In the present study, we reported a HIV infected patient with the AOAD harboring a novel E69V substitution in the GFAP gene. Furthermore, we analyzed the patient’s family and found dominant inherited asymptomatic AD and a new heterozygous point mutation in the GFAP gene.
The main clinical manifestation of our patient was the disturbance of his gait. Several mechanisms might be responsible for this symptom, including the direct effects of HIV, opportunistic infection, or HIV-associated diseases. First, HIV can directly cause neuronal damage and cognitive decline, such as HIV-associated neurocognitive disorders, especially in people with advanced stages of AIDS and low CD4 count. However, our patient showed high levels of CD4 without severe cognitive impairment after ART initiation. Second, opportunistic infections in the central nervous system, such as cryptococcal infection, tuberculosis, and viral infection, can cause gait disorder. Neurosyphilis, regarded as a great mimicker to neuro-ophthalmic, audio-vestibular, and psychiatric disorders, often presents concomitantly with other diseases, including metabolic disorders [8]. However, no suspected pathogen infection was found in the CSF of our patient. Third, HIV-associated diseases, such as lymphoma and progressive multifocal leukoencephalopathy, can cause gait disorder. However, all of the above-mentioned disorders show obvious lesions with abnormal signals on MR, which was not observed in our patient. Thus, we searched for other causes that would account for neurological manifestations, which led to the discovery of a novel GFAP gene variant. Currently, we are the first to report a GFAP mutation in a patient with AOAD living with HIV.
GFAP is a member of the intermediate filaments (IF), which contribute to the formation of cytoskeleton and share a common structure [9]. Mutations at K63, V87, E210, E223, R276, and R416 have been identified in the AOAD [10]. These mutations have a high level of conservation among other GFAP species and with the related type III intermediate filament proteins vimentin and desmin. K63Q is an alteration in the N-terminal portion of the protein before the start of coil 1A. The K63Q mutant yields protein aggregates and some ringlike structures [11]. E69V is located in the head domain of GFAP, but further studies are needed to explore the precise mechanism of action.
Analyses of the patient’s family expanded the spectrum of the phenotypic variabilities that are associated with GFAP mutations. Within families, previous reports have shown that the genotype was related to the phenotype [11]. Some case reports have shown mutant dominant missense GFAP mutations account for nearly all forms of AD and are autosomal dominant mutations. Families that carry GFAP mutations display clear evidence of variable phenotypes but recessive inheritance has not been observed. However, factors other than GFAP mutations may account for the variation of patient phenotypic manifestations.
AD patients typically have histories of systemic illnesses, such as infection, neoplasia, or hypertension, that is sometimes combined with substance abuse [12]. Secondary illnesses or intoxication could independently lead to the formation of rosenthal fibers, leading to the upregulation of GFAP expression. A history of HIV, HCV, and syphilis infection may be observed in these patients.
In summary, we are the first to report AOAD in PLWH. The affected patients in the family displayed an autosomal E69V mutation in the GFAP gene, and phenotypes do not support recessive inheritance.