Genetic dissection of Chiari malformation type 1 using endophenotypes and stratification

Abstract

Chiari malformation type 1 is a heterogeneous disease characterized by cerebellar tonsillar herniation through the foramen magnum. Symptomatology is diverse, and diagnosis and treatment are controversial. Some evidence suggests the presence of a genetic component to the disease. However, the specific genetic factors involved remain relatively unknown. Previous reviews have broadly addressed different aspects (clinical manifestations, anatomical trails, treatment) of CM-1 by itself or compared it with other types of Chiari malformation. In this mini-review, we focus our attention on the heterogeneity of this disease and its impact on the study of the genetic etiology of classic CM-1. Patient stratification strategies and endophenotypes definitions are offered to help overcome the heterogeneity. Chiari malformation type 1 Chiari malformation type 1 (CM-1) is the most prevalent form of the "Chiari malformations", and is characterized by a downward herniation of the caudal part of the cerebellum through the foramen magnum into the upper cervical region (Figure 1). It is a very heterogeneous disease whose current diagnosis relies on an imaging observation of cerebellar tonsil herniation (TH) of at least 3-5mm below the foramen magnum 1,2. This TH is usually attributed to a reduced size of the posterior cranial fossa (PCF) (classic CM-1), although other mechanisms may be involved (see below). That is, the subsequent smaller cranial space leads to overcrowded neural structures and the herniation of the cerebellum through the foramen magnum. This results in a direct compression of the neural tissue at the craniovertebral junction and, often, cerebrospinal fluid (CSF) disturbances (decreased velocity and elevated impedance), that can cause other related conditions such as syringomyelia or secondary hydrocephalus 3,4. CM-1 is quite heterogeneous with respect to symptomatology, epidemiology and treatment. The symptomatology presented by CM-1 patients is diverse, and its severity does not correlate with the degree of TH, with some asymptomatic cases presenting with prominent TH 3,5. The onset of symptoms generally develops gradually, however, trauma, coughing/sneezing or pregnancy can also precipitate the event 3,6,7. The incidence, prevalence and distribution of CM-1 is still unclear, and estimations vary depending on the criteria used to characterize the disease: TH criterion alone, TH criterion accompanied by symptomatology or a defining