The introduction of MS/MS into neonatal screening has enabled the screening of conditions that might otherwise have been missed, and thus believed to be extremely rare [3
]. This technique has significantly improved the efficacy of neonatal screening programs, demonstrating the importance of early identification and treatment of infants with disorders that would otherwise go unrecognized, before irreversible clinical damage occurs [5
A total of 62 of 11,060 symptomatic patients (0.56%) were diagnosed with IEM in our study, which was higher than the percentage in a Korean study [7
], which diagnosed 20 out of 6,795 symptomatic children with IEM (0.29%). However, several other studies [8
] including one Indian and two Chinese studies, reported even higher detection rates of 3.2%, 6.6% and 9.6%, respectively. The wide variation in detection rates is not surprising, given the different screening criteria for IEM used in different countries, and the inconsistent sample-collection methods. Samples in the study by Gu et al. [9
]. Included patients highly suspected of metabolic diseases from throughout the country, while most of our samples were from outpatients and inpatients in a single hospital. The detection rate in our series was thus much lower.
Amino acid disorders in our study accounted for 43.5% of total cases, with PKU being the most common type. This proportion was similar to two previous studies [6
]. All the HPA patients were of classical type, and no case of BH4
deficiency was found. The age at diagnosis of the PKU patients was much older than in other reports [8
], with a median age of 32 months (range: 1.3-135 months). Most patients had mental and language developmental delays at diagnosis. Apart from one patient diagnosed at 1 month of age who showed normal mental development after treatment, the remaining 10 patients suffered from mental retardation during follow-up, possibly as a result of older age at diagnosis. All the PKU patients were from the neighboring provinces including Anhui and Jiangxi Provinces. Although newborn screening for PKU and congenital hypothyroidism have been implemented for 30 years with a coverage rate of 97.5% in Zhejiang Province, the average coverage rate for newborn screening was still below 50% over the whole country in 2010. PKU patients may therefore not be detected at an early age in the regions with lower coverage rates, which could explain why all the PKU patients were from Anhui and Jiangxi Provinces, which have low newborn screening coverage rates. Mental retardation is difficult to reverse in children detected by symptomatic screening at an older age, indicating the need to improve the newborn screening coverage rate throughout China.
The second most common disease in this study was MSUD, as in other reports in Asian populations [4
]. Although diagnosed at an early age (< 1 month), MSUD patients commonly become symptomatic 4-5 days after birth and neuropathological symptoms occur very shortly after. Death may occur in patients without standard treatment. The patients in our study presented with neurological symptoms such as poor feeding, dystonia, poor response and somnolence, and cranial magnetic resonance imaging revealed abnormal signals in the thalamus, brainstem and cerebellum at diagnosis. Three patients showed mental and motor development delays after treatment with a low-protein diet and special amino acid formula. Treatment was discontinued by the parents in two patients because of financial problems or worry about the poor outcome. MSUD had the poorest outcome compared with other aminoacidemias, while NICCD had the best; all NICCD patients recovered, with normal liver function, after treatment with lactose-free milk powder and other medications.
Similar to other reports [6
], FAO disorders were uncommon in the Asian population. PCD was the most common type of FAO disorder in the current study. Most PCD patients were identified between 1 month and 7 years of age, and all but one of the PCD patients initially presented with convulsions. PCD may have a good outcome if detected at early age and given timely treatment. MCAD has been reported to be the most common type of FAO in Europe and USA, and its incidence was even higher than that of the aminoacidemias. However, only one case of MCAD was found during the present 3-year screening study, similar to the report by Han et al., from Shanghai [11
]. Other types of FAO disorders are also rarely found in the Chinese population. However, blood sampling was not performed under strictly fasting conditions for most children, and patients with some types of FAO may have been missed, thus underestimating the incidence of FAO.
Organic acidemias accounted for 41.9% of IEM cases in this study, with MMA, PA and MCD being the three most common types. PA and MMA should be differentiated by GC-MS because of their similar biochemical results, while elevated C3 and C3/C2 ratios are much higher in PA patients than in MMA patients. MCD had the best outcome, and all four MCD patients recovered dramatically after treatment with oral biotin, with no mental developmental delay. Mental retardation persisted, however, in the patients with PA and MMA despite treatment. All GA-I patients had motor developmental delay. The baby with HMG CoA lyase deficiency deteriorated rapidly and died before diagnosis. Our study indicated that irreversible neurological sequelae were likely to occur if patients with organic acidemias were not diagnosed and treated at an early stage of the disease. Newborn screening for IEM is thus imperative.
The major limitation of this study was the cut-off values used for screening symptomatic children. Because these cut-off values were based on newborns, some cases in the study population, with an age range from 0.04-168.2 months, may have been missed. Age-specific cut-off values need to be established in further studies. According to the report by McHugh et al. [12
]. Further validation of the cut-offs will ensure a more accurate and early diagnosis of IEM.
The small number of diagnosed IEM patients in China means that the experience of their treatment is still very limited, and no uniform treatment guidelines have been established. Poor medical compliance occurs in most patients; treatment was discontinued by their parents in nine children as a result of economic problems and loss to follow-up. Of the remaining 53 patients, most still had various symptoms, including convulsions, motor and mental developmental delays, and language delays. Only 10 patients become asymptomatic with normal physical and mental development during the follow-up period, and these 10 had all been diagnosed at a much earlier stage and received timely treatment. This provides evidence for the importance of expanded newborn screening throughout the province. Local governments should consider including expanded newborn screening in free healthcare coverage.