DiagnosisClinical DiagnosisNo features of spinocerebellar ataxia type 14 (SCA14) are pathognomonic; therefore, diagnosis depends on molecular genetic testing.Molecular Genetic TestingGene. The only gene in which mutations are known to cause SCA14 is PRKCG, which encodes protein kinase C gamma type (PCKγ) [Chen et al 2003]. Clinical testing Table 1. Summary of Molecular Genetic Testing Used in Spinocerebellar Ataxia Type 14View in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method ^{1Test AvailabilityPRKCGSequence analysisSequence variants 2Unknown 3ClinicalSequence analysis of select exonsSequence variants in exon 4 4Unknown 3Deletion / duplication analysis 5Exon, multiexonic, or whole-gene deletions or duplicationsUnknown 61. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole gene deletions/duplications are not detected. 3. The prevalence of SCA14 and the full spectrum of mutations are unknown. To date, large-scale mutation screening has been limited to methods that preferentially detect point and other small mutations in the coding region. However, it is possible that intronic changes, duplications, and deletions that can only be identified using other test methods exist. 4. Exons may vary by laboratory; it is estimated that about 50% of mutations may be in exon 4. 5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.6. No deletions or duplications involving PRKCG as causative of SCA14 have been reported; diagnostic yield may be very low. For issues to consider in interpretation of sequence analysis results, click here. Testing Strategy To confirm/establish the diagnosis in a proband. Establishing the diagnosis in a proband relies on molecular genetic testing.Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) DisordersNo known disorders are allelic to SCA14. However, a single mutation in exon 18 of PRKCG (p.Arg659Ser) was reported in four unrelated individuals with familial retinitis pigmentosa (RP) [Al-Maghtheh et al 1998]. Later studies identified PRP31 (rather than PRKCG) as the gene associated with RP11 [Vithana et al 2001].}

Natural HistoryClinical features of spinocerebellar ataxia type 14 (SCA14) are summarized in Table 2 (pdf). The initial finding is almost always subtle unsteadiness of gait that slowly worsens. 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].Mild to moderate dysarthria is common. Findings seen in other ataxia disorders (e.g., dysphagia, dysphonia) may also occur in SCA14.More than half of individuals have horizontal jerk nystagmus or saccadic intrusions. One third 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 cases.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]. Although this feature has not been observed in most families with SCA14, mild persistent multifocal myoclonus has been reported in a person with early onset [Vlak et al 2006] and a few other cases [van de Warrenburg et al 2003, Klebe et al 2005, Foncke et al 2010]. 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 mutations 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. 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 ]. Other extrapyramidal findings such as dystonia have also been reported [Nolte et al 2007, Visser et al 2007, Miura et al 2009, Foncke et al 2010]. 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]. Two studies in Japanese families found severe intellectual disability in one individual with early onset [Hiramoto et al 2006] and mild cognitive deficits in two members with adult-onset disease from another family [Miura et al 2009]. Three affected individuals in a Norwegian family were described to have learning difficulty with IQ in the normal to low range [Koht et al 2012].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, Nolte et al 2007, Wieczorek et al 2007, Miura et al 2009] may reflect general dysfunction in progressive diseases, rather than a feature specific to SCA14. Hearing impairment was observed in two persons with SCA14 [Stevanin et al 2004, Klebe et al 2005], but it is not clear if the impairment results from PRKCG mutations. One person with intractable epilepsy was reported in a Japanese family [Hiramoto et al 2006].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. Life span is not shortened and many persons live beyond age 70 years. 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.

Genotype-Phenotype CorrelationsBecause all reported features have not been assessed in detail in all affected individuals, evidence is currently insufficient to establish a specific correlation between genotypes and phenotypes. Some individuals with SCA14, particularly those with younger age of onset, exhibit axial myoclonus [Yamashita et al 2000, Yabe et al 2003, Klebe et al 2005], multifocal myoclonus [Vlak et al 2006, Visser et al 2007, Asai et al 2009], or myokymia [Stevanin et al 2004]. However, the clinical phenotype in these families is not identical and the PRKCG mutations involved do not cluster in one region.Cognitive deficits have been reported in a French family with a mutation in exon 18 affecting the C4 domain [Stevanin et al 2004] and in several French and Japanese families with different mutations in exon 4 affecting the C1 domain. In the American families with mutations in other PRKCG regions, two persons have had normal neuropsychological testing and two have developed dementia in older age [Chen et al 2005]; however, most affected persons have not had detailed cognitive testing. The true prevalence of this problem in SCA14 is yet to be determined. For the most part, mutations have been described in single families only, although compiled results of clinical testing have not been made public. Mutations that have occurred in more than one family include p.His101Tyr [Chen et al 2003, Nolte et al 2007], the founder p.Gly118Asp mutation in the Dutch population [van de Warrenburg et al 2003, Verbeek et al 2005b, Visser et al 2007], p.Phe643Leu in two French families, and p.Gly128Asp [Chen et al 2003, Morita et al 2006, Miura et al 2009]. Features such as myoclonus, cognitive deficits, tremor, and dystonia can differ between families that have the same mutation. Similarly, different mutations affecting the same residues (i.e., p.His101Tyr, p.His101Gln, and deletion p.Lys100His101del; p.Ser119Pro and p.Ser119Phe; p.Gly123Arg and p.Gly123Glu; and p.Cys131Arg and p.Cys131Tyr) may produce different extracerebellar symptoms (see Table 2).

Differential DiagnosisPersons with spinocerebellar ataxia type 14 (SCA14) may present with ataxia that is indistinguishable from other adult-onset inherited or acquired ataxias (see Ataxia Overview). SCA14 should particularly be considered if the proband or an affected relative displays axial myoclonus or cognitive impairment.SCA14 may mimic other disorders that are characterized by myoclonus including progressive myoclonus epilepsy with ataxia caused by mutations in PRICKLE1 [Bassuk et al 2008] and myoclonus-dystonia caused by mutations in SGCE (formerly DYT11) [Foncke et al 2010]. Conversely, these other diagnoses can be considered if a diagnosis of SCA14 is entertained because of the presence of myoclonus, but a mutation is not detected in PRKCG.In the absence of linkage assignment to a specific SCA locus, the most pragmatic and cost-effective testing strategy is to test first for mutations in the genes causing the more prevalent autosomal dominant SCAs (i.e., SCA1, 2, 3, 6, 7, and 8) and if none are found, to proceed with testing for a PRKCG mutation.Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with spinocerebellar ataxia type 14 (SCA14), the following evaluations are recommended:Medical history Neurologic examination Brain MRI Medical genetics consultationTreatment of ManifestationsAxial myoclonus may be improved by clonazepam or valproic acid [Yamashita et al 2000]. Although neither exercise nor physical therapy has been shown to stem the progression of incoordination or muscle weakness, individuals should continue to be active. Canes and walkers help prevent falls. Modification of the home with such conveniences as grab bars, raised toilet seats, and ramps to accommodate motorized chairs may be necessary. Weighted eating utensils and dressing hooks help maintain a sense of independence.Speech therapy and communication devices such as writing pads and computer-based devices may benefit those with dysarthria. When dysphagia becomes troublesome, video esophagram can identify the consistency of food least likely to trigger aspiration.Prevention of Secondary ComplicationsNo dietary factor has been shown to curtail symptoms; however, vitamin supplements are recommended, particularly if caloric intake is reduced. Weight control is important because obesity can exacerbate difficulties with ambulation and mobility. SurveillanceGait, coordination, and speech should be evaluated annually. Agents/Circumstances to AvoidAlcohol and sedation may make gait and coordination worse. Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov 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.OtherTremor-controlling drugs do not work well for cerebellar tremors.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Spinocerebellar Ataxia Type 14: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameHGMDPRKCG19q13​.42Protein kinase C gamma typePRKCGData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Spinocerebellar Ataxia Type 14 (View All in OMIM) View in own window 176980PROTEIN KINASE C, GAMMA; PRKCG 605361SPINOCEREBELLAR ATAXIA 14; SCA14Molecular Genetic PathogenesisMutant PKCγ aggregates in the cytoplasm of cultured cells transfected with mutant-PKCγ expression vectors [Lin & Takemoto 2007, Seki et al 2007, Doran et al 2008], but the role of these aggregates in the pathogenesis of SCA14 is not known. When treated with an inducer of autophagy, cultured SH-SY5Y cells transfected with mutant-PKCγ demonstrated accelerated clearance of aggregates, indicating that autophagy contributes to the degradation of mutant PKCγ [Yamamoto et al 2010]. In primary cultures of Purkinje cells transfected with mutant PKCγ, abnormal dendritic development occurred independent of aggregation [Seki et al 2009], translocation of mutant PKCγ in PC dendrites was prominently reduced, and both pruning of climbing fiber synapses from developing PCs and long-term depression expression were impaired [Seki et al 2011, Shuvaev et al 2011].PKCγ is a serine-threonine kinase. Studies of the effect of SCA14-related mutations on kinase activity have not been consistent across groups, but a dominant negative effect has not been documented [Seki et al 2005, Verbeek et al 2005a, Lin et al 2007, Seki et al 2007, Verbeek et al 2008, Asai et al 2009]. Aprataxin (APTX), the gene associated with autosomal recessive ataxia with oculomotor apraxia type 1 (AOA1) [Moreira et al 2001], was found to be a preferential substrate of mutant PKCγ [Asai et al 2009]. This observation suggests that the pathogenesis of SCA14 may involve altered phosphorylation-dependent pathways. Cells expressing mutant PKCγ exhibit increased oxidative stress-induced DNA damage and cell death [Seki et al 2007, Doran et al 2008, Asai et al 2009]. The ubiquitin-proteasome pathway has been implicated in this process [Seki et al 2007].The observation that mutant PKCγ fails to phosphorylate TRPC channels, resulting in sustained Ca²⁺ entry into the cell, supports a role for abnormal Ca²⁺-mediated signaling in neurodegeneration [Adachi et al 2008].A transgenic mouse model with ubiquitous expression of human mutant cDNA p.His101Tyr-PKCγ manifests loss of Purkinje cells at age four weeks and stereotypic clasping responses in the hind limbs [Zhang et al 2009].Normal allelic variants. PRKCG has 18 exons encompassing 25 kb of genomic DNA. Multiple silent allelic variants have been identified. The mutation c.285C>T was reported as a possible splice site mutation [Chen et al 2005], but later was found to be a polymorphism in individuals of North African descent [Klebe et al 2005]. Note: A nucleotide change resulting in an amino acid substitution (p.Arg659Ser) reported in families with RP11 [Al-Maghtheh et al 1998] is likely a normal variant because a mutation in another gene (PRPF31) was later found to be causative in these families [Vithana et al 2001].Pathologic allelic variants. Twenty-three missense mutations, one in-frame deletion, and a 102-bp deletion from the last coding nucleotide (codon 697) have been described (Table 2). The majority of mutations in PRKCG described to date are in exon 4 (13/25, or 52%); this exon appears to be a relative mutational hotspot (for more information, see Table 2). Other reported mutations are located in exons 1, 2, 3, 5, 7, 10, and 18. Normal gene product. The 3-kb mRNA encodes 697 amino acids. PKC is a multifunctional family of closely related serine/threonine protein kinases that function in a wide variety of cellular processes, such as membrane-receptor signal transduction and control of gene expression [Zeidman et al 1999, Newton 2001]. They are organized into three subgroups on the basis of diacylglycerol/phorbol ester binding and Ca⁺⁺ dependence [Nishizuka 2001, Amadio et al 2006]. PKCγ is a member of the conventional or typical subgroup because it is calcium activated and phospholipid dependent. It comprises [Newton 2001]:An amino-terminal regulatory domain containing a calcium-binding region and two cysteine-rich regions; and A carboxyl-terminal catalytic domain containing ATP-binding and substrate recognition sites. PKCγ is highly expressed in brain and spinal cord, with particularly high expression in Purkinje cells of the cerebellar cortex during dendritic development. It is thought to be a negative regulator of dendritic growth and branching [Schrenk et al 2002]. PKCγ also localizes in lens epithelial cells and the hippocampus and amygdala, regions of the brain associated with anxiety and memory. Abnormal gene product. The mutations identified to date result in amino acid substitutions, deletion of two residues, or deletion involving the termination codon that results in extension of the protein by 13 amino acids. In silico and in vitro investigations of some effects of these mutations on the function of the protein have been performed. Computer simulation studies on three missense mutations [Chen et al 2003] suggested that mutant gene products may be less stable than the normal protein. In vitro experiments on multiple missense mutations demonstrated protein aggregation [Lin & Takemoto 2007, Seki et al 2007, Doran et al 2008], altered kinase activity [Seki et al 2005, Verbeek et al 2005a, Lin et al 2007, Asai et al 2009] and altered substrate specificity [Asai et al 2009]. It is speculated that the SCA14 phenotype results from gain of function rather than haploinsufficiency because no chain-terminating mutations have been found, heterozygous PKCγ-null animals are neurologically normal, and mutant PKCγ showed a different substrate preference from wild type [Asai et al 2009].