Reply to: Fatal Familial Insomnia: A Rare Disease with Unique Clinico‐Neurophysiological Features

Baldelli et al. ¹ raise an important issue in respect to our report of a 54 year old man with D178N mutation in PRNP gene presenting with rapidly progressive autosomal dominant ataxia and vocal cord palsy. ² The D178N mutation in PRNP gene can have two phenotypic presentations—Fatal familial insomnia (FFI) or Creutzfeldt‐Jacob Disease (CJD). We concur with the thought process and this has been already discussed in the primary paper, given the significant overlap in the genetic mutations of both disorders. ²

In the family that we have reported, two of the symptomatically affected individuals were clinically assessed by the author (PLK) at different timepoints. Both patients had identical presentation with primarily ataxic features involving both upper and lower limbs, that suggested primarily cerebellar connections related dysfunction. Of course, as pointed out by Baldelli et al., whether the clinical symptoms could have been purely “thalamic astasia” remains difficult to be certain. In the classical paper on Thalamic Astasia, Masdeu et al., ³ described thalamic astasia as “motor incoordination with inability to stand” and attributed it to involvement of the ventolateral thalamic nucleus and its connections with cerebellar, spinothalamic and vestibular afferents. Our subjects, at initial presentation to the clinic did not have classical features of astasia. During the course of illness, he did develop inability to stand in association with motor incoordination that could be attributed to astasia. However, ataxic features with clinically documented vocal cord palsies, was in the forefront while sleep disturbances was deemed to be secondary and had not been the forefront during the course of illness. In retrospective, we could have considered video polysomnography to document reduced sleep time, impaired REM sleep, abnormal stage shifts and dysautonomia. It is also noteworthy point that subject (III‐3) (supplementary data of primary manuscript ² ) had been considered to have FFI as differential diagnosis and sleep study done was reported as normal (genetic testing not available).

The proband had heterozygous missense mutation in PRNP gene (D178N), which is common to CJD and FFI. However, it is well known that polymorphism of Methionine at position 129 coupled (in cis) with D178N is associated with FFI; whereas Valine at the same codon (in cis) with D178N allele manifests as CJD. The proband in our family had the D178N variant with modifier variant (M129V) detected in heterozygous state in the PRNP gene. In the absence of parental samples haplotype could not be confirmed.

Neuropathological studies ⁴ have shown that CJD^D178N–129V has a fairly distinctive pattern of involvement with spongiform change diffusely involving the cortex including hippocampus with variable gliosis in corpus striatum, similar to that observed in our case. Similarly, the PrP^sc deposits are characteristically punctate, and follows the same distribution as the spongiform change. The cerebellum is invariably spared. The D178N–129 M haplotype associated with FFI, in contrast, has prominent involvement of thalamus and olivary nuclei while cortical involvement occurs with increase in disease duration for longer than a year. The histopathological changes seen in our case wherein cortical involvement was prominent in contrast to thalamus and striatum, supports the diagnosis of CJD. ⁴ One of the mechanisms by which the Codon 129 polymorphism influences the disease phenotype is believed to be the relative proportion of glycosylated to unglycosylated isoform. The highly glycosylated isoform is prominent in FFI in contrast to unglycosylated isoform in CJD. This however could not be carried out due to lack of facility in our hospital. The available findings supported the more likely diagnosis of familial CJD.

Author Roles

1. Research Project: A. Conception, B. Organization, C. Execution;

2. Statistical Analysis: A. Design, B. Execution, C. Review and Critique;

3. Manuscript Preparation: A. Writing of the first draft, B. Review and Critique;

PLK: 1A, 1B, 1C, 3A, 3B

TSG: 1A, 1B, 1C, 3A,3B

MA: 1A, 1B, 1C, 3A,3B

RVL: 1A, 1B,1C, 3B

Disclosures

Ethical Compliance Statement: This was a reply letter and did not require IRB approval or patient consent. 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 the previous 12 months: P.L.K. reports funding received as a part of the Michael J. Fox Genetic Diversity for Parkinson's Disease Program (GAP‐India) and has no additional disclosures to report. T.S.G., A.M., and V.L.R. have no additional disclosures to report.