3.2.1. *VLDLR*-Associated Cerebellar Hypoplasia

*VLDLR*-associated cerebellar hypoplasia is an autosomal recessive genetic form of non-progressive congenital ataxia [113]. The main clinical symptom of the condition is a predominantly truncal ataxia with retarded ambulation, so that children either learn to walk after six years of age or never walk without aid. Dysarthria, strabismus, moderate-to-profound intellectual disability, and seizures are other features of the disorder. MRI findings comprise hypoplasia of the inferior portion of the cerebellum, affecting both the vermis and the hemispheres; pachygyria of the cerebral hemispheres with a negligibly but uniformly thickened cortex in the absence of a neat anteroposterior gradient, reduction is size of the brainstem, particularly the pons. The condition is monogenic, and due to mutations in *VLDLR*.

*Vldlr* only knock-out mice did not show the drastic brain phenotype that can be seen in double knock-out mice devoid of *vldlr* and *apoER2*, which, instead, recapitulate in full the phenotypic alterations of *Reeler* mutants or *dab1* knock-out mice [21,114]. As Reln interacts with both Vldlr and ApoER2, clear functional differences in how these two receptors transduce the glycoprotein signal have been postulated [114]. That the interaction of Reln with Vldrl occurs with much lower affinity than with ApoER2 [115] could explain the less severe phenotype of the *vldlr* knockout mice compared to *Reeler*. Remarkably, alterations that in mouse followed the knocking-out of *vldlr* were particularly noticeable in cerebellum and consisted in failure of the Purkinje neurons to form a well-defined monolayer and reduction of their dendritic arbor [114]. They thus recall in full the human MRI phenotype of *VLDLR*-associated cerebellar hypoplasia.

#### 3.2.2. Spinocerebellar Ataxia Type 37

Spinocerebellar ataxia type 37 (SCA37) is a late onset syndrome that affects adults, with dysarthria, slowly progressive gait and limb ataxia, severe dysmetria in the lower extremities, mild dysmetria in the upper extremities, dysphagia, and abnormal ocular movements. In most cases, the first clinical signs encompass tumbles, dysarthria, or stiffness followed by a typical cerebellar syndrome. The early presence of altered vertical eye movements is a characteristic clinical feature of SCA37 that foregoes the symptoms of ataxia. The progression is slow and affected individuals usually become wheelchair bound between ten and thirty-three years after the onset of the disease [116]. At MRI, there is an initial atrophy of the vermis. Later, atrophy rapidly affects the entire cerebellum, without alterations of the brainstem [117]. Molecular analysis has shown that an unstable repeat insertion in *DAB1* is the cause of the cerebellar degeneration and, on the basis of the genetic and phenotypic evidence, the mutation has been proposed as the molecular basis for SCA37 [118].

Notably, the *dab1* deficient mice that derived from a spontaneous mutation called *Scrambler* or from gene knockout were phenotypically indistinguishable from the homozygous *Reeler* mice [119].
