Twenty-five years ago, the underlying genetic cause for one of the most common and devastating inherited diseases in humans, spinal muscular atrophy (SMA), was identified. Homozygous deletions or, ...rarely, subtle mutations of
SMN1
cause SMA, and the copy number of the nearly identical copy gene
SMN2
inversely correlates with disease severity. SMA has become a paradigm and a prime example of a monogenic neurological disorder that can be efficiently ameliorated or nearly cured by novel therapeutic strategies, such as antisense oligonucleotide or gene replacement therapy. These therapies enable infants to survive who might otherwise have died before the age of two and allow individuals who have never been able to sit or walk to do both. The major milestones on the road to these therapies were to understand the genetic cause and splice regulation of
SMN
genes, the disease's phenotype-genotype variability, the function of the protein and the main affected cellular pathways and tissues, the disease's pathophysiology through research on animal models, the windows of opportunity for efficient treatment, and how and when to treat patients most effectively.This review aims to bridge our knowledge from phenotype to genotype to therapy, not only highlighting the significant advances so far but also speculating about the future of SMA screening and treatment.
The aim of newborn screening (NBS) program is to detect and manage treatable conditions in the early stages prior to the occurrence of long-term and irreversible sequalae. Phenylketonuria was the ...first screened disorder, but panels rapidly expanded after the introduction of tandem mass spectrometry technology into the program. Significant differences in the diseases screened by NBS were noted between programs in United States. Therefore, the recommended uniform screening panel was developed in 2006 to include a list of core disorders of NBS panels based on specific scoring system. Screening for these disorders may lead to incidental detection of secondary conditions. Identification of these conditions could be challenging due to unavailability of confirmatory testing, effective therapies and/or unclear natural history. In this review, we discuss several secondary findings of NBS and their associated disorders as well as the potential risk and benefits of their early diagnosis.
Carnitine is essential for the transfer of long-chain fatty acids across the inner mitochondrial membrane for subsequent β-oxidation. It can be synthesized by the body or assumed with the diet from ...meat and dairy products. Defects in carnitine biosynthesis do not routinely result in low plasma carnitine levels. Carnitine is accumulated by the cells and retained by kidneys using OCTN2, a high affinity organic cation transporter specific for carnitine. Defects in the OCTN2 carnitine transporter results in autosomal recessive primary carnitine deficiency characterized by decreased intracellular carnitine accumulation, increased losses of carnitine in the urine, and low serum carnitine levels. Patients can present early in life with hypoketotic hypoglycemia and hepatic encephalopathy, or later in life with skeletal and cardiac myopathy or sudden death from cardiac arrhythmia, usually triggered by fasting or catabolic state. This disease responds to oral carnitine that, in pharmacological doses, enters cells using the amino acid transporter B0,+. Primary carnitine deficiency can be suspected from the clinical presentation or identified by low levels of free carnitine (C0) in the newborn screening. Some adult patients have been diagnosed following the birth of an unaffected child with very low carnitine levels in the newborn screening. The diagnosis is confirmed by measuring low carnitine uptake in the patients' fibroblasts or by DNA sequencing of the SLC22A5 gene encoding the OCTN2 carnitine transporter. Some mutations are specific for certain ethnic backgrounds, but the majority are private and identified only in individual families. Although the genotype usually does not correlate with metabolic or cardiac involvement in primary carnitine deficiency, patients presenting as adults tend to have at least one missense mutation retaining residual activity. This article is part of a Special Issue entitled: Mitochondrial Channels edited by Pierre Sonveaux, Pierre Maechler and Jean-Claude Martinou.
•The OCTN2 carnitine transporter mediates high-affinity carnitine transport.•Defective OCTN2 activity reduces carnitine levels and impairs fatty acid oxidation.•Missense mutations in OCTN2 define the function of selected transporter domains.•Defects in carnitine biosynthesis do not reduce carnitine levels.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Early diagnosis of lysosomal storage diseases (LSDs) through newborn screening (NBS) has been adapted widely. The National Taiwan University Hospital Newborn Screening Center launched the four-plex ...tandem mass spectrometry LSD newborn screening test in 2015. The test determined activities of acid α-glucosidase (GAA; Pompe), acid α-galactosidase (GLA; Fabry), acid β-glucocerebrosidase (ABG; Gaucher), and acid α-l-iduronidase (IDUA; MPS-I) in dried blood spots (DBS). Through 2017, 64,148 newborns were screened for these four LSDs. The screening algorithm includes enzyme activity/ratio as the cutoffs for the first screening test and a second-tier test for Pompe disease screening. The second-tier Pompe disease screening test measured activity inhibition by acarbose. Twenty-nine newborns required a confirmatory test; six were confirmed to have Pompe disease, and nine were confirmed to have Fabry disease. The screen-positive rate for Pompe disease was 0.031%. Therefore, in Pompe disease newborn screening, a validated 2nd tier test is necessary to decrease false positives.
Purpose of developing the guidelines: Newborn screening (NBS) for congenital hypothyroidism (CH) was started in 1979 in Japan, and early diagnosis and treatment improved the intelligence prognosis of ...CH patients. The incidence of CH was once about one in 5,000–8,000 births, but has been increased with diagnosis of subclinical CH. The disease requires continuous treatment and specialized medical facilities should conduct differential diagnosis and treatment in patients who are positive by NBS to avoid unnecessary treatment. The Guidelines for Mass Screening of Congenital Hypothyroidism (1998 version) were developed by the Mass Screening Committee of the Japanese Society for Pediatric Endocrinology in 1998. Subsequently, the guidelines were revised in 2014. Here, we have added minor revisions to the 2014 version to include the most recent findings. Target disease/conditions: Primary congenital hypothyroidism. Users of the Guidelines: Physician specialists in pediatric endocrinology, pediatric specialists, physicians referring pediatric practitioners, general physicians, laboratory technicians in charge of mass screening, and patients.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Severe Combined Immunodeficiency (SCID) is the most profound inborn error of immunity affecting cellular and humoral immunity. Hematopoietic stem cell transplantation has been a curative treatment ...since 1968. Huge progress has been made since then in understanding the underlying genetics, improving outcomes from transplant, and introducing gene therapy in particular for adenosine deaminase deficient- and IL2 receptor gamma-deficient SCID. Newborn screening has been widely introduced across the world to enable definitive treatment before infection occurs. This article aims to review the latest evidence on how to achieve curative treatment with minimal short- and long-term toxicity, normal immune reconstitution and good quality of life.
•Newborn screening improves treatment success for severe combined immunodeficiency.•Reduced toxicity myelo-ablative conditioning regimens are well tolerated and lead to better longterm immune reconstitution.•The number of diseases able to be treated with gene therapy is expanding.•The role of gene therapy versus hematopoietic stem cell transplantation has yet to be determined.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
To evaluate various clinical aspects, specifically regarding immune status, in a large cohort of patients with DiGeorge syndrome.
Data were collected for 98 patients with DiGeorge syndrome treated at ...a tertiary medical center. This included general information, laboratory results, and clinical features.
The median age at diagnosis was 2.0 years (range, 0.0-36.5 years). The most common symptoms that led to diagnosis were congenital heart defect, speech delay, palate anomalies, and developmental delay. Common clinical features included recurrent infections (76 patients), congenital heart diseases (61 patients), and otorhinolaryngology disorders (61 patients). Twenty patients had anemia; the incidence was relatively high among patients aged 6-59 months. Thrombocytopenia was present in 20 patients. Recurrent chest infections were significantly higher in patients with T cell and T cell subset deficiencies. Decreased T cell receptor excision circles were more common with increasing age (P < .001). Of the 27 patients hospitalized due to infection, pneumonia was a leading cause in 13.
Awareness of DiGeorge syndrome's typical and uncommon characteristics is important to improve diagnosis, treatment, surveillance, and follow-up.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Critical congenital heart defects (CCHDs) are potentially life-threatening malformations that remain a significant cause of neonatal mortality and morbidity. Failure to diagnose these conditions ...shortly after birth may result in acute cardiovascular collapse and death. The identification of CCHDs by routine newborn clinical examination is routine in many countries, but consistently misses over a third of cases, and, although antenatal ultrasound screening can be very effective in early diagnosis, the provision and accuracy of ultrasound screening is highly variable. As most CCHDs present with mild cyanosis (hypoxaemia), which is frequently clinically undetectable, pulse oximetry is a rapid, simple, painless method of accurately identifying hypoxaemia, which has gained popularity as a screen for CCHD. This Special Issue of the International Journal of Neonatal Screening, devoted to "Neonatal Screening for Critical Congenital Heart Defects (CCHDs)", will consider the evidence for CCHD screening with pulse oximetry, the acceptability and cost-effectiveness of this intervention, the additional non-cardiac conditions which it may also identify, and international experiences of introducing CCHD screening across the globe.
Black race and Hispanic ethnicity are associated with higher mortality among patients with SCID who undergo HCT. We hypothesized that Black and Hispanic patients have a higher incidence of infection ...pre-transplant and greater age at treatment, and that newborn screening (NBS) could substantially narrow these disparities.
Patients with SCID who received HCT between 1982–2020 at one of 33 North American institutions in the Primary Immune Deficiency Treatment Consortium (PIDTC) were included. The probability of survival was estimated using the Kaplan-Meier method. Cox proportional hazards regression models were used for multivariable analysis. The effect of NBS on disparities was evaluated by performing stratified analyses based on the trigger for diagnosis. Changes in racial/ethnic disparities were assessed over time.
Of 925 patients included, 52% were non-Hispanic White, 22% were Hispanic, and 10% were Black. Genotypes varied by race and ethnicity as shown in Table 1. Overall survival (OS) among Black patients who received a transplant from donors other than matched siblings was significantly lower compared to non-Hispanic White patients (aHR 2.43, 95%CI 1.62, 3.65) after accounting for age, conditioning, donor, genotype, infection status, and year of HCT. OS among Hispanic patients was also lower (aHR 1.34, 95%CI 0.94, 1.90), but did not reach statistical significance (Figure 1). Display omitted Thirty-nine percent of both Black and Hispanic patients had an active infection at HCT compared to 34% of non-Hispanic White patients (p = 0.52). There were no racial/ethnic differences in age at treatment or baseline infection among those diagnosed by NBS, whereas disparities were noted among those diagnosed by family history (White: 57 days, Hispanic: 95 days, Black: 99 days; p = 0.02). When evaluated by treatment era, racial/ethnic disparities in age at treatment and baseline infection resolved in the modern era (after 2010).Table 1Frequency of SCID genotypes by Race and Ethnicity.GenotypeTotal N = 925NH White N = 477Hispanic N = 201Black N = 96Asian/PI N = 43Nat. American N = 42ADA55 (8.5)33 (10.0)9 (6.5)7 (10.6)0 (0.0)2 (6.9)CD3 delta10 (1.6)7 (2.1)0 (0.0)0 (0.0)0 (0.0)0 (0.0)DCLRE1C39 (6.1)11 (3.3)5 (3.6)0 (0.0)3 (8.6)16 (55.2)IL2RG274 (42.5)157 (47.4)41 (29.5)41 (62.1)21 (60.0)4 (13.8)IL7R67 (10.4)26 (7.9)31 (22.3)3 (4.5)1 (2.9)1 (3.4)JAK340 (6.2)19 (5.7)10 (7.2)8 (12.1)2 (5.7)0 (0.0)RAG180 (12.4)41 (12.4)17 (12.2)6 (9.1)3 (8.6)6 (20.7)RAG235 (5.4)10 (3.0)16 (11.5)0 (0.0)2 (5.7)0 (0.0)RMRP (CHH)13 (2.0)8 (2.4)2 (1.4)0 (0.0)1 (2.9)0 (0.0)Other/Unknown2811466230813
Black patients with SCID had a more than two-fold hazard of death compared to non-Hispanic White patients, even after accounting for age and infection status. Hispanic patients also demonstrated higher mortality, but this difference was not statistically significant. Disparities across all races and ethnicities in age at treatment and baseline infection were not noted among those diagnosed in the modern era.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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