Previous NBS programs for inherited metabolic diseases such as PKU greatly improved the health conditions of affected children [22, 23], facilitating the development of NBS disease panels. From this experience, it seems that overall MS/MS-based NBS has substantially improved outcomes of various metabolic disorders in general, but the long-term clinical benefits of NBS to screen infants with mut-type methylmalonic acidemia remain unclear. Furthermore, few studies investigated risk and prognostic factors for patients with mut-type identified by NBS. Therefore, the present study evaluated long-term outcomes of patients with mut-type methylmalonic acidemia identified by NBS and investigated risk factors and prognostic factors with a large sample size.
In line with the previous studies[23, 24], the number of neonatally symptomatic patients increases with every day of life and the severity of neonatal metabolic decompensation is a strong predictor of impaired physical and neurocognitive development. This emphasized the need for timely diagnosis during NBS process so that the results of NBS are available earlier to avoid severe metabolic impairment which results in long-term complications or death. This study clearly demonstrated that NBS shortened the time to diagnosis for mut-type methylmalonic acidemia, especially for individuals with favorable clinical and cognitive long-term outcomes. Major arguments against the inclusion of mut-type methylmalonic acidemia in the NBS program are that C3 with a low specificity should not be considered as a screening marker for this disease and the early onset of symptoms. Indeed, in our study, a portion of patients who remained asymptomatic had normal levels of C3, while the blood C3/C2 ratio concentration was beyond the normal range. Additionally, most of these patients had high levels of MMA in urine and also carried at least one likely pathogenic mutation, thus being deemed as affected. Therefore, it’d better determine an individual’s specific diagnosis by the detection of the blood C3 level and the C3/C2 ratio combined with urinary MMA and MCA on NBS.
Compared to clinically-diagnosed individuals, our study demonstrated only a minority of screened individuals presented with clinical symptoms at a high risk of neonatal metabolic acidosis and death. Despite metabolic crises, the overall health outcome remained favorable in screened individuals, which is confirmed by the high survival rate (87.5%), and the less occurrence of persisting clinical signs (16.1%). In this study, disease onset was found as one of the important risk factors for prognosis. And the overall survival was significantly better if the age at disease onset was older. Interestingly, it has become evident that the odds ratio of disease onset decreased if NBS is included, suggesting NBS could prevent neonatal metabolic crisis in about half of the screened individuals.
In accordance with the previous studies[25–27], patients in the NBS-detected cohort are more likely to have a stable clinical course with less frequent recurrences of metabolic decompensation in comparison with those diagnosed clinically. Consistent with earlier reports[7, 28, 29], milk refusal, vomiting, and drowsiness were the three most common manifestations of the initial metabolic crisis in our patients. Severe neurological manifestations such as seizures and coma tended to be more frequent in the clinically-diagnosed cohort than in the NBS-detected cohort. Similar observations have been reported that patients detected by NBS usually had symptoms at diagnosis being less severe[8]. Follow-up in this study also confirmed that clinically-diagnosed patients had poorer outcomes than those identified by NBS. In addition, in the normal outcome group, a majority of patients remained asymptomatic, which illustrated that a later metabolic decompensation could be avoidable by early diagnosis. Therefore, a slightly earlier diagnosis by NBS is related to a milder clinical course and better outcome.
In addition, it is widely acknowledged that mut-type methylmalonic acidemia could be divided into two subcategories (mut0and mut−)[30], due to the absence (mut0) or presence (mut−) of residual enzyme activity in the patient’s fibroblasts by the PI assay to supplementation with hydrocobalamin[3]. Almost all mut− patients usually have a better response to treatment of vitamin B12 [2, 30, 31]. Patients with mut-type methylmalonic acidemia usually receive the therapy combined with a low protein diet, hydrocobalamin supplementation (for responsive patients), and other oral medications in order to reduce the accumulation of toxic metabolites that eventually lead to metabolic decompensations and long-term complications[10]. In the present cohort, there is a significant interaction between cobalamin responsiveness and enzymatic subgroup on the probability of a poor outcome, with vitamin B12 unresponsiveness being the important risk factor of poor outcome. And patients had a significantly higher mortality risk if they started the treatment at an old age. Therefore, vitamin B12 loading tests to evaluate the response should be applied in every mut-type methylmalonic acidemia patient, and for responders, vitamin B12 should be recommended as a long-term treatment.
In conclusion, it is highly successful in applying the MS/MS-based NBS for mut-type methylmalonic acidemia, allowing an early diagnosis and specialized metabolic therapy promptly. NBS, allowing for early diagnosis and timely initiation of therapy, is beneficial for a favorable long-term outcome. This is confirmed by low frequencies of cognitive disabilities and premature mortalities in screened children. NBS can prevent disease manifestation among almost half of the screened children, but the onset of the disease is still the strongest factor for poor outcomes, there is a need for a safer and more effective treatment strategy for future research.