PA is an autosomal recessively inherited metabolic disorder caused by the deficiency of propionyl-CoA carboxylase due to PCCA or PCCB gene mutations. A lack of PCC impedes the normal metabolism of intestinal-derived propionic acid, valine, isoleucine, threonine, and methionine produced by protein and odd-chain fatty acid cholesterol side chains, which turn into propionic acid and methyl citrate. Moreover, due to the complex interaction between PCC and the tricarboxylic acid cycle[13], PCC deficiency further leads to a series of metabolic disorders in the body, which makes the clinical manifestations of propionic acidemia and its severity nonspecific.
3.1 Clinical manifestations
The clinical manifestations of propionic acidemia are mainly caused by the accumulation of the intermediate metabolites mentioned above, with a predominance of neurological symptoms. At the onset of classic neonatal PA, symptoms typically begin within hours to days of birth, usually including acute metabolic derangement, poor general status, feeding difficulties, vomiting, dehydration, body temperature instability, neurological involvement manifested as hypotonia or hypertonia, irritability, lethargy, or seizures. Late-onset PA may appear at any age, infancy, childhood, or even later, manifesting as growth retardation, intellectual disability, or similar to acute metabolic derangement triggered by metabolic stress, mainly in the form of infections but also with systemic complications such as seizures, ketoacidosis, recurrent vomiting, leukopenia, or myocardial disease.[3] The patient experienced febrile seizures at the age of 2 years and experienced seizures at the age of 3 years, which was consistent with the clinical characteristics of late-onset propionic acidemia. However, unlike a typical patient with propionic acidemia, this patient did not have metabolic disorders after birth and did not have developmental abnormalities, behavioral abnormalities, or dietary preference problems during growth and development. The child did not develop cardiomyopathy, leukopenia, or other symptoms associated with propionic acidemia during growth. At the age of 10 years, her younger brother (deceased) began to develop symptoms such as retching, walking and running, and shortness of breath during sleep. He was later diagnosed with dilated heart disease, but he did not have seizures.
3.2 Laboratory inspection
The typical laboratory test results of propionic acidemia include metabolic acidosis with anion pore enlargement, glucose metabolism disorders, elevated blood lactic acid, hyperammonaemia, decreased white blood cell count, decreased platelet count, anemia, and increased urinary ketone bodies[3]. Propionic acidemia straightforwardly restrains carbamoyl phosphate synthase Ι[14] or, in a roundabout way, influences carbamoyl phosphate synthase Ι[15] by diminishing the grouping of N-acetyl glutamate, resulting in hyperammonaemia, which has an impact on the nervous system. In addition, different biochemical impacts of propionic acid on striatal, glial, and cerebellar neurons and astrocytes are known from PCC research in rats[16-18], as well as metabolic aggravations caused by propionic acidemia itself, which can cause neurological harm. Hence, in clinical analysis, laboratory tests for propionic acidemia should be holistic and timely. Notwithstanding the above tests, the determination of organic acids in urine, blood, and cerebrospinal fluid by GS-MS analysis and the determination of acylcarnitine by MS/MS can aid in further diagnosis. According to the clinical diagnostic criteria for propionic acidemia in the guidelines[19], (1) urine gas chromatography‒mass spectrometry analysis suggested elevated 3-hydroxy propionic acid and methylcitric acid. (2) Dried blood spot acylcarnitine blood tandem mass spectrometry analysis indicated that levocarnitine ester C3 was significantly increased. The patient's carnitine metabolism test results showed that the levels of citrulline and C3 increased, while the level of C4DC decreased. The increase in C3 was consistent with the characteristics of propionic acidemia, but the degree of increase was not obvious. The increase in citrulline may be related to pyruvate carboxylase deficiency. There was no obvious abnormality in the urine organic acid test, which was inconsistent with the typical urine organic acid test results of propionic acidemia. The patient may have had late-onset propionic acidemia, and the clinical symptoms were only seizures, which were of low severity. In addition, enzymatic analysis can be performed to diagnose PAs caused by PCCs in skin fibroblasts and/or peripheral blood lymphocytes[3].
3.3 Imaging examination and EEG examination
In the neuroimaging examination of propionic acidemia, MRI can show brain atrophy[20-23], including cerebral cortex atrophy, caudate nucleus atrophy, delayed myelination[23], and various changes in the basal ganglia, such as initial basal ganglia swelling, followed by atrophy and various signal changes[3, 24]; MRS showed decreased peaks of N-acetyl aspartate and inositol and increased glutamine, reflecting the effect of hyperammonemia on the nervous system[25]; attenuation of white matter on CT; and an increase in the uptake of 18FDG in the basal ganglia and thalamus at the initial stage on PET and after a decrease in the uptake of the basal ganglia[24]. The examination results of the patient in this article showed that head CT revealed multiple ischemic degeneration foci in the bilateral frontal and parietal lobes and adjacent to the left lateral ventricle. MRI revealed bilateral prefrontotemporal white matter demyelination changes (Figure 1). Due to the high cost of neuroimaging, its role in treating PAs is limited. Clinicians should further weigh the pros and cons of this approach and be adept at applying it in PA treatment when appropriate. In this paper, the patient had late-onset propionic acidemia with epilepsy as a manifestation, and his EEG findings were abnormal EEG, extensive spike waves, and spike-slow complex wave bursts dominated by the head before the intermittent period (Figure 2). Seizures and EEG abnormalities are common in patients with propionic acidemia and may be related to the effects of hyperammonemia on the nervous system and the increased sensitivity of the basal ganglia to metabolic derangement[26, 27]. In addition, EEG changes are diverse and can be focal.
3.4 Molecular Genetics
The vital enzyme involved in the pathogenic mechanism of propionic acidemia is PCC, and the PCCA and PCCB genes are involved. Mutations in any of the two genes might prompt a lack of PCC enzymes and lead to the progression of metabolic disorders. To date, 185 PCCA gene variations and 172 PCCB gene variations have been included in the HGMD for the variations of the two genes. In these two genes, missense mutations, trailed by frameshift and splice mutations, prevailed. The most common Japanese PCCA gene mutations are 923_924insT, IVS18-6C>G, and R399Q, and the most common PCCB gene changes are R410W, T428I, and A153P[28]. Koreans are basically the PCCB gene T428I graph type, accounting for approximately 56.3% of Koreans[29]. However, no hotspot mutations in the PCCA or PCCB gene have been detected in Chinese patients. Trio-WES was performed twice, and the molecular pathological results showed that the patient had propionic acidemia, and the mutation position of the PCCB gene was c.815 (exon 8) G>T/p. R272L (NM_000532) (inherited from the mother), c.337 (exon 3)C>T/p. R113*,427 (NM_000532) (inherited from the father) is a compound heterozygous variant (Figure 3). According to the ACMG guidelines, the [c.815(exon8)G>T (NM_000532)] variant is classified as a likely pathogenic variant, and this variant is not found in common human carrier frequency databases such as thousand genomes and gnomAD, indicating that it is an extremely rare variant. According to the ACMG[10] guidelines, the [c.337(exon3)C>T(NM_000532)] variant is rated as a pathogenic variant, which has been included in the dbSNP database, and the rs number is rs186031457. The frequency of this variant in the general population carrier frequency databases is 0.0 in 1000 genomes, and it is not included in gnomAD, which is a very rare variant. The literature[11] reported that the mutation was detected in homozygous propionic acidemia patients, and relevant functional experiments have been verified in the literature[12].
3.5 Clinical Management
Current investigations have shown that there is no specific treatment for propionic acidemia. Consequently, treatment for propionic acidemia generally involves symptomatic treatment. At the point when a patient with diagnosed propionic acidemia has increased physical stress, for example, vomiting or infection, catabolism might increase, resulting in intense metabolic failure[30], a metabolic emergency. Treatment ought to be an inversion of catabolism[30] (giving glucose or intralipid) and expulsion of poisonous compounds, including intravenous carnitine[31], hemodialysis, and hemofiltration of ECMO. When hyperammonemia occurs, sodium benzoate/sodium phenylacetate and/or N-carbamoylglutarate[32-34] or arginine hydrochloride should be used. The advancement of crucial vital signs, urinary ketamine, and venous or arterial blood gases should be monitored at the beginning of the inversion of catabolism. Long-haul treatment of propionic acidemia includes dietary limitations (diet confining amino acids and odd-chain unsaturated fats as propionic precursors), carnitine supplementation and monitoring for complications, metronidazole and other antibiotics inhibiting intestinal bacteria[35], and liver transplantation if necessary[36-38]. The treatment plan for the patient in this paper was as follows: levetiracetam (1.0 g) twice daily and Xianyu capsules (4 capsules) three times daily for antiepileptic treatment; idebenone (30 mg) twice daily to improve cerebral metabolism and symptoms of memory impairment; vitamin B6 (20 mg) twice daily to nourish nerves; and ginkgo mi Huan oral liquid (10 ml) twice daily to improve cerebral ischemic symptoms. The symptoms significantly improved after the above treatment. The patient was followed up for half a year after the treatment, and no seizures occurred since the beginning of the treatment.
3.6 Prenatal Diagnosis
Propionic acidemia, as an uncommon and unfavorable prognostic inherited metabolic disorder, should receive great attention in the prevention of this link; for example, prebirth screening by DNA mutation analysis and determination of metabolites in amniotic fluid enzyme activity (in amniotic fluid cells or chorion)[39-42] and propionyl carnitine are often utilized in neonatal evaluation for propionic acidemia[43, 44], and early hereditary testing can clearly analyze, and direct genetic counseling may likewise forestall that the pathogenic gene is inherited in the family line.