We read with interest the case report by Kukkle and collaborators published in this journal in August 2020, 1 where the authors described a patient with rapidly progressive fatal cerebellar ataxia and vocal cord palsy. The patient presented with breathy voice and sleep‐related breathing disorders (SRBD); mild coordination deficits were found. The provided video fragments show the longitudinal progression of ataxia and vocal cord deficits and the appearance of impaired ocular movements with depth misperceptions. Family history was positive in four members, mainly for sleep disturbances (2/4) and cerebellar signs (4/4); all the relatives perished within 2 years from onset. While autonomic tests were normal and laboratory and imaging analyses were negative for prion disease, the patient and four relatives presented a heterozygous missense mutation in the PRNP gene (D178N), with codon 129 heterozygous methionine‐valine polymorphism (129MV), causative of either Fatal Familial Insomnia (FFI) or Creutzfeldt‐Jacob Disease (CJD). The patient, in absence of haplotype verification, was diagnosed with an atypical form of CJD.
In our opinion, the diagnosis of FFI should not be excluded in this case, particularly as the authors missed the following evaluations throughout the longitudinal diagnostic process. First, a familial and rapidly fatal disease presenting at onset with a sleep disorder as the initial complaint would require a video‐polysomnography to be performed. Indeed, SRBD are not so infrequent at FFI onset, sometimes associated with vocal cord dysfunction. 2 In addition, at the beginning of FFI, autonomic tests are usually normal, especially in 129MV patients. Blood pressure and heart rate circadian rhythms are the ones initially impaired, while acute responses of autonomic nervous system still work. 2 It should be also pointed out that progressive ataxia, highlighted here as an atypical feature, is indeed a typical motor manifestation of FFI 129MV patients, 3 that eventually evolves towards complete inability to stand and walk (“thalamic astasia”), as shown in the last video fragment. Moreover, erratically saccadic ocular movements were already described 4 in FFI (where they are not so infrequent ‐ P.C. personal data), and could explain the patient's visual depth misperception. Finally, the performed imaging and pathology exams are not sufficient to exclude FFI, as, in presence of inferior olivary degeneration, scarce data is presented on the thalamus and no semiquantitative in‐tissue examination of PrPsc deposition was executed. 5
FFI is a rare hereditary prion disease whose diagnosis can be challenging, but specific, in the presence of unique clinico‐neurophysiological features of sleep derangement and autonomic hyperactivation, progressing towards agrypnia excitata; 2 rapidly progressive dementia is not among these features. 129MV patients present fragmented and less prominent autonomic hyperactivation, ataxia can be the earliest symptom, while sleep and autonomic derangement, dysarthria, and bulbar dysfunctions can manifest at a later stage. 2 , 5
In conclusion, this patient and his relatives showed typical features of 129MV FFI. Patients reporting sleep disturbances and positive familiar history with rapidly fatal progression should always be suspected for FFI and undergo 24‐hours (if available) polygraphic sleep and autonomic assessment (blood pressure and heart rate) to exclude this rare but unique disorder.
Author Roles
(1) Research Project: A. Conception, B. Organization, C. Execution, D. Design; (2) Statistical Analysis: Not Applicable; (3) Manuscript: A. Writing of the First Draft, B. Review and Critique.
L.B.: 1A, 1B, 1C, 3A.
F.P.: 1A, 1B, 1C, 3B.
P.C.: 1A, 1B, 1C, 3B.
Disclosures
Ethical Compliance Statement: No institutional review board or consent was obtained since this is a work of commentary and no actual study was performed. Informed patient consent was not necessary for this work. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.
Funding Sources and Conflict of Interest: No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work.
Financial Disclosures for previous 12 months: The authors declare that there are no disclosures to report.
References
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