A Survey of Some Hereditary Metabolic Diseases R

486 Postgrad Med J: first published as 10.1136/pgmj.36.418.486 on 1 August 1960. Downloaded from

A SURVEY OF SOME HEREDITARY METABOLIC DISEASES R. W. E. WATTS, M.D., PH.D., M.R.C.P. Senior Lecturer, The Medical Unit, St. Bartholomew's Hospital, London, E.C. i

It has been recognized for many years that rectly forecast that it was due to a failure of there are a few entities in which a characteristic the single enzymatic reaction which normally combination of clinical and chemical abnormalities opens the benzene ring of the aromatic amino- is genetically transmitted. The number of diseases acids.25, 26, 27, 55, 58 Homogentisic acid forms a and apparently harmless metabolic anomalies brown or black polymer on oxidation; this re- which have been recognized as belonging to this action occurs readily and is accelerated by alkali. group has increased considerably since Garrod in It interferes in the Benedict's and Fehling's tests 190225 described alkaptonuria as an ' inborn meta- for urinary glucose with the formation of an bolic error'; and there are others such as diabetes orange precipitate and a dark brown supernatant mellitus, the causation of which appears to be at solution, but the tests for glucose which do not least partly hereditary. The original hypothesis depend upon the reducing properties of the sugar of a genetically determined enzyme block has are unaffected. Normal blood and urine do not proved a fruitful one, ana it has received experi- contain detectable amounts of homogentisic acid

mental support from the study of the specific and the level in alkaptonuric patient's blood (aboutby copyright. blocks in metabolism which occur in mutant 3 mg. per ioo ml.) is so low as to be near the strains of micro-organisms such as Neurospora. lower limit of measurement by the available pro- Some inherited chemically characteristic diseases cedures.66 are due to a failure of specific renal tubular re- Alkaptonuria may be detected in infancy by the absorptive processes and presumably result ulti- characteristic dark staining of the urine-soiled mately from an abnormality of the enzymic napkins. In later life, usually after the age of 40, mechanisms which effect active transport across the cartilages, tendons, ligaments and sclerae these cells. become demonstrably pigmented (' ochronosis '). All enzymes are probably proteins and the This is first apparent clinically as a bluish-grey inborn enzyme defects are therefore specialized discoloration of the auricular and nasal cartilages http://pmj.bmj.com/ examples within the group of diseases which are and superficial tendons. The affected cartilages due to inherited abnormalities of protein synthesis. feel abnormally rigid and the earliest scleral Limitation of space prevents a discussion of other deposits take the form of brown triangular areas inherited protein abnormalities such as the haemo- which have their bases directed towards the globinopathies, the congenital plasma protein corneoscleral junction; the sclerae subsequently deficiencies and the deficiencies of the blood- acquire a uniform grey tint. Brown pigmentation

clotting factors. The renal tubular reabsorption of the ' butterfly ' area of the face, over the thenar on September 24, 2021 by guest. Protected defects (e.g. cystinuria) have also been omitted and hypothenar eminences and of the nails as for this reason. well as a dark discoloration of the ceruminous and sebaceous secretions has been described and DISORDERS OF AMINO-ACID pigmentation of the bones, kidneys and of athero- METABOLISM matous plaques may be apparent at necropsy. Alkaptonuria Similar pigmentation occurs in chronic phenol In this disorder of aromatic amino-acid meta- poisoning (' carbolic ochronosis '). Alkaptonurics bolism there is a congenital deficiency of the characteristically develop osteoarthritic lesions in enzyme homogentisic acid oxidase which converts the spine and large joints of the limbs. The homogentisic acid (2 5-di-hydroxyphenyl acetic intervertebral discs are thin and calcified and acid) to maleyl aceto-acetic acid. The disease was ectopic calcification may develop in bursae and documented from the clinico-pathological and tendon sheaths. The depth of pigmentation of genetic aspects by A. E. Garrod, who also cor- the cartilage of the affected joints is not necessarily Postgrad Med J: first published as 10.1136/pgmj.36.418.486 on 1 August 1960. Downloaded from August i 96o WATTS: A Survey of some Hereditary Metabolic Diseases 487 directly proportional to the severity of the osteo- to the acidified urine. The urine also contains arthritis, and carbolic ochronosis is not particu- some tryptophane derivatives whose presence, as larly associated with articular degeneration. well as the lowered blood and urine levels of Most cases of alkaptonuria display a recessive 5-hydroxytryptamine and 5-hydroxyindole acetic (or homozygous) pattern of inheritance as judged acid respectively, could be explained on the basis by the occurrence of multiple cases of the disease of defective tryptophane hydroxylation. in individual sibships, the parents being overtly The pattern of inheritance is recessive and the normal, and an incidence of parental consan- individuals who are heterozygous for the abnormal guinuity which is greater than that prevailing gene concerned (e.g. the parents of affected homo- generally in the population from which the zygous individuals) can be detected by their im- families are drawn, the abnormal gene being rare. paired ability to metabolize a test dose of phenyl- In these families the affected members are homo- alanine normally as judged by the rate of dis- zygous and their parents are heterozygous for the appearance of the amino-acid from the blood abnormal gene concerned. A few pedigrees have plasma.48 The fasting plasma phenylalanine levels been reported,43 in which the disease appears to in the heterozygous subjects are also slightly have a dominant (or heterozygous) pattern of higher than normal. Low phenylalanine diets are inheritance; in these families affected individuals currently being tried therapeutically on the appear in successive generations, and the incidence assumption that the abnormally high concentra- of parental consanguinuity is no greater than that tions of phenylalanine or one of its metabolites are encountered generally in the population. This responsible for the neuropsychiatric disorders. genetic heterogeneity suggests that there may be They need to be given from earliest infancy and two biochemical lesions which can give rise to although the obvious chemical abnormalities of alkaptonuria. It is probable that the detailed the body fluids can be corrected in this way, and biochemical studies which have resulted in the the fits and electroencephalographic abnormalities formulation of the current concept of the aetiology abolished, their efficacy in promoting completely of the disease have all been performed on the normal mental development is still under long- commoner recessive variety. Alkaptonuria appears term assessment.56' 9 by copyright. to be about twice as common in males as it is in females in both genetic types, but no satisfactory Tyrosinosis explanation of this has so far been advanced. The recognition of this third inborn metabolic error of aromatic amino-acid metabolism rests Phenylketonuria (Phenylpyruvic upon the description of a single case of Medes" Oligophrenia; Phenylpyruvic Amentia) in which large amounts of tyrosine andp-hydroxy- Folling23 recognized that mental deficiency was phenylpyruvic acid were excreted in the urine. sometimes associated with the presence of large The conaition was associated with myasthenia amounts (0.5-I g. daily) of phenylpyruvic acid in gravis, but in view of the lack of evidence that the urine, and it has been shown that this asso- other myasthenics have any similar metabolic http://pmj.bmj.com/ ciation exists in about one-half to one per cent. of disturbance it is generally accepted that the all mental defectives. association was a fortuitous one, and that tyro- The vast majority of cases are of imbecile grade sinosis itself has no clinical manifestations apart and have abnormal electroencephalograms. Epi- from the urinary abnormality. Medes's6l results leptiform attacks and' organic' neurological signs suggest that a metabolic block exists between (usually extrapyramidal) have been reported in p-hydroxyphenylpyruvic and homogentisic acids.

about 30% and 6o% of cases respectively.5, on September 24, 2021 by guest. Protected Stature and head size are only slightly reduced, Albinism the skin and hair tend to be fairer than the This is a relatively common inborn metabolic average for the population from which the cases error, albinos constituting about i in 20,000 of are drawn, and the blood adrenaline level is said the population of Great Britain. There is an to be abnormally low. inherited failure to form melanin due to the ab- The aetiological biochemical lesion is a defi- sence of tyrosinase from t-he melanocytes. The ciency of one component of the phenylalanine pinkish white photosensitive skin, white hair, hydroxylase enzyme system."' 90 Abnormally translucent iris, nystagmus, photophobia and high levels of phenylalanine are found in the defective vision are well known clinical findings. blood and cerebrospinal fluid, and abnormal meta- The failure of pigment synthesis may not be bolites of this amino-acid are excreted in the complete, and in one genetically distinct (sex- urine. Phenylpyruvic acid is one of these and is linked) type the only albinotic change is found easily detected by the green coloration which it in the eye ('ocular albinism'). The commoner produces when ferric chloride solution is added generalized form appears to be inherited as an Postgrad Med J: first published as 10.1136/pgmj.36.418.486 on 1 August 1960. Downloaded from 48$ POSTGRADUATE MEDICAL JOURNAL August oi 6o autosomal (non-sex-linked) recessive character, also being due to the operation of a rare recessive although the situation is complicated by the fact gene.62 that there is-more than one abnormal gene which may, when present in double dose (homozygosity) Argininosuccinic Aciduria give rise to the condition. Thus albino parents This disease is characterized by the presence of who are homzygous for different abnormal genes argininosuccinic acid in the urine, blood and can beget non-albino children, the latter being cerebrospinal fluid. Argininosuccinic acid is an heterozygous for different genes responsible for intermediate compound in the ornithine cycle of albinism. urea formation,70 and its relatively high cerebro- Goitrous Cretinism spinal fluid level in the disease has suggested that it may be formed in the central nervous system The clinical association of non-endemic cre- due perhaps to a block in some hitherto unrecog- tinism and goitre is uncommon and three distinct nized metabolic process; the blood and urine biochemical lesions, each representing a block at urea levels are normal.1' 21, 92 different stages of thyroid hormone synthesis, Allen et al.' described the disease on the basis have been identified as causes of this syn- of their study of two sibs (aged three and six years drome.38, 49, 81, 82 The available data are com- respectively) whose parents were unrelated. Both patible with these conditions being due to the children had grossly abnormal electroencephalo- operation of rare recessive autosomal genes. grams and were severely mentally retarded, al- Disease though they had apparently developed normally Hartnup during the first year of life, and there was no Baron, Dent, Harris, Hart and Jepson5 reported definite evidence of microcephaly. One patient the clinical association of a pellagra-like rash, was epileptic, and motor inco-ordination with mental deficiency, neurological manifestations of choreo-athetoid features was present for several varying severity (cerebellar 'ataxia, nystagmus, weeks after a series of fits. Friable hair, cardiac involuntary movements) and a renal amino- systolic murmurs and elevated serum alkaline aciduria which, although generalized, does not phosphatase levels were noted in both cases. by copyright. involve all the amino-acids to the same degree.20 The urine also contains unusual amounts of indole 3-aminoisobutyric Aciduria compounds related to tryptophane (indolylacetic acid, indolylacetyl glutamine and indican). Three Some otherwise normal people excrete about sibs showed the full syndrome and one other (the 50-200 mg./24 hours of f-aminoisobutyric acid in youngest) had amino-aciduria only; the parents, their urine as opposed to the much smaller who were normal, were first cousins. Other amounts which are normally present. There is similar cases have been identified.47 It has not evidence that thi's represents a harmless inborn been finally decided whether this disease results anomaly of thymine metabolism, although its primarily from a block at some stage in the mode of inheritance has not been elucidated.39 http://pmj.bmj.com/ metabolism of tryptophane with secondary deficiency of nicotinic acid or whether it is primarily Cystathioninuria a disorder of amino-acid transport.39 Harris, Penrose and Thomas40 found large amounts of cystathionine, an intermediary in Maple Sugar Urine Disease methionine metabolism, in the urine of an elderly In this disease high levels of the branched- mental defective, and increased amounts of the

chain amino-acids valine, leucine and isoleucine same amino-acid were found in the patient's on September 24, 2021 by guest. Protected are found in the blood and urine, whereas the liver and kidney tissue post mortem, although levels of threonine, serine and alanine are excep- there was no evidence that it accumulated in the tionally low,93 and it has been suggested that the blood. Cystathionine cannot be detected in the underlying abnormality is a failure to metabolize urine of normal subjects, but a clinically normal the branch-chain amino-acids normally. The nephew and brother of the propositus excreted .affected children fail to thrive from the age of a amounts which, although less than those excreted few days; spasticity, opisthotonos and irregular by the propositus, were still appreciable. These jerky respirations are associated with feeding observations suggest that cystathioninuria may difficulties, inanition and death during the first be due to a genetically determined metabolic weeks of life. The urine smells characteristically lesion which results in a failure to convert cyst- of maple sugar: this is thought to be due to athionine to homoserine and cystine. certain a.-hydroxy acids which are present; the post-mortem appearances are non-specific. The Primary Hyperoxaluria available evidence is compatible with this disease Primary hyperoxaluria, which has a recessive Postgrad Med J: first published as 10.1136/pgmj.36.418.486 on 1 August 1960. Downloaded from Atigitsi lofo WATTS: A Survey of some Hereditary Metabolic Diseases 489 pattern, of .inheritance,* 76 causes severe pro- mental retardation, stunted growth, cataracts and gressive urolithiasis and nephrocalcinosis begin- hepatic cirrhosis become apparent. Proteinuria, a ning in childhood and is characterized by a con- generalized amino-aciduria and high concentra- tinuous high urinary excretion of oxalate, much of tions of glactose in the blood and urine are the which is derived from glycine. About the same obvious chemical accompaniments. The disease degree of isotope dilution occurred between the is due to a deficiency in the enzyme system, precursor glycine (labelled with 13C) and the which converts galactose-i-phosphate to glucose- urinary oxalate in patients with primary hyper- i-phosphate; this can be demonstrated in the oxaluria and a normal subject; this suggests that patient's erythrocytes as well as in isolated liver the fundamental abnormality in primary hyper- tissue. The crippling effects of this metabolic oxaluria is a failure to degrade glyoxylate normally lesion can be prevented by the administration of to formate and carbon dioxide with secondary a galactose-free diet from earliest infancy, which over-production of oxalate, rather than excessive is achieved by the use of protein hydrolysates or metabolism of glycine via the pathway:'7 proprietary lactose-free milk preparations. The affected children acquire tolerance for small CGlycine * Glyoxylate - -. Formate + COt amounts of milk as they grow older.45 Essential Pentosuria Oxalate (L-xyloketosuria) The first reported case of this condition was Such a metabolic lesion need involve only a small that of Salkowski and Jastrowitz in i89273 and it part of the normal glycine metabolic turnover in was one of the four original, inborn metabolic order to produce the amount of oxalate which errors described by Garrod. Only traces of patients with this disease excrete.9' The ali- L-xyloketose (L-xylulose) can be demonstrated mentary absorption of oxalate is not excessive in the blood of these patients and apart from the and there is no evidence of a primary renal defect excretion of several grams of L-xyloketose (L- in these cases.2 Numerous calcium oxalate mono- xylulose) daily there are no clinical or chemical hydrate crystals are found in the walls of small abnormalities. Most of the patients are of Central by copyright. muscular arteries and arterioles, the rete testis, European Jewish descent and the pattern of the myocardium, the growing regions of bones inheritance is recessive (homozygous). No abnor- and, less extensively, in other tissues as well as malities have so far been demonstrated in the in the kidneys at necropsy.32, 77 It has not proved subjects who are presumably heterozygous for possible to determine clinically the stage in the the abnormal gene. Essential pentosuria should evolution of the disease at which the extrarenal be- distinguished from the transient secondary deposition of oxalate (' oxalosis ') begins and the pentosuria (D-arabinosuria) which follows the precise level of the urinary oxalate excretion ingestion of large amounts of fruit. Pentoses cannot be correlated with the age at which obvious reduce Benedict's reagent so that most cases of stone formation begins or with its rate of pro- essential pentosuria are found during the course http://pmj.bmj.com/ gression; the prognosis is, however, bad.37 It of routine medical examination. appears that the blood oxalate level is not grossly L-xylulose is a normal metabolic intermediate elevated except at a very late stage in the evolution in one of the pathways of glucose metabolism; its of the disease.'8 Small amounts of oxalate have further metabolism is via the pentose-phosphate also been found in cerebrospinal fluid collected at cycle as a result of which its carbon atoms may post mortem, none being detectable in appropriate be reincorporated into glucose. D-glucuronic 77 control material.37 acid is another intermediate on this pathway of on September 24, 2021 by guest. Protected glucose metabolism and the administration: of DISORDERS OF CARBOHYDRATE glucuronogenic drugs increases the excretion of METABOLISM L-xyloketose in essential pentosurics and causes Galactosaemia it to appear in the urine of normal subjects,; Infants with this recessively inherited metabolic ribulose is also excreted under these circum- defect appear normal at birth,-but after a few days stances.6 There may be some as yet incom' of milk feeding become lethargic, vomit and fail pletely explored connection between L-xyloketose to thrive; abdominal distension and hepato- and ascorbic acid metabolism for the biosynthetic megaly develop and there is a prolonged period pathways from glucose to both compounds of neonatal jaundice. Should they survive infancy, appear to be identical as far as their immediate precursor. * Shepard, Krebs and Lee's79 report raises the possibility that a rare dominant variety of the disease may exist. The studies which form the basis of this review Essential Fructosuria were perfonned on the recessive-type. This recessively inherited biochemical anomaly Postgrad Med J: first published as 10.1136/pgmj.36.418.486 on 1 August 1960. Downloaded from 490 POSTGRADUATE MEDICAL JOURNAL Augiist I960 also produces no untoward clinical manifestations. a multibranched structure. It functions as a The urine contains fructose only when this sugar carbohydrate store to which glucose may be is present in the diet, the patient's ability to added, or from which it may withdrawn by metabolize a test dose of fructose is diminished, lengthening or shortening the polysaccharide and the parents who are presumably heterozygous chains. Glucose storage begins with the con- for the abnormal gene are not demonstrably version of glucose-6-phosphate (formed by the abnormal. It has been suggested that fructosurics reaction of glucose and adenosinetriphosphate are unable to metabolize the fraction of the under the influence of hexokinase) to glucose-i- dietary fructose which is normally metabolized phosphate by phosphoglucomutase. Glucose-i- directly to lactic acid.72 phosphate is built on to the pre-existing core of the glycogen molecule by phosphorylase; inor- Congenital Deficiency of Erythrocyte ganic phosphate is liberated and removed by Glucose-6-phosphate Dehydrogenase oxidative phosphorylation. The ' brancher' The red cells of patients in whom acute enzyme (' amylo-(i: 4-* 6) transglucosidase ') haemolysis follows the administration of prima- comes into action when about eight successive quine, sulphanilamide, acetanilide, naphthalene, glucose residues have been added and effects a thiazosulphone, phenylhydrazine, menaphthone branch point in the glycogen molecule. The and fava beans are deficient in glucose-6-phos- successive actions of phosphoglucomutase and phate dehydrogenase activity and contain abnor- the brancher enzyme build up an arborescent mally small amounts of reduced glutothione. structure. Glucose mobilization follows a similart The reduced glutathione content of the erythro- but reversed, pattern-phosphorylase hydrolyses cytes decreases further when an haemolytic crisis the outer polysaccharide chains until the branch is induced and in vitro incubation of a ' sensitive ' points are reached; these are hydrolyzed by the individual's red cells with acetylphenylhydrazine ' debrancher' enzyme (' amylo-i :6-glucosidase') also diminishes their reduced-glutathione co- and another series of glucose residues are made tent.13 The affected males inherit the condition accessible to the action of phosphorylase. The

from their mothers only, and the clinical mani- immediate product of phosphorylase action is by copyright. festations are more severe in males and in females glucose-i-phosphate which accounts for about who are homozygous for the gene than in the 92% of the glycogen hydrolyzed (the remainder corresponding heterozygous females. emerging as free glucose). Phosphoglucomutase converts glucose-i-phosphate to glucose-6-phos- Hereditary Spherocytosis phate which is converted to free glucose by Erythrocyte glycolysis is defective in this glucose-6-phosphatase in liver and kidney tissue. disease,67 and Tabechian, Altman and Young" have In muscle, where there is no glucose-6-phospha- suggested that this involves the step 2-phospho- tase, glucose-6-phosphate is either converted to glycerate->phosphoenolpyruvate which is nor- lactic acid or completely metabolized. mally catalyzed by enolase. The mode of inheri- The condition described by von Gierke86 in http://pmj.bmj.com/ tance is dominant, but a few cases have been which there is abnormal glycogen storage in the reported whose parents were proved to be liver and kidneys only, results from glucose-6- haematologically normal; these might be the phosphatase deficiency and is now referred to as results of fresh mutations or represent a different ' Type i glycogen-storage disease.' It occurs in metabolic lesion which causes spherocytosis. a severe form, associated with extremely low liver glucose-6-phosphatase levels,16 and in a clinically Hereditary Non-spherocytic Haemolytic milder form in which the enzyme deficiency is of on September 24, 2021 by guest. Protected Anaemia smaller degree. The severely affected infants fail This newly-recognized condition which is to thrive, have gross hepatomegaly and readily characterized by mild intermittent haemolytic become hypoglycaemic and ketotic. The glucose icterus and other symptoms attributable to epi- tolerance curve is flat and the hypoglycaemia is sodic intravascular haemolysis is considered on unaffected by adrenaline. Death' from inter- the basis of recent biochemical studies to be due current infection in early childhood is usual and to another abnormality of intraerythrocytic glu- the customarily recommended regime of frequent close metabolism which has a dominant pattern high protein feeds does not seem to influence the of inheritance.65 course of the disease. Patients with the milder variant may survive to adult life and they may The Glycogen-storage Diseases ultimately have few disabilities. Type i glycogen- The polysaccharide glycogen has a molecular storage disease has a recessive mode of inheritance, weight of several million and is composed entirely whether the two sub-types should- be regarded as of glucose-units which are linked together to form the same genetic entity appears to be uncertain. August I960 WATTS: A Survey of some Hereditary Metabolic Diseases 491 Postgrad Med J: first published as 10.1136/pgmj.36.418.486 on 1 August 1960. Downloaded from Hsia47 has shown that the presumed heterozygous The al, a2 and p,i-globulin fractions of the carriers of the abnormal gene have elevated levels serum proteins are elevated. of glucose-6-phosphate and fructose-6-phosphate Beurger and Grutz" described the juvenile in their erythrocytes. variety of the disease as a syndrome of acute In Type 2 glycogen-storage disease the poly- attacks of abdominal pain, with cutaneous xantho- saccharide accumulates in the myocardial, smooth matosis and milky whiteness of the serum under and skeletal muscle fibres. The heart is enlarged fasting conditions. The yellowish pink ' eruptive ' and globular, there are left axis deviation and xanthomata are surrounded by an inflammatory- ischaemic changes in the electrocardiogram, and looking red halo; they occur most commonly on the patients usually die from heart failure in the buttocks, back and limbs, but may be general- infancy. The pattern of inheritance is recessive, ized, and the oral mucosa may be involved. but nothing is known of the underlying enzymic Hepatosplenomegaly may be present and fever defect. with a polymorphocytosis accompanies the acute In Type 3 glycogen-storage disease15 the episodes. The occurrence of the latter cannot be glycogen has abnormally short outer chains due correlated with changes in the blood lipid level. to deficiency of ' debrancher' enzyme53 and A low fat diet or long-term heparin administra- glycogen deposits occur in the hepatic, myocardial tion diminish the serum turbidity, restore the and skeletal muscle cells. Hepatomegaly, cardio- plasma protein electrophoretic pattern to normal megaly, macroglossia, fasting hypoglycaemia and and cause the gradual disappearance of the sometimes generalized progressive muscular weak- cutaneous xanthomata. Buerger-Griutz's disease ness are apparent clinically. In some cases the has a recessive pattern of inheritance, some of the latter feature may be so prominent that the disease presumably heterozygous subjects have slightly resembles amyotonia congenita.57 increased serum lipid levels.9 Thannhauser85 has described an adult variant In the fourth type of glycogen-storage disease of the disease in which there may be few abnor- the glycogen molecules have abnormally long malities apart from the hyperlipaemia, and denies chains of glucose residues between the branch that these cases suffer from angina or myocardial points;15 this is believed to be due to a deficiency infarction at an unusually early age. The co- by copyright. of the ' brancher' enzyme. The physical pro- existence of cutaneous xanthomata and some perties of this abnormal glycogen resemble those impairment of glucose tolerance in adult idio- of amylopectin (a starch polysaccharide); it pathic hyperlipaemia sometimes results in these accumulates in the liver parenchyma and the cells cases being confused with examples of xanthoma of the reticuloendothelial system. The mani- diabeticorum. festations of diffuse hepatic cirrhosis dominate Familial hypercholesterolaemic xanthomatosis ap- the clinical picture, the blood sugar is normal, pears to be due to excessive cholesterol synthesis. there is no ketosis and the response to adrenaline The serum cholesterol level is greatly elevated, is sub-normal. Chemical investigation of the but the other plasma lipids are normal or only glycogen isolated from a liver biopsy specimen slightly increased. It is unrelated to normo- http://pmj.bmj.com/ has been used to confirm the diagnosis.54 59 cholesterolaemic xanthomatosis (eosinophilic xan- The disease progresses at a variable rate and it thomatous seems that patients may survive to the age of granuloma, lipid granuloma, Schiiller- about ten years; it may be that some cases which Christian's syndrome), which- is probably not have been labelled ' familial hepatic cirrhosis' genetically determined except in the acute have been examples of Type 4 glycogen-storage generalized form (Letterer-Siwe's disease).85 disease. In familial hypercholesterolaemic xanthomatosis the cutaneous lesions (' xanthoma tuberosum et on September 24, 2021 by guest. Protected Although cases of glycogen-storage disease can planum ') have an orange-yellow colour, a ' vel- be conveniently classified into these four groups,'5 vety' consistency and vary in diameter from a Calderbank, Kent, Lorber, Manners and Wright'2 few millimetres to several centimetres. They have encountered two sibs, one with glucose-6- occur phosphatase deficiency, the other with ' de- mainly on the eyelids, on the extensor brancher ' surfaces of the limbs and on the buttocks. Non- enzyme (amylo-i : 6-glucosidase) de- pigmented subcutaneous xanthomatous deposits ficiency. also occur. Tendon-xanthomata, which are a feature of this disease, occur most commonly in DISORDERS OF LIPID METABOLISM the tendo Achilles, the patella tendon and the Idiopathic hyperlipaemia is characterized by extensor tendons of the fingers. Death due to the gross elevation of the neutral fat and fatty acid cardiovascular complications of extensive atheroma fractions of the serum lipids, the cholesterol and may occur at an early age. Hypercholesterolaemia phospholipid fractions being only slightly raised. is the constant and may be the only feature of the Postgrad Med J: first published as 10.1136/pgmj.36.418.486 on 1 August 1960. Downloaded from 492 POSTGRADUATE- MEDICAL JOURNAL =4lglist I 96o disease, the cutaneous and cardiovascular mani- reticuloendothelial cells) are found mainly in the festations being variable. spleen, which is usually very large, the liver and The genetic analysis of familial hypercho- bone marrow; bone pain and deformities, blood lesterolaemia is rendered difficult by the normal, dyscrasias and brown pigmentation (most com- but variable, rise in the serum cholesterol with monly involving the face, backs of the hands and age. It appears to be transmitted in a dominant anterior aspects of the legs) are characteristic fashion, and it has been suggested that patients clinical findings. In the relatively rare infantile with extensive cutaneous lesions or marked type the child usually seems normal at birth, but atheroma at an early age are homozygous for the hepatosplenomegaly, cyanotic attacks, neurological abnormal gene. manifestations and poor mental development are- soon apparent, and death is usual during the first The Disorders in which Cerebrosides, year of life. Numerous Gaucher cells are demon- Sphingomyelins and Gangliosides stable in the thymus, adrenal, intestinal lymph Accumulate follicles and lungs, as well as in the organs which The ceramides are the amides of sphingosine are involved in the adult varietv. Gaucher cells (an amino-alcohol) with a higher fatty acid; the have not been found in the nervous tissue as sphingomyelins are choline or ethanolamine phos- opposed to the meninges of these patients. The phoric acid esters of the ceramides, and they ganglion cells of the brain are distended, but do differ from one another in respect of the fatty not contain abnormal amounts of cerebrosides. acid component of the ceramide moiety. The Pedigrees suggesting both dominant and recessive cerebrosides consist of a ceramide, the fatty acid patterns of inheritance for Gaucher's disease have of which is linked to a galactose or glucose been described.47 85 These apparent genetic residue. The cerebrosides of normal tissue con- differences have not been correlated with possible sist almost entirely of galactocerebrosides and minor chemical differences in the cerebrosides. only small amounts are present in cells other than There is a suggestion that infantile and adult those of the nervous system. The ceramides forms of the disease may be genetically distinct.47 appear to be intermediate in the biosynthesis of Niemann-Pick's disease in which sphingo- both the sphingomyelines and the cerebrosides: myelin accumulates in the reticuloendothelial by copyright. cells is attributed to imbalance of the intracellular SPHINGOMYELINS enzymes which effect the metabolic turnover of I t phospholipids. Clinical abnormalities usually Phosphoryl choline or phosphorylethanolamine become apparent when the infant is about three months old, hepatosplenomegaly results in gross abdominal distension with wasting, anaemia, CERAMIDES muscle hypotonia, mental retardation, yellowish- brown cutaneous pigmentation, generalized lymph-

adenopathy and progressive blindness and deaf- http://pmj.bmj.com/ ness. The macula lutea shows a cherry-red spot Glucose or galactose in about 50% of cases. ' Foam cells' (sphingo- I -if myelin-containing histiocytes) are often present CEREBROSIDES in the peripheral blood (cf. the invariable absence The gangliosides are related compounds, the exact of Gaucher cells from this situation) and the structures of which are not known. They contain plasma phospholipid level is low. Foam cells a ceramide linked to glucose, galactose, chondro- have been detected histologically in virtually samine and neuraminic acid (a polyhydroxy every organ except the central nervous system on September 24, 2021 by guest. Protected amino-acid), and have been isolated from some and the skin. The ganglion cells of the brain and normal tissues. retina are swollen and degenerate, but this is not In both the adult and infantile forms of due to an abnormal accumulation of sphingo- Gaucher's disease, either glucocerebrosides alone myelin within them. The sphingomyelin content or a mixture of galactocerebrosides and gluco- of the brain is normal although differences be- cerebrosides accumulate in the reticuloendothelial tween the fatty acid composition of specimens cells. This is attributed to imbalance of the prepared from normal brain and specimens pre- intracellular enzymes which effect the intercon- pared from the brains of patients with Niemann- version of the ceramides and cerebrosides.85 The Pick's disease have been reported. The ganglio- adult form of Gaucher's disease usually presents side content of the brain is increased and it seems in late childhood or early adult life, and may be that this is responsible for the apparent distension compatible with relatively little disability. In of the ganglion cells. Patients with the rare this type Gaucher cells (cerebroside-containing adult form of the disease are usually unaware of Postgrad Med J: first published as 10.1136/pgmj.36.418.486 on 1 August 1960. Downloaded from August I960 WATTS: A Suirvey of some Hereditary Metabolic Diseases 493 their disease until it is detected during a routine side chains converts coproporphyrin III to proto- examination. The lungs, liver and spleen are the porphyrin III. most extensively involved organs, and pulmonary Stage 6: Haem is formed from protopor- infiltration may cause diffuse pulmonary fibrosis phyrin III by the insertion of one atom of ferrous with cor pulmonale. It has been suggested that iron per molecule. Niemann-Pick's disease has a recessive pattern of inheritance, patients with the infantile form Acute Intermnittent Porphyria being homozygous for the gene concerned, those Attacks of severe intestinal colic, constipation with the adult variant being the corresponding and episodic neurological manifestations (pain', heterozygous individuals; further genetic studies hypoaesthesia, paresis, fits, coma and psychiatric of this disease are, however, needed. symptoms) sometimes accompanied by fever and Tay-Sachs disease (infantile amaurotic familial hypertension, and beginning at puberty, are idiocy) occurs mainly in Jews and has a recessive characteristic of this disease. The onset of an pattern of hereditary transmission. It is charac- acute attack can sometimes be traced to bar- terized chemically by the accumulation of very biturate administration; pregnancy also appears large amounts of gangliosides in the central to affect the disease adversely. The urine is dark nervous system in the absence of visceral sphingo- red (port-wine coloured) during the acute episodes myelin accumulation. The possibility that the and contains large amounts of porphobilinogen ganglioside content of the brain may be increased and 8-aminolaevulic acid; small amounts of the in other genetically-determined degenerative dis- zinc complexes of Series I and III uroporphyrins eases of the nervous system has not been investi- and coproporphyrins are also present. There is gated.85 Cases of Tay-Sachs disease appear no urinary abnormality until the first attack and normal at birth, but delayed mental development, relatively low levels of porphobilinogen and fits, amaurosis and the classical ' cherry-red ' spot 8-aminolaevulic acid excretion are found between in the region of the macula lutea are apparent the attacks. It is suggested that the uroporphyrins by the age of six months; and they usually die and coproporphyrins are formed secondarily from during the first two years of life. excreted porphobilinogen when this reaches very by copyright. high levels. Necropsy shows patchy demyelination The Porphyrias of the peripheral nerves and in the central nervous The porphyrias are primary disorders of por- system. phyrin synthesis, and they should be distinguished The biochemical lesion has not been identified, from the porphyrinurias in which the increased it may be that the conversion of porphobilinogen urinary and faecal porphyrin excretion is a to uroporphyrin III is blocked, or there may be secondary phenomenon (e.g. when there is ab- a defect in the balance of synthesis and utilization normally active erythropoesis). Porphyrin bio- of 8-aminolaevulic acid via other metabolic path- synthesis takes place according to the following ways so that it accumulates and is converted to simplified scheme: porphobilinogen in the liver. The clinical mani- http://pmj.bmj.com/ Stage i: One molecule of glycine and one festations cannot be accounted for by the known molecule of succinate combine to form 8-amino- pharmacological properties of porphobilinogen or laevulic acid. This reaction only occurs if the 8-aminolaevulic acid.34 50 Affected individuals succinate has been activated by Coenzyme-A and asymptomatic porphobilinogen excretors are ('succinyl Coenzyme-A'). believed to be heterozygous for the gene con- Stage 2: Twvo molecules of 8-aminolaevulic cerned.33, 87, 88, 89 Only symptomatic treatment acid combine to form one molecule of porpho- is available for the acute attacks, although Gold- bilinogen. This compound contains the five berg33 has suggested that corticotrophin or cor- on September 24, 2021 by guest. Protected membered ' pyrrole' ring which occurs in the tisone may be helpful if given early in the attack. porphyrins. Stage 3: Four molecules of porphobilogen com- Contgenital Porphyria bine to form uroporphyrin. Two isomeric uro- Large amounts of Series I porphyrins, which porphyrins can result at this stage and are de- cannot be utilized or metabolized in the normal scribed as belonging to ' Series I ' and ' Series III.' way, are synthesized in this disease. They accu- The physiologically important porphyrins belong mulate in the bones, teeth, erythrocytes and skin to Series III and normally only small traces of and are excreted in the urine and bile; the urine Series I porphyrins are formed. does not contain porphobilinogen or 8-amino- Stage 4: Uroporphyrin III forms copropor- laevulic acid. The bones and teeth, which are phyrin III by loss of the carboxyl groups from reddish-brown, and the urine fluoresce in ultra- four of its eight side chains. violet- light. The skin is abnormally photo- Stage 5: Partial dehydrogenation of two of the sensitive and bullous eruptions (hydroa aestivale), Postgrad Med J: first published as 10.1136/pgmj.36.418.486 on 1 August 1960. Downloaded from 494 POSTGRADUATE MEDICAL JOURNAL Augulst I960 which heal slowly and leave considerable scarring They -have to be distinguished from secondary and deformity, occur on the exposed skin sur- methaemoglobinaemia due to phenacetin, anti- faces. A chronic haemolytic anaemia possibly pyrine, acetanilide and nitrates. due to erythocyte-photosensitivity is usually present and there may be splenomegaly. Por- Gibson-Harrison Type (' Congenital Idiopathic phyria congenita is thought to be due to the Methaemoglobinaemia') operation of a rare recessive gene for which the This condition results from an inborn deficiency patients are homozygous.75 These investigators of the enzyme system which normally keeps the also make the novel suggestion that two series of iron of haemoglobin in the divalent state (ferro- erythrocytes and erythrocyte-precursors exist in haemoglobin). The chemical conditions within the same patient, porphyrin synthesis being ab- the erythrocyte, particularly on the venous side normal in one series and normal in the other. of the circulatory system, are such as to favour the Porphyria Cutanea Tarda conversion of ferrohaemoglobin to ferrihaemoglobin and a small proportion (about o.4°)) of The clinical manifestations of porphyria cLu- the total circulating haemoglobin is in this physio- tanea tarda are intermediate between those of logically inert form. 68 acute intermittent porphyria and porphyria con- Ferrihaemoglobin accounts for between io and 450O of the total circulating genita, but they are less disabling. Attacks of haemoglobin in congenital, idiopathic methaemo- intestinal colic and cutaneous photo-sensitivity globinaemia, the patients have life-long histories vith vacciniform lesions of the exposed skin of cyanosis and there may be slight compensatory areas begin in early adult life, but neurological polycythaemia.4 Apart from an inconstant asso- manifestations are rare and less severe than those ciation with mental defect,96 there is usually no which occur in acute intermittent porphyria. disability associated with the condition. Intra- During remissions, large amounts of protopor- venous injection of ascorbic acid or of methylene- phyrin and coproporphyrins are excreted in the blue temporarily relieves the cyanosis; these two faeces; this diminishes during the acute exacerba- substances appear to act in different ways.28 29

tions of the clinical manifestations when large by copyright. amounts of Series I and Series III uroporphyrins Trhe oxygen dissociation curve is shifted to the and coproporphyrins appear in the urine. Por- left; a similar shift is observed in haemoglobin phobilinogen is absent from the urine except solutions containing methaemoglobin in vitro, and possibly terminally. It has been suggested that has been attributed to interaction between the metabolic lesion in porphyria cutanea tarda haemoglobin and methaemoglobin. If this ex- involves the step: planation is correct, the observation suggests that Protoporphyrin III--haem methaemoglobin is present in all the erythro- and that the acute manifestations are related to cytes rather than being segregated in some of episodic disturbances of hepatic function which them. If the two pigments were segregated into inhibit the biliary excretion of the abnormal pig- different cells there could be no interaction http://pmj.bmj.com/ ments.35, 36 71 It seems likely that the cases between them and the oxygen dissociation curve which have been described under this title may would have a normal shape. comprise more than one entity.89 Adequate Tl"he data of Gibson and Harrison341 arc com- genetic studies require faecal as well as uriinary patible 'vith a recessivc pattern of inheritance, porphyrin analyses in order to detect asympto- but Codounis14 studied a family whose pedigrec matic cases. Where this has been done the results suggested dominant transmission. The enzymic have suggested a dominant pattern of inherit- defect xvas not investigated in the latter family ance.44 so it is uncerta n wvhether these cases vere of the on September 24, 2021 by guest. Protected Gibson-Harrison type, although the cyaniosis wvas Hereditary Coproporphyria relieved by ascorbic acid and by methylene-bluc. Large amounts of coproporphyrin III are excreted in the urine and faeces in this apparently Horlein- Weber Tvpe46 recessively-inherited anomaly.8 There are no This variety is due to an abnormality of the symptoms such as occur in the other porphyrias, globin moiety of haemoglobin which is thought although it has been suggested that there may be to make the iron atom unduly easily oxidizable a predisposition to riboflavine deficiency. so that the rate of production of ferrihaemoglobin exceeds the capacity of the erythrocyte-reducing The Congenital Methaemoglobinaemias systems. Between I 5 and 2500/ of the haemo- In these conditions the iron of an appreciable globini is in the form of ferrihaemoglobin, and proportion of the circulating haemoglobili is this is uinaffected by vitamin C and methylene- trivalent (methaemoglobin or ferrihaemoglobini). blue. 'The pattern of inheritance is dominiant; Postgrad Med J: first published as 10.1136/pgmj.36.418.486 on 1 August 1960. Downloaded from August I960 WATTS: A Survey of some Hereditary Metabolic Diseases 405 the abnormal haemoglobin (' haemoglobin M') to a lesser extent via an alternative (' shunt ') has characteristic electrophoretic properties. pathway which appears to leave the main route after the 4-amino-5-imidazole-carboxamide stage: The Congenital Hyperbilirubinaemias 74 + NH3 Crigler-Najjar Type'9, Glycine -j AIC-..+ Purine moeties of Glucuronide synthesis, including the formation + CO. t nucleic acids of bilirubin glucuronide (conjugated or direct -) I reacting bilirubin) is grossly defective in these I patients due to a recessively inherited deficiency Shunt' of glucuronyl transferase. The patients, who are Pat hwayv Catabolism deeply icteric by the second day of life, become spastic and choreoathetotic and die in early "Uric acid childhood. Their serum bilirubin consists vir- The underlying abnormality in gout appears to tually entirely of unconjugated (indirect reacting) involve excessive uric acid production via the bilirubin. Subjects (the parents and some sibs), ' shunt' pathway, but the precise nature of the who may be presumed to be heterozygous for metabolic lesions has not been elucidated.7' 78, 83, 97 the abnormal gene but are not jaundiced, show In contradistinction to this, the increased uric some impairment of their ability to make glucuro- acid production which may give rise to gouty nide conjugates. manifestations in patients suffering from such diseases as polycythaemia rubra vera and myeloid Gilbert Type 3, 31, 63 leukaemia results from increased nucleic acid This is a benign condition in which inter- turnover. 98 mittent jaundice is usually first noticed during The occurrence of multiple cases of gout in a the second or third decades. There is a small given family is well recognized, but except for a increase in the circulating unconjugated bilirubin, preponderance of male cases the pedigrees, as and the mode of inheritance appears to be judged by the clinical manifestations, are usually dominant. Impaired glucuronide synthesis has irregular, and apparently sporadic cases are by copyright. been demonstrated, and the Gilbert and Criger- common. The distribution of plasma urate levels Najjar types of congenital hyperbilirubinaemia among the relatives of gouty patients has been are presumably closely related to one another. studied by several groups of workers. Smyth, Cotterman and Freyburg80 concluded that hyper- Dubin-Johnson Type 22 uricaemia was an inherited character which Patients with this condition suffer no disability appeared in subjects who were heterozygous for apart from intermittent icterus which is usually the gene and about io% of these develop clinical first noted in early life. The hyperbilirubinaemia gout, for some, as yet, unexplained reasons. If is due to the presence of increased amounts of this is correct the rare cases in which very severe conjugated bilirubin so there is bilirubinuria. gout develops in early life might be homozygous http://pmj.bmj.com/ The aetiology of this condition is uncertain, it for the abnormal gene concerned. The data of appears to be familial; the liver looks greenish- Hauge and Harvald42 do not, however, fit this black on macroscopic examination and the liver relatively simple hypothesis. cells contain brown iron-free and bile-free pigment of uncertain composition.52 Hypophosphatasia Patients with this disease, which resembles Gout

rickets clinically and radiologically, have low on September 24, 2021 by guest. Protected The purine moieties of the nucleic acids are serum and tissue alkaline phosphatase activities, synthesized in the body from glycine and other and excrete large amounts (IOO-200 mg./l.) of small molecules (formate, CO2 and NH3) via ethanolamine phosphate in the urine. Ethanol- 4-amino-5-imidazole-carboxamide ('AIC '), the amine phosphate occurs in the cells of many structure of which is: tissues, but only trace amounts which could be H1N- 0-o derived from the breakdown of cephalins are normally present in the urine, and there is no L -NH evidence that it normally has any specific function in connection with bone formation. CH The clinical severity of the disease appears to be very variable, ranging from skeletal abnor- H2N C--- N malities which are sufficiently severe to be Normally, the endogenous urinary uric acid is apparent radiologically in utero to minor de- derived mainly from nucleic acid catabolism and formities which are only detected in later child- Postgrad Med J: first published as 10.1136/pgmj.36.418.486 on 1 August 1960. Downloaded from 496 POSTGRADUATE MEDICAI, JOURNAL, Auiguist 196o hood or adult life.24 6' It appears that the overt an-d the urinary excretions of i7-ketosteroids anid cases of hypophosphatasia are homozygous for a 3x, 170, 20oc-pregnantriol (a derivative of 170- rare abnormal gene; the heterozygous individuals hydroxy-progesterone) are high. The anatomical have been identified by their small but signi- abnormalities are apparent in the affected girls at cantly raised ethanolamine phosphate excretion. birth, but boys do not usually slow clinical evi- The wide variation in the normal serum alkaline dence of virilization until they are about one year phosphatase level makes this parameter unsuit- old. Untreated patients grow rapidly in early able as a means of identifying the heterozygotes, childhood but are of less than average height in although the average values for groups of these adult life, due to premature epiphyseal fusion. subjects have been found to be lower than those The costal cartilages calcify at an unusually early of control subjects.4' age. The continued parenteral administration of Cusworth and Dent20 reported that an adult cortisone to suppress the abnormal adrenocortico- patient with hypophosphatasia had a low. plasma trophin output brings about normal somatic threonine level, a small excretion of proline and growth and secondary sexual development pro- increased excretions of taurine, threonine and vided that it is begun in early infanicy. Th'lie serine. The relationship of these resuLlts to the dosage should be such as to maintaini a 17-keto- other chemical features of the syndrome is not steroid excretion level which is normal for thie apparent. patient's age. Some treated male patienits hiae fathered apparenitly normal children, but treate(d Congenital Serum Pseudocholinesterase females have very low fertility (although fewv of Deficiency those who have been treated with cortisone from Some otherwise normal individuals have ab- infancy have yet reached puberty). The patterni normally low levels of serum pseudocholinesterase of inheritance is recessive and females appear to activity and are therefore unduly sensitive to the be more commonly affected than males, although muscle-relaxant drug, suxamethonium.60 This this may only reflect the fact that the genital trait has a recessive pattern of inheritance and is abnormalities are more striking in females. Some

due to the formation of an enzyme protein with presumably heterozygous members of the families by copyright. catalytic properties wvhich differ from those of its have been shown to excrete somewhat larger normal counterpart.39 amounts of 30x, 17x, 20x-pregnantriol after the administration of adrenocorticotrophin than Congenital Adrenal Hyperplasia normals. There is a failure to complete the synthesis of The patients who are unable to retain sodium cortisol (hydrocortisone) in congenital adrenal develop an Addisonian crisis-like state when they hyperplasia and cases of this condition can be are about two weeks old and soon die, unless they classified clinically into three groups: are treated with desoxycorticosterone or fludro- i. Those wvith virilization only. cortisone as well as with cortisone. This acute 2. Those with virilization and inability to retain episode may be precipitated by an intercurrent http://pmj.bmj.com/ sodium. infection or by surgery as may similar episodes 3. Those with virilizationi and hypertension. in the children who have survived infancy. There Progesterone is hydroxylated at carbon atoms is evidence that it is the hydroxylation of carboni numbers 17, 2I and ii to form hvdrocortisone;1'0 atom number 2I wvhich is defective in both of although not necessarily in this order. 94 The these groups of cases, although the severities of excretion products of the adrenocortical steroids the virilizing and sodium-losing syndromes do have either 2I or I9 carbon atoms. The latter

not parallel one another. on September 24, 2021 by guest. Protected (the ' adrenal I7-ketosteroids ') are androgenic. In the third group, the hypertensioni begins in Failure of progesterone hydroxylation prevents the first years of life, there appears to be iniability the synthesis of hydrocortisone, the level of cir- to hydroxylate carbon atom number i i, anld culating adrenocorticotrophic hormone is in- abnormal amounts of powerful salt-retaining creased and the gland is stimuilated to produce steroids (e.g. I7x-desoxycorticosterone) are pro- abnornmal amounts of the incompletely hydroxy- duced. Treatment with cortisone acetate by lated precursor substances wNhich are degraded injection abolishes the hypertensioni anid restores in part to I 7-ketosteroids. A high circulating level normal development. of these androgens beginning during intrauterine life produces pseudohermaphroditism in girls and praecox with testes REFERENCES macrogenitosomia hypoplastic ALLEN, J. D., CUSWORTH, D. C., DENT, C. E, and in boys. WILSON, V. K. (I958), Lancet, i, i82. In the commonest type of congenital adrenal 2. ARCHER, I. E., DORMER, A. E., SCOWEN, E. F., andL WATTS, R. W. E. (I958), Brit. med. Y., i, 175. hyperplasia, virilization is the only manifestation, 3. ARIAS, 1. NI., and LONDON, 1. M. (957), Science, 126, sh6. Postgrad Med J: first published as 10.1136/pgmj.36.418.486 on 1 August 1960. Downloaded from August 1960 WVATTS: A Survey' of some Hereditary, Metabolic Diseases 497

4. BARCROFT, H., GIBSON, Q. H., HARRISON, D. C., and 52. JOHN, G. CG., and KNUDT)SON, K. P. (1956), Amer. 7. M;Ied., McMURRAY, J. (1945), C'lin. PSO'CS.5,145- 21, I38. 1.3ARON, D. N., DENT, C. E., HARRIS, H., HARI', r. w., 53. ILLIN(GWORTH, B., CORI, (J. '., and CORI. C. F. (1956), and JEPSON, J. B. (1956), Lanicet, ii, 421. 7. biol. (hen,., 2i8, 123. 6. BAYNE, S. (1958), Antni. Rep. (hemt. Soc., 55, 353. 54. ILLINGXVORTH, B., LARtNER, J., and CORI, (;. T. (1952), 7. BENEDICT, J. D., YU, T. F., BIEN, E. J., GJU'1'MI\LN, Ibid., I99, 631. A. B., and STET"I'EN, E \XV. (19i3), 7. clin. inVest., 3Z, 775. 55. KNOX, W. T'. (1i,8), Amer. 7. humian Genet., 10, 95. S. BERGER, H., and GOLBERG, A. (t95s), Brit. siied. 7., 56. K9NOX, XV. E., anl HSIA, D. Y. Y. (1957), Amer. 7. fed., ii, 85. 22, 687. 9. BOGGS, J. D., HSIA, D. Y. Y., MAIS, R., anl BI(;GLER, 57. KRIV'Fr, WN., POLGLAI;E, XV. J., GUNN, F. D., and J. A. (1957), New Eng. 7. Mled., 257, 1101. 'T'YLER, F. H. (1953), Pediatrics, I2, i65. io. BONGIOVANNI, A. M., anJ] EBERLEIN, XX'. R. (tr.,8), 58. LA DUE, B. N., ZANNONI, XT. C., LASTE:R, L., and Pediatrics, I6, 628. SEEGMILLER, J. E. (1958), 7. biol. Chem., 230, 251. ii. BUERGER, M., and GRUTZ, 0. (1932), Arch. demi-piatol. ii. 59. LARNER, J., ILLINGXVORTH, B., and CORI, G. r. (1952), S,yph., i66, 542. Ibid., i99, 641. 12. CALDERBANK, A., KENT, P. XX., LORBER, J., MAN- 6o. LEHMANN, H., and RYAN, E. (1956), Lancet, ii, 12f. NERS, D. J., and WRIGH r, A. ( 19'o), B3iochenl. 7., 74, 223. 6t. 'MEDES, G. A. (1932), Biochem. 7., 26, 917. 13. CHILDS, B., ZINKHAM, XVT., BROWNE, E. A., KIMBRO, 62. MNIEKES, J. H., HURST, P. L., and CRAIG, J. MI. (1954). E. L., and TORBERT, J. v. (1958),.7ohns Hopk. Iolsp. Bull., Pediatrics, 14, 462. 102, 21. 63. MIEUI,ENGRACHT, E. (1947). Quiart. 7. Med., N.S., iu, 83. 14. CODOUNIS, A. (1952), Brit. suted. 7., ii, 36S. 64. NITII'OMA, C., AULD, R. M., and UDENFRIEND, S. I5. CORI, G. 1. (1954), fHarvey Lect., 48, 145. (i957), Proc. Soc. exp. Biol. (N.Y.), 94, 631. i6. CORI, G. T., and CORI, C. F. (1952), .7. biol. ('hem., i99, 66i. 65. MOTULSKY, A. CG., CROSBY, WX'. H., and RAPPAPORT, 17. CRAWHALL, J. C., SCOXWEN, E. F., an] XWATTI.-, R. \V. E'. H. (1954), Blood, 9, 749. (1959), Lancet, ii, 8o6. 66. NEUBERGER, A., RIMINGTCON, C., and WXLLSON, i8. CRAXN'HALL, J. C., and XX'ATT'S, R. \XX. E. (196o), linpUb- J. MI. CG. (1947), Biochem. ., 41, 438. lished data. 67. PRANKERD, r. A. J., ALTMAN, K. I., and YOUNG, L. E. 19. CRIGLER, J. F., and NAJJAR, '. A. (1952), Pediatrics, (1955), Y. clin. Invest , 34, 1268. IO, I 69. 68. RAMSAY, XV. N. M. (19w4). ' Ferrihaemoglobin in Normal ' and 20. CUSXVORTH, D. C., and DENT, C. E1. (1960), Bis)chemn. Y., Blood,' in Haemoglobin,' ed. Rouglbton, F. J. XX'., 74, 550. Kendrew, J. C. London: Butterworths. 21. DENT, C. E. (1959), Proc. Roev. Soc. Med., 52, 885. 69. RATHI3SUN, J. C. (19g8), Amer. Y. Dis. Child., 75, 822. 22. DUBIN, 1. N., and JOIINSON, F. B. (1954), M1edicine, 33, 155. 70. RATNER, S. (1954), Advanc. Enzzymol., 15, 356. 23. FOLLING, A. (1934), Hoppe-SeYl. Z., 227, 169. 71. RIMIINGTON, C. (1952), Acta med. ,S'cand., 143, i6t, 171. 72. SACHS, B., STERNFELD, L., and KRAUS, G. (1942), 24. FRASER, D. (1957), Amier.7. Mled., 22, 730. 252. 25. GARROD, A. E. (1902), Lancet, ii, i6i6. Amler. Y7. I)is. Child., 63, 73. SALKOXXSKI, E., and JASTROWl'I'Z, MI. (1892), Zbl. med. 26. (;ARROD, A. E. (1908), Ibid, ii, i and 73. Wiss., 30, 337. ' 27. GARROD, A. E. (1923), Inborn Errors of Metabolism,' 74. SC1HMID, R., AXELROD, J., HAMMAKER, L., and by copyright. 2nd edition. London: Frowde and Hocider & Stoughton. ROSENTHAL, I. M. (195;7), . clii,. Intest., 36, 927. 28. GIBSON, Q. H. (19i3), Biochemn. Y7., 37, 615. 75. SCHMID, R., SCHWARTZ, S., and SUNDBERG, R. D. 29. GIBSON, Q. H. (1948), Ibid., 42, 13. (I955), Blood, IO, 4I6. 30. GIBSON, Q. H., and HARRISON, D. C. (1947), Lantcet, 76. SCOWEN, E. F., WATTS, R. W. E., and HALL, E. G. ii, 941. (I959), Ann. hutmant Genet., 23, 367. 31. GILBERT, A., and LEREBOULLET, P. (1901), Sent. mned. 77. SCOWEN, E. F., STANSFELD, A. G., and WATTS, (Paris), 21, 241. R. W. E. ('959), Y. Path. Bact., 77, 195. 32. GODWIN, J. T., FOWLER, M. F., DEMPSEY, E. F., and 78. SEEGMILLER, J. E., LASTER, L., LIDDLE, L. V., and HENNEMAN, P. H. (1958), New Eng. Y. Med., 259, 1ogg. STETTEN, DE W. (1958), Abst. CoMM. 4th int. Congr. 33. GOLDBERG, A. (0959), Qluart. Y7. Med., N.S., 28, 183. Biochem., Vienna, 13-62, p. 172. 34. GOLDBERG, A., PATON, W. D. M., and THOMPSON, 79. SHEPARD, T. H1., KREBS, E. G., and LEE, L. S. (1958), J. W. (1954), Brit. Yt. Pharnitacol., 9, 91. Amter..Y. Dis. Child., 96, 490. 35. GRANICK, S. (I954), 'Metabolism of HIaem and Chloro- 8o. SMYTH, C. J., COTTERMAN, C. W., and FREYBERG, phyll.' In 'Chemical Pathways of Metabolism,' v-ol. 2. ed. R. H. (1948), Y. clin. Invest., 27, 749. http://pmj.bmj.com/ (;REENBERG, D. M. New York: Academic Press Inc. 8i. S'rANBURY, J. B., and HEDGE, A. N. (1950), Y. clin. 36. GRAY, C. H., RIMINGTON, C., and THOMPSON, S. Endocrin., 10, 1471. (1948), Quiart. 7. Med., N.S., 17, 123. 82. STANBURY, J. B., OHIELA, K., and PITT-RIVERS, R. 37. HALL, E. G., SCOWEN, E. F., and XX'ATTS, R. XV. E. (1955), Ibid., 15, 54. (1960), Arc/i. Dis. Child., 35, io8. 83. s'FET'rFEN, DE W. (1954), Geriatrics, 9, i63. 38. HAMIL'T'ON, J. G., SOLEY, MI. H., REILLY, XV. A., anid 84. TABECHIAN, H., ALTNIAN, K. I., and YOUNG, L. E. EICtHORN, K. B. ('943), Anmer. 7. D)is. ('ild., 66, 495. (1956), Proc. Soc. exp. Biol. (N.Y.), 92, 712. 39. HARRIS, H. (1959), Human Biochem--ical Genetics.' Cati- 85. 'I'HANNHAUSER, S. J. (i9_8), Lipidoses: Disorders of bridge: 'I'he University Press. Intracellular Lipid Metabolism.' New York and London: 40. HIARRIS, H., PENROSE, L. S., and 'I'HOMIAS, D. H. H. G'rune & Stratton. VON E. Beitr. path. Aniat., 82, 497. (1959), Anti. humiolat Cetnet., 23, 442. 86. GIERKE, (1929), on September 24, 2021 by guest. Protected 41. HIARRIS, H., and ROBSON, E. B. (0959), Ibid., 23, 421. 87. XXALDENSTROM, J. (1937), Acta tied. Scapnd., Suppl., 82. 42. HAUGE, M., anId HIARN'ALD, B. ('955), Acta nsed. Scamd., 88. NVALDENSTROM, J. (1956), Acta Genet., 6, 122. 152, 247. 89. XVALDENs'rROM, J. (1957), Amer. Y. Med., 22, 758. 43. HOGBEN, L., XXWORRALL, R. L., an' ZIEVE, 1. (1932), go. XVALLACE, HI. XV., MOLDAVE, K., and NIEISTER, A. Proc. Roy. Soc. Edinb., 52, 264. (1957), Proc. Soc. exp. Biol. (N.Y.), 94, 632. 44. HOLTI, G., RIMINGTON-,C. TATE, 13. C., and 'ITHOMAS, 91. XVATTS, R. XV. E., and CRAWHALL, J. C. (1959), Biochem. G. (1958), Quiart. Y7. Med., N.S., 27, 1. 7., 73, 277. 45. HOLZEL, A., KOMROWER, G. M\1., and SCHXX'AR'TZ, X'. 92. WESTALL, R. CG. (1958), Abstr. COMM. 4th int. Congr. (1957), Amer. .Y. Med., 22, 703. Biochemp., Vienna, 13-34, p. i68. 46 HORLEIN, H., and WEBER, G. (1948), D)tsch. sued. Wschr., 93. WESTALL, R. CG., DANCIS, J., an] MILLER, S. (1957), 73, 476. A.M.A.Y.. Dis. Child., 94, 571. 47. I-ISIA, D. Y. Y. ('959), Inborn Errors of M'letabolisml.' 94. NVETTSTEIN, A. (1958), Cited by E. M\1ossetig in summnarizing Chicago: The Year Book Publishers Inc. report on Symposiurn IV of the 4th Int. Congr. Biochem. 48. HSIA, D. Y. Y., DRISCOLL, K. XX'., TROLL, X_., and 95. XN'OOLF, L. I., GRIFFITHS, R., MONCRIEFF, A., COATE, KNOX, XXV. E. (1956), NTature (Lond.), 178, I239. S., and DILLISTONE, F. (1958), Arch. Dis. Child., 33, 31. 49. I-IUTCHINSON, J. H., and N/IcGIR1R, E. M'V. (1956), Laicet, 96. XX'ORCESTER-DROUGHTr, C., WHITE, J. C., and SAR. i, 1035. GENTl', F'. (1953), Brit. med. .7., ii, 114. 97. XVYNGAARDEN, J. B3. (Q957), 7. clin. Invest., 36, 15o8. 50. JARRETI', A., RINIINGTON, C., anid XX'ILLOUGHBY, 98. YU, T. F., WASSERMIAN, L. R., BENEDICr. J. D., BIEN, D. A. (1956), Ibid., i, 125. E. J., GUTMAN, A. B., and STETTEN, 1D 'W. (1953), 5i. JERVIS, G. A. (1954), Res, Puibl. Ass. nlerv. snetnt. Dis., 33, 259. Almer. Y. .lIed., 15, 845.