Neuropathology—a central brainbank community unit, jointly reported a neuropathology of propionic acidemia

Written by - Cao Lingxiao, Editor-in-Chief, Wang Sizhen, Ed.
Xia Leaf Propionic Acidemia (PA) is an autosomal recessive organic acidemia
.
It is characterized by abnormal accumulation
of propionic acid and related metabolite precursors caused by propionyl-coenzyme a carboxylase (PCC) deficiency.
PA is a rare disease with a prevalence of 0.
09 to 5.
05 × 10 to 5 in Asia [1].


The clinical manifestations of PA are complex and can be divided into early-onset (age of onset < 1 year) and late-onset (onset < 1 year ≥ 1 year
).
Patients with early-onset form have severe clinical symptoms and usually die
in infancy.
Patients with late onset usually have mild symptoms and longer survival
.
Clinical symptoms of PA usually appear after birth or infancy and may affect the nervous, circulatory, urinary, and immune systems
.
However, the pathogenesis of PA is unknown
.
Therefore, neuropathological studies of PA are of great significance
for exploring its mechanism and treatment.
However, current neuropathological studies of PA are extremely rare
.
One case report on the pathology of brain tissue in propionic acidemia was 19 years ago, and there are only 7 global reports on the pathology of brain tissue in propionic acidemia [2
].

Since September 2018, the National Clinical Research Center for Neurological Diseases (hereinafter referred to as the National Center Brain Bank) has received brain tissue donated by volunteers from several top three hospitals to promote medical progress, and one of the children with propionic acidemia has been diagnosed and treated by Beijing Children's Hospital affiliated to Capital Medical University and Beijing Friendship Hospital affiliated to Capital Medical University, in order to promote medical breakthroughs in propionic acidemia.
The family donated his son to the National Center Brain Bank
located at Beijing Tiantan Hospital affiliated with Capital Medical University.
After repeated communication between doctors at the three hospitals, on September 14, 2022, the Central Brain Bank Community jointly published an article entitled "Neuropathological report of propionic acidemia" on Neuropathology, which explains the pathological changes
in brain tissue in clinically and genetically confirmed PA.


The child develops drowsiness and poor
feeding from 4 days postpartum.
At 3 months of age, the patient gradually falls into a coma and dies from complications
after liver transplantation.
Laboratory tests indicate metabolic acidosis, hyperammonia, amino acid metabolism disorders, and fatty acid metabolism disorders, which meet the laboratory diagnostic criteria
of PA.
Genetic analysis showed propionyl-CoA carboxylase subunit β (PCCB) c.
838dupC (rs769968548) and c.
1127G>T (rs142982097) complex heterozygous mutations
.
Twenty-three hours after his death, the collection, processing and systematic sampling
of brain tissue was carried out using the standardized process of the National Center for the construction of the brain bank.
HE staining is used to observe neuronal loss and histochemical changes; Astrocyte changes were observed with glial fibrous acid protein immunohistochemistry (GFAP, rabbit monoclonal, EPR1034Y, Abcam ab68428, USA, 1:600); Modification of myelin sheath was observed with myelinhication of alkaline protein immunohistochemistry (MBP, rabbit monoclonal, EPR21188, Abcam ab218011, USA, 1:8000), oligodendrocyte changes were observed with tubulin polymerization to promote protein immunohistochemistry (TPPP, rabbit monoclonal, EPR3316, Abcam ab92305, United States, 1: 800); Microglial alterations
were observed with transmembrane protein 119 immunohistochemistry (TMEM119, rabbit polyclonal, Abcam ab185333, USA, 1:1500).


Gross pathological examination with soft brain tissue (Figure 1A
).
The demarcation between gray-white matter and between the subcortical nucleus is unclear (Figure 1B
).
The hippocampal structure is almost invisible, and the amygdala is relatively large, which is consistent
with the developing brain.
Microscopic examination reveals pathological changes that predominate
the brainstem, motor cortex, basal ganglia, and thalamus.
Manifested by neuronal loss, cavernous degeneration, vacuole degeneration, Alzheimer's disease type II astrocytes, and microvascular congestion (Figures 2A-F).

Significant astrocytosis, oligodendrocyte loss, demyelination and microglial activation changes were observed by immunohistochemical staining (Figure 2H-J).


Figure 1 Extensive pathological changes in PA brain tissue (Source: Cao LX, et al.
, Neuropathology.
Figure 2
Micropathological changes in PA brain tissue (Source: Cao LX, et al.
, Neuropathology.
2022)
article conclusions and discussions, inspiration and prospects In summary, the clinical manifestations of this case are common neurological symptoms of early-onset propionic acidemia (PA), and laboratory and genetic analysis further confirm the diagnosis
.
On microscopic examination, the authors found significant spongiform degeneration, vacuolar degeneration, Alzheimer's type II astrocytes, microvascular congestion, as well as astrocytosis, oligodendrocyte loss, demyelinating and microglial activation changes
.
While confirming previous findings, this case report also describes changes in glial cells through histochemical staining, and points to the involvement of inflammatory responses and vascular microcirculation alterations in
the pathogenesis of PA.
This study also had some limitations, as brain tissue in this case could not be compared with age-matched normal brain tissue for control analysis
due to the scarcity of infant brain tissue donation.
It is hoped that in the future, the difference between
pathological changes in PA and brain tissue in infants and young children can be further explored through qualitative and quantitative comparison with age-matched brain tissue.
This case report is the world's first genetically diagnosed PA with a clear report of brain tissue pathological changes, and once again thanks to the selfless dedication
of donors and donor families.

Original link: https://doi.
org/10.
1111/neup.
12861

About the Author:

Lingxiao Cao, a doctoral candidate in neurology at Beijing Tiantan Hospital affiliated to Capital University of Science and Technology, has published 2 SCI papers as the first author and 2 core journal articles Chinese
.

Selected articles from previous issues [1] Nat Commun - Xu Tianle / Li Weiguang / Zhang Siyu teamwork to reveal the neuronal cluster organization rules in which fear and regression memory compete with each other [2] Brain-Yi Chenju/Niu Jianqin team found that activating the Wnt/β-catenin pathway can alleviate blood-brain barrier dysfunction in Alzheimer's disease[3] Prog Neurobiol Frontier ThinkingGenetic factors, aging and intestinal microbial disorders on "dry" and "wet type" Effects of immune response in retinal degeneration [4] Sci Adv-Xi Zhengxiong's team discovered a new mechanism of sports reward: midbrain red core-ventral covered glutamate neural pathway [5] Mol Psychiatry-Niu Jianqin/Xiao Lan team found that oligodendroglial precursor cells DISC-Δ3 variable shear inhibition of excitatory synaptic growth leading to schizophrenia [6] PNAS | Sun Bo's research group and collaborators found that time signals are the main factors regulating multicellular information networks[7] Cell Reports—Liu Sheng/Liu Yizhi's team mapped mammalian retinal ganglion cell multimodal maps [8] Cereb Cortex - default mode network in the treatment of electroshock in patients with depression [9] Mol Psychiatry - Xiong Wei research group to analyze the neural circuit mechanism of fear enhancing shock reflex [10] Transl Psychiatry—Early Damage to Cortical Circuit Plasticity and Connectivity in Mouse Models of Alzheimer's Disease Quality Research Training Course Recommended [1] Symposium on Patch Clamp and Optogenetics and Calcium Imaging Technology (October 15-16, 2022 Tencent Conference) [2] R Language Clinical Prediction Biomedical Statistics Training (October 15-16, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing) Conference/Forum Preview & Review

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; Witt, D.
R.
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, Propionic acidemia: a neuropathology case report and review of prior cases.
Arch Pathol Lab Med 2003, 127 (8), e325-8.

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