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VLDLR-Associated Cerebellar Hypoplasia

Synonyms: CAMRQ1; Cerebellar Ataxia, Mental Retardation, and Dysequilibrium Syndrome 1; Dysequilibrium Syndrome-VLDLR

, PhD, MD and , PhD.

Author Information
, PhD, MD
Neurogeneticist, Department of Genetics
Children's Hospital of Eastern Ontario
Associate Professor, Department of Pediatrics
University of Ottawa
Ottawa, Ontario, Canada
, PhD
Molecular Diagnostic Laboratory
Alberta Children’s Hospital
Associate Professor, Department of Medical Genetics
University of Calgary
Calgary, Alberta, Canada

Initial Posting: ; Last Update: August 8, 2013.

Summary

Disease characteristics. VLDLR-associated cerebellar hypoplasia (VLDLR-CH) is characterized by non-progressive congenital ataxia that is predominantly truncal and results in delayed ambulation, moderate-to-profound intellectual disability, dysarthria, strabismus, and seizures. Children either learn to walk very late (often after age 6 years) or never achieve independent ambulation.

Diagnosis/testing. Diagnosis is based on clinical findings, MRI findings, and molecular genetic testing of VLDLR.

Management. Treatment of manifestations: Physical therapy to promote ambulation, occupational therapy to help with fine-motor skill development, and educational support.

Surveillance: Routine neurologic evaluations.

Genetic counseling. VLDLR-CH is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible when the disease-causing mutations in a family are known.

Diagnosis

Clinical Diagnosis

VLDLR-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:

  • Non-progressive congenital ataxia that is predominantly truncal and results in delayed ambulation
  • Moderate-to-profound intellectual disability
  • Dysarthria
  • MRI findings (see Figure 1) that include:
    • Hypoplasia of the inferior portion of the cerebellar vermis and hemispheres
    • Simplified gyration of the cerebral hemispheres with minimally thickened but uniform cortex and lack of clear anteroposterior gradient
    • Small brain stem, particularly the pons
Figure 1

Figure

Figure 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...)

The following features are supportive of the diagnosis:

  • Strabismus
  • Seizures
  • Pes planus
  • Short stature

Molecular Genetic Testing

Gene. VLDLR is the only gene in which mutations are known to cause VLDLR-associated cerebellar hypoplasia.

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in VLDLR-Associated Cerebellar Hypoplasia

Gene Symbol 1 Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
VLDLRTargeted mutation analysisFounder deletion mutations including VLDLR 4100% 4
Sequence analysisSequence variants 5Unknown
Deletion/duplication analysis 6Exonic or whole-gene deletions or duplicationsUnknown

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. Founder mutation in the Hutterite population [Boycott et al 2005]

5. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

6. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

Testing Strategy

To 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:

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.

Clinical Description

Natural History

VLDLR-associated cerebellar hypoplasia (dysequilibrium syndrome [DES]) is a congenital non-progressive disorder characterized by cerebellar ataxia and intellectual disability [Boycott et al 2005, Glass et al 2005, Moheb et al 2008, Ozcelik et al 2008, Turkmen et al 2008, Boycott et al 2009, Kolb et al 2010, Ali et al 2012, Kruer et al 2013, Schlotawa et al 2013, Sonmez et al 2013]. Affected individuals share the following features.

Cerebellar ataxia. All affected individuals demonstrate significant truncal ataxia. Children either learn to walk very late (often >6 years of age) 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, Türkmen et al 2008], an interesting behavioral adaptation which likely depends on the presence of special environmental influences during child development [Herz et al 2008, Türkmen 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 [Glass et al 2005], and appear to be less frequent in non-Hutterite individuals. The seizures tend to be generalized.

Other

  • Pes planus, when reported, is present in the majority of affected individuals.
  • Short stature (height just below the 2nd centile) is a feature in a few affected individuals.
  • Deep tendon reflexes in the lower extremities tend to be brisk.
  • Microcephaly (-3 to -4 SD below the mean) has been reported in a few affected individuals.

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 Correlations

All 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.

Nomenclature

VLDLR-CH is a clinically and molecularly well-defined subgroup of dysequilibrium syndrome (DES).

The families reported from Turkey [Ozcelik et al 2008, Türkmen et al 2008] demonstrate quadrupedal locomotion. It was proposed by Ozcelik et al [2008] that this phenotype be referred to as “VLDLR-associated quadrupedal locomotion” (VLDLR-QL) or Unertan syndrome type 1. The behavioral adoption of quadrupedal locomotion by some affected individuals with VLDLR-CH does not warrant notation as a separate entity.

Prevalence

The actual frequency of VLDLR-CH is unknown.

More than 25 individuals with VLDLR-CH from the Hutterite population in Canada and the US have been followed for many years. This condition is present in all three Hutterite leuts (branches) (i.e., Schmiedeleut, Lehrerleut, and Dariusleut).

The estimated carrier frequency in the Hutterite population is one in 15 [Glass et al 2005].

Initially reported in the Hutterite population [Glass et al 2005, Boycott et al 2005], VLDLR-CH has now been reported in individuals world-wide [Boycott et al 2005, Glass et al 2005, Moheb et al 2008, Ozcelik et al 2008, Türkmen et al 2008, Boycott et al 2009, Kolb et al 2010, Ali et al 2012, Kruer et al 2013, Schlotawa et al 2013, Sonmez et al 2013]. Most families are consanguineous with homozygous mutations present in the affected individuals.

Differential Diagnosis

The 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. Because cerebellar hypoplasia and cerebellar atrophy can be difficult to distinguish on early imaging, 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:

  • Cerebellar ataxia, mental retardation, and dysequilibrium syndromes (CAMRQ). CAMRQ is a genetically heterogenous group of disorders characterized by congenital ataxia and intellectual disability. Aside from VLDLR (CAMRQ1; the primary focus of this GeneReview), mutations in WDR81 (CAMRQ2; Gulsuner et al [2011]), CA8 (CAMRQ3; Türkmen et al [2009]), and ATP8A2 (CAMRQ4; Onat et al [2013]) are causative. The core features of cerebellar ataxia and intellectual disability are shared among all the CAMRQs. CAMRQ 2, 3, and 4 have been reported in one or at most two families. CAMRQ2 is characterized by cerebellar hypoplasia and CAMRQ4 by cerebellar atrophy. Imaging information for CAMRQ3 is limited.
  • The lissencephalies with cerebellar hypoplasia (LCH). 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). 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, including 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. Approximately 50% of individuals with Joubert syndrome have biallelic mutations in one of the nineteen genes know to be associated with Joubert syndrome.
  • 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. Cerebellar atrophy is seen on neuroimaging. Mutations in SIL1 are identified in 50%-60% of affected individuals.
  • Infantile-onset spinocerebellar ataxia. Clinical features include severe, progressive neurodegenerative disorder characterized by normal development until age one year, followed by onset of ataxia, muscle hypotonia, loss of deep-tendon reflexes, athetosis, ophthalmoplegia, and sensorineural deafness in childhood. By adolescence affected individuals are profoundly deaf and no longer ambulatory; sensory axonal neuropathy, optic atrophy, autonomic nervous system dysfunction, and hypergonadotrophic hypogonadism in females become evident. Epilepsy can develop into a serious and often fatal encephalopathy. Neuroimaging features include atrophy of the cerebellum, brain stem, and spinal cord. This disorder is well recognized in Finland. Mutations in C10ORF2 are causative.
  • 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, a distal sensorimotor neuropathy predominant in the legs, and horizontal gaze-evoked 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.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with VLDLR-associated cerebellar hypoplasia (VLDLR-CH), the following evaluations are recommended:

  • Developmental assessment
  • Formal testing of cognitive function
  • Ophthalmologic examination
  • Neurologic evaluation
  • Medical genetics consultation

Treatment of Manifestations

The following are appropriate:

  • Physical therapy to promote ambulation
  • Occupational therapy to develop fine-motor skills required for activities of daily living.
  • Educational support

Surveillance

Routine visits to the neurologist are appropriate.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search 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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

VLDLR-associated cerebellar hypoplasia (VLDLR-CH) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes (i.e., carriers of one mutated allele).
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. There are no known instances of an individual with VLDLR-CH reproducing.

Other family members of a proband. Each sib of the proband’s parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing mutations have been identified in a family member, prenatal testing for pregnancies at increased risk is possible either through a clinical laboratory or a laboratory offering custom prenatal testing.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation(s) have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • National Institute of Neurological Disorders and Stroke (NINDS)
    PO Box 5801
    Bethesda MD 20824
    Phone: 800-352-9424 (toll-free); 301-496-5751; 301-468-5981 (TTY)
  • American Association on Intellectual and Developmental Disabilities (AAIDD)
    501 3rd Street Northwest
    Suite 200
    Washington DC 20001
    Phone: 800-424-3688 (toll-free); 202-387-1968
    Fax: 202-387-2193
    Email: anam@aaidd.org
  • International Network of Ataxia Friends (INTERNAF)
    Email: internaf-owner@yahoogroups.com
  • National Ataxia Foundation
    2600 Fernbrook Lane
    Suite 119
    Minneapolis MN 55447
    Phone: 763-553-0020
    Email: naf@ataxia.org
  • National Center on Birth Defects and Developmental Disabilities
    1600 Clifton Road
    MS E-87
    Atlanta GA 30333
    Phone: 800-232-4636 (toll-free); 888-232-6348 (TTY)
    Email: cdcinfo@cdc.gov

Molecular Genetics

Information 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 Databases

Data 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)

192977VERY LOW DENSITY LIPOPROTEIN RECEPTOR; VLDLR
224050CEREBELLAR ATAXIA, MENTAL RETARDATION, AND DYSEQUILIBRIUM SYNDROME 1; CAMRQ1

Normal 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, including a polymorphic CGG repeat in the 5’ untranslated region of the gene, have been identified.

Pathologic allelic variants. The disease-causing mutations reported to date in VLDLR include whole-gene and partial-gene deletions, frameshift, nonsense, and missense mutations.

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.

References

Literature Cited

  1. Ali BR, Silhavy JL, Gleeson MJ, Gleeson JG, Al-Gazali L. A missense founder mutation in VLDLR is associated with Dysequilibrium Syndrome without quadrupedal locomotion. BMC Med Genet. 2012;13:80. [PMC free article: PMC3495048] [PubMed: 22973972]
  2. Bomar JM, Benke PJ, Slattery EL, Puttagunta R, Taylor LP, Seong E, Nystuen A, Chen W, Albin RL, Patel PD, Kittles RA, Sheffield VC, Burmeister M. Mutations in a novel gene encoding a CRAL-TRIO domain cause human Cayman ataxia and ataxia/dystonia in the jittery mouse. Nat Genet. 2003;35:264–9. [PubMed: 14556008]
  3. Boycott KM, Bonnemann C, Herz J, Neuert S, Beaulieu C, Scott JN, Venkatasubramanian A, Parboosingh JS. Mutations in VLDLR as a cause for autosomal recessive cerebellar ataxia with mental retardation (dysequilibrium syndrome). J Child Neurol. 2009;24:1310–5. [PMC free article: PMC2849979] [PubMed: 19332571]
  4. Boycott KM, Flavelle S, Bureau A, Glass HC, Fujiwara TM, Wirrell E, Davey K, Chudley AE, Scott JN, McLeod DR, Parboosingh JS. Homozygous deletion of the very low density lipoprotein receptor gene causes autosomal recessive cerebellar hypoplasia with cerebral gyral simplification. Am J Hum Genet. 2005;77:477–83. [PMC free article: PMC1226212] [PubMed: 16080122]
  5. Brusse E, Maat-Kievit JA, van Swieten JC. Diagnosis and management of early- and late-onset cerebellar ataxia. Clin Genet. 2007;71:12–24. [PubMed: 17204042]
  6. Fogel BL, Perlman S. Clinical features and molecular genetics of autosomal recessive cerebellar ataxias. Lancet Neurol. 2007;6:245–57. [PubMed: 17303531]
  7. Glass H, Boycott K, Adams C, Barlow K, Scott JN, Chudley AE, Fujiwara T, Morgan K, Wirrell E, McLeod D. Autosomal recessive cerebellar hypoplasia in the Hutterite population: a syndrome of nonprogressive cerebellar ataxia with mental retardation. Dev Med Child Neurol. 2005;47:691–5. [PubMed: 16174313]
  8. Gulsuner S, Tekinay AB, Doerschner K, Boyaci H, Bilguvar K, Unal H, Ors A, Onat OE, Atalar E, Basak AN, Topaloglu H, Kansu T, Tan M, Tan U, Gunel M, Ozcelik T. Homozygosity mapping and targeted genomic sequencing reveal the gene responsible for cerebellar hypoplasia and quadrupedal locomotion in a consanguineous kindred. Genome Res. 2011;21:1995–2003. [PMC free article: PMC3227090] [PubMed: 21885617]
  9. Herz J, Boycott KM, Parboosingh JS. "Devolution" of bipedality. Proc Natl Acad Sci U S A. 2008;105:E25. [PMC free article: PMC2396673] [PubMed: 18487453]
  10. Kolb LE, Arlier Z, Yalcinkaya C, Ozturk AK, Moliterno JA, Erturk O, Bayrakli F, Korkmaz B, DiLuna ML, Yasuno K, Bilguvar K, Ozcelik T, Tuysuz B, State MW, Gunel M. Novel VLDLR microdeletion identified in two Turkish siblings with pachygyria and pontocerebellar atrophy. Neurogenetics. 2010;11:319–25. [PubMed: 20082205]
  11. Kruer MC et al Mutations in VLDLR associated with ataxia with secondary vitamin E deficiency. Mov Disord 2013. [PubMed: 23813796]
  12. Moheb LA, Tzschach A, Garshasbi M, Kahrizi K, Darvish H, Heshmati Y, Kordi A, Najmabadi H, Ropers HH, Kuss AW. Identification of a nonsense mutation in the very low-density lipoprotein receptor gene (VLDLR) in an Iranian family with dysequilibrium syndrome. Eur J Hum Genet. 2008;16:270–3. [PubMed: 18043714]
  13. Onat OE, Gulsuner S, Bilguvar K, Nazli Basak A, Topaloglu H, Tan M, Tan U, Gunel M, Ozcelik T. Missense mutation in the ATPase, aminophospholipid transporter protein ATP8A2 is associated with cerebellar atrophy and quadrupedal locomotion. Eur J Hum Genet. 2013;21:281–5. [PMC free article: PMC3573203] [PubMed: 22892528]
  14. Ozcelik T, Akarsu N, Uz E, Caglayan S, Gulsuner S, Onat OE, Tan M, Tan U. Mutations in the very low-density lipoprotein receptor VLDLR cause cerebellar hypoplasia and quadrupedal locomotion in humans. Proc Natl Acad Sci USA. 2008;105:4232–6. [PMC free article: PMC2393756] [PubMed: 18326629]
  15. Schlotawa L, Hotz A, Zeschnigk C, Hartmann B, Gärtner J, Morris-Rosendahl D. Cerebellar ataxia, mental retardation and dysequilibrium syndrome 1 (CAMRQ1) caused by an unusual constellation of VLDLR mutation. J Neurol. 2013;260:1678–80. [PubMed: 23670308]
  16. Sonmez FM, Gleeson JG, Celep F, Kul S. The very low density lipoprotein receptor-associated pontocerebellar hypoplasia and dysmorphic features in three Turkish patients. J Child Neurol. 2013;28:379–83. [PubMed: 22532556]
  17. Tissir F, Goffinet AM. Reelin and brain development. Nat Rev Neurosci. 2003;4:496–505. [PubMed: 12778121]
  18. Türkmen S, Guo G, Garshasbi M, Hoffmann K, Alshalah AJ, Mischung C, Kuss A, Humphrey N, Mundlos S, Robinson PN. CA8 mutations cause a novel syndrome characterized by ataxia and mild mental retardation with predisposition to quadrupedal gait. PLoS Genet. 2009;5:e1000487. [PMC free article: PMC2677160] [PubMed: 19461874]
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Chapter Notes

Revision History

  • 8 August 2013 (me) Comprehensive update posted live
  • 26 August 2008 (cg) Review posted live
  • 7 July 2008 (kmb) Original submission
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