Familial–sporadic schizophrenia

Subtyping schizophrenia by the presence/absence of a positive family history for schizophrenia spectrum disorders was proposed in the 1980s as a strategy expected to be more successful in resolving heterogeneity than symptom-based typologies.¹⁵² Although inclusion/exclusion criteria varied across studies, 'familial' (F) cases were typically defined as having 1 first-degree relative affected, while 'sporadic' (S) cases had none among either first- or second-degree relatives.¹⁵³ The F/S dichotomy rests on the assumption that the familial aggregation of cases is primarily of a genetic origin, while sporadic cases result from environmental insults (e.g. maternal obstetric complications) or de novo somatic mutations. In the majority of studies applying this classification, the proportion of familial cases was in the range of 8–15%, that is, lower than the 19% prevalence estimated by Gottesman et al.¹⁵⁴ from pooled European studies between 1920 and 1978. As the F/S subtypes were hypothesized to differ aetiologically, a number of studies, mostly of small to moderate sample size (<100), compared the phenotypic characteristics of the two groups.^{155, 156} No consistent and significant differences have been found in age at onset, symptom patterns, severity, treatment response and outcome,^{157, 158, 159} and the findings with regard to obstetric complications are inconclusive.^{160, 161, 162} Sporadic cases are more likely to be winter-born^{159, 163, 164} and have more electroencephalographic (EEG) abnormalities¹⁵³ and enlarged ventricles on CT scan or MRI.^{152, 165, 166} Familial cases, on the other hand, have more neurological signs,^{164, 167, 168, 169} poorer sustained attention performance;¹⁷⁰ cortical abnormalities on MRI¹⁷¹ and reduced temporoparietal resting regional blood flow.¹⁷²

By and large, the F/S classification has not been successful in identifying homogeneous phenotype groups for genetic research. The dichotomy, based on recurrence of manifest schizophrenia among biological relatives, might easily result in a misclassification unless: (i) ascertainment of all family members is complete; (ii) appropriate adjustments for family size, age, and lifetimes at risk are made; and (iii) the spectrum of disorders counted as recurrence cases is stringently defined. However, even if such confounding factors are adequately controlled for, and 'familiality' is represented as a continuous trait rather than a dichotomy,¹⁷³ the method remains open to error due to the likely presence of unexpressed genotypes in schizophrenia families.³⁹ Moreover, simulation power analyses¹⁷⁴ suggest that the F/S design can be useful only in the context of very large samples of nuclear families.

Date: 2016-04-22; view: 865