Jarrett Barnhill, MD
Behavioral manifestations associated with specific genetic disorders are termed behavioral phenotypes. These behavioral phenotypes also demonstrate the interaction between genes, brain structure and organization, and complex behaviors. The complexity of this interrelationship can be illustrated in behavioral studies of single gene (point mutations) as well as polygenic disorders (neurospychiatric disorders). Another approach to gene-behavior studies involves monozygotic twins. Monozygotic (MZ) or identical twins share the same genotype and are frequently used to assess the genetic contribution (heritability) to a particular disorder (Harris, 1995a). MZ twin studies have also been used to assess the role of genes in temperament/personality, as well as other complex psychological features. For example, MZ twins separated at birth and reared apart provide a natural experiment to test the interrelationship between genes and environmental factors. As a result of this model, twin studies have suggested that genes account for 50% of the variance manifested in adult personality traits (Tellegen et al., 1988). Even though the remaining variance in MZ twin studies is attributed to other developmental or experiential factors, heredity plays a significant role in a diverse group of human traits.
Significant hereditary influences are also reported in schizophrenia (Schulsinger & Parnas, 1990), autism (Szartzmari, Jones, Zwaigenbaum, & MacLean, 1998), anxiety and affective disorders (Beidel & Morris, 1993), Tourette disorder (Alsobrook, 1999), and obsessive compulsive disorder (Black, 1996). In schizophrenia, MZ twin studies reveal a concordance ratio of approximately 50%--three to four times the risk for DZ twins or siblings, and provide strong evidence for a genetic influence (Jeste, Galasko, Corey-Bloom, Walens, & Granholm, 1996). This genetic influence is more complex than a single gene mode of inheritance. In schizophrenia, it appears that the schizotypal personality disorder may represent the expression of the "schizophrenic genotype" (Schulsinger & Parnas, 1990). These findings also suggest that aside from the risk for a debilitating psychotic illness, the schizophrenic genotype also influences a wide range of brain functions-cognition, information processing, executive skills and problem solving abilities, autonomic arousal, attention, and motor co-ordination (Waddington, Lane, Scully, Larkin, & O'Callaghan, 1998).
In order to develop chronic schizophrenia, the person at risk may require both genetic vulnerability and additional CNS liabilities (Jeste et al., 1996). The role of early developmental insults is illustrated in studies of discordant twins pairs-only one twin has schizophrenia. These studies indicate that, compared to the unaffected sibling, the schizophrenic twin displayed a lower birth weight, higher incidence of intrauterine insults, and obstetrical complications. Most cases of schizophrenia have no family history of the disorder, suggesting a polygenic inheritance as well as an increased incidence of phenocopies (Jones & Cannon, 1998). These exceptions argue against a simple pattern of inheritance and highlight the difficulties inherent in genetic studies of a heterogeneous psychiatric disorder such as schizophrenia.
Studies of brain development also provide an example of the interplay between genes, anatomy and behavior. If the focus is narrowed to specific neurotransmitter systems, the search for neurochemical phenotypes ought to simplify the process. For example, serotonin pathways are well defined and their basic neurochemistry is well studied. Based on clinical research, serotonin (5-HT) is implicated in autism (McDougle, Price, & Volkmar, 1994), obsessive compulsive disorder (Sreingard & Dillon-Stout, 1992), mood and anxiety disorders (Burgess, 1991), as well as stereotypies and movement disorders (Banford, Bhaumik, & Naik, 1998). This wide range of developmental disorders suggests that serotonin is a major player in diverse neuronal systems-sixteen 5-HT receptor sites are currently under study. Beginning with neurogenesis, 5-HT is involved with various phases in brain development. Throughout gestation, 5-HT is involved in cell differentiation and dendritic arborization before finally settling into the role of neurotransmitter (Aronson & Dreyfuss, 1998). Postnatally, 5-HT neurons are constantly remodeled by "environmental" events that affect receptor sensitivity, second messenger systems, or regulator genes (Zimmerman, Jinnah, & Lockhart, 1995). Other neurotransmitter systems share similar patterns of developmental and are also altered by "environmental influences" such as gestational insults, toxins, and viruses on genotypic expression. Fetal alcohol exposure (FAE) and syndrome (FAS) provide examples of the negative influences of alcohol on brain development, altering the phenotype of the exposed fetus without changing the genotype (Harris, 1995c).
Lesch-Nyhan Syndrome (LNS) is an example of a single gene abnormality. LNS is an X-linked recessive (Xq22.2) disorder of purine metabolism manifested by an absence of the enzyme, HGPRT (Johnson & Patel, 1996). The behavioral phenotype of LNS manifests as compulsive self-mutilation. Because a form of SIB is associated with a specific genetic abnormality, comparisons with other forms of self-injury may provide insight into this complex pattern of behavior. This type of comparative study also provides the clinician with an opportunity to differentiate subtypes of a nonspecific behavior such as SIB. The capacity to narrow the focus may assist in the development of genetic and neurochemical models for other forms of SIB. This process involves some of the following questions:
1. What is the relationship between SIB and hereditary forms of psychiatric disorders? For example, there appears to be a relationship between LNS and mood disorders (Johnson & Patel, 1996). As a result of this information, the researcher could perform linkage studies or search for genetic markers. The clinician could study the effects of mood disorders and treatments on baseline rates of SIB-a reduction in the frequency or severity of the SIB with an antidepressant (Burgess, 1991).
2. Is there a relationship between SIB and other repetitive or compulsive behaviors? Some forms of SIB are also associated with high levels of stereotypic behavior, compulsions and eye blink frequency (Bodfish & Lewis, 1998; Bodfish, Powell, Golden, & Lewis, 1995). Many forms of SIB resemble compulsions-high frequency/low severity-in which tissue injury results from repetition (Herpetz, 1995). In LNS, the compulsive urge to self-mutilate falls on the severe end of this continuum-severe tissue damage. Like some obsessive compulsion spectrum disorders, SIB in LNS is less consistently responsive to serotonergic agents such as SSRIs.
3. Are there other abnormal movements that out the self-injury until it "feels right". This form of SIB is associated with more severe abnormal movements. SIB in Tourette Disorder (Robertson & Yakely, 1993) differs from LNS based on topography and severity of injury. Both groups rd×ürt an irresistible urge to self-injure, but differ in the effects of restraint. LNS patients describe a sense of relief while restrained. TS patients report that restraint may increase the urge to self-injure, further supporting the idea that a sensory tic may play a role in TS but not LNS (Johnson & Patel, 1996).
4. Are there similarities in treatment response that suggest a common neurobiology or pathogenesis? The bewildering array of neurotransmitters and relative nonspecific effects of most pharmacological agents confound this question. It is apparent that LNS involves dysfunctional DA1 neurons. Animal models using perinatal exposure to 6-OHDA (toxic to the developing DA neurons) support the role of this DA system in subsequent self-injury (Breese et al., 1995). The picture is complicated by the interaction between other dopamine systems, adenosine, serotonin, and second messenger systems. These studies also suggest that the absence of HPRT, the missing enzyme in LNS, plays an important role in the normal development and integrity of these neurons. Interestingly, exposure to 6-OHDA in adult animals produces Parkinson-like symptoms, reiterating the differences between the effects of developmental insults versus acquired lesions later in life (Breese et al., 1995). This dynamic is also present in genetic disorders with varying ages of onset. The later onset disorders may have a slower course, less severe symptoms, and a decreased load of toxic metabolic products (Harris, 1995b).
The methodology for the differential diagnosis of SIB in LNS is borrowed from cladistic analysis-a model for the classification of fossils in paleontology. A similar methodology is applied in the use of decision trees in clinical psychiatry. In either model, classification begins with an analysis of common features (global or generalized) and proceeds to the differentiation of subtypes based on increasingly specific clinical or laboratory findings. The cladistic analysis of SIB would include the following steps towards zeroing in on the differential diagnosis of SIB:
Typology and topography of SIB (Herpetz, 1995)-In contrast to high frequency/low intensity (OCD-spectrum), LNS is associated with severe self-mutilating behaviors (Mace & Mauk, 1995). Face, lips, and fingers are major sites for SIB (Johnson & Patel, 1996)
Associated level of developmental disorders-rates of SIB are higher in persons with severe/profound MR, and autistic spectrum disorder. MR is not a diagnostic criterion for LNS (Buitelaar, 1993).
Comorbid primary psychiatric disorders-Aside from mood disorders, persons with LNS do not have higher rates of borderline personality, schizophrenia, or other psychoses, although there can be significant anxiety when previously effective restraints are removed (Mace & Mauk, 1995).
Comorbid primary neurological disorder-frontal lobe seizures (Gedeye, 1992), CP, Tourette Syndrome, and other movement disorders (Robertson & Yakeley, 1995). The SIB in LNS shares characteristics of compulsive spectrum disorders (Hollander & Benzaquen, 1996).
Pattern of reinforcement-LNS displays a pattern of intrinsic reinforcement, compulsive urge to mutilate, and a need to escape painful self-mutilation without evidence of peripheral neuropathy, but sensitivity to social reinforcement contingent of SIB-free intervals (Guess & Carr, 1991).
Pain sensitivity/affective arousal-There seems to be no analgesia to self-injury, hypesthesia, local autonomic changes, or allodynia (Russ et al, 1992).
Effects of restraint-Restraint appears soothing, and self-restraint is frequent. Many patients with LNS appear agitated or distressed when restraints are removed (Mace & Mauk, 1995).
Pattern of inheritance or association with developmental syndrome or metabolic disorder (Harris, 1995b).
Laboratory findings-elevated uric acid; absent HPRT. Other purine disorders have been associated with SIB and abnormal movements (Zimmerman et al., 1998).
The goal of this method of analysis is to define subtypes of SIB that may be helpful in treatment planning. For example, SSRIs can be helpful in some forms of compulsive SIB (high frequency of repetitive behaviors/tissue damage from repetition) in a variety of developmental disorders (Banford et al., 1998). In LNS, Tourette syndrome, and perhaps other movement disorders, the SSRIs may be less helpful (Hollander & Benzaquen, 1996). Atypical antipsychotic drugs (APDs) and fluphenazine may be helpful in some forms of SIB associated with LNS or MR (Sweeney & Zamecnik, 1981). Atypical APDs are not uniformly more effective than typical APDs in the treatment of self-mutilating behaviors in acute schizophrenia with self-injury (Dworkin, 1994; Schroeder et al., 1995). In contrast to SIB based on florid delusions or hallucinations, atypical neuroleptics may have a clear advantage in chronic schizophrenia with significant cognitive impairment and negative symptoms (Dwrokin, 1994). SIB in the chronic schizophrenic subtypes (high rates of ritualization) may fail to respond to typical APDs (fluphenazine), but improve significantly with risperidone, clozapine, olanzapine or quetiapine. The presence of altered pain sensitivity, overproduction of endorphins/enkaphalins to distress, and some forms of compulsive SIB may predict a response to naltrexone and other opiate antagonists (Sandman & Hetrick, 1995; Sandman et al.,1997).
There is much research to be done on subtype analysis of SIB. If we are to move beyond a purely empirical approach, this sort of subtyping may be helpful in our understanding of basic mechanisms, and matching effective treatment to bio-behavioral subgroups (Mace & Mauk, 1995). The methodology discussed in this paper is one tool that might allow us to begin with the behavioral phenotype of a known genetic disorder (LNS) and begin to clinically differentiate subtypes based on selected core features. The ultimate goal is to move away from chronic undifferentiated treatment and use the emerging neurosciences or cladistic analysis to help the treating clinician struggling with SIB.
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For further information:
Jarrett Barnhill, MD
Director, Developmental Neuropharmacology Clinic
University of North Carolina School of Medicine
Chapel Hill, NC 27599-7160