DiagnosisClinical DiagnosisVLDLR-associated cerebellar hypoplasia (VLDLR-CH) is a subgroup of dysequilibrium syndrome (DES), a spectrum of genetically heterogeneous conditions that combines non-progressive cerebellar ataxia with intellectual disability inherited in an autosomal recessive manner.A clinical diagnosis of VLDLR-CH is suspected in individuals with the following major diagnostic features (Figure 1):FigureFigure 1. MRI of the brain demonstrating typical neuroimaging findings of VLDLR-CH
A. Sagittal T1W
B. Coronal T2W images demonstrating hypoplasia of the inferior vermis and cerebellar hemispheres
C. Axial T1W image demonstrating (more...)Non-progressive congenital ataxia that is predominantly truncal and results in delayed ambulationModerate-to-profound intellectual disabilityDysarthriaMRI findings (see Figure 1) that include:Hypoplasia of the inferior portion of the cerebellar vermis and hemispheresSimplified gyration of the cerebral hemispheres with minimally thickened but uniform cortex and lack of clear anteroposterior gradientSmall brain stem, particularly the ponsThe following features are supportive of the diagnosis:StrabismusSeizuresPes planusShort statureMolecular Genetic TestingGene. VLDLR is the only gene in which mutation is known to cause VLDLR-associated cerebellar hypoplasia.Clinical testingTargeted mutation analysis used to identify the deletion of VLDLR present in the Hutterite population [Boycott et al 2005].Sequence analysis of the coding region of VLDLRTable 1. Summary of Molecular Genetic Testing Used in VLDLR-Associated Cerebellar HypoplasiaView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method ^{1Test AvailabilityVLDLRTargeted mutation analysisDeletion of 199,163 bp including VLDLR 2100% 2ClinicalSequence analysisSequence variants 3Unknown1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Founder mutation in the Hutterite population3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyTo confirm/establish the diagnosis in a proband. For individuals with clinical and MRI findings consistent with VLDLR-CH, molecular genetic testing is appropriate to establish the diagnosis:For individuals from the Hutterite population, molecular genetic testing should start with targeted mutation analysis to identify the common deletion.For individuals from Iran or Turkey, molecular genetic testing should start with the mutations identified in those populations.For all others, sequence analysis is necessary. Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.Carrier testing for the Hutterite population involves testing for the common VLDLR deletion.Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) DisordersNo other phenotypes are associated with mutations in VLDLR.}

Natural History VLDLR-associated cerebellar hypoplasia (dysequilibrium syndrome, DES) is a congenital non-progressive disorder characterized by cerebellar ataxia and intellectual disability. The affected individuals described to date [Glass et al 2005, Moheb et al 2008, Ozcelik et al 2008, Turkmen et al 2008] share the following features.Cerebellar ataxia. All affected individuals demonstrate significant truncal ataxia. Children either learn to walk very late (age >6 years) or never achieve independent ambulation. For those able to ambulate independently, gait is wide-based; affected individuals are not able to perform a tandem gait. Affected individuals from Turkey demonstrate quadrupedal locomotion in which the palms of the hands touch the ground and the elbows, back, and knees are straight [Ozcelik et al 2008, Turkmen et al 2008], an interesting behavioral adaptation which likely depends on the presence of special environmental influences during child development [Herz et al 2008, Turkmen et al 2008]. Limb ataxia is present but not severe.Cognitive impairment. All reported affected individuals have cognitive impairment, ranging from moderate to profound. Most individuals can follow simple commands. Some can communicate verbally using short phrases or sentences. Adults are unable to live independently.Dysarthria. Those who are able to communicate verbally demonstrate dysarthria.Strabismus. The majority of individuals have strabismus.Seizures. Seizures were reported in 40% of the affected individuals from the Hutterite population, but have rarely been reported in non-Hutterite individuals [Glass et al 2005]. Seizures in affected individuals from the Hutterite population tended to be generalized; in two individuals seizures were refractory to medical treatment.OtherPes planus, when reported, is present in the majority of affected individuals.Short stature (height just below the 2^nd centile) is a feature in a few affected individuals.Deep tendon reflexes in the lower extremities tend to be brisk.Life span. There has been no formal study of life span in this disorder, but experience from the Hutterite population suggests that life span is not significantly reduced.

Genotype-Phenotype CorrelationsAll mutations identified to date in VLDLR are presumed to be associated with loss of function of the VLDLR protein. The phenotype in the reported families, including neuroimaging, is indistinguishable.

Differential DiagnosisThe classification of autosomal recessive ataxias has greatly expanded during the past few years [see Hereditary Ataxia Overview, Brusse et al 2007, Fogel & Perlman 2007].The differential diagnosis of VLDLR-associated cerebellar hypoplasia (VLDLR-CH) includes autosomal recessive conditions characterized by congenital or very-early-onset cerebellar ataxia associated with cerebellar hypoplasia. Cerebellar hypoplasia and cerebellar atrophy can be difficult to distinguish on early imaging, so conditions characterized by the latter should also be considered. Childhood- and adult-onset ataxia associated with diverse phenotypes are to be excluded.Groups of conditions to consider in the differential diagnosis:The lissencephalies with cerebellar hypoplasia (LCH). Six subtypes of LCH have been defined [Ross et al 2001]. The presentation of lissencephaly ranges from the classic pattern of pachygyria/agyria to less severe phenotypes. The cerebellar manifestations range from relatively preserved hemispheres to marked hypoplasia with foliation defects. The malformations seen in VLDLR-CH fall within the LCH spectrum. LCH type b, secondary to mutations in RELN, is distinguished from VLDLR-CH by more significant lissencephaly with an anterior greater than posterior gradient, a malformed hippocampus, and profound cerebellar hypoplasia with complete absence of detectable folia. The other forms of LCH are easily distinguished from VLDLR-CH based on the severity of the cortical phenotype or additional features.The pontocerebellar hypoplasias/atrophies (PCH). Six subtypes of PCH have been defined [Barth 1993, Patel et al 2006, Edvardson et al 2007]. Neuroimaging features include cerebellar vermis hypoplasia and hypoplasia of the pons that is more severe than the small pons seen in VLDLR-CH. Additional features such as progressive motor degeneration similar to that in spinal muscular atrophy in PCH type 1 and dyskinesia in PCH type 2 are distinguishing.Joubert syndrome and related disorders (JSRDs). Clinical features include truncal ataxia, developmental delays, and episodic hyperpnea or apnea and/or atypical eye movements or both. The characteristic finding on MRI is the "molar tooth sign" in which hypoplasia of the cerebellar vermis and accompanying brain stem abnormalities resemble a tooth. Cognitive abilities range from severe cognitive impairment to normal. Variable features include retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and endocrine abnormalities. The nosology of the JSRDs is still evolving. Four causative genes in which mutations appear to account for no more than 10% of cases each of Joubert syndrome are NPHP1, CEP290, AHI1, and TMEM67 (MKS3); the other causative genes are unknown.Congenital disorders of glycosylation (CDG). The CDGs are characterized by abnormalities of glycoprotein glycosylation. Serum transferrin isoelectric focusing is abnormal in most forms of CDG. Onset is most commonly in infancy and manifestations range from severe developmental delay and hypotonia with multiple organ system involvement to hypoglycemia and protein-losing enteropathy with normal development. Neuroimaging findings can include cerebellar atrophy.Other conditions to consider:Cayman-type cerebellar ataxia (OMIM 601238). Clinical features include cerebellar ataxia with wide-based gait, psychomotor retardation, intention tremor, and dysarthria. Affected individuals are from a Grand Cayman Island isolate. Neuroimaging is characterized by cerebellar hypoplasia. Mutations in ATCAY are causative [Bomar et al 2003].Marinesco-Sjögren syndrome. Clinical features include cerebellar ataxia, early-onset cataracts, mild to severe cognitive impairment, hypotonia, and muscle weakness. Neuroimaging is characterized by cerebellar atrophy. Mutations in SIL1 are identified in approximately 50% of affected individuals.Infantile-onset spinocerebellar ataxia (OMIM 271245). Clinical features include infantile onset of a severe ataxic syndrome characterized by a progressive course, cerebellar ataxia, hypotonia, sensory neuropathy, optic atrophy, ophthalmoplegia, hearing loss, involuntary movements, and seizures. Neuroimaging features include atrophy of the cerebellum, brain stem, and spinal cord. This disorder is well recognized in Finland. Mutations in C10ORF2 are causative [Nikali et al 2005].ARSACS (autosomal recessive spastic ataxia of Charlevoix-Saguenay) is a progressive disorder characterized by early-onset ataxia, dysarthria, spasticity, extensor plantar reflexes, distal muscle wasting, a distal sensorimotor neuropathy, and horizontal gaze nystagmus. Neuroimaging reveals atrophy of the superior vermis. Mutations in SACS are causative.Ataxia-telangiectasia (A-T). Clinical features include progressive cerebellar ataxia beginning between ages one and four years, oculomotor apraxia, frequent infections, choreoathetosis, telangiectasias of the conjunctivae, immunodeficiency, and an increased risk for malignancy, particularly leukemia and lymphoma. Cerebellar atrophy is seen on neuroimaging but may not be obvious in very young individuals. Mutations in ATM are causative.

ManagementEvaluations Following Initial Diagnosis To establish the extent of disease in an individual diagnosed with VLDLR-associated cerebellar hypoplasia (VLDLR-CH), the following evaluations are recommended:Developmental assessmentExamination of cognitive functionOphthalmologic examinationNeurologic evaluationTreatment of ManifestationsThe following are appropriate:Physical therapy to promote ambulationOccupational therapy to develop fine-motor skills required for activities of daily living.Educational supportSurveillanceRoutine visits to the neurologist are appropriate.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. VLDLR-Associated Cerebellar Hypoplasia: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDVLDLR9p24​.2Very low-density lipoprotein receptorVLDLR homepage - Mendelian genesVLDLRData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for VLDLR-Associated Cerebellar Hypoplasia (View All in OMIM) View in own window 192977VERY LOW DENSITY LIPOPROTEIN RECEPTOR; VLDLR 224050CEREBELLAR ATAXIA, MENTAL RETARDATION, AND DYSEQUILIBRIUM SYNDROME 1; CAMRQ1Normal allelic variants. VLDLR spans approximately 32.7 kb of genomic DNA and contains 19 exons. The 3.6-kb cDNA contains an open reading frame of 2.6 kb and encodes a protein of 873 amino acids. A number of polymorphisms have been identified including the presence of a polymorphic CGG repeat in the 5’ untranslated region of the gene.Pathologic allelic variants. See Table 2. The disease-causing mutations reported to date in VLDLR include a whole-gene deletion and nonsense mutations [Boycott et al 2005, Moheb et al 2008, Ozcelik et al 2008, Turkmen et al 2008].Table 2. Selected VLDLR Pathologic Allelic VariantsView in own windowDNA Nucleotide Change Protein Amino Acid Change Reference Sequencesc.1342C>Tp.Arg448XNC_000009​.11
NM_003383​.3
NP_003374​.3c.2339delTp.Ile780Thrfs*3c.769C>Tp.Arg257XSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).Normal gene product. VLDLR encodes a protein of 873 amino acids and is expressed abundantly in the heart, skeletal muscle, kidney, and brain. VLDLR is part of the reelin signaling pathway, which guides neuroblast migration in the developing cerebral cortex and cerebellum [Tissir & Goffinet 2003]. In an evolutionarily conserved pathway, reelin engages two lipoprotein receptors, VLDLR and apolipoprotein E receptor-2 (Apoer2), which results in phosphorylation of disabled-1 (Dab1) and activation of an intracellular signaling cascade that allows neuroblasts to complete migration.VLDLR belongs to a subset of cell surface receptors called the LDL receptor protein family. Family members share a number of domains arranged in a similar pattern: ligand-binding repeat domain, EGF repeat, YWTD domain, O-linked sugar domain, transmembrane domain, and a cytoplasmic domain containing a NPXY motif. VLDLR was initially identified to function in the receptor-mediated endocytosis of apoE-containing lipoproteins.Abnormal gene product. All of the reported mutations to date are predicted to be associated with loss of function of the VLDLR protein. In the absence of this receptor, neuroblasts are unable to complete migration and adopt their ultimate position in the developing central nervous system.