Propionic Acidemia Research Articles

The utility of methylmalonic acid, methylcitrate acid, and homocysteine in dried blood spots for therapeutic monitoring of three inherited metabolic diseases.

Routine metabolic assessments for methylmalonic acidemia (MMA), propionic acidemia (PA), and homocysteinemia involve detecting metabolites in dried blood spots (DBS) and analyzing specific biomarkers in serum and urine. This study aimed to establish a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous detection of three specific biomarkers (methylmalonic acid, methylcitric acid, and homocysteine) in DBS, as well as to appraise the applicability of these three DBS metabolites in monitoring patients with MMA, PA, and homocysteinemia during follow-up. A total of 140 healthy controls and 228 participants were enrolled, including 205 patients with MMA, 17 patients with PA, and 6 patients with homocysteinemia. Clinical data and DBS samples were collected during follow-up visits. The reference ranges (25th-95th percentile) for DBS methylmalonic acid, methylcitric acid, and homocysteine were estimated as 0.04-1.02 μmol/L, 0.02-0.27 μmol/L and 1.05-8.22 μmol/L, respectively. Following treatment, some patients achieved normal metabolite concentrations, but the majority still exhibited characteristic biochemical patterns. The concentrations of methylmalonic acid, methylcitric acid, and homocysteine in DBS showed positive correlations with urine methylmalonic acid (r = 0.849, p < 0.001), urine methylcitric acid (r = 0.693, p < 0.001), and serum homocysteine (r = 0.721, p < 0.001) concentrations, respectively. Additionally, higher levels of DBS methylmalonic acid and methylcitric acid may be associated with increased cumulative complication scores. The LC-MS/MS method established in this study reliably detects methylmalonic acid, methylcitric acid, and homocysteine in DBS. These three DBS metabolites can be valuable for monitoring patients with MMA, PA, and homocysteinemia during follow-up. Further investigation is required to determine the significance of these DBS biomarkers in assessing disease burden over time.

Condução inicial de paciente com erro inato do metabolismo em hospital de pequeno porte

Propionic acidemia is part of the organic acidemias that constitute a group of inherited autosomal recessive diseases caused by the deficiency of enzymes involved in the catabolism of branched-chain amino acids resulting in the tissue accumulation of one or more carboxylic acids. The objective of this case report is to portray the success obtained with the institution of early treatment due to high clinical and laboratory suspicion of inborn error of metabolism in an infant with seizures, reduced level of consciousness, pancytopenia, metabolic acidosis with high anion gap. and hyperammonemia. The treatment consisted of emergency dialysis, protein restriction with supplementation of cofactors and monitoring of serum ammonia levels. Although conducted in a small hospital, with the diagnostic suspicion as well as the early institution of specific treatment, it was possible to obtain a favorable outcome, this report reinforces the importance for pediatricians and neonatologists of having the hypothesis of inborn error of metabolism as differential diagnosis in a patient with such clinical and laboratory findings since the manifestation occurs mostly in the first months of life.

Spectrum of Organic Aciduria Diseases in Tunisia: A 35-year Retrospective Study.

Organic aciduria diseases (OADs) occur worldwide, with differences in prevalence and patterns between populations. To describe the spectrum of OADs identified in Tunisia over a 35-years period. This retrospective study included patients who were diagnosed with OADs between 1987 and 2022 in the Laboratory of Biochemistry, Rabta Hospital, Tunisia. Organic acids were analyzed using gas chromatography-mass spectrometry. A total of 30,670 urine samples were analyzed for OADs, of which 471 were positive for OADs. The estimated incidence of OADs in Tunisia was 6.78 per 100,000 live births. Methylmalonic (n = 146) and propionic (n = 90) acidurias were the most common OADs (estimated incidence: 2.10 and 1.30 per 100,000 live births, respectively). There were 54 cases of L-2-hydroxyglutatric acidurias and 30 cases of pyroglutamic acidurias, which makes it one of the highest in the world. The main clinical features were hypotonia (65%) and feeding difficulties (41%). Age at diagnosis was highly variable, ranging from 1 day to 49 years. Only 27% of the patients were diagnosed within the first month of life. The prevalence of OADs was highest in the Center-East and Southeast regions. In Tunisia, OADs are relatively frequent, but there are shortcomings regarding the diagnosis of these disorders. The frequency and health/social impact of these disorders warrant the need for implementing newborn screening programs and suitable patient management.

Heart Diseases in Patients with Organic Acidemia

Objective: Organic acidemias are intoxication-type inborn errors of the metabolism with multiple organ involvement. Patients with organic acidemia usually present in the neonatal or infantile period with high anion gap metabolic acidosis and hyperammonemia. The present study investigates the presence of congenital heart defects and secondary heart diseases in patients with organic acidemia. Material and Methods: Included in the study were 31 patients of whom 14 were diagnosed with methylmalonic acidemia (MMA), 11 with propionic acidemia and six with isovaleric acidemia. The cardiac findings of all patients included in the study were evaluated. Results: Of the sample, 63.64% were identified with accompanying congenital heart disease, with the most common diagnosis being propionic acidemia and the most common heart defects being atrial septal defects and mitral regurgitation. Conclusion: The accumulation of toxic intermediate metabolites due to enzyme deficiency is thought to be the main mechanism behind the cardiac involvement noted in organic acidemias. In the presence of unexplained deterioration, the potential for organic acidemia to accompany congenital heart disease should be kept in mind, and so it is important to screen patients with organic acidemias by echocardiography.

Heart Transplantation in a Patient with Propionic Acidemia

Propionic acidemia is a rare autosomal recessive error of metabolism, consisting of the deficiency of the mitochondrial enzyme propionyl-CoA carboxylase, which is involved in the transformation of propionyl-CoA into d-methylmalonyl-CoA, which is usually diagnosed in childhood and clinically characterized by hyperammonemia

Validity and reliability of the MetabQoL 1.0 and assessment of neuropsychiatric burden in organic acidemias: Reflections from Turkey

ObjectivesThe MetabQoL 1.0 is the first disease-specific health related quality of life (HrQoL) questionnaire for patients with intoxication-type inherited metabolic disorders. Our aim was to assess the validity and reliability of the MetabQoL 1.0, and to investigate neuropsychiatric burden in our patient population. MethodsData from 29 patients followed at a single center, aged between 8 and 18 years with the diagnosis of methylmalonic acidemia (MMA), propionic acidemia (PA) or isovaleric acidemia (IVA), and their parents were included. The Pediatric Quality of Life Inventory (PedsQoL) was used to evaluate the validity and reliability of MetabQoL 1.0. ResultsThe MetabQoL 1.0 was shown to be valid and reliable (Cronbach's alpha: 0.64–0.9). Fourteen out of the 22 patients (63.6%) formally evaluated had neurological findings. Of note, 17 out of 20 patients (85%) had a psychiatric disorder when evaluated formally by a child and adolescent psychiatrist. The median mental scores of the MetabQoL 1.0 proxy report were significantly higher than those of the self report (p = 0.023). Patients with neonatal-onset disease had higher MetabQoL 1.0 proxy physical (p = 0.008), mental (p = 0.042), total scores (p = 0.022); and self report social (p = 0.007) and total scores (p = 0.043) than those with later onset disease. ConclusionsThis study continues to prove that the MetabQoL 1.0 is an effective tool to measure what matters in intoxication-type inherited metabolic disorders. Our results highlight the importance of clinical assessment complemented by patient reported outcomes which further expands the evaluation toolbox of inherited metabolic diseases.

Regulating PCCA gene expression by modulation of pseudoexon splicing patterns to rescue enzyme activity in propionic acidemia

Pseudoexons are nonfunctional intronic sequences that can be activated by deep-intronic sequence variation. Activation increases pseudoexon inclusion in mRNA and interferes with normal gene expression. The PCCA c.1285-1416A>G variation activates a pseudoexon and causes the severe metabolic disorder propionic acidemia by deficiency of the propionyl-CoA carboxylase enzyme encoded by PCCA and PCCB. We characterized this pathogenic pseudoexon activation event in detail and identified hnRNP A1 to be important for normal repression. The PCCA c.1285-1416A>G variation disrupts an hnRNP A1-binding splicing silencer and simultaneously creates a splicing enhancer. We demonstrate that blocking this region of regulation with splice-switching antisense oligonucleotides restores normal splicing and rescues enzyme activity in patient fibroblasts and in a cellular model created by CRISPR gene editing. Interestingly, the PCCA pseudoexon offers an unexploited potential to upregulate gene expression because healthy tissues show relatively high inclusion levels. By blocking inclusion of the nonactivated wild-type pseudoexon, we can increase both PCCA and PCCB protein levels, which increases the activity of the heterododecameric enzyme. Surprisingly, we can increase enzyme activity from residual levels in not only patient fibroblasts harboring PCCA missense variants but also those harboring PCCB missense variants. This is a potential treatment strategy for propionic acidemia.

CO67 Development of an Investigator Global Assessment of Severity in Propionic Acidemia

CO67 Development of an Investigator Global Assessment of Severity in Propionic Acidemia

Studying a propionic acidaemia mouse model reveals epigenetic mechanisms in the heart.

Studying a propionic acidaemia mouse model reveals epigenetic mechanisms in the heart.

Disrupted propionate metabolism evokes transcriptional changes in the heart by increasing histone acetylation and propionylation

Propiogenic substrates and gut bacteria produce propionate, a post-translational protein modifier. In this study, we used a mouse model of propionic acidaemia (PA) to study how disturbances to propionate metabolism result in histone modifications and changes to gene expression that affect cardiac function. Plasma propionate surrogates were raised in PA mice, but female hearts manifested more profound changes in acyl-CoAs, histone propionylation and acetylation, and transcription. These resulted in moderate diastolic dysfunction with raised diastolic Ca2+, expanded end-systolic ventricular volume and reduced stroke volume. Propionate was traced to histone H3 propionylation and caused increased acetylation genome-wide, including at promoters of Pde9a and Mme, genes related to contractile dysfunction through downscaled cGMP signaling. The less severe phenotype in male hearts correlated with β-alanine buildup. Raising β-alanine in cultured myocytes treated with propionate reduced propionyl-CoA levels, indicating a mechanistic relationship. Thus, we linked perturbed propionate metabolism to epigenetic changes that impact cardiac function.

Functional analysis of novel variants identified in cis in the PCCB gene in a patient with propionic acidemia

Next-generation sequencing has improved the diagnosis of inborn errors of metabolism, allowing rapid confirmation of cases detected by clinical/biochemical studies or newborn screening. The challenge, however, remains for establishing the pathogenicity of the identified variants, especially for novel missense changes or small in-frame deletions. In this work we report a propionic acidemia patient exhibiting a severe neonatal form with coma and hyperammonaemia. Genetic analysis identified the previously described pathogenic PCCB variant p.R512C in the maternal allele and two novel PCCB variants in cis in the paternal allele, p.G246del and p.S322F. Expression analysis in a eukaryotic system confirmed the deleterious effect of the novel missense variant and of the one amino acid deletion, as they both exhibited reduced protein levels and reduced or null PCC activity compared to the wild-type construct. Accordingly, the double mutant resulted in no residual activity. This study increases the knowledge of the genotype-phenotype correlations in the rare disease propionic acidemia and highlights the necessity of functional analysis of novel variants to understand their contribution to disease severity and to accurately classify their pathogenic status. In conclusion, two novel PCCB pathogenic variants have been identified, expanding the current mutational spectrum of propionic acidemia.

P364 Fat and glucose metabolism during exercise in patients with methylmalonic and propionic acidemia

P364 Fat and glucose metabolism during exercise in patients with methylmalonic and propionic acidemia

Evaluating renin and aldosterone levels in children with organic acidemia-therapeutic experience with fludrocortisone.

Hyporeninemic hypoaldosteronism has been reported in only a few cases with methylmalonic acidemia (MMA) and has been attributed to the renal involvement. This study aims to investigate renin-aldosterone levels along with the renal functions of the patients with organic acidemia.This is a cross-sectional study conducted in patients with MMA, propionic acidemia (PA), and isovaleric acidemia (IVA). Serum renin, aldosterone, sodium, and potassium levels were measured, and glomerular filtration rates (GFR) were calculated. Comparisons were made between the MMA and non-MMA (PA+IVA) groups.Thirty-two patients (MMA:PA:IVA = 14:13:5) were included. The median GFR was significantly lower in the MMA group than in the non-MMA group (p < 0.001). MMA patients had the highest incidence of kidney damage (71.4%), followed by PA patients (23%), while none of the IVA patients had reduced GFR. GFR positively correlated with renin levels (p = 0.015, r = 0.433). Although renin levels were significantly lower in the MMA group than the non-MMA group (p = 0.026), no significant difference in aldosterone levels was found between the two groups. Hyporeninemic hypoaldosteronism was found in 3 patients with MMA who had different stages of kidney damage, and fludrocortisone was initiated, which normalized serum sodium and potassium levels. Conclusions: This study, which has the largest number of patients among the studies investigating the renin-angiotensin system in organic acidemias to date, has demonstrated that hyporeninemic hypoaldosteronism is not a rare entity in the etiology of hyperkalemia in patients with MMA, and the use of fludrocortisone is an effective treatment of choice in selected cases. What is Known: • Hyperkalemia may be observed in cases of methylmalonic acidemia due to renal involvement and can be particularly prominent during metabolic decompensation. • Hyporeninemic hypoaldosteronism has been reported to be associated with hyperkalemia in only a few cases of methylmalonic acidemia. What is New: • Hyporeninemic hypoaldosteronism was found in one-fifth of cases with methylmalonic acidemia. • Fludrocortisone therapy leads to the normalization of serum sodium and potassium levels.

A common benign intronic deletion masking a pathogenic deep intronic PCCB variant - genome sequencing and RNA studies to the rescue

Propionic acidemia (PA) is an autosomal recessive metabolic disorder caused by variants in PCCA or PCCB, both sub-units of the propionyl-CoA carboxylase (PCC) enzyme. PCC is required for the catabolism of certain amino acids and odd-chain fatty acids. In its absence, the accumulated toxic metabolites cause metabolic acidosis, neurologic symptoms, multi-organ dysfunction and possible death. The clinical presentation of PA is highly variable, with typical onset in the neonatal or early infantile period.We encountered two families, whose children were diagnosed with PA. Exome sequencing (ES) failed to identify a pathogenic variant, and we proceeded with genome sequencing (GS), demonstrating homozygosity to a deep intronic PCCB variant. RNA analysis established that this variant creates a pseudoexon with a premature stop codon. The parents are variant carriers, though three of them display pseudo-homozygosity due to a common large benign intronic deletion on the second allele. The parental presumed homozygosity merits special attention, as it masked the causative variant at first, which was resolved only by RNA studies.Arriving at a rapid diagnosis, whether biochemical or genetic, can be crucial in directing lifesaving care, concluding the diagnostic odyssey, and allowing the family prenatal testing in subsequent pregnancies. This study demonstrates the power of integrative genetic studies in reaching a diagnosis, utilizing GS and RNA analysis to overcome ES limitations and define pathogenicity. Importantly, it highlights that intronic deletions should be taken into consideration when analyzing genomic data, so that pseudo-homozygosity would not be misinterpreted as true homozygosity, and pathogenic variants will not be mislabeled as benign.

Collaborative evaluation study on 18 candidate diseases for newborn screening in 1.77 million samples.

Analytical and therapeutic innovations led to a continuous but variable extension of newborn screening (NBS) programmes worldwide. Every extension requires a careful evaluation of feasibility, diagnostic (process) quality and possible health benefits to balance benefits and limitations. The aim of this study was to evaluate the suitability of 18 candidate diseases for inclusion in NBS programmes. Utilising tandem mass spectrometry as well as establishing specific diagnostic pathways with second-tier analyses, three German NBS centres designed and conducted an evaluation study for 18 candidate diseases, all of them inherited metabolic diseases. In total, 1 777 264 NBS samples were analysed. Overall, 441 positive NBS results were reported resulting in 68 confirmed diagnoses, 373 false-positive cases and an estimated cumulative prevalence of approximately 1 in 26 000 newborns. The positive predictive value ranged from 0.07 (carnitine transporter defect) to 0.67 (HMG-CoA lyase deficiency). Three individuals were missed and 14 individuals (21%) developed symptoms before the positive NBS results were reported. The majority of tested candidate diseases were found to be suitable for inclusion in NBS programmes, while multiple acyl-CoA dehydrogenase deficiency, isolated methylmalonic acidurias, propionic acidemia and malonyl-CoA decarboxylase deficiency showed some and carnitine transporter defect significant limitations. Evaluation studies are an important tool to assess the potential benefits and limitations of expanding NBS programmes to new diseases.

Clinical and demographic characteristics of organic acidaemias in children in a tertiary care hospital in Sri Lanka: A 4-year experience in a single centre

Background: Organic acidaemias (OAs) are a biochemically heterogeneous group of inborn errors of metabolism. They are rare and infrequently reported worldwide. Most OAs are clinically apparent in the neonatal period or early infancy while some can present as a chronic progressive form or even an asymptomatic form. Objectives: To describe the clinical presentation, demographic characteristics and the incidence of OAs in Sri Lankan children. Method: A retrospective descriptive cross-sectional study was conducted over a 4-year period by reviewing records of children suspected of having OAs referred to the Department of Chemical Pathology, Lady Ridgeway Hospital. Demographic information, clinical manifestations, biochemical investigations and mutational results were recorded and analysed using descriptive statistics. Definitive diagnosis was established by gas chromatography and mass spectroscopy (GC-MS) of urine for organic acids. Results: Among the 458 patients suspected, 20 (4.3%) were confirmed to have an OA resulting in an incidence of 13/319,000 live births per year. The mean ages at onset of symptoms and diagnosis were 11.8 months (range; day 1 to 5 years) and 27.1 months (range; day 10 to 12 years) respectively. Among the 20 patients were 5 (25%) with propionic acidaemia and 4 (20%) with beta-ketothiolase deficiency. Nineteen (95%) presented acutely. Common manifestations were respiratory distress in 12 (60%) and persistent or recurrent vomiting in 10 (50%). Learning difficulty, dyskinesia and macrocephaly were some chronic manifestations. Biochemically, 15 (75%) had acidosis and 9 (45%) had ketosis. There were 13 (65%) deaths of which 6 were neonates with acute presentation. Conclusions: Propionic acidaemia and beta-ketothiolase deficiency were the common OAs identified. Common clinical presentations were respiratory distress and persistent or recurrent vomiting. Acidosis was a common biochemical finding.

Retrospective study of propionic acidemia using natural language processing in Mayo Clinic electronic health record data

BackgroundPropionic acidemia (PA) is a rare autosomal recessive organic acidemia that classically presents within the first days of life with a metabolic crisis or via newborn screening and is confirmed with laboratory tests. Limited data exist on the natural history of patients with PA describing presentation, treatments, and clinical outcomes. ObjectiveTo retrospectively describe the natural history of patients with PA in a clinical setting from a real-world database using both structured and unstructured electronic health record (EHR) data using novel data extraction techniques in a unique care setting. Design/MethodsThis retrospective study used EHR data to identify patients with PA seen at the Mayo Clinic. Unstructured clinical text (medical notes, pathology reports) were analyzed using augmented curation natural language processing models to enhance analysis of data extracted by structured data fields (International Classification of Diseases 9th or 10th revision [ICD-9/−10] codes, Current Procedural Terminology [CPT] codes, and medication orders). De-identified health records were also manually reviewed by clinical scientists to ensure data accuracy and completeness. The index date was defined as the patient's date of PA diagnosis at the Mayo Clinic. Results were reported as aggregate descriptive statistics relative to patients' index dates. Complications, therapeutic interventions, laboratory tests, procedures, and hospitalization encounters related to PA were described at and within 6 months of the patient's index date, and from medical history available before the index date. ResultsIn total, 13 patients with PA were identified, with visits occurring from 1998 to 2022. Age at diagnosis ranged from birth to 3 years; age at initial evaluation at the Mayo Clinic ranged from 3 days to 28 years. The mean number of Mayo Clinic outpatient visits was 31 (median duration of care, 2 years). PA-related complications were documented in 85% of patients and included nutritional difficulties (46%), metabolic decompensation events (MDEs; 38%), neurologic abnormalities (38%), and cardiomyopathy (7%). One pair of affected siblings had mild symptoms and no complications or MDEs. All 5 patients with a history of MDEs presented with developmental delays. Among patients with MDEs, the mean frequency of outpatient clinical care visits was 10 per year, and 3 patients required inpatient hospitalization (mean duration, 16 days). The incidence of severe complications was higher among patients with MDEs than those without MDEs. Of the patients with MDEs, 2 experienced crises while receiving treatment at the Mayo Clinic, with 9 total MDEs occurring between the 2 patients. Symptoms at presentation included hyperammonemia (78%), fever and/or decreased nutritional intake (67%), hyperglycemia/hypoglycemia (56%), intercurrent upper respiratory infection and/or lethargy (44%), constipation (33%), altered mental status (33%), and cough (33%). ConclusionsThis study highlights the range and frequency of clinical outcomes experienced by patients with PA and demonstrates the clinical burden of MDEs.

Domino liver transplantation for maple syrup urine disease in children: A single-center case series.

Domino liver transplant (DLT) represents another type of liver donor to expand the donor pool. Recent reports of successful DLT in children with maple syrup urine disease (MSUD) show promising long-term outcomes. It was a retrospective study. All children with MSUD were paired with either recipients with end-stage liver disease (ESLD) or non-MSUD metabolic disease. Each pair underwent simultaneous liver transplant (LT), where the MSUD recipient received the graft from a living-related donor and the liver explanted from the MSUD donor was transplanted to the respective paired domino recipient. We report our experience regarding the techniques and outcomes of DLT at our center. Eleven children with MSUD and 12 respective DLT recipients were enrolled, one of which was domino split-liver transplantation. DLT recipients included seven ESLD, two propionic acidemia (PA), one glycogen storage disease(GSD) type-1, one GSD type-3, and one Citrullinemia. Post-LT ICU and hospital stays were comparable (p > .05). Patient and graft survival was 100% and 66.6% in the MSUD group and DLT recipients at a mean follow-up of 13.5 and 15 months. There was no death in the MSUD group as compared to four in the DLT group. The amino acid levels rapidly normalized after the LT in the children with MSUD and they tolerated the normal unrestricted diet. No vascular, biliary, or graft-related complications were seen in the post-transplant period. No occurrence of MSUD was noted in DLT recipients. DLTs have excellent post-surgical outcomes. DLT should be strongly considered and adopted by transplant programs worldwide to circumvent organ shortage.

Kidney urinary biomarkers in patients with branched-chain amino acid and cobalamin metabolism defects.

There is a clinical need for early detection of chronic kidney disease (CKD) in patients with organic acidurias. We measured kidney markers in a longitudinal study over 5 years in 40 patients with methylmalonic aciduria (Mut0 ), propionic aciduria (PA), cobalamin A (CblA), and cobalamin C (CblC) deficiencies. Neutrophil gelatinase-associated lipocalin (NGAL), calprotectin (CLP), kidney injury molecule-1 (KIM-1), dickkopf-3 (DKK-3), albumin and beta-2-microglobulin (B2MG) in urine, as well as cystatin C (CysC) in serum were quantified. In Mut0 patients, mean concentrations of B2MG, KIM-1, and DKK-3 were elevated compared with healthy controls, all markers indicative of proximal tubule damage. In PA patients, mean B2MG, albumin, and CLP were elevated, indicating signs of proximal tubule and glomerulus damage and inflammation. In CblC patients, mean B2MG, NGAL, and CLP were increased, and considered as markers for proximal and distal tubule damage and inflammation. B2MG, was elevated in all three diseases, and correlated with DKK-3 in Mut0 /CblA and with eGFR(CysC) and KIM-1 in PA patients, respectively. None of the markers were elevated in CblA patients. Significant deterioration of kidney function, as determined by steady increase in CysC concentrations was noted in seven patients within the observation period. None of the investigated biomarker profiles showed a clear increase or added value for early detection. In conclusion, we identified disease-specific biomarker profiles for inflammation, tubular, and proximal damage in the urine of Mut0 , PA, and CblC patients. Whether these biomarkers can be used for early detection of CKD requires further investigation, as significant kidney function deterioration was observed in only a few patients.

Gene therapy for organic acidemias: Lessons learned from methylmalonic and propionic acidemia.

Organic acidemias (OA) are a group of rare autosomal recessive disorders of intermediary metabolism that result in a systemic elevation of organic acid. Despite optimal dietary and cofactor therapy, OA patients still suffer from potentially lethal metabolic instability and experience long-term multisystemic complications. Severely affected patients can benefit from elective liver transplantation, which restores hepatic enzymatic activity, improves metabolic stability, and provides the theoretical basis for the pursuit of gene therapy as a new treatment for patients. Because of the poor outcomes reported in those with OA, especially methylmalonic and propionic acidemia, multiple gene therapy approaches have been explored in relevant animal models. Here, we review the results of gene therapy experiments performed using MMA and PA mouse models to illustrate experimental paradigms that could be applicable for all forms of OA.