SCA27 caused by a chromosome translocation: further delineation of the phenotype
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- Misceo, D., Fannemel, M., Barøy, T. et al. Neurogenetics (2009) 10: 371. doi:10.1007/s10048-009-0197-x
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We report of a spinocerebellar ataxia (SCA)27 in a daughter and her mother whose karyotype is 46, XX t(5;13)(q31.2;q33.1). The translocation breakpoint is identical in both patients, disrupting the gene-encoding fibroblast growth factor 14 isoform b (FGF14-1b). Clinically, both show signs of SCA, although the daughter is the most affected with early onset cerebellar ataxia, microcephaly, and severe mental retardation. FGF14-1b is the predominant isoform in brain, where it interacts with the voltage gated Na channel. Fgf14−/− mice develop ataxia and paroxysmal dyskinesia and have cognitive deficits. One missense and one non-sense mutation in FGF14 have previously been linked to SCA27. Truncation of one allele in our patients suggests that haploinsuffiency of FGF14 can cause SCA27.
KeywordsCognitive impairmentInherited translocationFGF14MicrocephalySCA27
We report of a spinocerebellar ataxia (SCA)27 in a daughter and her mother carrying a translocation between chromosomes 5 and 13, disrupting the gene encoding the fibroblast growth factor 14 isoform b (FGF14-1b) . Two previous reports have described autosomal dominant SCA27 caused by FGF14 point mutations [2–4]. Patients exhibit signs of cerebellar dysfunction, extrapyramidal tremors and dyskinesia, peripheral neuropathy, impairment of positional sensation, and academic underachievement. Onset is usually in early adulthood with gait unsteadiness and upper limbs tremors.
The mother, age 42, works as a cleaner. As a child, she was pharmacologically treated for seizures. She went to a special school for learning disabilities. On examination, she became unsteady while standing with her eyes closed (Electronic supplementary material E-Video 2). She was unable to keep her balance standing on one foot catching a ball. She managed to stand on a roller board for 3 s (reference value >11 s) with open eyes. Sensory modalities were normal. Deep tendon reflexes were slightly increased, whereas plantar reflexes were equivocal. She had high arched feet. EMG was normal. F-responses and nerve conduction velocities were reduced (lower limbs 44.3 m/s), suggesting mild degree of demyelination. EEG was normal. She did not consent to be examined with cerebral MRI. Testing with the Wechsler Abbreviated Scale of Intelligence and VMI gave an IQ of approximately 2 SD below average. The mother has healthy parents, which are not available for analysis. She has one 16-year-old son and three brothers; one has 1 daughter, one has two sons, and one does not have children. All these family members are healthy.
Comparison of clinical features in three SCA27 families
Daughter (proband this report)
Mother (this report)
Age at tremor onset (y)
Age at ataxia onset (y)
PS n = 7; SS n = 4; SE n = 3
Upper motor neuron involvement
Cerebellar atrophy (MRI)
F145S or Asp163fsX12 mutation in FGF14
SCA27 was described in a Dutch pedigree with a missense mutation in FGF14 exon 4 [2, 4] and in a German patient carrying a frameshift mutation in FGF14 exon 5 . In our family, the identical translocation breakpoint in the mother and daughter disrupts the gene-encoding FGF14-1b on der(13). The only difference between the genes encoding FGF14-1b and FGF14-1a is an alternative exon 1 in the latter , which is unaffected by the translocation in our patients. Tremors were noted in the first two reports of SCA27, and in the Dutch family. This was an early sign of the disease, while ataxia became evident later. In our proband, tremor and ataxia were already evident at age 2. The mother exhibits milder dysfunctions without tremors, which may be attributed to phenotypic variation in SCA27 as the same genomic aberration was detected in both. FGF14-1b is the predominant isoform in brain, with cerebellum showing highest expression, followed by hippocampus, amygdala, cerebral cortex, striatum, and thalamus [5, 6]. In human and mouse, FGF14 interacts with the voltage-gated Na channel , and loss of FGF14 function has been shown to reduce excitability of hippocampal neurons. Fgf14−/− mice  develop ataxia and paroxysmal dyskinesia and have cognitive deficits [6, 8]. Truncation of one allele in a previous SCA27 patient  and in our patient suggest that haploinsuffiency of FGF14 can cause SCA27.
We thank the family for their collaboration and contribution to this study. We are indebted to Eli Ormerod who performed the G-banding. This work was founded by project support from the University of Oslo. DM and EF were supported by “Sigurd K. Thoresens Foundation”, “University of Oslo Research Fund (UNIFOR)”, and “Ullevål University Hospital Research Fund (VIRUUS)”.