Spinocerebellar Ataxia Type 14
Summary
Clinical characteristics.
Spinocerebellar ataxia type 14 (SCA14) is characterized by slowly progressive cerebellar ataxia, dysarthria, and nystagmus. Axial myoclonus, cognitive impairment, tremor, and sensory loss may also be observed. Parkinsonian features including rigidity and tremor have been described in some families. Findings seen in other ataxia disorders (e.g., dysphagia, dysphonia) may also occur in SCA14. The average age of onset is in the 30s, with a range from childhood to the seventh decade. Life span is not shortened.
Diagnosis/testing.
The diagnosis of SCA14 is established in a proband with a pathogenic variant in PRKCG identified by molecular genetic testing.
Management.
Treatment of manifestations: Physical therapy to maintain mobility and function; occupational therapy to optimize activities of daily living; adaptive devices to maintain/improve independence in mobility; clonazepam or valproic acid to help improve axial myoclonus; speech therapy and communication devices for those with dysarthria; modify food consistency to reduce aspiration risk; consider nutritional and vitamin supplementation to meet dietary needs.
Surveillance: At least yearly neurologic, physical medicine, and speech and language evaluation. Periodic assessment for dysphagia and assessment of cognitive abilities.
Agents/circumstances to avoid: Alcohol and sedation may make gait and coordination worse.
Genetic counseling.
SCA14 is inherited in an autosomal dominant manner. Offspring of an affected individual have a 50% chance of inheriting the PRKCG pathogenic variant. Prenatal testing for pregnancies at increased risk is possible if the diagnosis has been established by molecular genetic testing in an affected family member.
Diagnosis
Formal diagnostic criteria for spinocerebellar ataxia type 14 have not been established.
Suggestive Findings
Spinocerebellar ataxia type 14 (SCA14) should be considered in individuals with the following clinical and imaging findings:
- Slowly progressive cerebellar ataxia
- Myoclonus, dystonia, rigidity, and tremor
- Sensory loss
- Dysarthria
- Nystagmus
- Cognitive impairment (some individuals)
- Depression (some individuals)
- Family history consistent with autosomal dominant inheritance
- Mild to moderately severe cerebellar atrophy that is primarily midline on brain MRI examination
Establishing the Diagnosis
The diagnosis of SCA14 is established in a proband with a pathogenic variant in PRKCG identified by molecular genetic testing (see Table 1).
Because the phenotype of SCA14 is indistinguishable from many other inherited disorders with ataxia, recommended molecular genetic testing approaches include use of a multigene panel or comprehensive genomic testing.
Note: Single-gene testing (sequence analysis of PRKCG, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.
- An ataxia multigene panel that includes PRKCG 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 is recommended (see Table 1).For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
- Comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is another good 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 Spinocerebellar Ataxia Type 14
| Gene 1 | Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by Method |
|---|---|---|
| PRKCG | Sequence analysis 3 | <100% 4 |
| Gene-targeted deletion/duplication analysis 5 | Unknown 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.
Data derived from the subscription-based professional view of HGMD [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.
- 6.
One intragenic multiexon deletion of 1,717 nucleotides of genomic DNA has been reported (see Table 6).
Clinical Characteristics
To date, more than 60 individuals and/or families with a pathogenic variant in PRKCG have been identified [Chelban et al 2018, Shirafuji et al 2019]. The following description of the phenotypic features associated with this condition is based on these reports.
Table 2.
Features of Spinocerebellar Ataxia Type 14
| Feature | % of Persons w/Feature | Comment |
|---|---|---|
| Gait ataxia | 100% | The initial symptom in most individuals |
| Dysarthria | 70% | |
| Abnormal eye movements | 60% | Nystagmus, saccadic pursuit, & others |
| Myoclonus | 10% | Axial, multifocal |
| Tremor | 15% | Rigidity can be present. |
| Decreased sensation | 17% | Mostly vibration sense |
| Pyramidal signs | 60% | Some w/↓ reflexes; a few w/extensor plantar responses (Babinski reflex) |
| Cognitive deficits | 20% | Mostly mild to moderate |
| Depression | 7 families/individuals | |
| Hearing deficits | 4 individuals | ↓ to loss |
| Cerebellar atrophy | 100% | Mostly mild to moderate; severe in a few |
Individuals with SCA14 typically present with a slowly progressive pure ataxia, but many individuals also manifest other symptoms. In a cohort study that identified 13 families carrying pathogenic variants in PRKCG, more than a third of individuals had a complex phenotype [Chelban et al 2018].
Onset. Accurate age of onset is often difficult to determine. The usual onset is in early adult life, typically in the 30s (age range: 3-70 years) [Yamashita et al 2000, Brkanac et al 2002, Chen et al 2003, Hiramoto et al 2006, Vlak et al 2006, Ganos et al 2014, Chelban et al 2018].
Ataxia. The initial finding is almost always subtle unsteadiness of gait that slowly worsens. Almost all persons remain ambulatory, but many fall frequently and require the assistance of stair railings and canes. Some people require a wheelchair late in life.
Dysarthria. Mild-to-moderate dysarthria is common. Findings seen in other ataxia disorders (e.g., dysphagia, dysphonia) may also occur in individuals with SCA14.
Abnormal eye movements. More than half of individuals have horizontal jerk nystagmus or saccadic intrusions.
Myoclonus. Five persons in a Japanese family with early onset had episodic axial myoclonus manifest as irregular tremulous movements of the trunk and head lasting minutes to hours [Yamashita et al 2000]. Mild persistent multifocal myoclonus has been reported in a person with early onset [Vlak et al 2006] and in a few other individuals [van de Warrenburg et al 2003, Klebe et al 2005, Foncke et al 2010, Ganos et al 2014, Chelban et al 2018]. An individual homozygous for a deletion that results in extension of the protein by 13 amino acids had early onset and developed generalized myoclonus in late teenage years [Asai et al 2009]. Identification of PRKCG pathogenic variants in persons with phenotypes similar to progressive myoclonic ataxia (Ramsay Hunt syndrome) [Visser et al 2007] and myoclonus-dystonia [Foncke et al 2010] suggest that SCA14 should be considered in individuals with these clinical syndromes.
Stevanin et al [2004] reported facial fasciculations and/or myokymia in several individuals in one family.
Parkinsonism. Parkinsonian features including rigidity and tremor were described in some families [Stevanin et al 2004, van de Warrenburg et al 2004, Fahey et al 2005, Klebe et al 2005, Dalski et al 2006, Vlak et al 2006, Nolte et al 2007, Visser et al 2007, Asai et al 2009, Sailer et al 2012, Chelban et al 2018].
Dystonia was described in several individuals [Nolte et al 2007, Visser et al 2007, Miura et al 2009, Foncke et al 2010] and more recently has been described as a common feature in SCA14 [Chelban et al 2018].
Sensory loss. One fifth of affected families show mild or moderate sensory loss, mostly decreased vibration sense.
Tendon reflexes vary from decreased to normal to hyperactive. Extensor plantar reflexes are present in a few individuals.
Cognitive deficits may be part of the SCA14 phenotype [Stevanin et al 2004]. Intellectual impairment, attention deficit, and deficient executive function were identified in 13 of 18 (72%) individuals in a French family [Stevanin et al 2004] and in a few families in another French study [Klebe et al 2005]. Mild cognitive deficits were found in two members with adult-onset disease in a Japanese family [Miura et al 2009]. Three affected individuals in a Norwegian family were described as having learning difficulty with IQ in the normal to low range [Koht et al 2012]. One of two affected individuals in one family and two of six affected individuals in another family had mild deficits in concentration and memory [Chelban et al 2018]. In a large cohort study of recessive cognitive disorders, different homozygous PRKCG variants were identified in cousins with moderate cognitive impairment and ataxia in two families [Najmabadi et al 2011]. However, a detailed neuropsychological study of Norwegian families found no significant cognitive deficit in ten individuals with SCA14 compared to intrafamilial controls – although verbal IQ, verbal executive function, and psychomotor speed tended to be slightly reduced in the affected individuals [Wedding et al 2013].
Prognosis. Life span is not shortened and many persons live beyond age 70 years.
Other
- Memory loss after age 70 years observed in several affected individuals may be coincidentally occurring age-related dementia [Chen et al 2005].
- Depression found in some families with SCA14 [Chen et al 2003, Chen et al 2005, Vlak et al 2006, Nolte et al 2007, Wieczorek et al 2007, Miura et al 2009, Ganos et al 2014] may reflect general dysfunction in progressive diseases, rather than a feature specific to SCA14.
- Hearing impairment was observed in four persons with SCA14 [Stevanin et al 2004, Klebe et al 2005, Coutelier et al 2017, Shirafuji et al 2019], but it is not clear if the impairment results from PRKCG pathogenic variants.
- Seizures. One person with intractable generalized tonic-clonic epilepsy was reported in a Japanese family; however, she had experienced birth asphyxia and intellectual impairment from infancy [Hiramoto et al 2006]. It is likely that her seizures were not related to SCA14.
Neuroimaging. Brain MRI in all affected persons has shown mild-to-moderately severe cerebellar atrophy that is primarily midline. Atrophy of the brain stem or cerebral cortex is not observed in young individuals with SCA14; mild cerebral atrophy reported in some elderly individuals [Dalski et al 2006] may have been age-related.
Neuropathology studies on postmortem brain tissue has been reported in two individuals with SCA14. Loss of Purkinje cells in the cerebellum and decreased staining of residual Purkinje cells for PKCγ antibody were found in one individual at age 66 years [Chen et al 2003]. Severe loss of Purkinje cells in all lobules of the neocerebellum associated with Bergmann gliosis and mislocalized PKCγ staining of the remaining Purkinje cells associated with large cytoplasmic aggregates in the soma were found in an individual at age 90 years [Wong et al 2018].
Genotype-Phenotype Correlations
No genotype-phenotype correlations have been identified.
Penetrance
Clinically unaffected individuals with PRKCG pathogenic variants who are older than age 60 years have been described in at least three families [Yabe et al 2003, Chen et al 2005].
Nomenclature
The term "olivopontocerebellar atrophy" (OPCA) was used to denote SCA in the past. Prior to the discovery of the genes that differentiate members of the group, the autosomal dominant cerebellar ataxias (ADCA) were divided into subgroups depending on the presence of clinical features in addition to ataxia. ADCA III, to which SCA14 would belong, referred to a pure form of late-onset cerebellar ataxia without additional features.
Prevalence
SCA14 probably accounts for fewer than 1% of all autosomal dominant ataxia diagnoses and accounts for approximately 1.5% to 6.7% of autosomal dominant cerebellar ataxia without trinucleotide repeat expansions [Chen et al 2005, Klebe et al 2005, Basri et al 2007, Chelban et al 2018]. The range in prevalence may reflect variable prevalence among individuals of different ethnic backgrounds.
A founder variant (p.Gly118Asp) has been reported in the Dutch population [van de Warrenburg et al 2003, Verbeek et al 2005]. The p.Phe643Leu variant found in two French kindreds was suggested to represent a founder variant in this population (see Molecular Genetics) [Stevanin et al 2004, Klebe et al 2005].
Differential Diagnosis
Persons with spinocerebellar ataxia type 14 (SCA14) may present with ataxia that is indistinguishable from other adult-onset inherited or acquired ataxias (see Hereditary Ataxia Overview).
Note: SCA14 should particularly be considered if the proband or an affected relative displays axial myoclonus, dystonia, or cognitive impairment.
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with spinocerebellar ataxia type 14 (SCA14), 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 Spinocerebellar Ataxia Type 14.
| System/Concern | Evaluation | Comment |
|---|---|---|
| Neurologic | Neurology referral to assess for cerebellar motor dysfunction (gait ataxia, dysarthria, tremor, dystonia, nystagmus) | Use standardized scale to establish baseline for ataxia (SARA, ICARS, or BARS). |
| Speech | For those w/dysarthria: speech/language evaluation | If dysarthria is atypical or severe enough to cause communication problems |
| Cognition | Neuropsychiatric evaluation for those w/problems in learning &/or attention | For example: MMSE, MoCA, WISC & WAIS |
| Miscellaneous/ Other | Consultation w/clinical geneticist &/or genetic counselor |
BARS = Brief Ataxia Rating Scale; ICARS = International Co-operative Ataxia Rating Scale; MMSE= Mini-Mental State Exam; MoCA= Montreal Cognitive Assessment; SARA= Scale for the Assessment and Rating of Ataxia; WAIS = The Wechsler Adult Intelligence Scale; WISC= Wechsler Intelligence Scales for Children
Treatment of Manifestations
Table 4.
Treatment of Manifestations in Individuals with Spinocerebellar Ataxia Type 14
| Manifestation/ Concern | Treatment | Considerations/Other |
|---|---|---|
| Ataxia | Assessment & care by physical medicine, OT/PT |
|
| Axial myoclonus | Clonazepam or valproic acid | May be effective 1 |
| Dysarthria | Speech & language therapy | Consider alternative communication methods as needed (e.g., writing pads, digital devices). |
| Dysphagia | Modify food consistency to reduce aspiration risk. | Video esophagram may help define best consistency. |
| Poor weight gain | Nutrition assessment | Consider nutritional & vitamin supplementation to meet dietary needs. |
| Intellectual disability | Assessment by an educational psychologist & IEP evaluation | Ensure appropriate social work involvement to connect families w/local resources, respite, & support. |
IEP = individualized education plan; OT = occupational therapy; PT = physical therapy
- 1.
Yamashita et al [2000]
Surveillance
Table 5.
Recommended Surveillance for Individuals with Spinocerebellar Ataxia Type 14
| System/Concern | Evaluation | Frequency |
|---|---|---|
| Neurologic |
| Yrly or more often for an acute exacerbation |
| Dysarthria |
| Yrly |
| Dysphagia | Assess aspiration risk | As neurologic function improves, consider advancing food consistency & diet. |
| Intellectual disability | Assess cognitive abilities based on improving neurologic function/cognition | W/age, reassess changing needs for social & educational services. |
OT = occupational therapy; PT = physical therapy
Agents/Circumstances to Avoid
Alcohol and sedation may worsen gait and coordination.
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 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.
Other
Tremor-controlling drugs do not work well for cerebellar tremors.