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.

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 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.

Erros inatos do metabolismo no Hospital das Clínicas de Ribeirão Preto: um legado de múltiplas especialidades / Inborn Errors of Metabolism - a legacy of multiple specialties

Erros inatos do metabolismo (EIM) são doenças genéticas decorrentes, em sua maioria, de deficiências enzimáticas que levam a graves distúrbios metabólicos, e que vem sendo cada vez mais diagnosticados. No presente texto relata-se um histórico sobre a evolução da abordagem diagnóstica e tratamento de EIM no HCFMRP-USP.Na FMRP-USP os EIM vêm sendo objeto de estudo em pós-graduação desde a década de 1980, dado o grande apelo clínico nas áreas de Genética Clínica, Pediatria e Neurologia Infantil, até então com auxílio do Laboratório de Patologia, além de convênio com a APAE de São Paulo para o diagnóstico de fenilcetonúria. Já iniciados os Programas de Pós-Graduação da FMRP-USP, a primeira tese a respeito foi realizada em 1980, sobre cistinúria, na Área de Genética; deficiência de glicose-6-fostato desidrogenase(G6PD) foi objetivo da segunda, em 1987, na de Pediatria. Desde essa época, garantem a rotina de investigação a realização da cromatografia de aminoácidos pelo Centro de Química de Proteínas daFMRP-USP, o convênio com o Serviço de Genética do HC de Porto Alegre-RS e a triagem urinária no Laboratório de Nutrologia, este, resultado de Mestrado em Neurologia em 1990. Nas duas últimas décadas vieram os ambulatórios especializados, o Programa de Triagem Neonatal, o tratamento por Reposição Enzimática e o apoio do Centro de Transplante de Células Tronco. Cabe ressaltar que até2009, apenas mais uma tese foi apresentada. A perpectiva para o desenvolvimento dessa área é a consolidação de uma linha de pesquisa voltada exclusivamente para os EIM na FMRP-USP.

Inborn errors of metabolism (IEM) are genetic diseases, mostly due to enzyme deficiencies leading to severe metabolic damages, increasingly diagnosed. The aim is to describe the history of the development of IEM diagnosis and treatment in the Hospital of Clinics of Ribeirão Preto, São Paulo University (HCFMRP-USP). At the beginnings of the Post-Graduate Programs in the School of Medicine of Ribeirão Preto of São Paulo University (FMRP-USP), the first thesis on IEM was performed in 1980 on cystinuria in the area of Genetics; G6PD goal was the second in 1987 in Pediatrics. Since that time, IEM diagnosis was possible, in the sequence, due to the chromatography of amino acids routine by the Center for Protein Chemistry, FMRP-USP in 1984, the partnership with the Department of Genetics, Hospital of Clinics of Porto Alegre. RS in 1988 and the urine screening in the Nutrology Laboratory of FMRP-USP, that resulted of a Master in Neurology in 1990. In the last two decades: the specialized out patients clinics, the Program for Neonatal Screening, treatment by enzyme replacement and support of the Stem Cell Transplantation Center were implemented. It is noteworthy that by 2009, just one more thesis was presented.The perspective for the development of this area is the consolidation of a line of research focused exclusively on the EIM in FMRP-USP.

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.

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.

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.