Genetic Identification Is Critical for the Diagnosis of Parkinsonism: A Chinese Pedigree with Early Onset of Parkinsonism

Abstract

Background: A number of hereditary neurological diseases display indistinguishable features at the early disease stage. Parkinsonian symptoms can be found in numerous diseases, making it difficult to get a definitive early diagnosis of primary causes for patients with onset of parkinsonism. The accurate and early diagnosis of the causes of parkinsonian patients is important for effective treatments of these patients.

Methods: We have identified a Chinese family (82 family members over four generations with 21 affected individuals) that manifested the characterized symptoms of parkinsonism and was initially diagnosed as Parkinson's disease. We followed up with the family for two years, during which we carried out clinical observations, Positron Emission Tomography-Computed Tomography neuroimaging analysis, and exome sequencing to correctly diagnose the case.

Results: During the two-year follow-up period, we performed comprehensive medical history collection, physical examination, and structural and functional neuroimaging studies of this Chinese family. We found that the patient exhibited progressive deteriorated parkinsonism with Parkinson disease-like neuropathology and also had a good response to the initial levodopa treatment. However, exome sequencing identified a missense mutation, N279K, in exon 10 of MAPT gene, verifying that the early parkinsonian symptoms in this family are caused by the genetic mutation for hereditary frontotemporal lobar dementia.

Conclusions: For the inherited parkinsonian patients who even show the neuropathology similar to that in Parkinson's disease and have initial response to levodopa treatment, genetic identification of the molecular basis for the disease is still required for defining the early diagnosis and correct treatment.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1. Pedigree of the family.

Squares represent male family members; circles, female family members; filled symbols, affected subjects; a diagonal line through a symbol, deceased; short arrow, proband.

Fig 2. Brain MRI and CT scans of two patients of the family.

A,B: brain MRI scan of the proband at the age of 42; C-F: brain MRI scan of the proband at the age of 44; G,H: brain MRI scan of the patient Ⅳ20 at the age of 46. Atrophy of whole brain was present in both patients. The frontotemporal atrophy was the most noticeable, while in the proband the hippocampus was relatively well-preserved.

Fig 3. PET imaging of DATs via 11C-CFT in pedigree with p.N279K MAPT mutation.

A-C: Axial positron emission tomographic images of 11C-CFT uptake in three family members, A, Ⅳ-1, B, Ⅳ-3, C, Ⅳ-20; D-F: The transverse CT in three family members, D, Ⅳ-1, E, Ⅳ-3, F, Ⅳ-20; G-I: Integrated imaging of Axial positron emission tomographic images and transverse CT in three family members, G, Ⅳ-1, H, Ⅳ-3, I, Ⅳ-20. The region with the highest signal intensity indicates the intake of 11C-CFT by regional dopamine transporter.

Fig 4. PDRP via 18F-FDG in pedigree with p.N279K MAPT mutation.

Parkinson’s disease-related pattern (PDRP) identified by network analysis of 18F-FDG PET scans from two family members–patient Ⅳ-3 matched with non-patient Ⅳ-1. A, B: Axial PDRP of [18F]-FDG PET scans from two family members, A, Ⅳ-1, B, Ⅳ-3; C, D: Sagittal PDRP of [18F]-FDG PET scans from two family members, C, Ⅳ-1, D, Ⅳ-3. Red signals in putamen (B), globus pallidum (B), cerebellum (D) and sensorimotor cortex (D) indicate the brain regions with increased metabolic activity, whereas blue signals in extensive prefrontal areas (D) indicate the brain regions with decreased metabolic activity.

Fig 5. Sanger sequences of MAPT p.N279K mutation in this family.

Ⅳ-3, Ⅳ-5, Ⅳ-20 are patients carrying the MAPT p.N279K mutation; IV-1, IV-6, IV-21, III-9, III-32 are unaffected family members.