Objective: We report a patient presenting with both bv-FTD & PD phenotypes, alongside a complex family history featuring multiple neurodegenerative disorders.

Background: The CHMP2B & LRRK2 genes encode proteins involved in endosomal pathways & are located on chromosomes 3 & 12, respectively. Mutations in CHMP2B gene are associated with behavioral variant of frontotemporal dementia (bv-FTD), known as FTD3, which is sometimes accompanied by amyotrophic lateral sclerosis (ALS). In contrast, LRRK2 gene mutations account for ~6% of familial Parkinson’s disease (PD) cases, with symptoms similar to—but milder than—those seen in idiopathic PD. These mutations are inherited in autosomal dominant manner, frequently with positive family history. Diagnosis is confirmed through genetic testing.

Method: A 66-year-old woman developed progressive, asymmetric resting tremors in both hands. Two years later, she began experiencing gait abnormalities followed by bowel/bladder incontinence. By age 70, she exhibited cognitive decline marked by impaired language fluency, perseveration, social disinhibition, apathy, & both auditory & visual hallucinations. Her family history included maternal grandmother, mother, and sister with symptoms consistent with bv-FTD phenotype, with her mother also developing ALS by age 70, & brother & maternal first cousin with PD (see pedigree).

On examination, her MoCA score was 20/30, with deficits in delayed recall, attention, & word fluency. Neurological findings included left-arm rigidity, asymmetric bradykinesia, & resting tremors with intentional & postural components in both hands, without weakness/abnormal reflexes. Her gait was characterized by an asymmetrically reduced arm swing & en-bloc turn.

Results: MRI brain revealed nonspecific small vessel disease. DaTscan demonstrated decreased radiotracer uptake in bilateral basal ganglia. Autonomic testing revealed parasympathetic cardiovagal dysfunction. Genetic testing identified heterozygous variants in CHMP2B (c.21G>C, p.K7N) and LRRK2 (c.6461_6463delinsTCT, p.C2154_M2155delinsFL), while other FTD and PD genetic panels were negative.

Conclusion: This case, with multigenerational maternal inheritance of various neurodegenerative disorders, may represent a novel phenotypic spectrum associated with digenic CHMP2B-LRRK2 variants. The dual syndromic phenotype observed in this patient underscores the need for further research into the pathogenic interplay between these two genes.

Pedigree

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-case-for-novel-phenotypes-associated-with-digenic-chmp2b-lrrk2-mutations/