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 (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...)

• 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

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 mutation is known to be responsible for VLDLR-associated cerebellar hypoplasia.

Clinical testing

• Targeted mutation analysis is used to identify the deletion of VLDLR present in the Hutterite population [Boycott et al 2005].

• Sequence analysis of the coding region of VLDLR is available on a clinical basis.

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

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1	Test Availability
VLDLR	Targeted mutation analysis	Deletion of 199,163 bp including VLDLR 2	100% 2	Clinical
	Sequence analysis	Sequence variants 3	Unknown

Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

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

2. Founder mutation in the Hutterite population

3. 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 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:

• 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.

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

No 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.

Other

• Pes 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 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 DES and may also have been referred to as DES-VLDLR.

The families reported from Turkey [Ozcelik et al 2008, Turkmen 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 consanguineous families from Iran [Moheb et al 2008] and Turkey [Ozcelik et al 2008, Turkmen et al 2008].

Evaluations 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 assessment

• Examination of cognitive function

• Ophthalmologic examination

• Neurologic evaluation

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.

Testing 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.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

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.

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.

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 family members is possible once the mutations have been identified in the family.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk 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. DNA banking is particularly relevant when the sensitivity of currently available testing is less than 100%. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. Both disease-causing alleles of an affected family member must be identified in the family before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Literature Cited

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Revision History

• 26 August 2008 (cg) Review posted live

• 7 July 2008 (kmb) Original submission