Historical Perspective on Clinical Trials of Carnitine in Children and Adults.

The metabolic roles of carnitine have been greatly clarified over the past 50 years, and it is now well established that carnitine is a key player in mitochondrial generation of energy and metabolism of acetyl coenzyme A. A therapeutic role for carnitine in treatment of nutritional deficiencies in infants and children was first demonstrated in 1958, and since that time it has been used to treat a number of inborn errors of metabolism. Carnitine was approved by the US Food and Drug Administration in 1985 for treatment of 'primary carnitine deficiency', and later in 1992 for treatment of 'secondary carnitine deficiency', a definition that included the majority of relevant metabolic disorders associated with low or abnormal plasma carnitine levels. Today, carnitine treatment of inborn errors of metabolism is a safe and integral part of many treatment protocols, and a growing interest in carnitine has resulted in greater recognition of many causes of carnitine depletion. Notwithstanding, there is still a lack of data from randomized clinical trials, even on the use of carnitine in inborn errors of metabolism, although ethical issues may be a contributing factor in this regard.

Fifty years of newborn screening.

Newborn screening has evolved fast following recent advances in diagnosis and treatment of disease, particularly the development of multiplex testing and applications of molecular testing. Formal evidence of benefit from newborn screening has been largely lacking, due to the rarity of individual disorders. There are wide international differences in the choice of disorders screened, and ethical issues in both screening and not screening are apparent. More evidence is needed about benefit and harm of screening for specific disorders and renewed discussion about the basic aims of newborn screening must be undertaken.

Newborn Screening: Current Practice and Our Journey over the Last 60 Years.

BACKGROUND: Inborn errors of metabolism comprise a set of more than 2000 known disorders which can result in significant morbidity and may be rapidly fatal. Diagnosing these disorders at birth and treating immediately, however, may often result in a normal to near-normal life for the affected infant. Thus, newborn screening (NBS) has saved or improved the lives of countless individuals since its inception in the 1960s. CONTENT: This review covers NBS, from its early beginnings up to the current day practice. We follow the evolution of NBS, as well as describe the need and how disorders are added to NBS programs, the testing and how its performance is monitored, and the follow-up to the testing. We also briefly touch on NBS outside the United States. SUMMARY: Newborn screening in the United States is a major public health success story and it continues to grow and evolve to cover more disorders and utilize new technological advances.

Newborn screening for inborn errors of metabolism in Japan. A history of the development of newborn screening.

In 1977, the Ministry of Health and Welfare (MHW) directed prefectural officials in charge of maternal and child health to start publicly funded newborn mass-screening (NBS) for phenylketonuria (PKU), maple syrup urine disease (MSUD), histidinemia, homocystinuria and galactosemia and a study group of MHW formulated the treatment guideline for the target diseases. In 1980, MHW launched the Japan Cooperative Project on Special Formula (JCPSF) to ensure a stable supply of special formula and also organized the committee for JCPSF. From 1977 to 2003, a study group of MHW conducted a follow-up study of the patients detected by the screening. From the follow-up it was concluded that dietary therapy was unnecessary for histidinemia and the screening for the disease was discontinued. In 1995, the guideline for the treatment of PKU was revised to keep lower blood phenylalanine levels. The guideline committee for the treatment of BH4 deficiency was establish in 1996 to obtain better prognosis. In 2012, the MHW decided to initiate publicly funded NBS using MS/MS for inborn errors of amino acid, organic acid, and fatty acid metabolism. The Japanese nationwide NBS has been performed for 35 years. This paper reviews the Japanese history of the development of NBS which has enabled more IEM patients to lead active and productive lives today.

The History of Pediatric and Adult Hearing Screening.

OBJECTIVES/HYPOTHESIS: To document the history of hearing seeing in children and adults. STUDY DESIGN: A literature search in all languages was carried out with the terms of hearing screening from the following sources: Pub Med, Science Direct, World Catalog, Index Medicus, Google scholar, Google Books, National Library of Medicine, Welcome historical library and The Library of Congress. METHODS: The primary sources consisting of books, scientific reports, public documents, governmental reports, and other written material were analyzed to document the history of hearing screening. RESULTS: The concept of screening for medical conditions that, when found, could influence some form of the outcome of the malady came about during the end of 19th century. The first applications of screening were to circumscribe populations, schoolchildren, military personnel, and railroad employees. During the first half of the 20th century, screening programs were extended to similar populations and were able to be expanded on the basis of the improved technology of hearing testing. The concept of universal screening was first applied to the inborn errors of metabolism of newborn infants and particularly the assessment of phenylketonuria in 1963 by Guthrie and Susi. A limited use of this technique has been the detection of genes resulting in hearing loss. The use of a form of hearing testing either observational or physiological as a screen for all newborns was first articulated by Larry Fisch in 1957 and by the end of the 20th century newborn infant screening for hearing loss became the standard almost every nation worldwide. CONCLUSIONS: Hearing screening for newborn infants is utilized worldwide, schoolchildren less so and for adults many industrial workers and military service undergo hearing screening, but this is not a general practice for screening the elderly. LEVEL OF EVIDENCE: NA Laryngoscope, 131:S1-S25, 2021.

Newborn screening in Spain, with particular reference to Galicia: Echoes of Louis I. Woolf.

After briefly recalling the main events leading to the establishment of newborn screening programmes, this paper details the early history of their introduction in Spain and sketches their expansion to cover the whole Spanish population. Spain is exceptional in that its screening methods have in general been based on planar chromatographic techniques developed or inspired by Louis I. Woolf, rather than on bacterial inhibition tests, as is illustrated by the practice of the newborn screening laboratory of Galicia (N.W. Spain).

Akhenaten and the strange physiques of Egypt's 18th dynasty.

Akhenaten was one of Egypt's most controversial pharaohs, in part because of his strange appearance in images produced after he had declared Aten, the Sun-disc, his one-and-only god. Whether these were symbolic representations or realistic ones that indicate a deforming genetic disorder is the subject of continuing debate. The authors present evidence that the bizarre physical features portrayed in these images are not only realistic but were shared by many members of Egypt's 18th Dynasty. The features are best explained by either 2 different familial disorders-the aromatase excess syndrome and the sagittal craniosynostosis syndrome-or a variant of the Antley-Bixler syndrome caused by a novel mutation in one of the genes controlling the P450 enzymes, which regulate steroidogenesis and cranial bone formation.

Legacies of Garrod's brilliance. One hundred years--and counting.

One hundred years ago--in 1908--Archibald Garrod delivered his four Croonian Lectures. In these formerly forgotten, but now famous, dissertations, Garrod first used the expression, 'inborn errors of metabolism', to describe four rare disorders: albinism, alkaptonuria, cystinuria, and pentosuria. This prescient work proposed that such disorders resulted from enzymatic defects in the catabolic pathways for amino acids and sugars. Thus, Garrod can rightfully be called the first human geneticist. Much influenced by his colleague Bateson, who brought Mendel's work to his attention, Garrod then was the first to apply Gregor Mendel's law of gene segregation to humans, the first to propose recessive inheritance in humans, and the first to point out the importance of consanguinity. He even mentioned the role of ethnicity in inherited disorders. This would have been legacy enough, but Garrod did much more. He wrote about such other 'modern' topics as genetic predisposition to common disorders; the critical importance of physicians who were also scientists; and the proper role of the university in society. Although Garrod's work and ideas were not appreciated during his lifetime, they have echoed and reverberated ever since. He can rightly be deemed one of the most profound intellectuals of the 20th century, whose bequests to science and medicine continue to increase in value. All of us who study inborn errors of metabolism and who apply our knowledge in the hope of improving the diagnosis and treatment of affected patients are, in a genuine sense, Garrodians.

Chemical individuality: concept and outlook.

Sir Archibald Garrod's concept of chemical individuality introduced a century ago provided the basis for the entire discipline of inborn errors of metabolism. Human disorders are defined by variation in disease-causing mutations, environmental influences, genetic factors other than the primary genetic defect, and evolution itself. Myriad examples support the prescience of Garrod with respect to these issues, each of which has therapeutic implications. Just as Garrod predicted that the future of biochemical genetics would be intertwined with the concept of chemical variability, we might forecast that variation will influence emotions, dreams, and the human thinking process itself.

Dominant versus recessive: molecular mechanisms in metabolic disease.

Inborn errors of metabolism used to be regarded as simple monogenic traits, but a closer look at how different alleles of a gene determine different phenotypes shows that the molecular mechanisms in the individual case are often complicated. Most metabolic disorders represent a spectrum of phenotypes from normal via attenuated to severe (and sometimes prenatally fatal), and disease manifestation is often influenced by other specific genetic or exogenous factors. The terms 'dominant' or 'recessive' relate to the functional consequences of differing alleles in the (compound) heterozygous individual; the terms are irrelevant for homozygous individuals and inappropriate for X-linked disorders. Mutations affecting the same amino acid residue may be associated with different inheritance patterns. True dominant inheritance in metabolism is rare; it may be found e.g. in tightly regulated biosynthetic pathways or when minor changes in metabolite concentrations have a functional effect. Some disorders such as erythropoietic protoporphyria show pseudodominant inheritance due to prevalent loss-of-function polymorphisms in the general population and are better acknowledged as recessive traits. The term 'variable expressivity' is not helpful with regard to autosomal recessive disorders when variable phenotypes are explained by different mutations in the respective gene. Clonal unmasking of a heterozygous mutation through somatic loss of the second allele, the main pathomechanism in inherited tumour predisposition syndromes, is rare in metabolic disorders, but focal congenital hyperinsulinism is a notable exception. Somatic mosaicism for an OTC gene mutation is given as an example of an apparently heterozygous mutation pattern in a boy with an X-linked disease.

Garrod's Croonian Lectures (1908) and the charter 'Inborn Errors of Metabolism': albinism, alkaptonuria, cystinuria, and pentosuria at age 100 in 2008.

Garrod presented his concept of 'the inborn error of metabolism' in the 1908 Croonian Lectures to the Royal College of Physicians (London); he used albinism, alkaptonuria, cystinuria and pentosuria to illustrate. His lectures are perceived today as landmarks in the history of biochemistry, genetics and medicine. Garrod gave evidence for the dynamic nature of metabolism by showing involvement of normal metabolites in normal pathways made variant by Mendelian inheritance. His concepts and evidence were salient primarily among biochemists, controversial among geneticists because biometricians were dominant over Mendelists, and least salient among physicians who were not attracted to rare hereditary 'traits'. In 2008, at the centennial of Garrod's Croonian Lectures, each charter inborn error of metabolism has acquired its own genomic locus, a cloned gene, a repertoire of annotated phenotype-modifying alleles, a gene product with known structure and function, and altered function in the Mendelian variant.

The centenary of Garrod's Croonian lectures.

Archibald Garrod's Croonian lectures, Inborn errors of metabolism, were delivered at the Royal College of Physicians in June 1908. Although their significance remained dormant for many years, and is still not fully appreciated, they are now recognised as the foundation of medical genetics.

From chemistry of life to chemistry of disease: the rise of clinical biochemistry.

Any young scientific discipline may experience difficulties in determining its position. For a young discipline placed at the juncture between potent branches of science with a long tradition, as is the case for Clinical Biochemistry, this is especially true. In such a situation, a look backwards to identify first origins and to follow trends of development can be helpful. Moreover, the close relationship between the history and the philosophy of science should provide insight into the nature of our present work and the potential for future work. Our discipline originated with the emergence of modern chemistry at the end of the 18th century. Methods for the chemical analysis of plant and animal material were developed first. The examination of chemical processes in living organisms followed. Only after these successes did chemical investigations of causes and mechanisms of human disease become possible. A few selected milestones in this evolution can illustrate the medical, philosophical, intellectual and social background which has shaped the rise of Clinical Biochemistry.