Cerebellar ataxias, are a group progressively expanding spectrum of heterogeneous disorders. The clinical features and life expectancies are varied based on genetic and phenotypic presentations. 1 We present a familial case with an autosomal dominant inheritance of rapidly progressive ataxia with vocal cord palsy, due to D178N mutation in the PRNP gene.
Case Report
A 54‐year‐old man (III‐8; Fig. 1.1) presented with a 2‐month history of breathy voice and sleep disturbances in the form of choking sensations and snoring events. A neurological consult was sought because of similar symptoms leading to progressive death in his maternal uncle and 3 siblings (Fig. 1.1). He was noted to have hoarseness of voice and mild lack of coordination in the finger‐to‐nose and heel‐knee‐shin tests along with impaired tandem gait (Video S1, segment 1). Cognitive functioning was normal. His workup, including complete blood count and autonomic function tests, were normal. Paraneoplastic antineuronal antibodies and autoimmune encephalitis panel tested were negative. In addition, the result of magnetic resonance imaging of the brain was normal. At 2 months he was noted to have worsening of his ataxic gait and impaired ocular pursuits (Video S1, segment 2). Because of the rapid progression of clinical symptoms, a possibility of prion disorder was considered. His repeat brain magnetic resonance imaging was also normal (Fig. 2.1), indicating the absence of features consistent with prion disease, his electroencephalogram was within normal limits, and 14‐3‐3 protein analysis in the cerebrospinal fluid was negative as well. At 7 months, he became completely dependent for daily living with hypophonic and breathy speech. He was also noted to have cortical visual deficits in the form of difficulty in perceiving depths (Video S1, segment 3). Laryngoscopy revealed abductor vocal cord palsy. No clinical myoclonus was noted until his last assessment during the 10th month. He finally succumbed about 16 months from the initial assessment.
FIG. 1.
1.1: Schematic representation of the family: circles indicate female and squares indicate male, filled‐in squares indicate affected; arrow indicates the proband. The genotypes for the mutation Asp178Asn (chr20:4680398G>A; c.532G>A; NM_000311.3) are represented as “+” for variant/mutant allele and “−” for the wild‐type allele in red color. The genotypes of the mutation Met129Val (chr20:4680251A>G; c.385A>G; NM_000311.3) are represented as “+” for variant/mutant allele and “−” for the wild‐type allele in blue color. The annotation is based on Hg19/Grch37 of the human reference assembly. The genetic results of the generation IV has not been revealed (*Indicates the genotyped samples in generation IV). 1.2:Representative Sanger profiles of PRNP mutations. Chromatograms showing (A) reference nucleotide for codon Asp178. (B) Variant nucletotide for Asp178Asn (c.532G>A; NM_000311.3). (C) Reference nucleotide for codon Met129. (D) Heterozygous variant nucleotide for codon Met129Val (c.385A>G; NM_000311.3) (E) Homozygous variant nucleotide for codon Met129Val (c.385A>G; NM_000311.3).
FIG. 2.
2.1: Magnetic resonance imaging brain axial sequences showing diffusion weighted (A), apparent diffusion coefficient (B), fluid attenuated inversion recovery (FLAIR) (C), and T2‐weighted image (D)—all of which are within normal limits. 2.2: Sections from different neuroanatomical areas were examined. Frontal cortex revealed spongiform change (A) with reactive astrocytosis (B). Prion (PrPsc) deposits were seen mostly in diffuse synaptic pattern (C) and very focally around vacuoles (D). The caudate nucleus (E–G) revealed mild spongy change/> (E), dense gliosis, and atrophy (F) with focal specked PrPsc deposits in neuropil (G). Inset (G) is positive control showing dense perivascular prion deposits. Mild spongiform change also seen in the hippocampal dentate gyrus (H) and in the cerebellum (I) and dense gliosis in olivary nucleus of medulla (J), but no prion deposits were seen in these areas. The nucleus ambiguous in medulla oblongata (K, L, arrows,*) revealed neuronal loss and prominent gliosis (L,*) in the nuclear area, highlighted by GFAP (M,*). A,E,H,I,K,L: hematoxylin‐eosin; B,E,J,M: GFAP; C,D,G: PrPsc. Magnification = Scale bar. CON, Control; GFAP, glial fibrillary acidic protein; PrPsc, Scrapie isoform of Prion Proteing.
Four of his family members (II‐3, III‐1, III‐3, III‐6) had similar symptoms at onset and later developed ataxic features leading to death within 2 years of onset without any established diagnosis (Fig. 1.1, Table S1). The clinical and laboratory findings were retrospectively reviewed. The median age of onset was 54 years (41–67 years). Of the 3 affected siblings of the proband, 2 had documented vocal cord paresis (III‐1 and III‐3), and III‐6 had palatal paresis within 1 year of onset of the symptoms. The other symptoms in the family included cerebellar signs (4/4), progressive decline in memory (1/4), hallucinations (1/4), myoclonic jerks (1/4), sleep disturbances (2/4), and alpha circadian rhythm (1/4).
Based on the strong family history of similar illness, genetic testing in the index patient and other family members were done after obtaining written consent (Fig. 1.1). DNA was processed by next‐generation sequencing technique using focused clinical exome panel (MedGenome) to identify the causal variant. 2 Analysis revealed a heterozygous missense mutation in the PRNP gene (D178N), which has been reported with both Creutzfeldt‐Jakob disease (CJD) and fatal familial insomnia (FFI). 3 In addition, a known modifier variant (M129V) was detected in the heterozygous state in the PRNP gene (Fig. 1.2). The mutation along with the modifier was screened in the family members by Sanger sequencing. A total of 16 individuals were screened in the family (1 affected; 15 asymptomatic aged 18–49 years). The similarly affected family member (III‐1) was heterozygous for the mutation and the modifier variant. Eight asymptomatic individuals screened had the mutation (D178N), of whom 3 individuals were heterozygous (M129V) and 5 were homozygous (methionine) at codon 129. (Fig. 1.2A,B). The polymorphism methionine at position 129 coupled (in cis) with D178N has been associated with FFI; whereas valine at the same codon (in cis) with the D178N allele manifests as CJD. 4 The modifier variant along with the mutation has been suggested to affect the molecular structure of the human prion protein, rendering it unstable. 4 , 5 In the proband (III‐8; Fig. 1.1), the modifier variant was heterozygous; however, in the absence of parental samples the haplotype is not known.
Histological examination of the brain and spinal cord removed at autopsy revealed diffuse cortical atrophy with neuronal loss and mild but diffuse, fine, spongiform change most prominent in superficial and deep layers of the cortex (frontal and parietal, relatively mild in temporal and occipital cortices). The caudate, amygdala, and hippocampal Ammon's horn showed very mild spongy change. The cerebellum revealed folial atrophy, depletion of Purkinje neurons, and spongiform change along with the Bergmann glial layer. The spinal cord revealed atrophy consequent to the loss of anterior horn cells and gliosis. Immunostaining for PrPsc showed abnormal Prion protein deposits in a fine synaptic pattern throughout the cortex with weak staining intensity. Fine scattered specked prion deposits were detectable in the caudate nucleus and hippocampal Ammon's horn. Thalamus, brain stem, spinal cord, and cerebellum were spared. Sections from the brainstem, including the medulla, were examined with immunohistochemistry for tau (to exclude, immunoglobulin‐like cell adhesion molecule 5 IgLON5) and prion. Neither tau nor prion protein deposits were detected. Interestingly, the nucleus ambiguous near tractus solitarious in the medulla oblongata and the inferior olivary nucleus revealed neuronal loss and dense gliosis, but no prion protein deposits (Fig. 2.2).
Discussion
Phenotypically, this South Indian family presented with features of the autosomal dominant progressive cerebellar syndrome, abductor vocal cord palsy, and eye movement abnormalities leading to death within 2 years. The occurrence of abductor vocal cord palsy was typical in this family, leading to clinical presentation. Memory issues were not at the forefront of the clinical presentation, and myoclonus was not documented in our subjects, which stand out distinctly from other published familial CJD with the D178N‐129V haplotype and FFI with the D178N‐129M haplotype.
FFI is primarily characterized by insomnia, laryngeal stridor, sleep breath disturbance, rapidly progressive dementia, dysautonomia, motor dysfunction (myoclonus, ataxia, dysarthria, dysphagia, and pyramidal signs), and neuropsychiatric issues with thalamic degeneration, especially in the mediodorsal and anterior ventral nuclei. 6 FFI may have overlapping features with CJD, including rapidly progressive dementia, myoclonus, and motor dysfunction such as pyramidal and extrapyramidal dysfunction; however, the neuropathological findings of CJD are specific and include neuronal loss, gliosis, and vacuolation/spongiform changes. 7 , 8 Our patient exhibited neuronal loss and spongiform changes in the cortex, hippocampus, and cerebellum and had no observable changes in thalamus or inferior olives.
Vocal cord paralysis is an atypical feature generally not associated with either of the clinical phenotypes. Recently, 3 sporadic case reports describing vocal cord paralysis during the course of CJD have been reported. However, genetic etiology was not identified. 9
In a review of 12 cases from different kindreds who had CJD with the D178N‐129V haplotype, the major signs included memory loss, irritability, depression, and abnormal behavior. 10 These patients also had features of ataxia with dysarthria and aphasia. Tremor and myoclonus were also noted. The mean life expectancy following clinical onset of symptoms was 14 months for 129VV and 27 months for 129VM patients. Recently, a family with the 178N‐129V haplotype was reported in India where the primary presentation was memory issues followed by difficulty in walking and myoclonus. 11
Atypical clinical presentation with the lack of elevated 14‐3‐3 in the cerebrospinal fluid made clinical diagnosis challenging and paved the way for a genotype‐first approach. This family shows a varied clinical presentation of familial CJD, which expands the disease‐associated phenotype and geographical variations of this rare disorder.
Author Roles
(1) Research Project: A. Conception, B. Organization, C. Execution; (2) Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique.
P.L.K.: 1A, 1B, 1C, 2A, 2B
S.G.T.: 1A, 1B, 1C, 2A, 2B
A.M.: 1A, 1B, 1C, 2A, 2B
V.L.R.: 1A, 1B, 1C, 2A, 2B
Disclosures
Ethical Compliance Statement: This was a retrospective case report and did not require IRB approval. Written declaration of patient consent was obtained from the patient and family. Informed, written consent from next of kin taken for performing autopsy. 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.
Supporting information
Video S1. Segment S1: Video done during the first assessment shows, minimal speech changes, lack of finger‐nose coordination, and tandem difficulties. Segment 2: Video done after 2 months shows worsening of speech, significant worsening of balance and gait with wide‐based stance. Segment 3: Video done after 10 months shows severe breathy voice (abductor vocal cord palsy), impaired saccades, and lack of finger‐nose coordination. During finger‐nose coordination testing, his impaired visual depth perception can also be appreciated. He requires support to stand and cannot walk independently.
Table S1. Supplementary table provides the demographical and clinical features of affected individuals in the family.
Relevant disclosures and conflicts of interest are listed at the end of this article.
References
- 1. Sullivan R, Yau WY, O'Connor E, Houlden H. Spinocerebellar ataxia: an update. J Neurol 2019;266(2):533–544. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Geetha TS, Lingappa L, Jain AR, et al. A novel splice variant in EMC1 is associated with cerebellar atrophy, visual impairment, psychomotor retardation with epilepsy. Mol Genet Genomic Med 2018;6(2):282–287. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. Goldfarb LG, Petersen RB, Tabaton M, et al. Fatal familial insomnia and familial Creutzfeldt‐Jakob disease: disease phenotype determined by a DNA polymorphism. Science 1992;258(5083):806–808. [DOI] [PubMed] [Google Scholar]
- 4. Petersen RB, Parchi P, Richardson SL, Urig CB, Gambetti P. Effect of the D178N mutation and the codon 129 polymorphism on the metabolism of the prion protein. J Biol Chem 1996;271(21):12661–12668. [DOI] [PubMed] [Google Scholar]
- 5. Paz SA, Vanden‐Eijnden E, Abrams CF. Polymorphism at 129 dictates metastable conformations of the human prion protein N‐terminal β‐sheet. Chem Sci 2017;8(2):1225–1232. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Cortelli P, Gambetti P, Montagna P, Lugaresi E. Fatal familial insomnia: clinical features and molecular genetics. J Sleep Res 1999;8(suppl 1):23–29. [DOI] [PubMed] [Google Scholar]
- 7. Gambetti P, Parchi P, Petersen RB, Chen SG, Lugaresi E. Fatal familial insomnia and familial Creutzfeldt‐Jakob disease: clinical, pathological and molecular features. Brain Pathol 1995;5(1):43–51. [DOI] [PubMed] [Google Scholar]
- 8. Zerr I, Kallenberg K, Summers DM, et al. Updated clinical diagnostic criteria for sporadic Creutzfeldt‐Jakob disease. Brain 2009;132(10):2659–2668. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. Kasuga K, Takeuchi R, Takahashi T, et al. Multifocal hits for propagation of prion protein in sporadic Creutzfeldt‐Jakob disease. Neurol Neuroimmunol Neuroinflamm 2014;2(1):e53. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Gambetti P, Kong Q, Zou W, Parchi P, Chen SG. Sporadic and familial CJD: classification and characterisation. Br Med Bull 2003;66:213–239. [DOI] [PubMed] [Google Scholar]
- 11. Sawal N, Chakravarty K, Puri I, et al. Familial Creutzfeldt–Jakob disease: the first reported kindred from South‐East Asia. Ann Indian Acad Neurol 2019;22:225–227. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
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Supplementary Materials
Video S1. Segment S1: Video done during the first assessment shows, minimal speech changes, lack of finger‐nose coordination, and tandem difficulties. Segment 2: Video done after 2 months shows worsening of speech, significant worsening of balance and gait with wide‐based stance. Segment 3: Video done after 10 months shows severe breathy voice (abductor vocal cord palsy), impaired saccades, and lack of finger‐nose coordination. During finger‐nose coordination testing, his impaired visual depth perception can also be appreciated. He requires support to stand and cannot walk independently.
Table S1. Supplementary table provides the demographical and clinical features of affected individuals in the family.