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.
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
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| 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].
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.
Genetic Counseling
Genetic counseling is the process of providing individuals and families with
information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them
make informed medical and personal decisions. The following section deals with genetic
risk assessment and the use of family history and genetic testing to clarify genetic
status for family members; it is not meant to address all personal, cultural, or
ethical issues that may arise or to substitute for consultation with a genetics
professional. —ED.
Mode of Inheritance
Spinocerebellar ataxia type 14 (SCA14) is inherited in an autosomal dominant manner.
Risk to Family Members
Parents of a proband
Many individuals diagnosed with SCA14 have an affected parent.
An individual diagnosed with SCA14 may have the disorder as the result of a
de novo pathogenic variant [
van Gaalen et al 2013]. However, too few unselected cases have been studied to derive a reliable estimate of the proportion of cases that result from a
de novo variant.
Molecular genetic testing is recommended for the parents of a proband with an apparent de novo pathogenic variant.
If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent.* Though theoretically possible, no instances of germline mosaicism have been reported.
* Misattributed parentage can also be explored as an alternative explanation for an apparent de novo pathogenic variant.
The family history of some individuals diagnosed with SCA14 may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, late onset of the disease in the affected parent, or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed unless appropriate molecular genetic testing has been performed on the parents of the proband.
Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:
If a parent of the proband is affected or has the pathogenic variant, the risk to the sibs of inheriting the variant is 50%. Intrafamilial variability in age of onset and clinical features is observed in SCA14.
If the proband has a known SCA14-related pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [
Rahbari et al 2016].
If the parents have not been tested for the PRKCG pathogenic variant but are clinically unaffected, sibs of a proband are still presumed to be at increased risk for SCA14 because of the possibility of age-related penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism.
Offspring of a proband. Each child of an individual with SCA14 has a 50% chance of inheriting the PRKCG pathogenic variant.
Other family members. The risk to other family members depends on the genetic status of the proband's parents: if a parent has the pathogenic variant, members of the parent's family may be at risk.
Prenatal Testing and Preimplantation Genetic Testing
Once the PRKCG pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for SCA14 are possible. However, in general, age of onset, severity of disease, specific symptoms, and rate of disease progression are variable and cannot be accurately predicted by molecular genetic testing.
Note: Some reported PRKCG variants have been associated with functional evidence for pathogenicity, many variants are recurrent, and others have convincing cosegregation evidence. However, if the pathogenicity of a PRKCG variant has not been confirmed, results from molecular genetic testing should be used with extreme caution for prenatal testing at the present time.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testingis. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
