Several inherited metabolic disorders have been associated with stroke particularly in newborns, children, and young adults. In part 1, we discussed the genetics, stroke pathophysiology, clinical presentation, diagnosis, and treatment of Fabry disease and mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes. In part 2, we overview homocystinuria, organic acidurias, and urea cycle disorders.

Stroke is commonly attributed to conventional pathophysiologic mechanisms such as atherothrombosis, cardiogenic causes, and degenerative small-vessel occlusive disease, or may be caused by less common nonatherosclerotic etiologies such as thrombophilic states and hemoglobinopathies. Cryptogenic stroke, however, has been reported in up to 40% of cases, especially when young adults are involved,¹ and remains a clinical diagnostic and treatment challenge. Advances in our understanding of molecular genetics and cellular metabolic pathways have led to the detection of strokes caused by inherited metabolic disorders. These disorders (Table 1) may underlie cryptogenic stroke and provide a pathway for novel treatment opportunities if properly diagnosed.

Objective To test the hypothesis that patients with deep intracerebral hemorrhage (ICH) would encounter hematoma expansion (HE) more frequently compared to patients with lobar ICH. Methods Patients with ICH with neuroimaging to calculate HE were analyzed from the multicenter Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) cohort. Patients with laboratory coagulopathy or preceding anticoagulant use were excluded to assess relationships of ICH location alone (deep vs lobar) with HE, defined as >33% relative growth. Odds ratios (ORs) and 95% confidence intervals (CIs) for these relationships were estimated with logistic regression. Sensitivity and specificity determined HE thresholds best associated with poor 3-month outcomes (modified Rankin score 4-6) stratified by location. Results There were 1,049 patients with deep and 408 patients with lobar ICH analyzed. Deep ICH locations were more likely to have HE (adjusted OR 1.57, 95% CI 1.08–2.29) after adjustment for age, sex, race, baseline hematoma size, and intraventricular hemorrhage. However, this difference was nonsignificant (adjusted OR 1.35, 95% CI 0.81–2.24) after controlling for time from symptom onset to admission CT in a subgroup analysis of 729 patients with these data. Yet, the threshold of HE best associated with poor outcomes was smaller in deep (30%) compared to lobar (50%) ICH. Conclusions While HE was more frequent in deep than lobar ICH, this could be due to differences in symptom onset to admission CT times in our cohort. However, patients with deep ICH appear particularly vulnerable to the deleterious effects of small volumes of HE. Further studies should clarify whether ICH location needs to be considered in HE treatment paradigms.