Target Diseases for Neonatal Screening in Germany
Challenges for Treatment and Long-Term Care
Background: Neonatal screening in Germany currently comprises 19 congenital diseases, 13 of which are metabolic diseases. Approximately one in 1300 newborns suffers from one of these target diseases. Early diagnosis and treatment enable the affected children to undergo better development and even, in many cases, to have a normal life.
Methods: This review is based on pertinent publications retrieved by a selective search in the PubMed and Embase databases.
Results: Positive screening findings are confirmed in approximately one out of five newborns. The prompt evaluation of suspected diagnoses is essential, as treatment for some of these diseases must be initiated immediately after birth to prevent long-term sequelae. The most commonly identified diseases are primary hypothyroidism (1:3338), phenylketonuria/hyperphenylalaninemia (1 : 5262), cystic fibrosis (1 : 5400), and medium-chain acyl-CoA dehydrogenase deficiency (1 : 10 086). Patient numbers are rising as new variants of the target diseases are being identified, and treatments must be adapted to their heterogeneous manifestations. Precise diagnosis and the planning of treatment, which is generally lifelong, are best carried out in a specialized center.
Conclusion: Improved diagnosis and treatment now prolong the lives of many patients with congenital diseases. The provision of appropriate long-term treatment extending into adulthood will be a central structural task for screening medicine in the future.
Neonatal screening for the early detection of congenital diseases necessitates the continuous improvement of treatments, not just for patients with the classic forms of these diseases, but also for those with variant forms that have only come to light through screening. Early diagnosis, improved outcomes, and longer life expectancies are raising the demand for long-term care into adulthood. The infants who received a diagnosis of phenylketonuria in 1969, when neonatal screening for this disease began in Germany, are now over fifty years old.
Since then, more than 34 million newborns have been screened in Germany (1), and more than 14 000 children have received an early diagnosis of a congenital metabolic disorder or endocrinopathy (1). It is now estimated that one in 1300 newborns has one of the target diseases of screening (Table 1); with this figure, one can easily calculate the approximate number of new cases per year. The inclusion of additional target diseases that are now under evaluation in pilot studies (2) will presumably lead to a further rise in the number of patients with metabolic diagnoses.
Successful neonatal screening must comprise both a valid screening method and rapid and reliable testing to confirm the diagnosis (3). As there is a high rate of unclear or false positive findings for some diseases, e.g., very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency or adrenogenital syndrome (CAH) (4), the findings of initial screening represent no more than the suspicion of a disease. According to current data from the German screening program, only one in five positive screens is followed by a confirmed diagnosis of a target disease (5). Moreover, regular evaluation of the screening process by the German Society for Neonatal Screening (DGNS) has shown that 18% of the findings requiring confirmation are not, in fact, correctly followed up (1), so that an admonitory message back to the testing institution is needed (“tracking”). For this purpose, so-called tracking centers have been established in some German states.
When screening leads to the diagnosis of a target disease in a newborn who is only mildly symptomatic or asymptomatic, it may be unclear whether early treatment is justified at all. Screening therefore faces the major present and future challenge, once the diagnosis is confirmed, of correctly stratifying patients by their risk of developing symptomatic disease, so that the appropriate prophylactic and therapeutic measures can be taken for the patients who need them.
The Wilson and Jungner screening criteria (6) remain the basis for determining the diseases that are to be included in the screening catalog. In many countries, such as Australia or the USA, screening is carried out for far more diseases than in Germany (7, 8). 49 of the 61 diseases that are screened for in the USA (80%) are congenital metabolic diseases (Figure 1). In contrast, the national neonatal screening program in the United Kingdom now encompasses only 10 diseases (9), six of which are congenital metabolic diseases. Early detection and treatment are known to lead to better outcomes for a much larger number of diseases, yet a disease should only be included in the screening catalog after a rigorous assessment of the concrete benefit that will accrue to patients as a result (10, 11). The number of treatable metabolic diseases is rising rapidly: according to a recent review, 116 of the more than 1400 known metabolic diseases were treatable in 2021, and 44 of these were identified only in the last 8 years (12).
In this review, we aim to present the complexity of neonatal screening as it is currently available in Germany and to describe the prerequisites for its optimal implementation and further development (Figure 2). For this purpose, a selective literature search on the current target diseases was carried out in April 2021 in the PubMed and Embase databases. The target diseases (Table 1) and disease-specific challenges are presented below (Table 2).
This article should enable the reader to:
- know the target diseases in Germany and the respective screening processes;
- gain an overview of the challenges of neonatal screening with regard to confirmatory testing and treatment;
- be aware of what must be done to ensure proper long-term care.
The target diseases and current challenges
Very-long-chain acyl-CoA dehydrogenase deficiency
VLCAD deficiency is the most common defect of the mitochondrial oxidation of long-chain fatty acids, affecting approximately one in 75 000 newborns (5). It impairs energy production from long-chain fatty acids and manifests with cardiomyopathy, skeletal myopathy, rhabdomyolysis, hypoglycemia, and coma. The phenotype is variable and may be asymptomatic (13); some asymptomatic women with this deficiency have even been identified only through the abnormal screening tests of their newborn children. This has led to a major change in the management of the disease in recent years.
Confirmatory diagnostic testing after positive neonatal screening plays a special role in VLCAD deficiency, because the disease-specific metabolites C14 : 1 and C:14 : 2 may both be elevated in healthy newborns who are in a marked postnatal catabolic state, leading to a false positive screen (14). Conversely, in truly affected newborns who are in an anabolic state, the levels of these metabolites may be only very mildly elevated at the time of screening and may also be normal on follow-up testing (second screening), leading to a missed diagnosis (15). A positive screen must, therefore, be followed up by enzymatic or genetic testing (16, 17).
Early risk stratification is essential because the varying degrees of severity of the disease call for different treatments (18). For example, mildly affected newborns can still be fully breastfed (Box).
The elements of treatment are the avoidance of a catabolic state and the consumption of a low-fat and fat-modified diet (19). This necessitates interdisciplinary care in collaboration with qualified dietitians who are trained in metabolic medicine (www.vdd.de), along with frequent biochemical and clinical monitoring. Various experimental treatments are being tested, including the use of anaplerotically active odd-chain C7-fatty acids (triheptanoin) (20).
Medium chain acyl CoA dehydrogenase (MCAD) deficiency
MCAD deficiency is a congenital enzyme defect in which long-chain fatty acids from the diet can only be shortened to medium-chain fatty acids, so that the full amount of energy cannot be obtained from fat. Accordingly, MCAD deficiency generally has milder manifestations than VLCAD deficiency, but metabolic crises can occur, leading to hypoglycemia, coma, and death (21). Screening also detects variant forms for which it is still unclear whether patients will develop symptoms in catabolic situations without preventive measures. The treatment consists of the strict avoidance of fasting, along with age-appropriate guidelines for the intervals of meals, including at night. No dietary therapy is needed. Good communication with the parents and teaching is necessary for the parents to understand the management instructions.
Mitochondrial trifunctional protein defects and carnitine cycle defects
All of these enzyme defects impair the oxidation of long-chain fatty acids. Biochemical screening tests alone cannot distinguish long-chain 3-OH-acyl-CoA dehydrogenase (LCHAD) deficiency from mitochondrial trifunctional protein (MTP) deficiency, or carnitine palmitoyl transferase 2 (CPT-2) deficiency from carnitine acylcarnitine translocase (CACT) deficiency; further enzymatic or genetic testing is required (22). The energy deficiency and the accumulation of toxic fatty acid metabolites lead to metabolic crises that manifest with cardiomyopathy, skeletal myopathy, recurrent rhabdomyolysis, hypoglycemia, and coma. In LCHAD and MTP deficiencies, irreversible neuropathy and retinopathy develop as well (23). As in VLCAD deficiency, the elements of treatment are a low-fat and fat-modified diet and avoidance of the catabolic state.
Phenylketonuria (PKU) is due to a genetically based enzyme defect that impairs the breakdown of the amino acid phenylalanine. If untreated, it causes severe mental impairment (21). PKU is treated with a low-protein diet and synthetic amino acid supplementation. For patients with tetrahydrobiopterin-responsive PKU, additional treatment with the cofactor tetrahydrobiopterin successfully restores protein tolerance. Patients with the mild form of PKU (hyperphenylalaninemia) do not need dietary therapy. Elevated phenylalanine levels in screening tests may also be due to defects in the enzymes involved in tetrahydrobiopterin recycling. These diseases cause neurotransmitter dysfunction and their treatment differs from that of PKU.
Maple syrup urine disease
Maple syrup urine disease (MSUD) is caused by a genetically based defect in an enzyme involved in the breakdown of branched-chain amino acids. It leads to the accumulation of the toxic metabolite leucine and can cause cerebral edema and coma as early as the neonatal period, with resulting severe psychomotor retardation over the long term. Hemodialysis may be needed initially for the rapid elimination of leucine. The treatment consists of a protein-reduced diet with supplementation of a mixture of synthetic amino acids, as well as of valine and isoleucine. Avoidance of a catabolic state is essential in order to prevent the breakdown of endogenous proteins. The treatment must be continued for life. In the United States, liver transplantation is a frequent therapeutic option (24).
Tyrosinemia type 1
Tyrosinemia type 1 is due to a genetically based impairment of the breakdown of the amino acid tyrosine. Without treatment, severe liver dysfunction and acute liver failure may arise in the first few days of life because of the accumulation of toxic metabolites. The disease can also cause renal dysfunction and neurological crises. Nitisinone, an effective drug against tyrosinemia type 1, has been available since 1992: it prevents the formation of toxic intermediate products from the blocked breakdown of tyrosine (25). Patients also need a low-protein diet with synthetic amino acid supplementation. A few cases of women have already been described who have given birth to healthy children after nitisinone therapy during pregnancy.
Glutaric aciduria type 1
Glutaric aciduria type 1 (GA1) is an organoacidopathy due to a genetically based defect in an enzyme involved in the breakdown of the amino acids lysine and tryptophan. During periods of catabolism and increased endogenous protein degradation, unpredictable metabolic crises arise, leading to an irreversible dystonic movement disorder with high morbidity and mortality. The treatment is analogous to that of other organoacidopathies: basic treatment consists of low-lysine/low-protein diet and supplementation with L-carnitine, and intensified emergency treatment is given as necessary in the setting of intercurrent infectious diseases, febrile vaccination reactions, or surgery (26).
Isovaleric acidemia (IVA) is an organoacidopathy due to a genetically based defect in an enzyme involved in the breakdown of the branched-chain amino acid leucine, leading to the accumulation of isovaleric acid. About half of all individuals affected with classic IVA develop encephalopathy in the neonatal period, which manifests with poor feeding, vomiting, apathy, and seizures. Mild variants and other genotypes of the disease have come to light since the introduction of screening (27); different phenotypes call for different treatments. Asymptomatic mild forms of IVA do not require L-carnitine supplementation; patients with the classic form need in addition to L-carnitine a protein-reduced diet with synthetic amino acid supplementation, along with the avoidance of catabolic states.
This congenital deficiency of the enzyme biotinidase impairs the metabolism of biotin. As biotinidase is required for free biotin recycling, a deficiency reduces the available amount of biotin. The manifestations of biotinidase deficiency resemble those of biotin deficiency: there are neurological and cutaneous symptoms including seizures and developmental delay, muscle hypotonia, hearing loss, skin rashes, and alopecia. Lifelong biotin supplementation prevents these manifestations effectively. Patients can have either severe biotinidase deficiency, with less than 10% residual enzyme activity, or partial biotinidase deficiency, with 10–30% residual enzyme activity.
In galactosemia, the simple sugar galactose cannot be metabolized, and toxic galactose metabolites are formed. The disease becomes symptomatic a few days after the infant begins to consume milk. The most severe manifestation is acute liver failure in the first few days after birth, but there can be other manifestations as well, including failure to thrive, cataracts, protracted hyperbilirubinemia, and hepatic cirrhosis (28). Galactosemia screening involves the determination of galactose-1-phosphate uridyltransferase (GALT) activity along with the total galactose concentration: this enables the correct identification of classic galactosemia (GALT deficiency) independent of milk (lactose) intake. The treatment is lifelong and consists of a lactose-free, low-galactose diet. As both breast milk and the commonly available types of infant formula contain galactose, infants are given soy milk instead.
Untreated congenital hypothyroidism (CH) causes severe mental and motor retardation with short stature (cretinism). Cohort studies have shown that patients’ cognitive outcome, as measured by IQ, depends very strongly on the initial dose of L-thyroxine (LT4) and the early initiation of L-thyroxine therapy. Patients already have a lower IQ in the long term if the treatment is started after day 14 of life (29, 30). A current challenge in CH screening is the issue of the evaluation and treatment of minor variants. Lowering of the TSH cut-off value in several screening programs has led to the classification of patients with only mild TSH elevation as having congenital hypothyroidism. These children often receive treatment, although it has not yet been clearly shown that mildly elevated TSH levels are associated with impaired cognitive development (31). Unnecessary L-thyroxine therapy carries the risk of iatrogenic hyperthyroidism.
Congenital adrenal hyperplasia
Congenital adrenal hyperplasia (CAH) is an inborn disorder of steroid hormone synthesis due to different enzyme difficiencies in the adrenal cortex. Most commonly, 21-hydroxylase deficiency occurs with impaired cortisol and aldosterone synthesis resultung in an elevated concentration of th androgenic steroid metabolite 17-hydroxyprogesterone (17-OHP). The characteristic clinical manifestations are hypoglycemia due to cortisol deficiency and salt wasting due to aldosterone deficiency, potentially leading to death (32). Affected girls have virilization of the external genitalia. The benefit of substitution therapy is well established: it allows the affected patients to live nearly normally and leads at the same time to the normalization of androgen levels (33).
Confirmatory diagnostic testing presents a major challenge, because 17-OHP levels can also be physiologically elevated in the presence of various stressors, and overdiagnosis must be prevented.
Cystic fibrosis (CF) is a congenital disorder affecting the chloride channels of exocrine glands. The genetic defect lies in the transmembrane conductance regulator (CFTR) protein. CF is a multisystem disease that involves the lungs and upper respiratory tract, the pancreas, and the liver. Beyond the biochemical and clinical evidence, its definitive diagnosis requires the demonstration of CFTR dysfunction through elevated chloride levels in sweat, and/or two disease-causing mutations, and/or abnormal electrophysiological findings. The complexity of confirmatory diagnostic testing, and of treatment, implies that patients with CF should be referred early to a certified cystic fibrosis center (34). The treatment is still mainly symptomatic, but initial mutation-specific therapies are now being used with success.
Severe combined immunodeficiency
This is a group of severe congenital disorders of the immune system in which the T lymphocytes are dysfunctional or deficient, leading to a high susceptibility to infection from infancy onward, and to severe infections. Early diagnosis enables the implementation of strict hygienic measures as well as early bone marrow or stem cell transplantation, which is much more likely to bring about a cure if it is carried out before the disease becomes overt (35). Untreated children with SCID often die before age two.
In summary, although the screening process is complex and we are confronted with major challenges in treatment and long-term care (Figure 2), a recent study has shown that 95,6% of the currently screened patients have a normal somatic development, and 87.7% have normal cognitive development, while a small risk of acute metabolic imbalance remains (36). The follow-up intervals in this study were were, however, much too short for long-term prognosis. With new treatments that will soon be introduced, including personalized therapy approaches, it is expected that the outcome will improve still further.
The success of neonatal screening as secondary prevention depends on subsequent appropriate treatment. Different disease phenotypes call for different treatments. Not even lifelong treatment can assure an asymptomatic state for every disease. Life expectancy and outcome data now mainly come from small patient cohorts (37); registries for these diseases are, therefore, urgently needed. New, experimental treatments are being studied in clinical trials. The ongoing bench-to-bedside translation of research findings into treatment requires treatment in dedicated Metabolic Centers and the expertise of trained specialists. In the future, the recognition of specialized metabolic medicine as a postgraduate training pathway in Germany (like endocrinology, pulmonology and immunology) would be an important and necessary step toward ensuring that all patients with inborn errors of metabolism receive the highly complex care that they need.
Conflict of interest statement
The authors state that they have no conflict of interest.
Manuscript submitted on 12 April 2021, revised version accepted on 11 November 2021.
Translated from the original German by Ethan Taub, M.D.
Prof. Dr. med. Ute Spiekerkötter
Klinik für Allgemeine Kinder- und Jugendmedizin
Mathildenstr. 1, D-79106 Freiburg, Germany
Cite this as:
Spiekerkoetter U, Krude H: Target diseases for neonatal screening in Germany—challenges for treatment and long-term care. Dtsch Arztebl Int 2022; 119: 306–16. DOI: 10.3238/arztebl.m2022.0075
Institute of Experimental Pediatric Endocrinology, Charité—University Medical Center Berlin: Prof. Dr. med. Heiko Krude
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