Cases Of Homocystinuria Research Articles

In memoriam: S. Harvey Mudd.

S. Harvey Mudd died January 21, 2014, succumbing to pneumonia after heart surgery. On hearing of his death a colleague noted “We have lost a generation of Biochemistry in a single man”. Harvey was the acknowledged international authority on diseases of methionine metabolism. He wrote the chapters on methionine and sulfur metabolism in the last four editions of “Metabolic Basis of Inherited Disease”, a source of information used world-wide. Physicians all over the world suspecting a metabolic defect involving methionine in a patient would routinely consult him and send samples for analysis. His devotion to discovering the underlying reasons for the patient’s complications was legendary. Dr. Mudd was born in 1927 in Bryn Mawr, Pennsylvania. He grew up in an academic family and signed his papers S. Harvey Mudd in order to distinguish himself from his father, Stuart Mudd, also a well-known scientist who served as Chairman of the Department of Microbiology at the University of Pennsylvania. His mother, Dr. Emily B. H. Mudd, founded the Marriage Council of Philadelphia and was a Professor in the Department of Psychiatry, also at the University of Pennsylvania. After high school Harvey enlisted in the Navy in 1945. Soon after the Second World War ended he was discharged, having served less than a year. He attended Harvard University and graduated cum laude with an AB degree in 1949. A formative influence on his lifelong commitment to science was the following summer he spent as a student in the laboratory of Dr. George Wald. Wald was a spellbinding speaker and inspirational teacher who subsequently received the Nobel Prize in 1967 for his work on the pigments of the eye and the role of vitamin A in vision. Following this, Harvey entered Harvard Medical School and managed to spend the summer of 1950 in the laboratory of another Nobel laureate, Fritz Lipmann. Lipmann was a brilliant and innovative thinker who conceived the concept of high-energy bonds in biochemistry and also discovered Coenzyme A. In 1953 Harvey received an M.D. degree from Harvard and then completed his internship at Massachusetts General Hospital. He then returned to Lipmann’s laboratory as a Research Fellow for two years where he studied the uncoupling of oxidative phosphorylation. It was during this time he met and married Marion Heinrich in 1955. Because Harvey’s initial period in the Navy was less than one year, he was subject to the draft of M.D.s that was in place during the Korean War. At that time a limited number of newly graduated M.D.s were selected to serve in the Public Health Service at the National Institutes of Health, a much sought after position. Harvey was selected to work in the laboratory of Dr. Giulio Cantoni in 1956 and remained at NIH for his entire career. Dr. Cantoni was the discoverer of S-adenosylmethionine (AdoMet), the principal doHow to Cite this Article: Blom HJ,Stabler S, Wagner C. 2015. In Memoriam: S. Harvey Mudd.

Introduction to the Komrower Memorial Lecture 2010

Introduction to the Komrower Memorial Lecture 2010

Blood Spot Homocysteine: A Feasibility and Stability Study

Homocystinuria is an autosomal recessive disorder usually caused by deficiency of cystathionine β-synthase, leading to grossly increased plasma and urine concentrations of homocysteine. There is considerable evidence that early detection and treatment can prevent the clinical consequences of the enzyme deficiency (1)(2); therefore, screening for the disorder has been advocated (1). Many cases of homocystinuria have secondary hypermethioninemia. Neonatal screening for homocystinuria by measurement of increased methionine concentrations in dried blood spots (DBS) has been performed in some centers but has poor sensitivity. Approximately 20% of cases are missed, partly because of low methionine concentrations in breast milk and some infant formulas (3). The measurement of homocysteine in DBS has not been used as a screen for homocystinuria, partly because of uncertainty about the suitability of DBS samples. Homocysteine concentrations are unstable in whole blood stored at room temperature and increase by ∼1.0 μmol/L per hour (4). This is attributable to in vitro erythrocyte transmethylation reactions that lead to continuous production and release of homocysteine (5). It is not known whether homocysteine is released from erythrocytes in blood that has been spotted on filter paper and dried, either during the spotting and drying process or during storage at room temperature. A recent report assessed stability in screening cards that were stored at 4 °C, which does not reflect routine practice (6). Another investigated the stability of DBS samples, using whole blood to which large concentrations of aqueous homocysteine calibrator had been added, thus potentially masking any increase in homocysteine attributable to release from erythrocytes (7). The lack of information on the stability …

Hyperhomocysteinemia and arteriosclerosis: historical perspectives

Early concepts of the origin of arteriosclerosis were introduced in the 19th century by Rokitansky and Virchow, who described mural thrombosis, inflammatory damage to arterial intima, increased intimal permeability to plasma, mucoid degeneration of arterial wall, deposition of plasma lipids in plaques, and fibrosis and calcification of plaques. Experimental production of arteriosclerosis by feeding animal foods to rabbits was attributed to protein intoxication by Ignatowsky in 1908 and to dietary cholesterol by Anitschkow in 1913. Newburgh confirmed the protein hypothesis in 1915-1925 but failed to identify which amino acid produced plaques because methionine (1922) and homocysteine (1932) had not yet been discovered. Cases of homocystinuria from inherited deficiency of cystathionine synthase were found to be associated with thrombosis and vascular disease in 1964. The index case of methionine synthase deficiency (cobalamin C disease) was found by McCully in 1969 to be associated with arteriosclerosis, leading to the homocysteine theory of arteriosclerosis. The theory explains experimental arteriosclerosis by deficiency of vitamin B6 in monkeys, choline deficiency in rats, thyroid deficiency in rats, and methionine deficiency in monkeys. The thrombogenic and atherogenic effects of homocysteine were demonstrated in rabbits, baboons and other species, reproducing the pathological findings found in homocystinuria. Clinical and epidemiological studies in the past two decades have demonstrated that elevated plasma homocysteine is a potent independent risk factor for arteriosclerosis in the general population, supporting the validity of the theory.

Two Cases of Homocystinuria From Coastal Andhra Pradesh

Two Cases of Homocystinuria From Coastal Andhra Pradesh

The pancreatic beta cell fraction in children with errors of amino acid metabolism.

Blocks of pancreas were obtained from the following cases of errors of amino acid metabolism: eight cystinosis, eight tyrosinosis, five phenylketonuria, three hypermethioninemia, two hyperprolinemia and two maple syrup urine disease. Blocks were also obtained from four cases of homocystinuria and 72 control patients of the same age range who had died from a variety of conditions believed not to affect the pancreas. Sections were cut from each pancreatic block and stained with haematoxylin or for insulin and pancreatic polypeptide (PP) by the immunoperoxidase method. Measurements were performed separately in the PP rich and the PP poor regions of all sections. The fractional surface area of section occupied by insulin stained cells (%) and the cellular density (nuclei/100 microgram2) of each specimen were estimated. The beta cell fractional area in the PP poor region of the experimental cases was plotted against the logarithm of gestational age and compared to a reference grid of the 10th, 50th and 90th centile estimates of the control cases (Fig. 1). The distribution of results from the cases of tyrosinosis, phenylketonuria and cystinosis were skewed positively; four of eight tyrosinosis and three of five phenylketonuria cases lying above the 90th centile (P less than 0.001). The beta cell fractional area of the cystinosis cases was also significantly increased (Table 1, P less than 0.05). The results from the cases dying from maple syrup urine disease, hyperprolinemia, hypermethioninemia or homocystinuria were distributed as might be expected to occur by chance.

The Manchester regional screening programme: a 10-year exercise in patient and family care.

Up to the end of 1978 the Willink Biochemical Genetics Unit had screened 506821 babies for metabolic abnormalities over 10 years--98-99% of the children born in the region. Sixty-nine cases of phenylketonuria (PKU), 42 cases of histidinaemia, and six cases of homocystinuria were detected. As well as treating affected children, the staff of the unit have concentrated on providing full support for their families and maintaining good communications with parents, general practitioners, health visitors, and midwives. A clinic liaison sister has provided valuable support for health visitors and an important link between the unit and community services. A study of the costs of screening and treating cases of PKU for the year 1978 showed that this was cheaper, by pound 569000, than the costs of looking after patients with untreated PKU.

Clinical and Biochemical Findings of Two Cases of Homocystinuria

Clinical and Biochemical Findings of Two Cases of Homocystinuria

HOMOCYSTINURIA: A REPORT IN TWO SIBLINGS

1. Two cases of homocystinuria at ages 14 and 21 are described, in which the typical features of the disorder were found: subluxation of the optical lenses, mental retardation, seizures, pes cavus, blotchiness of the skin. Additionally, emotional lability was prominent and breath-holding attacks had been present in infancy. Neither had suffered any apparent vascular occlusive episode. Prominent in both of the children described was generalized osteoporosis and narrowing of joint spaces. 2. Homocystine and methionine were found to be elevated in urine, plasma and cerebrospinal fluid.

Homocystinuria

The report of two cases of homocystinuria by Gerritsen and Waisman (Pediatrics, 33: 413, 1964) raises an important clincal point. The two cases reported by myself and others (Arch. Dis. Child., 38: 425, 1963) both had bilaterally dislocated lenses and this abnormality has been present in all other cases seen by us since then. Gerritsen and Waisman do not make entirely clear statements with respect to eye abnormalities in their patients. For case K.T. we are only told "There was no complaint of any visual difficulty" (p. 415), and nothing is said about the examination of the eye.