VLDLR cerebellar hypoplasia (VLDLR-CH)

Disease Overview

VLDLR Cerebellar Hypoplasia (VLDLR-CH) is a rare neurodevelopmental condition that affects the development of the brain.¹ It is characterized by a small size and an underdeveloped cerebellum (part of the brain that controls movement and coordination), resulting in balance, movement, and coordination issues. These issues typically present at birth (are congenital) or infancy, do not worsen over time, and mainly affect the center of the body (trunk) rather than the arms or legs.² Some children with this condition may learn to walk later, often after the age of 6, or may not be able to walk independently. Other signs and symptoms may include moderate to severe intellectual disability, seizures, slurred, slow or impaired speech (dysarthria), crossed or lazy eyes (strabismus), flat feet, and short stature.^1,2

VLDLR-CH is caused by disease-causing changes (pathogenic genetic variants) in the VLDLR gene, which provides instructions for making a very low-density lipoprotein (VLDL) receptor protein ^1,2

The diagnosis is based on a combination of the signs and symptoms, clinical assessment, brain image exams (magnetic resonance imaging or MRI) of the brain, and genetic testing. There is no cure for this condition, and treatment/management typically focuses on supportive care and therapies to maximize the individual’s abilities and improve the quality of life. Genetic counselling, testing of family members, and reproductive testing are important once a diagnosis is confirmed.²

This condition was first identified in the Hutterite population in the 1970s and 1980s (the genetic cause was identified later, around 2005). Hutterites are a German-speaking religious group that began during the Protestant Reformation in the 1500s. They later migrated to North America in the late 1800s and formed three separate, intermarrying communities called leuts: Schmiedeleut, Dariusleut, and Lehrerleut (the condition has been reported in all three).²

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Synonyms

• cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 1
• cerebellar hypoplasia, VLDLR-associated
• cerebellar ataxia and intellectual disability with or without quadrupedal locomotion 1 (CHMRQ1)
• cerebellar ataxia, congenital, and intellectual disability, autosomal recessive
• dysequilibrium syndrome; des
• VLDLR Cerebellar Hypoplasia
• Cerebellar Ataxia, Intellectual Disability, and Dysequilibrium Syndrome 1 (CAMRQ1)
• dysequilibrium syndrome-VLDLR (DES-VLDLR)
• VLDLR-associated cerebellar hypoplasia (VLDLRCH)
• VLDLR-related cerebellar hypoplasia

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Signs & Symptoms

VLDLR-CH can cause a wide spectrum of clinical signs and symptoms with varying levels of severity, even within members of the same family. Most symptoms develop at birth (congenital), although they can develop even during infancy. Since numerous symptoms have been reported for this condition, not all of them are seen in a single individual, and they can differ from one person to another. The symptoms do not worsen with time (are non-progressive). Life expectancy is generally typical. The most common findings of this condition are loss of balance and coordination caused by problems in the cerebellum (cerebellar ataxia) and intellectual disability.^1-3,5-7

The signs and symptoms that have been reported include:

• • Developmental delays and other problems
    • Developmental delay, reported in all affected people
    • Intellectual disability, typically moderate to severe, reported in all affected people
    • Delayed walking, often after age 6, seen in most affected people
    • Slurred, slow, or otherwise impaired speech (dysarthria), seen in most affected people

• • Neurological problems

• • • Loss of balance and coordination caused by problems in the cerebellum (cerebellar ataxia) seen in all affected people
      • Mainly affects the trunk (body’s center or truncal) rather than the arms or legs
    • Unsteady or uncoordinated walking caused by problems with balance or muscle control (gait ataxia)
    • Walking on all four limbs (hands and feet) instead of upright on two legs (quadrupedal gait)
    • Low muscle tone (hypotonia)
    • Repeated seizures due to abnormal electrical activity in the brain (epilepsy)
    • Shaking that happens during a voluntary movement, like reaching for an object (intention tremor)
    • Involuntary muscle contractions affecting one specific body part (focal dystonia)
    • Strong or overactive reflex responses (hyperreflexia)
    • Trouble doing quick, alternating movements, like flipping the hands back and forth rapidly (dysdiadochokinesis)
    • Inability to control movement distance, causing overshooting or undershooting when reaching for something (dysmetria)
    • Involuntary, repeated pushing or sticking out of the tongue due to muscle contractions (tongue protrusion dystonia)
  • Cranial features
    • Decreased head size (microcephaly)
  • Opthalmologic problems
    • Repetitive side-to-side, up-and-down, or circular uncontrolled eye movements (nystagmus)
    • Strabismus (seen in most affected people)
    • Trouble moving the eyes properly where the person moves their head instead (ocular apraxia)
    • Tiny, widened red blood vessels seen in the white part of the eyes (ocular telangiectasia) – reported in only one person
  • Musculoskeletal and growth problems
    • Short stature
    • Flat feet (pes planus)
  • Brain features (visualized through MRI of the brain)
    • Underdeveloped or small-sized cerebellum (cerebellar hypoplasia) seen in most affected people
    • Underdeveloped or small-sized pons, a structure of the lower part of the brain that controls breathing and movement signals (pontine hypoplasia), seen in most affected people
    • Fewer or shallower folds than normal in the surface of the brain (simplified cortical gyration) seen in most affected people
    • Unusually thick and few folds in the brain due to improper brain development (pachygyria).

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Causes

VLDLR-CH is caused by disease-causing changes (pathogenic variants) in the VLDLR (very low-density lipoprotein receptor) gene. ^1,3 This gene provides instructions for making the VLDLR protein, a receptor on the surface of developing neurons. VLDLR is a key part of a process known as the “Reelin signaling pathway”, which guides the growth and movement of neurons to their proper locations in the developing brain during the prenatal period. The Reelin signaling pathway has also been linked to several human brain disorders, including schizophrenia, bipolar disorder, and autism spectrum disorder. ⁷ In this pathway the main signaling protein is called reelin, whose main function is to guide neuron migration and support the formation of connections involved in learning and memory. ^{4, 7} During early brain development, reelin binds to the VLDLR receptor to start the signaling events that move neurons to their final destinations. ⁴

Disease-causing genetic variants in both copies of the VLDLR gene (biallelic variants) cause the loss of function of the VLDLR protein.⁶ These genetic changes prevent the neurons from producing any functional VLDLR protein. Without this protein, the developing neurons cannot reach the appropriate parts of the brain (cerebellum and cerebral cortex). This can result in abnormal brain development leading to movement and coordination issues, along with other major features of this condition.¹

Inheritance:

VLDLR-CH inheritance is autosomal recessive.  Recessive genetic disorders occur when an individual inherits a disease-causing gene variant from each parent. This means that the condition appears only when both VLDLR gene copies have the variant that causes the disease.^1-3   If an individual receives one normal gene and one disease-causing gene variant, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the gene variant and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.

VLDLR-CH is often observed in families with some degree of relatedness between the parents (consanguinity), or in isolated populations due to a founder variant (a genetic change that started in a small group of ancestors and is passed down through generations in that population).

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Affected populations

This is a very rare condition with a prevalence estimate of about <1/1,000,000.^5. To this date, about 70 individuals with this condition have been reported worldwide.⁶ Most reported individuals belong to the Hutterite sect of North America and isolated and/or consanguineous families with Turkish, Omani, Iranian, Iraqi, Indian, and European backgrounds.⁷ A founder variant has been reported in the Hutterite population. Moreover, the estimated carrier frequency (how often a disease-causing gene variant carrier appears in a population) in this population is 1 in 15.²

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Disorders with Similar Symptoms

Some conditions have overlapping symptoms with VLDLR-CH that are associated with autosomal recessive congenital or early-onset cerebellar ataxia, cerebellar hypoplasia, developmental delay, and intellectual disability. Those conditions include: ^2,3

• Joubert Syndrome and related conditions, characterized by developmental delay, intellectual disability, atypical eye movements, and poor balance and coordination of the body’s trunk. Joubert syndrome is distinguished by a characteristic “molar tooth sign” on brain imaging.

• Congenital disorders of glycosylation (CDG), characterized by developmental delay, intellectual disability, low muscle tone, poor balance and coordination and (strabismus).  The difference lies in the underlying cause, as CDG results from problems in glycosylation, a process where sugars are added to proteins, affecting many body systems beyond the brain.

• Cayman-type cerebellar ataxia, characterized by cerebellar ataxia and hypoplasia, speech impairments, developmental delay, intellectual disability, and intention tremor, which may help with the differential diagnosis.

• Ataxia-telangiectasia (A-T), which shares coordination difficulties and abnormal eye movements but differs in that symptoms worsen over time (progressive), and individuals often develop telangiectasias, which are small, visible dilated blood vessels, along with immune system problems.

• CAMRQ2, CAMRQ3,and  CAMRQ4 conditions are particularly similar to VLDLR-CH, as they also involve congenital cerebellar ataxia and intellectual disability. The key difference is genetic, as these conditions are caused by changes in different genes.

• RELN Lissencephaly with cerebellar hypoplasia, characterized by congenital cerebellar ataxia, intellectual disability, severe developmental delay, low muscle tone, epilepsy, and strabismus. Brain imaging shows more profound brain abnormalities compared to VLDLR-CH.

• Marinesco–Sjögren syndrome, characterized by congenital cerebellar ataxia, mild to severe intellectual disability, low muscle tone, and muscle weakness. It may be distinguished by additional features such as muscle disease and, in many cases, cataracts.

• Pontocerebellar hypoplasia (PCH), which shares cerebellar underdevelopment and hypotonia but is often more severe, with involvement of the pons, feeding difficulties, and a progressive decline in motor function over time.

• ARSACS (autosomal recessive spastic ataxia of Charlevoix-Saguenay), which presents with coordination problems similar to VLDLR-CH but includes additional features such as muscle wasting, nerve damage (neuropathy), spasticity (muscle stiffness), and characteristic eye movement abnormalities.

• Infantile-onset spinocerebellar ataxia, which is similar overlaps in terms of poor coordination, hypotonia, and possible seizures.However, it is typically progressive and may include additional features such as loss of reflexes, vision problems, and hearing loss.

Since the symptoms overlap with many other conditions, there is a possibility for this condition being underdiagnosed or misidentified as cerebral palsy in some cases.

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Diagnosis

Diagnostic evaluation of an infant suspected of having VLDLR-CH involves a combination of clinical evaluation, neuroimaging, and genetic testing. Since the symptoms overlap with many other conditions, there is a possibility for this condition being underdiagnosed or misidentified as cerebral palsy in some cases.²

• Clinical evaluation: VLDLR-CH is suspected in individuals with these key diagnostic features: Poor movement and balance issues (especially involving the trunk), delayed walking that does not worsen with time (non-progressive congenital ataxia), moderate to severe intellectual disability, and speech impairment (dysarthria).

• Neuroimaging (through brain MRI scan): Common findings include an underdeveloped cerebellum and/or pons. Other features may include simplified cortical gyration or pachygyria, as described under “Brain features” in the Symptoms section.

• Genetic Testing: Once VLDLR-CH is suspected, genetic testing is essential to confirm the diagnosis. This testing looks for disease-causing genetic variants in the VLDLR gene. Testing can be done in several ways:

• • Single gene testing, which examines only the VLDLRgene
  • Targeted gene panel testing, which checks a group of genes that are linked to ataxia and brain development disorders (diseases where there is poor control or balance due to differences in brain development)
  • Whole exome sequencing, a broader approach that looks at nearly all of a person’s genes.

If disease-causing variants in the VLDLR gene are found in a family, doctors can offer carrier screening. This type of testing checks if relatives carry the gene variant, which can help with understanding their own health risks and with family planning.

Once the VLDLR disease-causing variants have been identified in an affected family member, families can opt for testing options, such as prenatal genetic diagnosis (testing during pregnancy) or preimplantation genetic diagnosis (testing embryos created by in vitro fertilization before pregnancy begins)

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Standard Therapies

There is currently no cure or gene therapy for VLDLR-CH. Management focuses on treating symptoms and improving quality of life through a multidisciplinary approach, meaning that several healthcare specialists work together to support the affected child and family. Care plans are individualized and depend on the type and severity of symptoms. ²

Early intervention and developmental therapies are important and may include: ²

• Physical therapy to improve muscle strength, balance, and coordination, which may support walking or other movement skills.

• Occupational therapy focusing on fine motor skills and daily activities such as feeding, dressing, and writing.

• Speech therapy to help children with speech delays or communication difficulties.
  • Some children may benefit from Augmentative and Alternative Communication (AAC), which includes tools that support communication when speech is limited, such as picture systems or electronic devices that produce speech.

Medical management involves monitoring and treating specific symptoms.

• Neurological care may include testing for seizures using an electroencephalogram (EEG), which records the brain’s electrical activity. If seizures occur, they are typically treated with standard anti-seizure medications.

• Brain imaging with MRI (magnetic resonance imaging) may also be used to evaluate structural differences in the brain.

• Eye examinations are recommended to assess strabismus, a condition in which the eyes are misaligned, which may be treated with patching, glasses, or surgery.

• Orthopedic evaluation may help address issues such as flat feet or muscle stiffness, sometimes with braces or other supports.

Children are also monitored for growth and nutrition, especially if feeding difficulties affect weight gain.  Regular follow-up visits, including neurological exams and rehabilitation reviews, help adjust therapies and supportive equipment as the child grows.

Family support is an important part of care. Genetic counselling can help families understand the condition, discuss testing for relatives, and consider future reproductive options. Social services may assist with access to special education, mobility equipment, financial support, and respite care for caregivers. Planning for long-term support and adult services is also important as children with VLDLR-CH grow older.

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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/ . All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/

For information about clinical trials sponsored by private sources, contact:
https://www.centerwatch.com/

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

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References

1. VLDLR-associated cerebellar hypoplasia: MedlinePlus Genetics. (n.d.). https://medlineplus.gov/genetics/condition/vldlr-associated-cerebellar-hypoplasia/
2. Boycott, K. M., MacDonald, S. K., & Parboosingh, J. S. (2020, February 27). VLDLR Cerebellar hypoplasia. GeneReviews® – NCBI Bookshelf. https://www.ncbi.nlm.nih.gov/books/NBK1874/
3. OMIM. VLDLR-Associated Cerebellar Hypoplasia; VLDLRCH. Online Mendelian Inheritance in Man. Updated 2024. Accessed October 28, 2025. https://omim.org/entry/224050
4. 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 U S A. 2008 Mar 18;105(11):4232-6. doi: 10.1073/pnas.0710010105. Epub 2008 Mar 7. PMID: 18326629; PMCID: PMC2393756.
5. Orphanet: Dysequilibrium syndrome. (n.d.). https://www.orpha.net/en/disease/detail/1766?name=VLDLR&mode=gene
6. Holling, T., Abdelrazek, I.M., Elhady, G.M. et al. A homozygous nonsense variant in the alternatively spliced VLDLR exon 4 causes a neurodevelopmental disorder without features of VLDLR cerebellar hypoplasia. J Hum Genet 69, 623–628 (2024). https://doi.org/10.1038/s10038-024-01279-w
7. Wali, G. M., & Wali, G. (2021). Broadening the clinical spectrum of very low density lipoprotein receptor associated dysequilibrium syndrome. Movement Disorders Clinical Practice, 8(4), 619–623. https://doi.org/10.1002/mdc3.13184

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