IOPD is a diseases onset at 0–12 months with a median age of 2.4 months ,which can present clinical symptoms at any age. Intrauterine onset of Pompe disease is still very rare. Combined with literature review, a total of 6 cases of intrauterine onset Pompe disease have been reported. Our infant was healthy before 38 weeks' gestation, but developed cardiac hypertrophy shortly, and showed a low cry, difficulty breathing, and feeding difficulties after birth. Therefore, it is defined as classic infantile Pompe disease, but the disease begins before birth.
Pompe disease has various manifestations. Infantile cardiomyopathy is mainly manifested by left ventricular myocardial hypertrophy . In this report, 6 neonates with intrauterine onset were also found to have myocardial changes by intrauterine ultrasound, but the manifestations were various forms, including hypertrophic cardiomyopathy, dilated cardiomyopathy, myocardial mass, etc. All children eventually progressed to myocardial hypertrophy after birth. Other laboratory indicators such as myocardial enzymes and BNP also increased to varying degrees. The electrocardiograms were different, with ventricular hypertrophy as the main manifestation.
All the cases in this report were tested for GAA activity after birth, and they all carried GAA-related gene mutations. Although all the children had intrauterine onset, unfortunately, no prenatal diagnosis could be made. Chien, YH suggested that the best results are obtained when the child is treated very early in the first few days of life, so early diagnosis is particularly important . Prenatal diagnostic methods include amniocentesis or chorionic villus sampling . However, GAA enzyme reduction does not confirm the diagnosis, and enzyme testing may provide equivocal results. Therefore, enzyme determination results should be performed by targeted mutational analysis to confirm the prenatal diagnosis of Pompe disease . For the pregnant mother with baby of Pompe disease before or unexplained intrauterine cardiac lesions, it is recommended to perform GAA determination and further gene testing to confirm the intrauterine diagnosis in order to earlier treatment.
At present, it is recognized that the effective treatment for Pompe disease is enzyme replacement therapy(ERT). Some studies have confirmed that the left ventricular function can improve after early ERT. In an analysis of 14 infants with Pompe disease, cardiac function of the baby treated with ERT before 5 months old restored and left ventricular hypertrophy showed marked resolution two months after ERT. However, the cardiac function of the infants with ERT treatment after 5 months or along with significantly elevated LV mass index, may not be completely resolved. From 2010 to 2015,14 infants born in Taipei, China started ERT with an average age of 12 days(the earliest was 6 days after birth), whose left ventricular function improved after 3–4 months of treatment, and all patients had normal cognitive and motor function 1 year after starting ERT. Therefore, early diagnosis and early treatment of the disease can help to improve the prognosis.As early as October 2005 to March 2007, a pilot study in Taiwan, China confirmed the feasibility and impact of dry blood spot enzyme analysis of NBS【15】. Therefore, it is of great significance to carry out newborn screening for Pompe disease.
There were 6 infants in our study, 4 of whom received ERT treatment and the earliest treatment was 2H after birth (case 3), the latest was 2M after birth (case 4).2 patients did not receive treatment (case 5,6). The myocardial thickness of the treated children in this article all returned to normal, but there was still one patient (case 2) who died of respiratory failure due to infection. ERT also has limitations, such as autoimmune intolerance and hypersensitivity. The treatment effect of infantile GAA deficiency depends on cross-reacting immunologic material (CRIM) status, and CRIM-negative patients have poorer ERT efficacy and prognosis . A database of discovered CRIM-negative status has been established. From the database, 2 of the current cases are CRIM-negative (cases 3 and 5). Among them, case 5 had a short follow-up time and had appeared mild hepatomegaly, hypotonia, active lower extremity reflexes at 6 weeks after birth,suggesting a poor long-term prognosis.
Although our case was diagnosed early, due to lack of effective treatment, the disease continued to progress. One child with a heterozygous mutation of this gene was reported in the Pompe disease gene bank,whose CRIM was positive.It seems that the gene mutation at this site is not too serious, but our case(case 6) had a homozygous gene mutation at the same site, and had clinical symptoms after birth. After symptomatic treatment, the vital signs were stable for a short time, but the child had serious developmental delay. When she was 6 months after birth, her left lung was consolidation and myocardial hypertrophy increased with decreasing cardiac function and severe hypotonia. The mechanism of respiratory failure in children with Pompe is mostly due to extensive pathological changes in the muscle and nerve components of the respiratory system because of glycogen accumulation . However, there has been no reports of patients with pompe disease with homogeneous solid changes in the lungs. It was strange that the left lung consolidation density was the same as the liver, but the child does not have obvious dyspnea or shortness of breath. It may be a gradual and slow process, and it is considered to be related to the progression of pompe disease. Glycogen storage was observed in nearly all tissues and cell types in a completely enzyme deficient Pompe disease knockout mouse model . Lysosomal glycogen accumulation in tracheal and bronchial smooth muscle was also found in a mouse model of Pompe disease . Therefore, lung consolidation in children is considered to be related to the accumulation and deposition of glycogen in the primary disease.
Infantile Pompe disease is a rare hereditary disease that can occur in utero, and most of the first symptoms are cardiac changes. Therefore, for fetuses with intrauterine cardiac disease, enzyme assays and genetic testing should be completed as soon as possible before birth, so as to provide information for family members to make early decision. In addition, ERT treatment can be carried out as soon as possible after birth to prevent organ damage and improve long-term prognosis.