Clinical and neuropsychological workup
The patient was a 77-year-old woman with 14 years of education who used to work as a community worker. She had a progressive course of disease, right-handed, arrived at the Neurology ward of Changzhou No.2 People's Hospital Affiliated to Nanjing Medical University in Changzhou City, presented with a 3-year history of speech disorder. Three years ago, she had no obvious inducement to appear speech disorder, manifested as poor language expression ability, lack of speech, difficulty in finding words, unable to name, the words fail to convey the meaning, speech errors in spontaneous speech and naming according the description of her son. But language comprehension was relatively preserved, she could engage in simple housework and take care of herself. Half a year ago, she gone out and can’t find the way home, easy to be suspicious of others, memory showed a progressive decrease, placed things can not find all the time along with agraphia. She showed no exertion of lifting limbs, no dragging of lower limbs, no obvious slowness of movement, no hallucinations, no abnormal mental behavior, no diplopia, blurred vision, no dysphagia, coughing when drinking water, no limb convulsions, no confusion. In June 2022, the patient went to the outpatient clinic of our hospital for head MRI, which showed that the left parietal and temporal lobe was atrophied and the left paracele was dilated compared with the right. The patient took some drugs such as donepezil, citicoline, and oxiracetam. The patient now had a progressive deterioration in verbal expression, few solid words in spontaneous speech, an inability to name daily necessities, and difficulty repeating words, sentences and phrases.
The patient’s family pedigree is shown in Figure. 1. Her father developed “dementia” at the age of 65 years and died at 70 years, her youngest brother developed “dementia” at 60 years and died at 65 years. No other family member had a history of dementia, motor dysfunction, or neurodegenerative diseases. The patient had a 3-years history of hashimoto thyroiditis, and was currently using unimethylate. T3, T4, and TSH were all in the normal range.
Her performance was remarkable for impaired single-word retrieval in spontaneous speech and naming, as well as impaired repetition of sentences and phrases. Although she could understand words and sentences, she was unable to communicate with others, often saying irritably “I used to be fine”. Physical examination of the nervous system showed her right upper limb swinging less than the right side when walking, but there were no other positive physical findings. The patient’s neuropsychological test scores were as follows: MMSE 2, MoCA 1, CDR 1 and ADL 30. The language impairment was assessed using a language assessment scale suitable for Chinese people - aphasia battery of Chinese(ABC). The scale consists of four sub-items, including spontaneous speech (information content and fluency), listening comprehension, paraphrasing, and naming. In the four test items, the patient scored the highest in listening comprehension, “Yes or No” questions were answered correctly 80%, the verbal command was 50%, and the listening comprehension was 20%. Her scores on the other three sub-items were below 50%.
Neuroimaging
MRI of her head revealed marked lateral atrophy in the left parietal cortex (Figure. 2). On brain MRI in 2017, only the left parietal lobe was atrophied with mild widening of posterior cingulate and parieto-occipital sulci classified as Koedam score grade 1, and other cerebral lobes were not significantly atrophied. The atrophy of the parietal lobe gradually progressed, with substantial sulcal widening rated Koedam grade 2 in 2020. By 2022 there was extreme posterior cingulate and parieto-occipital sulcal dilation, Koedam grade 3. Since 2020, the atrophy of the temporal and frontal lobes could be observed in addition to the parietal atrophy.
Based on the patient’s clinical and neuroimaging data, we considered a diagnosis of lvPPA2, characterized by impaired single-word retrieval in spontaneous speech and naming, and impaired repetition of sentences and phrases, with relatively preserved single-word comprehension, object knowledge, motor speech, and no speech errors in spontaneous speech or naming. MRI of head revealed marked lateral atrophy in the left parietal cortex and a gradual change over a period of six years.
GRN gene
Whole exome sequencing was performed on the DNA of patient's peripheral blood. We examined gene mutations associated in AD, FTD, or other dementiarelated neurodegenerative diseases. A heterozygous 10-bp frameshift deletion (C.274_283del ATGCGGGGAT)was identified in exon 4 of the GRN gene (NM_002087.4), leading to alteration of cysteine to alanine at amino acid 92 and creation of a premature stop codon at position 161 (Figure. 3). Regrettably, genetic testing could not be performed on her deceased brother who had similar symptoms, and testing was declined by her niece. There were no additional disease-causing mutations in additional screened genes. This GRN deletion was absent from the Human Gene Mutation Database (https://www.hgmd.cf.ac.uk), ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/), Genome Aggregation Database (gnomAD; https://gnomad. broad institute.org), and 1000Genomes databases(last accessed June 24, 2023). According to American College of Medical Genetics and Genomics (ACMG) guidelines, 1) Loss of function is a known mechanism of the disease (PVS1). 2) The mutation was absent in the healthy population (PM2). Therefore, we concluded this to be a novel causative mutation of lvPPA in this patient.