Three affected members of a family admitted to the Outpatient Clinic of Ege University Medical School Department of Neurology because of unsteady gait were evaluated as well as two healthy siblings. In addition, two siblings who could not be brought to hospital because of problems in ambulation were examined at home. Detailed neurologic examination was performed on all. In three affected siblings admitted to hospital and in two unaffected siblings video head impulse test (vHIT) recordings was performed. Nerve conductions and cranial magnetic resonance imaging (MRI) of the three affected siblings that could come to hospital was studied. To rule out all other causes of acquired and inherited late-onset ataxia and neuropathy, blood tests including routine biochemistry, protein electrophoresis, serum and urine immunofixation electrophoresis, ANA, anti dsDNA, anti SSA, anti SSB, paraneoplastic autoantibodies consisting of Anti-Hu, Anti-Yo, Anti-Ri, Anti-MA2, Anti-CV2, Anti-amphiphysin, celiac autoantibodies (Anti-endomysial, Anti-gliadin), cerebrospinal fuid (CSF) analysis, whole body computerized tomography (CT), spinocerebellar ataxia gene panel was carried out prior to genetic analysis of the RFC1 gene in the index patient. RFC1 gene screening was performed on all seven siblings. The study was approved by the ethics committee of Ege University Medical School (reference number: 99166796-050.04-1646946) and all the patients gave their written informed consent for the study. RFC1 repeat expansion screening was performed by flanking PCR in the index case and in his four affected and two unaffected sibs flanking PCR bands were only present in both unaffected sibs, and not in the affected five, upon which all siblings were subjected to RP-PCR. The RP-PCR confirmed the homozygous presence of the AAGGG repeat expansion in the index case and his four affected sibs [5].
The family comprised seven siblings born from healthy non-consanguineous parents. CANVAS phenotype was present in five of them. No other family members from other generations were reported to be affected (Fig. 1).
The index patient was a 67-year-old man who had a 10-year history of progressive unsteady gait. His complaints increased in the dark, and he reported oscillopsia during head movements. Numbness and tingling in the distal parts of extremities was present since the age of 55 years and chronic cough that was resistant to antitussive medications for over thirty years. He defined erectile dysfunction for the last five years. His past medical history was significant for cardiac arrhythmia.
On neurological examination, eye movements in all directions were in normal range without any spontaneous or gaze evoked nystagmus. Clinical head impulse test revealed catch-up saccades in horizontal planes bilaterally. Ankle jerks were absent. Other deep tendon reflexes were normal. Hypoesthesia with stocking-and-glove distribution was present. There was no dysmetria or dysdiadochokinesia on cerebellar system examination. However, he had wide based gait with inability to walk tandem and he had dysarthria. Nerve conduction studies revealed absence of sensory nerve action potentials indicating sensory axonal neuropathy or ganglionopathy. Cranial MRI showed cerebellar atrophy mainly involving the vermis (Fig. 2).
The demographic findings, symptomatology, age of symptom onset and neurological examination findings of the patients is given in Table 1. The eldest sibling was female, the other four were male. Chronic cough was present in all and it was the first symptom followed by sensory symptoms, oscillopsia and imbalance. Patients 1 and 2 with a longer disease history had additional cerebellar features including dysmetria, dysdiadochokinesia and dysarthria. On examination, patients 1 and 2 with the longer disease duration had severe ataxia, necessitating assistance for ambulation. Clinical HIT was positive in all and vHIT performed on three patients (patients 3, 4 and 5) revealed very low vestibulo-ocular reflex (VOR) gains in all three canals bilaterally. VOR gains recorded from unaffected siblings were in normal range as expected (Table 2). Patients number 3 and 4 defined erectile dysfunction. Sensory potentials could not be recorded from the index patient and recordings from patient number 4 and 5 revealed findings consistent with sensory axonal neuropathy. Cranial MRI of the index patients and patients number 4 and 5 displayed cerebellar atrophy, mainly involving the vermis. RP-PCR, revealed the homozygous expansion of the AAGGG repeat in the RFC1 gene in five affected sibs.
Table 1
Demographic features, symptomatology, age of symptom onset and neurological examination findings of the patients
Patient | | Patient 1 | Patient 2 | Patient 3* | Patient 4 | Patient 5 |
Age at diagnosis | | 76 | 72 | 67 | 62 | 57 |
Gender | | female | male | male | male | male |
Age at onset | | 45 | 42 | 35 | 36 | 33 |
First symptom | | chronic cough | chronic cough | chronic cough | chronic cough | chronic cough |
| Cerebellar | imbalance (52) | imbalance (53) | imbalance (57) | imbalance (51) | imbalance (52) |
dysmetria dysdiadochokinesia (56) | dysmetria dysdiadochokinesia (58) | dysarthria (60) |
dysarthria (60) | dysarthria (63) | |
Symptoms (age at onset) | Sensory | paresthesia (50) | paresthesia (49) | paresthesia (55) | paresthesia (48) | paresthesia (50) |
| Ocular | oscilopsia (55) | oscillopsia (53) | oscillopsia (60) | oscillopsia (51) | oscillopsia (52) |
| Autonomic | unknown | unknown | erectile dysfunction (62) | erectile dysfunction (62) | absent |
| Chronic cough | present (45) | present (42) | present (35) | present (36) | present (33) |
Neurological examination | | dysarthria, ataxia | dysarthria, ataxia | mild dysarthria | | |
need assistance for ambulation (65) | need assistance for ambulation (63) | mild ataxia | mild ataxia | clumsy in tandem walking |
dysmetria | dysmetria | unable to walk tandem | clumsy in tandem walking | |
dysdiadochokinesia | dysdiadochokinesia | HIT+/+ | HIT+/+ | HIT+/+ |
HIT+/+ | HIT+/+ | | | |
*index patient |
HIT: Head impulse test |
Table 2
Vestibulo-ocular reflex gains recorded by video head impulse test
Patients | RP | RL | RA | LP | LL | LA |
Patient 3 | 0,30 ± 0,01 | 0,05 ± 0,03 | 0,10 ± 0,03 | 0,30 ± 0,02 | 0,04 ± 0,02 | 0,09 ± 0,02 |
Patient 4 | 0,17 ± 0,04 | 0,15 ± 04 | 0,26 ± 0,07 | 0,25 ± 0,06 | 0,28 ± 0,07 | 0,17 ± 0,05 |
Patient 5 | 0,29 ± 0,06 | 0,18 ± 0,05 | 0,28 ± 0,04 | 0,27 ± 0,08 | 0,22 ± 0,06 | 0,28 ± 0,07 |
Sib 6* | 1,01 ± 0,04 | 0,94 ± 0,04 | 1,04 ± 0,05 | 1,09 ± 0,06 | 1,09 ± 0,04 | 0,98 ± 0,07 |
Sib 7* | 0,95 ± 0,07 | 0,98 ± 0,03 | 0,95 ± 0,06 | 0,99 ± 0,08 | 1,05 ± 0,05 | 0,72 ± 0,06 |
*Genetically CANVAS negative sibs |
RP: right posterior semicircular canal |
RL: right lateral semicircular canal |
RA: right anterior semicircular canal |
LP: left posterior semicircular canal |
LL: left lateral semicircular canal |
LA: left anterior semicircular canal |