FFI, Fatal Familial Insomnia

Clinic

• FFI is a rare genetic degenerative brain disorder, characterized by an insomnia that may be initially mild, but progressively worsens, leading to significant physical and mental deterioration.
• They have dysfunction of the autonomic nervous system, such as body temperature regulation, sweating, breathing or regulating the heart rate.
• Specific symptoms observed depend on the part of the autonomic nervous system that is affected by the disease.
• In all instances, FFI is caused by an abnormal variant in the prion-related protein (PRNP) gene
• In FFI, the abnormal prions build up primarily within thalamus. This leads to the progressive loss of neurons
• There is no cure, but investigators are researching ways to best treat and manage FFI.
• FFI is classified as a transmissible spongiform encephalopathy (TSE) or a prion disease.
• FFI is characterized by adult onset of progressive disturbance and loss of circadian rhythms, dysautonomia with increased sympathetic activity, and cognitive impairment with fluctuating vigilance, impaired long-term memory, disorientation, and oneiric states (Dream-like states)
• Motor disturbances include myoclonus, cerebellar ataxia, and pyramidal signs. The disease rapidly leads to a somnolent or comatose state and is typically fatal after 9 or 30 months on average (bimodal course). Neuropathologic examination shows marked neuronal loss and gliosis predominantly in thalamic nuclei and inferior olives, while deposition of abnormal prion protein may be relatively sparse.

Signs / Symptoms

• Its characteristic symptom is progressive insomnia that may first be mild, but it then become progressively worse until an affected individual gets very little sleep.
• Insomnia usually begins suddenly and can rapidly worsen over the next few months.
• When sleep is achieved, vivid dreams may occur.
• Lack of sleep leads to physical /mental deterioration that ultimately progresses to coma /death.
• Although insomnia is usually the first symptom, some individuals may present with progressive dementia, in which there are worsening problems with thought, cognition, memory, language, and behavior.
• Initially, the signs may be subtle and include unintended weight loss, forgetfulness, inattentiveness, problems concentrating, or speech problems.
• Episodes of confusion or hallucinations can eventually occur.

Other symptoms

• Diplopia
• Nystagmus
• Dysphagia
• Dysarthria = Slurred speech
• Ataxia
• Tremors or twitchy, jerking muscle spasms (myoclonus), or Parkinson’s-like symptoms may also develop.

• Dysfunction of the autonomic nervous system
  • Fever
  • Tachycardia
  • Hypertension
  • Hyperhidrosis
  • Lachrymation
  • Constipation
  • Variations in body temperature
  • Sexual dysfunction including Erectile dysfunction
  • Anxiety
  • Depression
  • Irregular pattern of respiration (Biot)

Case report

• 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.
• 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 PrP^sc 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 ; 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.

Related Disorders

• FTD (Frontotemporal degeneration)
• Alzheimer’s disease
• Huntington disease
• Progressive supranuclear palsy
• Dementia with Lewy Bodies
• Corticobasal degeneration
• Hashimoto encephalopathy
• Paraneoplastic syndromes
• MSA (Multiple system atrophy)
• Agrypnia excitata

Remedies

1. OP, PHOS
2. Lach, Stram, Nat-m, Sul
3. Sil, Bell , Calc, , Merc, Hyos, Ars