoplasia of portions of the cerebellum, polymicroglia, decreased Purkinje cell counts, and increased cortical metabolism. Even if gene therapy could be given to an autistic child, there is a possibility that permanent, irreversible neurologic remodeling has already occurred. Therefore, the symptoms of autism may be unchanged by therapy.

Lastly, if a child has already lived his life with the pervasive developmental and social delays of autism, gene therapy might already be beyond hope. Learned behavior and experience are important parts of the development of self. Reversing an underlying physical disorder when the child has already defined himself by his autism may not result in the reversal of the behaviors of autism.

Plenty of attention has been focused on “genetic” metabolic diseases in which a defective gene causes an enzyme to be either absent or ineffective in catalyzing a particular metabolic reaction effectively. A potential approach to the treatment of genetic disorders in man is gene therapy. This is a technique whereby the absent or faulty gene is replaced by a working gene, so that the body can make the correct enzyme or protein and consequently eliminate the root cause of the disease. Although there is a role for gene therapy in the prevention of mental retardation, it will most likely benefit only those people who have single-gene disorders, such as Lesch-Nyhan disease, Gaucher disease and phenylketonuria (PKU) that cause severe mental retardation (Moser, 1995)

The most likely candidates for future gene therapy trials will be rare diseases such as Lesch Nyhan syndrome, a disease in which the patient is unable to produce hypoxathine-guanine phosphoribosyltransferase (HGPRT), an enzyme which speeds up the recycling of purines from broken down DNA and RNA. This deficiency leads to a bizarre impulse for self-mutilation, including very severe biting of the lips and fingers. The normal version of the defective gene in this disease has now been cloned. Mutations of the HPRTI gene cause three main problems. First is the accumulation of uric acid that normally would have been recycled into purines. Excess uric acid forms painful deposits in the skin (gout) and in the kidney and bladder (urate stones). The second problem is self-mutilation. Affected individuals have to be restrained from biting their fingers and tongues. Finally, there is mental retardation and severe muscle weakness.

In 1990, the first approved gene therapy clinical trial took place when Ashanthi DeSilva, a 4 year old girl with ADA-deficient Severe Combined Immunodeficiency, was given her own T cells engineered with a retroviral vector carrying a normal ADA gene by the NIH team of Anderson, Blaese and Rosenberg (Blaese et al, 1995). The first gene therapy trial targeting an internal organ took place in 1992 when Jim Wilson treated patients with Familial Hypercholesterolemia with a portal vein infusion of autologous hepatocytes transduced ex vivo with a retroviral vector carrying an LDLr cDNA (Wilson, 1992). The first non-viral gene therapy clinical trial also began in 1992 when Gary Nabel injected a DNA/liposome complex (the DNA plasmid carrying an HLA-B7 gene) directly into HLA-B7 tumors (Nabel, 1992).

All of this talk of advances of gene therapy makes us wonder about complex mental disorders that focus on more than just enzyme deficiency. Researchers are still a long way off in answering the question of whether gene therapy holds the key to unlock the secrets of debilitation childhood disorders such as autism. The first step would be to identify the defects in the chromosomes which results in autism. Researchers found that a patient with autism was missing nearly 1,000 pieces of the genetic sequence on Chromosome 15 (Smith, 2000). Missing pieces of chromosomes mean that some of the instructions for building the body or mind are missing. Without these instructions, the body or mind may not be built correctly. Using this discovery, researchers will try to match the missing chromosome piece to some of the genes they think play a role in autism. If they can match a gene to the missing section of the chromosome, they may be able to uncover how the gene changes the body to cause autism. These findings may also lead to treatments that correct the changes caused by the missing chromosome piece.

Researchers found that nearly 40 percent of people with autism in their study had a change in their gene linkage that could be a factor in causing their autism (Ingram, 2000). The sequence or pattern of a person’s genes controls how the body builds its parts, in essence acts as a blueprint. An alteration in that sequence changes how your body and mind are built, which may lead to autism. Specifically, 39 percent of the people with autism in the study had a change in one of the two copies of the HOXA1 gene, which is located on Chromosome 7. The percentage of people who had the change in one of these genes, but did not have autism or related to anyone with autism, was much lower (only 22 percent). Because twice as many people with autism had the gene change compared to people who did not have autism but possessed the gene change, the HOXA1 gene could play a role in causing autism (Ingram, 2000). In addition, 33 percent of people in the study, who did not have autism, but were related to someone with autism, also had the change in their gene, which supports the idea that the HOXA1 gene plays a role in causing autism. These findings suggest that the genetic sequence of these families is linked to autism and autism-like symptoms in some way. But researchers do not think that the change in the HOXA1 gene by itself causes autism. If the gene change was the only cause, then everyone who had that genetic alteration would be diagnosed with autism. Since this is not the case, researchers postulate that the HOXA1 gene is only one of many genes that may contribute to the autism (Ingram, 2000).

Since autism is such a complex disorder, it would be prudent to analyze a few aspects of this disorder such as self injurious behavior and mental retardation. We can model these behaviors with a known disorder that has some of the features of autism, mainly Lesch-Nyhan syndrome. As mentioned above, Lesch-Nyhan syndrome is one of the diseases that are currently targeted for gene therapy. Because it is hard to pinpoint specific defects that are associated with autism, researchers would have a difficult time creating “normal” genes to target these defects. The promise of gene therapy for autism lies in the alleviation of some of the more drastic symptoms that is associated with this disorder. The task of curing autism completely with gene therapy is remarkably difficult and not within current research capabilities. In theory, a complete treatment for autism would quite possibly require therapies that are individualized to each person because of the rich diversity of personalities, abilities, and behavior that is generated by the uniqueness of individual brains. The circuitry of the brain is determined and established by not only heritable influences but also environmental influences. These factors must be accounted for when pursuing the monumental tasks of altering innate, programmed behavior that is seen in developmental disorders such as autism.

References:


1. Moser, H.G. (1995) A role for gene therapy in mental retardation. Mental Retardation and Developmental Disabilities research Reviews: Gene Therapy, 1, 4-6.
2. Blaese, R.M., Culver, K.W., Miller, A.D., Carter, C.S., Fleisher, T., Clerici, M., Shearer, G., Change, L., Chiang, Y., Tolstoshev, P., Greenblat, J.J., Rosenberg, S.A., Klien, H., Berger, M., Muller, C.A., Ramsey, J.W., Muul, L., Morgan R.A.. and Anderson, W.F.: T lymphocyte-directed gene therapy for ADA deficiency SCID: Initial trial results after 4 years. Science, 270: 475-480, 1995
3. Wilson, J.M.: Ex vivo gene therapy of familial hypercholesterolemia. Hum. Gene Ther. 3:179-222, 1992.
4. Nabel, G.J., Change, A., Nabel, E.G., Plautz, G., Fox, B.A., Haung, L., and Shu, S.: Immunotherapy of malignancy by in vivo gene transfer into turmors. Hum. Gene Ther. 3:399-410, 1992.
5. Smith M, Filipek PA, Wu C, Bocian M, Hakim S, Modahl C, and Spence MA. Analysis of a 1 megabase deletion in 15q22-q23 in an autistic patient: identification of candidate genes for autism and of homologous DNA segments in 15q22-q23 and 15q11-q13. American Journal of Medical Genetics 96:765-770, 2000.
6. Ingram JL, Stodgell CJ, Hyman SL, Figlewicz DA, Weitkamp LR, and Rodier PM. Discovery of allelic variants of HOXA1 and HOXB1: genetic susceptibility to autism spectrum disorders. Teratology, 62:393-405, 2000

 

Authors:

Sufian Agwani, M.D. and Theodor Rais, M.D.
Child and Adolescent Psychiatry
University of Toledo Medical Center

Theodor Rais, M.D.
Associate Professor
Director
Child and Adolescent Psychiatry
University of Toledo Medical Center

Copyright Priory Lodge Education Limited 2009

First Published January 2009

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