Vps13d Movement Disorder
Summary
Clinical characteristics.
VPS13D movement disorder is a hyperkinetic movement disorder (dystonia, chorea, and/or ataxia) of variable age of onset that can be associated with developmental delay. Onset ranges from birth to adulthood. Individuals can present in childhood with motor delays and gait instability. Cognitive impairment ranging from mild intellectual disability to developmental delay has been reported, and several individuals have normal cognitive function. Individuals have also presented as young adults with gait difficulties caused by spastic ataxia or ataxia. In addition to gait ataxia, affected individuals had limb ataxia, dysarthria, and eye movement abnormalities (macro-saccadic oscillations, nystagmus, and saccadic pursuit). Additional features reported in some individuals include peripheral neuropathy and/or seizures. The disorder progresses to spastic ataxia or generalized dystonia, which can lead to loss of independent ambulation.
Diagnosis.
The diagnosis of VPS13D movement disorder is established in a proband by identification of biallelic pathogenic variants in VPS13D on molecular genetic testing.
Management.
Treatment of manifestations: Standard treatment for seizures; spasticity treatments include baclofen, tizanidine, benzodiazepines, dantrolene sodium, gabapentin, botulinum toxin injections, and intrathecal baclofen; treatment options for dystonia include trihexyphenidyl, botulinum toxin injections, benzodiazepines, baclofen, and levodopa. A multidisciplinary team including occupational and physical therapists and a physiatrist is important; supportive developmental therapies should be provided as needed.
Surveillance: Monitor for urinary urgency, contractures, and seizures; evaluate fall risk and gait stability; monitor developmental progress and educational needs.
Genetic counseling.
VPS13D movement disorder 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 if the VPS13D pathogenic variants in the family are known.
Diagnosis
Suggestive Findings
VPS13D movement disorder should be suspected in individuals with the following clinical, laboratory, and imaging findings.
Clinical presentation
- Infantile-onset hypotonia and severe developmental delay or motor delay that progresses to severe generalized dystonia or spastic ataxia
- Childhood-onset chorea or dystonia
- Early-adulthood-onset progressive spastic ataxia, dystonia, and myoclonus
Additional clinical features
- Macro-saccadic intrusions; these large abnormal back-and-forth eye movements with stationary inter-saccadic intervals are often triggered by saccades.
- Pyramidal signs (e.g., hyperreflexia, Babinski signs)
- Peripheral axonal neuropathy
- Seizures
Laboratory findings
- Elevated CSF lactate (in 1 individual) [Gauthier et al 2018]
- Enlarged mitochondria with altered morphology on muscle biopsy; identified in the only individual evaluated by muscle biopsy [Gauthier et al 2018, Seong et al 2018]
Brain MRI findings
- Symmetric T2-weighted and FLAIR hyperintensities in the caudate and putamen
- Hyperintense T2-weighted and FLAIR signal abnormalities of periventricular and subcortical regions
- Hypointense basal ganglia (globus pallidus)
- Thin corpus callosum [Gauthier et al 2018]
- Mild cerebellar atrophy, often involving the vermis [Seong et al 2018]
Note: Brain MRI findings can be striking, but imaging results vary among individuals with VPS13D movement disorder. Imaging findings can resemble those seen in Leigh syndrome. Some individuals with VPS13D movement disorder have had normal brain MRI examinations.
Establishing the Diagnosis
The diagnosis of VPS13D movement disorder is established in a proband by identification of biallelic pathogenic variants in VPS13D on molecular genetic testing (see Table 1).
Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, 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 VPS13D movement disorder is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with developmental delay and/or movement disorder are more likely to be diagnosed using genomic testing (see Option 2).
Option 1
When the phenotypic and laboratory findings suggest the diagnosis of VPS13D movement disorder, molecular genetic testing approaches can include single-gene testing or use of a multigene panel:
- Single-gene testing. Sequence analysis of VPS13D detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. Perform sequence analysis first. If only one or no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.
- A multigene panel that includes VPS13D 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 over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. Of note, given the relatively recent description of VPS13D movement disorder, some panels for developmental delay and/or movement disorder may not yet include this gene. (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 an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Option 2
When the phenotype is indistinguishable from many other inherited disorders characterized by developmental delay and/or movement disorder, 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.
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 VPS13D Movement Disorder
| Gene 1 | Test Method | Proportion of Pathogenic Variants 2 Detectable by This Method |
|---|---|---|
| VPS13D | Sequence analysis 3 | 23/24 4 |
| Gene-targeted deletion/duplication analysis 5 | 1/24 6 |
- 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.
Gauthier et al [2018], Seong et al [2018]
- 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.
- 6.
Partial duplication of VPS13D exons 24 to 30 was reported in one family [Gauthier et al 2018].
Clinical Characteristics
Clinical Description
To date, 19 individuals from 12 families have been identified with VPS13D movement disorder. This disorder is characterized by hyperkinetic movement (dystonia, chorea, or ataxia) of variable onset that can be associated with developmental delay. Onset ranging from birth to age 39 years has been reported. Eleven individuals presented in childhood with mainly motor delays and gait instability. Of those, two individuals had arm tremor, one had chorea, and one had torticollis at presentation. Eight individuals presented as young adults with gait difficulties caused by spastic ataxia or ataxia. In addition to gait ataxia, those presenting in young adulthood also had limb ataxia, dysarthria, and eye movement abnormalities (macro-saccadic oscillations, nystagmus, and saccadic pursuit). The disorder progresses to spastic ataxia or generalized dystonia, which can lead to loss of independent ambulation.
Developmental delay. Eleven individuals presented as children with mainly motor delay. However, four individuals have mild intellectual disability and two have developmental delay.
Movement disorder. Dystonia in reported individuals has included generalized dystonia, cervical dystonia, laryngeal dystonia, and bibrachial dystonia with tremor. Other movement disorders reported include chorea and, more rarely, stereotypies and myoclonus.
Pyramidal signs. Most individuals had hyperreflexia, extensor cutaneous plantar signs, and lower-limb (more than upper-limb) spasticity.
Peripheral neuropathy has been reported and is characterized by decreased or absent ankle reflexes (in 2 families) and abnormal deep sensory function. EMG and nerve conduction studies in a few individuals showed sensorimotor axonal neuropathy. Pes cavus is described in one individual. Several adults also had muscle atrophy and lower-limb weakness.
Oculomotor findings have included horizontal macro-saccadic pursuits and square wave jerks. These two entities are often confused and macro-saccadic oscillations are more typical of a cerebellar involvement. In addition, individuals presented with jerky pursuit, hypermetric saccades, and gaze-evoked nystagmus.
Seizures. Three individuals were reported to have childhood-onset seizures. No further details about seizure type or EEG findings were available. One individual was treated with phenobarbital and diazepam.
Brain MRI findings can be striking, but imaging results vary among individuals with VPS13D movement disorder. Reported findings include symmetric T2-weighted and FLAIR hyperintensities in the caudate and putamen, hyperintense T2-weighted and FLAIR signal abnormalities of periventricular and subcortical regions, hypointense basal ganglia (globus pallidus), thin corpus callosum [Gauthier et al 2018], and mild cerebellar atrophy, often involving the vermis [Seong et al 2018]. Imaging findings can resemble those seen in Leigh syndrome. Some individuals with VPS13D movement disorder have had normal brain MRI.
Muscle biopsy in one individual showed abnormal subsarcolemmal mitochondrial accumulation and mild lipidosis suggestive of mitochondrial disease. However, enzymatic analysis for respiratory chain function was normal [Gauthier et al 2018].
Other
- Male infertility associated with azoospermia or oligospermia was reported in two individuals.
- Abnormal head size. Both microcephaly (in 2 individuals) and macrocephaly (1 individual) have been described; no further details were available.
- Hearing loss. One individual was reported to have progressive hearing loss; no further details were available.
Genotype-Phenotype Correlations
No clear genotype-phenotype correlations are known.
Nomenclature
VPS13D movement disorder was initially described as spinocerebellar ataxia with saccadic intrusions (SCASI) associated with the spinocerebellar ataxia, recessive type 4 (SCAR4) locus [Swartz et al 2002].
Prevalence
VPS13D movement disorder is rare and has been described in 19 individuals from 12 families. The families are mainly of European descent (French Canadian, German, Dutch, Slovenian, Italian) [Gauthier et al 2018, Seong et al 2018]. One Indonesian and one Egyptian family have also been described [Gauthier et al 2018, Seong et al 2018].
Differential Diagnosis
Table 2.
Disorders to Consider in the Differential Diagnosis of VPS13D Movement Disorder
| Disorder | Gene(s) | MOI | Clinical Features of the Differential Diagnosis Disorder | |
|---|---|---|---|---|
| Overlapping w/VPS13D movement disorder | Distinguishing from VPS13D movement disorder | |||
| Spastic ataxia 1 1 | VAMP1 | AD | Spastic ataxic gait |
|
| Spastic ataxia 2 1 | KIF1C | AR | Pediatric-onset spastic ataxic gait | No extrapyramidal involvement |
| Spastic ataxia 3 1 | MARS2 | AR |
| Hearing impairment |
| Spastic ataxia 4 1 | MTPAP | AR | Spastic ataxia | Neuropathy w/loss of reflexes |
| Spastic ataxia 5 1 | AFG3L2 | AR |
|
|
| Leigh syndrome 2 | Many | AR XL mt | Bilateral basal ganglia lesions | Cardiac or skeletal muscle involvement |
| HSP (incl SPG3A, SPG4, SPG7, SPG11) 3 | ATL1 SPAST SPG7 SPG11 | AD AR | Pediatric-onset spastic gait | No cerebellar features |
| SCAR2 1 | PMPCA | AR | Pediatric-onset ataxic gait | Cerebellar atrophy |
| SCAR7 1 | TPP1 | AR | Pediatric-onset ataxic gait | Posterior column involvement |
AD = autosomal dominant; AR = autosomal recessive; HSP = hereditary spastic paraplegia; MOI = mode of inheritance; mt = mitochondrial
SCAR = spinocerebellar ataxia, autosomal recessive; XL = X-linked
- 1.
See Hereditary Ataxia Overview.
- 2.
See Mitochondrial DNA-Associated Leigh Syndrome and NARP.
- 3.
These are the more common subtypes of hereditary spastic paraplegia with onset in childhood.
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with VPS13D movement disorder, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.
Table 3.
Recommended Evaluations Following Initial Diagnosis in Individuals with VPS13D Movement Disorder
| System/Concern | Evaluation | Comment |
|---|---|---|
| Musculoskeletal | Physiatry & physiotherapy evaluation | To ensure proper bracing & walking aids |
| Neurologic | Neurologic evaluation | EEG, EMG/NCS if clinically indicated |
| Eyes | Ophthalmologic evaluation | Evaluate for macrosaccadic intrusions. |
| Endocrine | Fertility evaluation in males of reproductive age | Evaluate for male infertility, oligospermia. |
| Miscellaneous/ Other | Developmental assessment | Incl evaluation of motor, speech/language, general cognitive, & vocational skills |
| Consultation w/clinical geneticist &/or genetic counselor |
EEG = electroencephalogram; EMG = electromyogram; NCS = nerve conduction study
Treatment of Manifestations
Seizures. Standardized treatment with antiepileptic drugs (AEDs) by an experienced neurologist. Many different AEDs may be effective, and no one AED has been demonstrated to be effective specifically for this disorder. Education of parents regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for parents or caregivers of children diagnosed with epilepsy, see Epilepsy & My Child Toolkit.
Spasticity. Recommendations for spasticity treatment include baclofen, tizanidine, benzodiazepines, dantrolene sodium, gabapentin, botulinum toxin injections, and intrathecal baclofen, which are established treatments in a similar condition, Friedreich ataxia [Corben et al 2014].
Dystonia. Treatment options for dystonia include trihexyphenidyl, botulinum toxin injections, benzodiazepines, baclofen, and levodopa [Jinnah & Factor 2015]. Deep brain stimulation has not been reported as a treatment for VPS13D hyperkinetic movement disorder.
Ataxia. No specific pharmacologic treatments for ataxia have been approved. Riluzole is probably effective in reducing ataxia symptoms (European Federation of Neurological Societies [EFNS] – level B rating) and varenicline is probably effective in improving gait and stance in individuals with spinocerebellar ataxia type 3 (SCA3) (EFNS – level B rating ) [van de Warrenburg et al 2014]. Neither of these medications has been tested in individuals with VPS13D spastic ataxia.
A multidisciplinary team including occupational and physical therapists as well as a physiatrist is important in the care of individuals with this complex movement disorder.
Developmental Delay / Intellectual Disability Educational Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States (US); standard recommendations may vary from country to country.
Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy. In the US, early intervention is a federally funded program available in all states.
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.
Ages 5-21 years. In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21. Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.
Gross motor dysfunction. Physical therapy is recommended to maximize mobility. Consider use of durable medical equipment 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.
Oral motor dysfunction. Assuming that the individual is safe to eat by mouth, feeding therapy, typically from an occupational or speech therapist, is recommended for affected individuals who have difficulty feeding due to poor oral motor control.
Communication issues. Consider evaluation for alternative means of communication (e.g., Augmentative and Alternative Communication [AAC]) for individuals who have expressive language difficulties.
Surveillance
No specific surveillance guidelines exist. The authors recommend following standard ataxia and spasticity guidelines. Care should include regular visits to a neurologist and physiatrist. A speech therapist and a urologist should be consulted when indicated.
Table 4.
Recommended Surveillance for Individuals with VPS13D Movement Disorder
| System/Concern | Evaluation |
|---|---|
| Genitourinary | Ask about urinary urgency. |
| Musculoskeletal | Monitor contractures. |
| Neurologic | Monitor those w/seizures as clinically indicated; evaluate fall risk & gait stability. |
| Miscellaneous/Other | Monitor developmental progress & educational needs. |
Agents/Circumstances to Avoid
No specific agents or circumstances are to be avoided aside from excessive alcohol use, which could worsen ataxia.
Evaluation of Relatives at Risk
It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from developmental services and/or seizure management when appropriate.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Therapies Under Investigation
Studies are currently under way to understand the role of VPS13D in mitochondrial integrity and ultimately develop targeted treatments that can enhance mitochondrial function.
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe 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.