Vldlr Cerebellar Hypoplasia
Summary
Clinical characteristics.
VLDLR 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. Brain MRI findings include hypoplasia of the inferior portion of the cerebellar vermis and hemispheres, simplified gyration of the cerebral hemispheres, and small brain stem – particularly the pons.
Diagnosis/testing.
The diagnosis of VLDLR cerebellar hypoplasia is established in a proband with suggestive clinical and brain MRI findings by identification of biallelic pathogenic variants in VLDLR on molecular genetic testing.
Management.
Treatment of manifestations: Seizures and strabismus are treated in the standard manner. Referral to an early intervention program is recommended for access to occupational, physical, and speech therapy, as well as infant mental health services and special educators.
Surveillance: Annual neurologic and rehabilitation 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, prenatal testing for pregnancies at increased risk and preimplantation genetic testing are possible when the pathogenic variants in a family are known.
Diagnosis
VLDLR 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.
Suggestive Findings
VLDLR cerebellar hypoplasia should be 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 the following:
- 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.
MRI of the brain demonstrating typical neuroimaging findings of VLDLR-CH A. Sagittal T1-weighted
Establishing the Diagnosis
The diagnosis of VLDLR cerebellar hypoplasia is established in a proband by identification of biallelic pathogenic variants in VLDLR on molecular genetic testing (see Table 1).
Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing or multigene panel) and comprehensive genomic testing (chromosomal microarray analysis, exome sequencing, exome array, genome sequencing) depending on the phenotype.
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of VLDLR cerebellar hypoplasia is often recognizable, individuals with the distinctive MRI findings described in Suggestive Findings can often be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of VLDLR cerebellar hypoplasia has not been considered are more likely to be diagnosed using genomic testing (see Option 2).
Option 1
When the phenotypic and radiographic findings suggest the diagnosis of VLDLR cerebellar hypoplasia, molecular genetic testing approaches can include single-gene testing or use of a multigene panel:
- Single-gene testing. Sequence analysis of VLDLR is performed first to detect small intragenic deletions/insertions and missense, nonsense, and splice site variants. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications.Note: Targeted analysis for pathogenic variants can be performed first in individuals of Hutterite ancestry. See Table 6.
- A multigene panel that includes VLDLR and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder a multigene panel that also includes deletion/duplication analysis can be considered if only one or no pathogenic variant is found on sequencing.For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Option 2
When the diagnosis of VLDLR cerebellar hypoplasia is not considered because of its rarity and/or because an individual has atypical phenotypic features, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible.
If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in VLDLR Cerebellar Hypoplasia
| Gene 1 | Method | Proportion of Pathogenic Variants 2 Detectable by Method |
|---|---|---|
| VLDLR | Sequence analysis 3 | 85% 4 |
| Gene-targeted deletion/duplication analysis 5 | 15% 4 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
Data derived from Human Gene Mutation Database [Stenson et al 2017]
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Clinical Characteristics
Clinical Description
VLDLR cerebellar hypoplasia is a congenital non-progressive disorder characterized by cerebellar ataxia and intellectual disability.
To date, more than 50 individuals have been identified with a pathogenic variant in VLDLR [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, Azmanov et al 2013, Kruer et al 2013, Schlotawa et al 2013, Sonmez et al 2013, Giorgio et al 2016, Micalizzi et al 2016, Valence et al 2016, Wilker et al 2019]. The following description of the phenotypic features associated with this condition is based on these reports.
Table 2.
Features of VLDLR Cerebellar Hypoplasia
| Feature | Number (%) of Persons w/Feature | Comment |
|---|---|---|
| Cerebellar hypoplasia | 44/44 (100%) | |
| Pontine hypoplasia | 36/44 (81.8%) | |
| Simplified cortical gyration | 43/44 (97.7%) | |
| Cerebellar ataxia | 53/53 (100%) | Predominantly truncal; peripheral ataxia reported in some |
| Hypotonia | 28/37 (75.7%) | |
| Dysarthria | 34/42 (81.0%) | |
| Nystagmus | 11/47 (23.4%) | |
| Strabismus | 40/51 (78.4%) | |
| Cognitive impairment | 53/53 (100%) | Moderate to profound |
| Developmental delay | 53/53 (100%) | |
| Delayed ambulation | 53/53 (100%) | Independent ambulation (if achieved) often in mid-childhood. |
| Epilepsy | 7/53 (13.2%) | |
| Brisk reflexes | 31/40 (77.5%) | |
| Microcephaly | 8/38 (21.1%) | Head circumference -2SD to -4SD |
| Dysmorphism | 1/53 (1.89%) | May not be related to VLDLR-CH |
| Short stature | 19/42 (45.2%) |
Brain MRI. All affected individuals demonstrate hypoplasia of the inferior portion of the cerebellar vermis and hemispheres. In addition, the majority of patients show a simplified gyration of the cerebral hemispheres with minimally thickened but uniform cortex, lack of clear anteroposterior gradient, and small brain stem (particularly the pons). Some individuals are described as demonstrating neuroimaging features of pontocerebellar hypoplasia.
Cerebellar ataxia. All affected individuals demonstrate significant truncal ataxia. Children either learn to walk very late (often after 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, Türkmen et al 2009], an interesting behavioral adaptation which likely depends on the presence of special environmental influences during child development [Herz et al 2008, Türkmen et al 2009]. Limb ataxia is present in most individuals but is not severe.
Intellectual disability. All reported affected individuals have intellectual disability, 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.
Other
- Nystagmus is reported in some individuals and is described as gaze evoked.
- Epileptic 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.
- Deep tendon reflexes in the lower extremities tend to be brisk.
- Microcephaly (2-4 SD below the mean) has been reported in a few affected individuals.
- Short stature (height just below the 2nd centile) is a feature 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
No genotype-phenotype correlations have been identified.
Nomenclature
VLDLR-CH is a clinically and molecularly well-defined subgroup of dysequilibrium syndrome (DES).
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].
Differential Diagnosis
The differential diagnosis of VLDLR cerebellar hypoplasia (VLDLR-CH) includes autosomal recessive conditions characterized by congenital or very early-onset cerebellar ataxia associated with cerebellar hypoplasia. Because cerebellar hypoplasia can be difficult to distinguish from cerebellar atrophy on early imaging, conditions characterized by the latter should also be considered (see Table 3).
Note: Diverse phenotypes associated with childhood- and adult-onset ataxia are to be excluded (see Hereditary Ataxia Overview, Table 3. Autosomal Recessive Cerebellar Ataxias: Single-Gene Disorders).
Table 3.
Genes and Disorders of Interest in the Differential Diagnosis of VLDLR Cerebellar Hypoplasia
| Gene(s) | Disorder | Brain Imaging | Neurologic Findings |
|---|---|---|---|
| AHI1 CPLANE1 CC2D2A CEP290 (~34 genes) 1 | Joubert syndrome & related disorders 2 | "Molar tooth sign" (hypoplasia of cerebellar vermis & assoc brain stem abnormalities resembling a tooth) |
|
| ALG1 ALG6 PMM2 (~42 genes) 3 | Congenital disorders of glycosylation | Cerebellar atrophy |
|
| ATCAY | Cayman-type cerebellar ataxia (OMIM 601238) 4 | CH |
|
| ATM | Ataxia-telangiectasia 5 | Cerebellar atrophy (may not be obvious in very young individuals) |
|
| ATP8A2 | CAMRQ4 (OMIM 615268) | Cerebellar atrophy |
|
| CA8 | CAMRQ3 (OMIM 613227) |
| |
| EXOSC3 RARS2 SEPSECS TSEN2 TSEN34 TSEN54 VRK1 6 | PCH types 1 & 2 (see EXOSC3-PCH & TSEN54-PCH) | Cerebellar vermis hypoplasia & hypoplasia of the pons (more severe than small pons seen in VLDLR-CH) |
|
| RELN | RELN lissencephaly w/CH 7 (OMIM 257320) | Cerebellar signs of RELN-LCH that differ from VLDLR-CH:
|
|
| SACS | ARSACS (autosomal recessive spastic ataxia of Charlevoix-Saguenay) | Atrophy of superior vermis |
|
| SIL1 | Marinesco-Sjögren syndrome 8 | Cerebellar atrophy |
|
| TWNK | Infantile-onset spinocerebellar ataxia 9 | Atrophy of cerebellum, brain stem, & spinal cord |
|
| WDR81 | CAMRQ2 (OMIM 610185) | CH |
|
CAMRQ = cerebellar ataxia, mental retardation, and dysequilibrium syndrome; CDG = congenital disorder of glycosylation; CH = cerebellar hypoplasia; DD = developmental delay; ID = intellectual disability; LCH = lissencephaly with cerebellar hypoplasia; PCH = pontocerebellar hypoplasia
- 1.
To date, pathogenic variants in 34 genes are known to cause Joubert syndrome. AHI1, CPLANE1, CC2D2A, and CEP290 are some of the most commonly involved genes.
- 2.
Variable features include: retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and endocrine abnormalities.
- 3.
PMM2-CDG (CDG-Ia), ALG6-CDG (CDG-Ic), and ALG1-CDG (CDG-Ik) represent some of the more frequently identified CDG types. Forty-two different enzymes in the N-linked oligosaccharide synthetic pathway or interactive pathways are currently recognized to be deficient in each of the types of CDG-N-linked or among the multiple-pathway disorders (see Congenital Disorders of N-Linked Glycosylation and Multiple Pathway Overview).
- 4.
Affected individuals are from a Grand Cayman Island isolate.
- 5.
Also characterized by immunodeficiency, frequent infections, telangiectasias of the conjunctivae, and increased risk for malignancy (particularly leukemia and lymphoma)
- 6.
About 50% of individuals with pontocerebellar hypoplasia type 1 (PCH1) have pathogenic variants in EXOSC3. See Pontocerebellar hypoplasia: OMIM Phenotypic Series for other genes associated with PCH in OMIM.
- 7.
The presentation of lissencephalies with cerebellar hypoplasia (LCH) 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. Forms of LCH other than RELN-LCH are easily distinguished from VLDLR-CH based on the severity of the cortical phenotype or additional features.
- 8.
Also characterized by early-onset cataracts
- 9.
Infantile-onset spinocerebellar ataxia is well recognized in Finland.
- 10.
By adolescence affected individuals are profoundly deaf and no longer ambulatory; sensory axonal neuropathy, optic atrophy, autonomic nervous system dysfunction, and hypergonadotropic hypogonadism in females become evident.
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with VLDLR cerebellar hypoplasia (VLDLR-CH), the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.
Table 4.
Recommended Evaluations Following Initial Diagnosis in Individuals with VLDLR Cerebellar Hypoplasia
| System/Concern | Evaluation | Comment |
|---|---|---|
| Neurologic | Neurologic evaluation |
|
| Developmental | Developmental assessment | Adaptive, cognitive, & speech/language evaluation |
| Musculoskeletal | Orthopedics / physical medicine & rehabilitation / PT/OT evaluation | To incl assessment of:
|
| Eyes | Ophthalmologic evaluation | To assess for strabismus |
| Miscellaneous/ Other | Consultation w/clinical geneticist &/or genetic counselor | To incl genetic counseling & reproductive options |
| Family support/resources |
|
OT = occupational therapy; PT = physical therapy
Treatment of Manifestations
Treatment of seizures and strabismus is done in the standard manner.
Developmental Disability / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
Ages 0-3 years. In the US, early intervention is a federally funded program available in all states that provides in-home services to target individual therapy needs.
Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social, or cognitive delay. The early intervention program typically assists with this transition. Developmental preschool is center based; for children too medically unstable to attend, home-based services are provided.
All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies (US) and to support parents in maximizing quality of life. Some issues to consider:
- Individualized education plan (IEP) services:
- An IEP provides specially designed instruction and related services to children who qualify.
- IEP services will be reviewed annually to determine whether any changes are needed.
- As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate.
- Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
- PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
- As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
- A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
- Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
- Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Motor Dysfunction
Gross motor dysfunction
- Physical therapy is recommended to maximize mobility and to promote ambulation.
- Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
Fine motor dysfunction. Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing.
Communication issues. Consider evaluation for alternative means of communication (e.g., Augmentative and Alternative Communication [AAC]) for individuals who have expressive language difficulties. An AAC evaluation can be completed by a speech-language pathologist who has expertise in the area. The evaluation will consider cognitive abilities and sensory impairments to determine the most appropriate form of communication. AAC devices can range from low-tech, such as picture exchange communication, to high-tech, such as voice-generating devices. Contrary to popular belief, AAC devices do not hinder verbal development of speech, and in many cases can improve it.
Surveillance
Table 5.
Recommended Surveillance for Individuals with VLDLR Cerebellar Hypoplasia