Progressive Cognitive Decline and Pyramidal Signs in a Patient With a Novel Homozygous c.395A>T; p.Lys132Met Mutation in CHCHD2

ABSTRACT

Biallelic CHCHD2 variants are rare. We report a consanguineous man with a novel homozygous CHCHD2 c.395A>T (p.Lys132Met) variant who developed progressive cognitive decline, apraxia, oculomotor impairment, and pyramidal signs without parkinsonism. Clinicians should consider CHCHD2 in familial dementia with pyramidal signs, even when motor parkinsonism is absent.

1. Introduction

Parkinson's disease (PD) is the second most common neurodegenerative disorder worldwide. Analyses of the Global Burden of Disease (GBD) 2021 study estimate that 11.77 million people were living with PD globally in 2021, with age‐standardized incidence, prevalence and disability‐adjusted life‐year (DALY) rates of 15.63, 138.63 and 89.59 per 100,000 population, respectively [1]. The burden is unevenly distributed. In the Middle East and North Africa (MENA) region the age‐standardized point prevalence in 2019 was 82.6 per 100,000, a 15.4% increase since 1990, with an age‐standardized DALY rate of 84.4 per 100,000 [2]. In Iran specifically, GBD 2021 data indicate that the age‐standardized incidence and prevalence of PD rose by 23.1% and 33.2%, respectively, between 1990 and 2021 [3]; PD ranked fourth among neurological disorders by age‐standardized DALY rate (73.8 per 100,000), behind headache disorders, Alzheimer's disease (AD) and other dementias (473.6 per 100,000), and idiopathic epilepsy [4]. Against this background of a predominantly sporadic, late‐onset and rising disease burden, monogenic forms remain rare but are disproportionately informative about pathogenic mechanisms.

The coiled‐coil‐helix‐coiled‐coil‐helix domain containing 2 (CHCHD2) gene, which encodes a bi‐organellar regulator of mitochondrial electron flow and of nuclear transcription, is linked to familial cases [5, 6]. Mutations in CHCHD2 lead to higher levels of misfolded α‐synuclein in the substantia nigra of affected patients [5]. Familial PD patients with pathogenic mutations in the CHCHD2 gene may exhibit both motor and non‐motor symptoms. Mechanistically, CHCHD2 dysfunction impairs mitochondrial electron transport, increases reactive oxygen species, and promotes accumulation of misfolded α‐synuclein, linking mitochondrial failure to Lewy body pathology [6, 7]. While heterozygous CHCHD2 variants cause late‐onset typical parkinsonism, the phenotype of biallelic (homozygous) variants remains poorly characterized, with only one prior published case [8].

The present study reported the second case of a familial PD patient with an atypical parkinsonism presentation and a homozygous variant of CHCHD2, demonstrating progressive cognitive impairment and pyramidal signs.

2. Case History/Examination

A 50‐year‐old Persian male was referred to our Movement Disorders Center with a 2‐year history of progressive cognitive decline and psychomotor slowing. His wife reported slowness of thinking, impaired executive function, and behavioral changes as the initial manifestations. The patient complained of drooling, with no history of falling, urinary symptoms, constipation, or sleep behavior disorders. The patient also reported an increased appetite, with no notable changes in food preferences. He had no previous medical condition, and he was not taking any medications. His social history and personal habits were unremarkable, and there was no history of developmental delay or of significant educational or occupational difficulty. His family history was remarkable; four paternal uncles (II:3–II:6) were diagnosed with PD, but they were not genetically tested. His parents, as well as paternal grandparents, were first cousins (Figure 1). On physical examination, the patient had no parkinsonian features such as bradykinesia, rigidity, or tremor; however, he had an obvious delay in understanding and performing the requested tasks. His tandem gait and finger‐to‐nose tests were normal, although he showed apraxia when asked to do the tests. Hoffmann and Babinski signs were positive bilaterally. Other tendon reflexes were normal, and there was no sign of sensory deficit. Regarding eye movements, he could not generate voluntary horizontal or vertical saccades nor direct gaze on command despite repeated and varied instruction. Smooth pursuit movements and optokinetic responses could not be reliably assessed due to inability to sustain fixation or follow directed commands. Despite repeated attempts, he could not perform the Montreal cognitive assessment (MoCA), mini‐mental state examination (MMSE), or extensive neuropsychological evaluation owing to his inability or unwillingness to cooperate with the tasks. His Luria sequence test was abnormal.

FIGURE 1.

Three‐generation pedigree of the patient's family. Squares: males; circles: females. Filled symbol: index patient (III:3) with cognitive decline, pyramidal signs, and Parkinson's disease. Hatched symbols: individuals with clinically diagnosed Parkinson's disease (II:3–II:6). Diagonal line: deceased individual. Double horizontal line (Generation I): consanguinity (first cousins). Arrow: index patient (III:3). Genetic testing was performed only in the index patient: homozygous CHCHD2 c.395A>T (p.Lys132Met). Genetic testing was not performed in other family members.

3. Differential Diagnosis, Investigations and Treatment

Brain magnetic resonance imaging (MRI) demonstrated generalized cortical and cerebellar vermian atrophy. No basal ganglia signal abnormalities, white matter changes, restricted diffusion, focal lesions, vascular changes, or hydrocephalus were identified. Differential diagnoses included microtubule‐associated protein tau frontotemporal dementia (MAPT‐FTD), hereditary spastic paraplegias, C9orf72 frontotemporal dementia, leukodystrophies, mitochondrial disorders, prion disease, corticobasal degeneration, autosomal recessive PD, autosomal dominant PD, progressive supranuclear palsy, and adult‐onset Niemann–Pick disease type C.

Regarding AD as a differential diagnosis, several features argue against typical AD. The onset was dyspraxis and behavioral disorders rather than amnestic; bilateral Hoffmann and Babinski signs without other explanation, and failure to generate voluntary saccades are not features of typical AD and fall outside the NIA‐AA core clinical criteria [9]; brain MRI showed generalized cortical atrophy with cerebellar vermian atrophy, rather than the medial temporal predominance expected in AD; the pedigree shows four affected paternal uncles carrying a clinical diagnosis of parkinsonism rather than dementia, whereas monogenic AD is autosomal dominant.

Equally, the case does not fulfill the Movement Disorder Society clinical diagnostic criteria for Parkinson's disease [10], since motor parkinsonism (bradykinesia with rest tremor and/or rigidity) was never demonstrable, and the criteria for Parkinson's disease dementia [11] cannot be applied in the absence of antecedent parkinsonism. The phenotype therefore lies outside both prototypes and a CHCHD2‐associated neurodegenerative syndrome is one of the possibilities. Adult‐onset Niemann–Pick disease type C was additionally considered, since it can present with progressive cognitive decline and impaired volitional gaze in a patient born to consanguineous parents and is potentially treatable, but genetic study did not confirm it [12]. Progressive supranuclear palsy (PSP) was also considered, but the patient did not fulfill criteria for diagnosing PSP. Table 1 compares the typical AD, typical PD, and the presented case.

TABLE 1.

Clinical differentiation of typical Alzheimer's disease dementia, classical Parkinson's disease, and the present case of homozygous CHCHD2 c.395A>T; p.Lys132Met.

Feature	Typical Alzheimer's disease dementia	Classical Parkinson's disease (±PD dementia)	Present case (homozygous CHCHD2 p.Lys132Met)
Core diagnostic requirement	Insidious‐onset, progressive cognitive decline interfering with function; amnestic presentation most typical (NIA‐AA core clinical criteria) [9]	Motor parkinsonism (bradykinesia plus rest tremor and/or rigidity) is obligatory (MDS criteria) [10]; PD dementia requires dementia arising in the context of established PD [11]	Neither is fulfilled: motor parkinsonism was never demonstrable, and formal cognitive quantification was not possible
Usual age at onset	Typically > 65 years; early‐onset AD (< 65 years) accounts for a small minority	Mean onset near 60 years; young‐onset PD (< 50 years) is uncommon	48 years (2‐year history at presentation aged 50)
Presenting cognitive profile	Episodic memory impairment usually first; visuospatial and language variants recognized	Executive, attentional and visuospatial impairment, generally after motor onset	Psychomotor slowing, executive dysfunction and behavioral change; no amnestic‐predominant onset
Motor parkinsonism	Absent; prominent extrapyramidal signs early are atypical	Present by definition; asymmetric onset, levodopa‐responsive	Absent (no bradykinesia, rigidity or rest tremor)
Pyramidal signs (Hoffmann/Babinski)	Not a feature; presence argues against typical AD	Not a feature; prominent pyramidal signs are an MDS exclusion criterion [10]	Bilateral Hoffmann and Babinski signs
Limb apraxia	May appear late; uncommon at presentation	Not characteristic	Present at presentation, on tandem‐gait and finger‐to‐nose testing
Eye movements	Saccades typically preserved	Saccadic hypometria; vertical supranuclear gaze palsy is an MDS exclusion criterion [10]	Voluntary horizontal and vertical saccades could not be generated on command
Prodromal non‐motor features (hyposmia, RBD, constipation, orthostatism)	Not expected	Frequent, often antedating motor onset	Absent (no REM sleep behavior disorder, constipation or urinary symptoms)
Brain MRI	Medial temporal/hippocampal atrophy predominates	Normal or non‐specific; marked cortical atrophy is atypical	Generalized cortical and cerebellar vermian atrophy, atypical for both
Family structure	Usually sporadic; monogenic AD is autosomal dominant (APP, PSEN1, PSEN2)	Mostly sporadic; monogenic forms < 10%; CHCHD2‐related PD is autosomal dominant	Consanguineous pedigree; four affected paternal uncles; homozygous CHCHD2 variant in the proband
Response to cholinesterase inhibitor ± memantine	Modest symptomatic benefit typically observed	Rivastigmine has established benefit in PD dementia	No discernible benefit over 12 months; continued functional decline

In the presented case, due to the patient's familial history and clinical manifestations, whole‐exome sequencing (WES) was requested, reporting a homozygous variant of the CHCHD2 gene [GRCh38 chr7:g.56170610T>A; NM_016139.4:c.395A>T; p.(Lys132Met)]. This gene was previously associated with PD [13]. According to the variant databases Human Gene Mutation Database (HGMD) and ClinVar, it is a novel variant of the CHCHD2 gene, satisfying PM1 (location within the functionally critical C‐terminal CHCH domain, near the second CX9C motif essential for disulfide bond formation and mitochondrial targeting), PM2‐supporting (absent from gnomAD v4), PP3 (multiple in silico tools predict deleterious effects on protein function), and PP4 (phenotype specific for CHCHD2‐related neurodegeneration in a consanguineous family with multi‐generational parkinsonism) of the ACMG/AMP framework. Collectively, this variant may be characterized as a variant of uncertain significance (VUS) with features suggestive of likely pathogenicity, pending functional validation and segregation studies [5]. He was treated with Donepezil up to 20 mg per day and Memantine up to 28 mg per day. Donepezil, a reversible acetylcholinesterase inhibitor, was selected to address cholinergic deficits contributing to cognitive impairment. Memantine, an NMDA receptor antagonist, was added to target glutamatergic excitotoxicity implicated in neurodegenerative cognitive impairment.

4. Outcome and Follow‐Up

A remarkable family history of PD, supported by a genetic variant in a gene formerly described in familial PD, supported a diagnosis of an atypical, CHCHD2‐associated familial PD. The treatment did not show any benefit, and during a 1‐year follow‐up, his cognitive decline worsened, functional capacity deteriorated, and he lost independence in activities of daily living.

5. Discussion

In addition to extrapyramidal signs and symptoms, it is suggested that patients with familial PD with pathogenic variants of SNCA and LRRK2 (both with autosomal dominant pattern of inheritance) may present a general or single‐domain cognitive decline as a presenting symptom or develop later as a manifestation of PD with dementia (PDD) [14, 15].

The clinical presentation of the mutated CHCHD2 gene in familial PD was first described in 2015 [16]. Previously reported cases of familial PD with mutations in the CHCHD2 gene presented with symptoms mainly compatible with typical manifestations [16]. The clinical spectrum included bradykinesia, rigidity, and gait disturbance as motor manifestations, and depression and smelling deficit as non‐motor symptoms. However, the presented case did not show typical parkinsonism manifestations. Although not ethnically and geographically consistent with our case, it is helpful to mention that Jansen et al. investigated the prevalence and potential pathogenicity of CHCHD2 gene variants in 1243 European subjects diagnosed with PD, reporting 4 patients with pathogenic variants in the CHCHD2 gene, suggesting that the mutations in the mentioned gene may play a role in early‐onset PD as a rare risk factor in the western European population [13].

Two converging lines of evidence support our diagnosis. First, a novel homozygous CHCHD2 variant, in a gene with established causality for familial PD, was identified as the sole candidate on WES. Second, four second‐degree relatives independently carry a clinical diagnosis of PD, consistent with autosomal dominant heterozygous carrier status. The absence of white matter changes argues against a leukodystrophy [17]; the disease course, which is longer than is typical of prion disease, and neuroimaging findings argue against prion disease [18]. The symmetric onset and absence of motor symptoms argue against idiopathic corticobasal syndrome [19]. While the VUS classification prevents definitive causal attribution, the convergence of genetic, familial, neuroimaging, and clinical evidence renders CHCHD2‐associated neurodegeneration the most diagnostically compelling explanation.

Previously reported by one of the authors contributing to the present study (M.S.), the first case of PD with a homozygous variant of the CHCHD2 gene was reported in 2018 [8]. The mentioned study reported a 30‐year‐old Persian woman with rest tremor, bradykinesia, autonomic dysfunction, and without any pyramidal or cerebellar signs, who was diagnosed with early‐onset autosomal recessive form of PD due to a history of consanguinity in her parents, and no family history of neurodegenerative disorders [8]. Following WES, a novel homozygous variant in the CHCHD2 gene [c.211G>C (p.Ala71Pro)] was reported, making it the first reported homozygous variant of this gene compatible with autosomal recessive PD [8]. The patient also experienced cognitive decline and psychiatric disorders progressing through the disease course, and she died at the age of 38 [8]. Perhaps our reported mutation and the aforementioned (p.Ala71Pro) mutation are related to the C‐terminal CHCH fold and central hydrophobic domains, respectively; there are no data on the clinical significance of their pathogenicity. Notably, the two currently reported homozygous CHCHD2 variants differ substantially in genomic position and in the protein domain they affect. The first homozygous variant, p.Ala71Pro (c.211G>C) [8], is located in the central hydrophobic domain of CHCHD2, a region involved in protein–protein interactions and mitochondrial intermembrane‐space targeting. In contrast, the variant reported here (p.Lys132Met (c.395A>T)) is located in the C‐terminal CHCH domain, near the second CX9C motif, which is essential for disulfide bond formation, nuclear translocation under hypoxic stress, and transcriptional activation of the COX4I2 promoter. These domain‐specific differences may underlie the phenotypic distinctions between the two cases, where the patient carrying the former variant (p.Ala71Pro) presented with classical early‐onset PD features (rest tremor, bradykinesia, autonomic dysfunction) at age 30, with cognitive and psychiatric features emerging later [8].

It is important to acknowledge that the identified CHCHD2 variant is classified as a VUS [5]; therefore, definitive causality cannot be established on genetic grounds alone. The identification of a homozygous CHCHD2 variant in a consanguineous pedigree with four second‐degree relatives affected by clinically diagnosed Parkinson's disease, combined with CHCHD2's established role in mitochondrial dysfunction and neurodegeneration, renders this the most plausible genetic contributor to the patient's phenotype. Functional studies and segregation analysis are essential to confirm pathogenicity. This case is presented as a compelling clinico‐genetic association rather than a definitively established cause‐and‐effect relationship.

The present study reported the second case of a PD patient with a homozygous variant of the CHCHD2 gene. The findings from this study, along with previous literature, could contribute to our understanding of the potential impact of the CHCHD2 gene on cognitive function. Of note, segregation analysis was not feasible due to logistical constraints. This constitutes a limitation, and segregation studies are strongly recommended. Furthermore, standard WES has limited sensitivity for tandem repeat expansions, and dedicated methods are required for their detection. Comprehensive multigene panel testing and targeted repeat‐expansion analysis are recommended in future evaluations. The absence of formal neuropsychological profiling, including assessment of visuospatial function, language, episodic memory, and behavioral symptoms, is explicitly acknowledged as a significant limitation of the phenotypic characterization.

Author Contributions

Mehri Salari: conceptualization, methodology, supervision, validation, writing – original draft, writing – review and editing. Arash Soltani: writing – original draft. Masoud Etemadifar: conceptualization, methodology, writing – review and editing. Kamran Rezaei: data curation, project administration, visualization, writing – original draft, writing – review and editing.

Funding

The authors have nothing to report.

Disclosure

We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this article is consistent with those guidelines. The present paper is also approved by the ethics committee of Shahid Beheshti University of medical sciences. The patient has given written and informed consent for the online publication of the videos.

Ethics Statement

We hereby confirm that the present study conforms to the ethical standards and guidelines of the journal. Patient consent was obtained for this research.

Consent

The patient had received and completed the written informed consent form to publish this paper.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

There is no specific data for this paper to be available in a depository.