Clinical perspectives on the genetics of schizophrenia: A bottom-up orientation

Abstract

Phenomenology has been the reference point that investigators have used in their efforts to understand schizophrenia. Although symptoms and signs are crucial for the diagnosis of schizophrenia, there is an ongoing debate since Kraepelin attempted to group symptoms to understand the etiology of schizophrenia. Several operational criteria have been developed to establish the diagnosis of schizophrenia, making it obvious that there are no precise symptomatological boundaries. There is little clear indication which of the systems is valid for genetic and other biological research. Despite the enormous effort to find a linkage between schizophrenia and one or more loci, the results are far from conclusive. Another approach is the search for candidate genes of which DICS1 and 22q11 deletion syndrome are examples. In all studies into the genetic underpinnings of schizophrenia, however, the clinical vantage point is neglected in that a broad clinical phenotype with respect to, e.g., developmental issues, symptoms and comorbidity is narrowed down to one categorical diagnosis. This is illustrated by the lack of exclusion criteria in genetic studies and by the occurrence of schizophrenia-like psychoses in a broad array of genetic syndromes. In case of 22q11 deletion syndrome, the psychotic symptoms emerge in the context of brain anomalies, a plethora of somatic abnormalities and specific neurocognitive deficits. Prader-Willi syndrome is a hypothalamic disorder in which psychotic symptoms may occur that resemble schizophrenia. It is concluded that not only schizophrenia is a highly variable disease but that the genetic samples are even much more heterogeneous.

Contrasting Monosymptomatic Patients with Hallucinations and Delusions in First-Episode Psychosis Patients: A Five-Year Longitudinal Follow-Up Study

“…These illnesses have proven to be heterogeneous with regard to clinical features and etiology. Categorically based diagnoses have proven insufficient in the search for genetic correlates and specific brain morphology [3,4] . Consequently studying more homogenous subgroups of psychotic illnesses based on individual symptoms and a dimensional approach might further our understanding of psychotic illnesses.…”

Copy number variants in a sample of patients with psychotic disorders: is standard screening relevant for actual clinical practice?

“…Moreover, a single gene defect never codes for a categorical psychiatric disorder, but may lead to a biological dysfunction that has a certain probability to be associated with the development of an array of psychiatric symptoms 14,17,18. This can best be illustrated by the discovery of the DISC1 gene in one family that was originally thought to be causally related to schizophrenia,34 but later appeared to be involved in a biochemical cascade with consequences for neuronal functions predisposing for psychiatric symptoms across diagnostic boundaries 35,36…”

<p>Metabolic Parameters in Patients with Prader-Willi Syndrome and DiGeorge Syndrome with Respect to Psychopathological Manifestation</p>

“…Prader-Willi syndrome (PWS) is a rare genetic disorder occurring in 1:10,000-1:30,000 births with a lack of expression of genes inherited from the paternal chromosome 15q11-13 either from paternal deletion (75%), uniparental maternal disomy (mUPD) (20%) or as a result of other chromosomal anomalies. 10,11 It is a multisystemic, neurodevelopmental disorder with frequently delayed motor and intellectual development and characteristic dysmorphic features such as almond-shaped eyes downturned mouth, narrow forehead and small hands and feet as well as distinctive appearance of further symptoms with age. 10,12,13 At about 2-4 years of age, the first signs of indolent hunger arise accompanied by challenging behaviors.…”

“…20 The 22q11.2 deletion syndrome, also known as DiGeorge syndrome (DGS) is the most common chromosomal microdeletion with autosomal dominant inheritance pattern and with prevalence rate estimated at 1:4000 individuals. 11,21 DGS is a cluster of congenital malformations resulting from the loss of a fragment of chromosome 22 with a variable presentation, which usually consists of cardiac and palatal abnormalities, immunodeficiency with thymic hypoplasia, dysmorphic features such as hooded eyelids or nasal dimple, endocrine disturbances with hypoparathyroidism and varying level of cognitive impairment. 21 The behavioral phenotype of DGS consists of poor social skills with social withdrawal accompanied by restricted affect.…”