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486

A SURVEY OF SOME HEREDITARYMETABOLIC 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 thatthere are a few entities in which a characteristiccombination of clinical and chemical abnormalitiesis genetically transmitted. The number of diseasesand apparently harmless metabolic anomalieswhich have been recognized as belonging to thisgroup has increased considerably since Garrod in190225 described alkaptonuria as an ' inborn meta-bolic error'; and there are others such as diabetesmellitus, the causation of which appears to be atleast partly hereditary. The original hypothesisof a genetically determined enzyme block hasproved a fruitful one, ana it has received experi-mental support from the study of the specificblocks in metabolism which occur in mutantstrains of micro-organisms such as Neurospora.Some inherited chemically characteristic diseasesare due to a failure of specific renal tubular re-absorptive processes and presumably result ulti-mately from an abnormality of the enzymicmechanisms which effect active transport acrossthese cells.

All enzymes are probably proteins and theinborn enzyme defects are therefore specializedexamples within the group of diseases which aredue to inherited abnormalities of protein synthesis.Limitation of space prevents a discussion of otherinherited protein abnormalities such as the haemo-globinopathies, the congenital plasma proteindeficiencies and the deficiencies of the blood-clotting factors. The renal tubular reabsorptiondefects (e.g. cystinuria) have also been omittedfor this reason.

DISORDERS OF AMINO-ACIDMETABOLISM

AlkaptonuriaIn this disorder of aromatic amino-acid meta-

bolism there is a congenital deficiency of theenzyme homogentisic acid oxidase which convertshomogentisic acid (2 5-di-hydroxyphenyl aceticacid) to maleyl aceto-acetic acid. The disease wasdocumented from the clinico-pathological andgenetic aspects by A. E. Garrod, who also cor-

rectly forecast that it was due to a failure ofthe single enzymatic reaction which normallyopens the benzene ring of the aromatic amino-acids.25, 26, 27, 55, 58 Homogentisic acid forms abrown or black polymer on oxidation; this re-action occurs readily and is accelerated by alkali.It interferes in the Benedict's and Fehling's testsfor urinary glucose with the formation of anorange precipitate and a dark brown supernatantsolution, but the tests for glucose which do notdepend upon the reducing properties of the sugarare unaffected. Normal blood and urine do notcontain detectable amounts of homogentisic acidand the level in alkaptonuric patient's blood (about3 mg. per ioo ml.) is so low as to be near thelower limit of measurement by the available pro-cedures.66

Alkaptonuria may be detected in infancy by thecharacteristic dark staining of the urine-soilednapkins. In later life, usually after the age of 40,the cartilages, tendons, ligaments and scleraebecome demonstrably pigmented (' ochronosis ').This is first apparent clinically as a bluish-greydiscoloration of the auricular and nasal cartilagesand superficial tendons. The affected cartilagesfeel abnormally rigid and the earliest scleraldeposits take the form of brown triangular areaswhich have their bases directed towards thecorneoscleral junction; the sclerae subsequentlyacquire a uniform grey tint. Brown pigmentationof the ' butterfly ' area of the face, over the thenarand hypothenar eminences and of the nails aswell as a dark discoloration of the ceruminousand sebaceous secretions has been described andpigmentation of the bones, kidneys and of athero-matous plaques may be apparent at necropsy.Similar pigmentation occurs in chronic phenolpoisoning (' carbolic ochronosis '). Alkaptonuricscharacteristically develop osteoarthritic lesions inthe spine and large joints of the limbs. Theintervertebral discs are thin and calcified andectopic calcification may develop in bursae andtendon sheaths. The depth of pigmentation ofthe cartilage of the affected joints is not necessarily

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WATTS: A Survey of some Hereditary Metabolic Diseases

directly proportional to the severity of the osteo-arthritis, and carbolic ochronosis is not particu-larly associated with articular degeneration.Most cases of alkaptonuria display a recessive

(or homozygous) pattern of inheritance as judgedby the occurrence of multiple cases of the diseasein individual sibships, the parents being overtlynormal, and an incidence of parental consan-guinuity which is greater than that prevailinggenerally in the population from which thefamilies are drawn, the abnormal gene being rare.In these families the affected members are homo-zygous and their parents are heterozygous for theabnormal gene concerned. A few pedigrees havebeen reported,43 in which the disease appears tohave a dominant (or heterozygous) pattern ofinheritance; in these families affected individualsappear in successive generations, and the incidenceof parental consanguinuity is no greater than thatencountered generally in the population. Thisgenetic heterogeneity suggests that there may betwo biochemical lesions which can give rise toalkaptonuria. It is probable that the detailedbiochemical studies which have resulted in theformulation of the current concept of the aetiologyof the disease have all been performed on thecommoner recessive variety. Alkaptonuria appearsto be about twice as common in males as it is infemales in both genetic types, but no satisfactoryexplanation of this has so far been advanced.

Phenylketonuria (PhenylpyruvicOligophrenia; Phenylpyruvic Amentia)

Folling23 recognized that mental deficiency wassometimes associated with the presence of largeamounts (0.5-I g. daily) of phenylpyruvic acid inthe urine, and it has been shown that this asso-ciation exists in about one-half to one per cent. ofall mental defectives.The vast majority of cases are of imbecile grade

and have abnormal electroencephalograms. Epi-leptiform attacks and' organic' neurological signs(usually extrapyramidal) have been reported inabout 30% and 6o% of cases respectively.5,Stature and head size are only slightly reduced,the skin and hair tend to be fairer than theaverage for the population from which the casesare drawn, and the blood adrenaline level is saidto be abnormally low.The aetiological biochemical lesion is a defi-

ciency of one component of the phenylalaninehydroxylase enzyme system."' 90 Abnormallyhigh levels of phenylalanine are found in theblood and cerebrospinal fluid, and abnormal meta-bolites of this amino-acid are excreted in theurine. Phenylpyruvic acid is one of these and iseasily detected by the green coloration which itproduces when ferric chloride solution is added

to the acidified urine. The urine also containssome tryptophane derivatives whose presence, aswell as the lowered blood and urine levels of5-hydroxytryptamine and 5-hydroxyindole aceticacid respectively, could be explained on the basisof defective tryptophane hydroxylation.The pattern of inheritance is recessive and the

individuals who are heterozygous for the abnormalgene concerned (e.g. the parents of affected homo-zygous individuals) can be detected by their im-paired ability to metabolize a test dose of phenyl-alanine normally as judged by the rate of dis-appearance of the amino-acid from the bloodplasma.48 The fasting plasma phenylalanine levelsin the heterozygous subjects are also slightlyhigher than normal. Low phenylalanine diets arecurrently being tried therapeutically on theassumption that the abnormally high concentra-tions of phenylalanine or one of its metabolites areresponsible for the neuropsychiatric disorders.They need to be given from earliest infancy andalthough the obvious chemical abnormalities ofthe body fluids can be corrected in this way, andthe fits and electroencephalographic abnormalitiesabolished, their efficacy in promoting completelynormal mental development is still under long-term assessment.56' 9

TyrosinosisThe recognition of this third inborn metabolic

error of aromatic amino-acid metabolism restsupon the description of a single case of Medes"in which large amounts of tyrosine andp-hydroxy-phenylpyruvic acid were excreted in the urine.The conaition was associated with myastheniagravis, but in view of the lack of evidence thatother myasthenics have any similar metabolicdisturbance it is generally accepted that theassociation was a fortuitous one, and that tyro-sinosis itself has no clinical manifestations apartfrom the urinary abnormality. Medes's6l resultssuggest that a metabolic block exists betweenp-hydroxyphenylpyruvic and homogentisic acids.

AlbinismThis is a relatively common inborn metabolic

error, albinos constituting about i in 20,000 ofthe population of Great Britain. There is aninherited failure to form melanin due to the ab-sence of tyrosinase from t-he melanocytes. Thepinkish white photosensitive skin, white hair,translucent iris, nystagmus, photophobia anddefective vision are well known clinical findings.The failure of pigment synthesis may not becomplete, and in one genetically distinct (sex-linked) type the only albinotic change is foundin the eye ('ocular albinism'). The commonergeneralized form appears to be inherited as an

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autosomal (non-sex-linked) recessive character,although the situation is complicated by the factthat there is-more than one abnormal gene whichmay, when present in double dose (homozygosity)give rise to the condition. Thus albino parentswho are homzygous for different abnormal genescan beget non-albino children, the latter beingheterozygous for different genes responsible foralbinism.

Goitrous CretinismThe clinical association of non-endemic cre-

tinism and goitre is uncommon and three distinctbiochemical lesions, each representing a block atdifferent stages of thyroid hormone synthesis,have been identified as causes of this syn-drome.38, 49, 81, 82 The available data are com-patible with these conditions being due to theoperation of rare recessive autosomal genes.

Hartnup DiseaseBaron, Dent, Harris, Hart and Jepson5 reported

the clinical association of a pellagra-like rash,mental deficiency, neurological manifestations ofvarying severity (cerebellar 'ataxia, nystagmus,involuntary movements) and a renal amino-aciduria which, although generalized, does notinvolve all the amino-acids to the same degree.20The urine also contains unusual amounts of indolecompounds related to tryptophane (indolylaceticacid, indolylacetyl glutamine and indican). Threesibs showed the full syndrome and one other (theyoungest) had amino-aciduria only; the parents,who were normal, were first cousins. Othersimilar cases have been identified.47 It has notbeen finally decided whether this disease resultsprimarily from a block at some stage in themetabolism of tryptophane with secondary defi-ciency of nicotinic acid or whether it is primarilya disorder of amino-acid transport.39

Maple Sugar Urine DiseaseIn this disease high levels of the branched-

chain amino-acids valine, leucine and isoleucineare found in the blood and urine, whereas thelevels of threonine, serine and alanine are excep-tionally low,93 and it has been suggested that theunderlying abnormality is a failure to metabolizethe branch-chain amino-acids normally. The.affected children fail to thrive from the age of afew days; spasticity, opisthotonos and irregularjerky respirations are associated with feedingdifficulties, inanition and death during the firstweeks of life. The urine smells characteristicallyof maple sugar: this is thought to be due tocertain a.-hydroxy acids which are present; thepost-mortem appearances are non-specific. Theavailable evidence is compatible with this disease

also being due to the operation of a rare recessivegene.62

Argininosuccinic AciduriaThis disease is characterized by the presence of

argininosuccinic acid in the urine, blood andcerebrospinal fluid. Argininosuccinic acid is anintermediate compound in the ornithine cycle ofurea formation,70 and its relatively high cerebro-spinal fluid level in the disease has suggested thatit may be formed in the central nervous systemdue perhaps to a block in some hitherto unrecog-nized metabolic process; the blood and urineurea levels are normal.1' 21, 92

Allen et al.' described the disease on the basisof their study of two sibs (aged three and six yearsrespectively) whose parents were unrelated. Bothchildren had grossly abnormal electroencephalo-grams and were severely mentally retarded, al-though they had apparently developed normallyduring the first year of life, and there was nodefinite evidence of microcephaly. One patientwas epileptic, and motor inco-ordination withchoreo-athetoid features was present for severalweeks after a series of fits. Friable hair, cardiacsystolic murmurs and elevated serum alkalinephosphatase levels were noted in both cases.

3-aminoisobutyric AciduriaSome otherwise normal people excrete about

50-200 mg./24 hours of f-aminoisobutyric acid intheir urine as opposed to the much smalleramounts which are normally present. There isevidence that thi's represents a harmless inbornanomaly of thymine metabolism, although itsmode of inheritance has not been elucidated.39

CystathioninuriaHarris, Penrose and Thomas40 found large

amounts of cystathionine, an intermediary inmethionine metabolism, in the urine of an elderlymental defective, and increased amounts of thesame amino-acid were found in the patient'sliver and kidney tissue post mortem, althoughthere was no evidence that it accumulated in theblood. Cystathionine cannot be detected in theurine of normal subjects, but a clinically normalnephew and brother of the propositus excretedamounts which, although less than those excretedby the propositus, were still appreciable. Theseobservations suggest that cystathioninuria maybe due to a genetically determined metaboliclesion which results in a failure to convert cyst-athionine to homoserine and cystine.

Primary HyperoxaluriaPrimary hyperoxaluria, which has a recessive

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pattern, of .inheritance,* 76 causes severe pro-gressive urolithiasis and nephrocalcinosis begin-ning in childhood and is characterized by a con-tinuous high urinary excretion of oxalate, much ofwhich is derived from glycine. About the samedegree of isotope dilution occurred between theprecursor glycine (labelled with 13C) and theurinary oxalate in patients with primary hyper-oxaluria and a normal subject; this suggests thatthe fundamental abnormality in primary hyper-oxaluria is a failure to degrade glyoxylate normallyto formate and carbon dioxide with secondaryover-production of oxalate, rather than excessivemetabolism of glycine via the pathway:'7

CGlycine * Glyoxylate - -. Formate + COt

Oxalate

Such a metabolic lesion need involve only a smallpart of the normal glycine metabolic turnover inorder to produce the amount of oxalate whichpatients with this disease excrete.9' The ali-mentary absorption of oxalate is not excessiveand there is no evidence of a primary renal defectin these cases.2 Numerous calcium oxalate mono-hydrate crystals are found in the walls of smallmuscular arteries and arterioles, the rete testis,the myocardium, the growing regions of bonesand, less extensively, in other tissues as well asin the kidneys at necropsy.32, 77 It has not provedpossible to determine clinically the stage in theevolution of the disease at which the extrarenaldeposition of oxalate (' oxalosis ') begins and theprecise level of the urinary oxalate excretioncannot be correlated with the age at which obviousstone formation begins or with its rate of pro-gression; the prognosis is, however, bad.37 Itappears that the blood oxalate level is not grosslyelevated except at a very late stage in the evolutionof the disease.'8 Small amounts of oxalate havealso been found in cerebrospinal fluid collected atpost mortem, none being detectable in appropriatecontrol material.37 77

DISORDERS OF CARBOHYDRATEMETABOLISM

GalactosaemiaInfants with this recessively inherited metabolic

defect appear normal at birth,-but after a few daysof milk feeding become lethargic, vomit and failto thrive; abdominal distension and hepato-megaly develop and there is a prolonged periodof neonatal jaundice. Should they survive infancy,

* Shepard, Krebs and Lee's79 report raises the possi-bility that a rare dominant variety of the disease mayexist. The studies which form the basis of this reviewwere perfonned on the recessive-type.

mental retardation, stunted growth, cataracts andhepatic cirrhosis become apparent. Proteinuria, ageneralized amino-aciduria and high concentra-tions of glactose in the blood and urine are theobvious chemical accompaniments. The diseaseis due to a deficiency in the enzyme system,which converts galactose-i-phosphate to glucose-i-phosphate; this can be demonstrated in thepatient's erythrocytes as well as in isolated livertissue. The crippling effects of this metaboliclesion can be prevented by the administration ofa galactose-free diet from earliest infancy, whichis achieved by the use of protein hydrolysates orproprietary lactose-free milk preparations. Theaffected children acquire tolerance for smallamounts of milk as they grow older.45

Essential Pentosuria (L-xyloketosuria)The first reported case of this condition was

that of Salkowski and Jastrowitz in i89273 and itwas one of the four original, inborn metabolicerrors described by Garrod. Only traces ofL-xyloketose (L-xylulose) can be demonstratedin the blood of these patients and apart from theexcretion of several grams of L-xyloketose (L-xylulose) daily there are no clinical or chemicalabnormalities. Most of the patients are of CentralEuropean Jewish descent and the pattern ofinheritance is recessive (homozygous). No abnor-malities have so far been demonstrated in thesubjects who are presumably heterozygous forthe abnormal gene. Essential pentosuria shouldbe- distinguished from the transient secondarypentosuria (D-arabinosuria) which follows theingestion of large amounts of fruit. Pentosesreduce Benedict's reagent so that most cases ofessential pentosuria are found during the courseof routine medical examination.

L-xylulose is a normal metabolic intermediatein one of the pathways of glucose metabolism; itsfurther metabolism is via the pentose-phosphatecycle as a result of which its carbon atoms maybe reincorporated into glucose. D-glucuronicacid is another intermediate on this pathway ofglucose metabolism and the administration: ofglucuronogenic drugs increases the excretion ofL-xyloketose in essential pentosurics and causesit to appear in the urine of normal subjects,;ribulose is also excreted under these circum-stances.6 There may be some as yet incom'pletely explored connection between L-xyloketoseand ascorbic acid metabolism for the biosyntheticpathways from glucose to both compoundsappear to be identical as far as their immediateprecursor.

Essential FructosuriaThis recessively inherited biochemical anomaly

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also produces no untoward clinical manifestations.The urine contains fructose only when this sugaris present in the diet, the patient's ability tometabolize a test dose of fructose is diminished,and the parents who are presumably heterozygousfor the abnormal gene are not demonstrablyabnormal. It has been suggested that fructosuricsare unable to metabolize the fraction of thedietary fructose which is normally metabolizeddirectly to lactic acid.72

Congenital Deficiency of ErythrocyteGlucose-6-phosphate DehydrogenaseThe red cells of patients in whom acute

haemolysis follows the administration of prima-quine, sulphanilamide, acetanilide, naphthalene,thiazosulphone, phenylhydrazine, menaphthoneand fava beans are deficient in glucose-6-phos-phate dehydrogenase activity and contain abnor-mally small amounts of reduced glutothione.The reduced glutathione content of the erythro-cytes decreases further when an haemolytic crisisis induced and in vitro incubation of a ' sensitive 'individual's red cells with acetylphenylhydrazinealso diminishes their reduced-glutathione co-tent.13 The affected males inherit the conditionfrom their mothers only, and the clinical mani-festations are more severe in males and in femaleswho are homozygous for the gene than in thecorresponding heterozygous females.

Hereditary SpherocytosisErythrocyte glycolysis is defective in this

disease,67 and Tabechian, Altman and Young" havesuggested that this involves the step 2-phospho-glycerate->phosphoenolpyruvate which is nor-mally catalyzed by enolase. The mode of inheri-tance is dominant, but a few cases have beenreported whose parents were proved to behaematologically normal; these might be theresults of fresh mutations or represent a differentmetabolic lesion which causes spherocytosis.

Hereditary Non-spherocytic HaemolyticAnaemia

This newly-recognized condition which ischaracterized by mild intermittent haemolyticicterus and other symptoms attributable to epi-sodic intravascular haemolysis is considered onthe basis of recent biochemical studies to be dueto another abnormality of intraerythrocytic glu-close metabolism which has a dominant patternof inheritance.65

The Glycogen-storage DiseasesThe polysaccharide glycogen has a molecular

weight of several million and is composed entirelyof glucose-units which are linked together to form

a multibranched structure. It functions as acarbohydrate store to which glucose may beadded, or from which it may withdrawn bylengthening or shortening the polysaccharidechains. Glucose storage begins with the con-version of glucose-6-phosphate (formed by thereaction of glucose and adenosinetriphosphateunder the influence of hexokinase) to glucose-i-phosphate by phosphoglucomutase. Glucose-i-phosphate is built on to the pre-existing core ofthe glycogen molecule by phosphorylase; inor-ganic phosphate is liberated and removed byoxidative phosphorylation. The ' brancher'enzyme (' amylo-(i: 4-* 6) transglucosidase ')comes into action when about eight successiveglucose residues have been added and effects abranch point in the glycogen molecule. Thesuccessive actions of phosphoglucomutase andthe brancher enzyme build up an arborescentstructure. Glucose mobilization follows a similartbut reversed, pattern-phosphorylase hydrolysesthe outer polysaccharide chains until the branchpoints are reached; these are hydrolyzed by the' debrancher' enzyme (' amylo-i :6-glucosidase')and another series of glucose residues are madeaccessible to the action of phosphorylase. Theimmediate product of phosphorylase action isglucose-i-phosphate which accounts for about92% of the glycogen hydrolyzed (the remainderemerging as free glucose). Phosphoglucomutaseconverts glucose-i-phosphate to glucose-6-phos-phate which is converted to free glucose byglucose-6-phosphatase in liver and kidney tissue.In muscle, where there is no glucose-6-phospha-tase, glucose-6-phosphate is either converted tolactic acid or completely metabolized.The condition described by von Gierke86 in

which there is abnormal glycogen storage in theliver and kidneys only, results from glucose-6-phosphatase deficiency and is now referred to as' Type i glycogen-storage disease.' It occurs ina severe form, associated with extremely low liverglucose-6-phosphatase levels,16 and in a clinicallymilder form in which the enzyme deficiency is ofsmaller degree. The severely affected infants failto thrive, have gross hepatomegaly and readilybecome hypoglycaemic and ketotic. The glucosetolerance curve is flat and the hypoglycaemia isunaffected by adrenaline. Death' from inter-current infection in early childhood is usual andthe customarily recommended regime of frequenthigh protein feeds does not seem to influence thecourse of the disease. Patients with the mildervariant may survive to adult life and they mayultimately have few disabilities. Type i glycogen-storage disease has a recessive mode of inheritance,whether the two sub-types shouldbe regarded asthe same genetic entity appears to be uncertain.

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Hsia47 has shown that the presumed heterozygouscarriers of the abnormal gene have elevated levelsof glucose-6-phosphate and fructose-6-phosphatein their erythrocytes.

In Type 2 glycogen-storage disease the poly-saccharide accumulates in the myocardial, smoothand skeletal muscle fibres. The heart is enlargedand globular, there are left axis deviation andischaemic changes in the electrocardiogram, andthe patients usually die from heart failure ininfancy. The pattern of inheritance is recessive,but nothing is known of the underlying enzymicdefect.

In Type 3 glycogen-storage disease15 theglycogen has abnormally short outer chains dueto deficiency of ' debrancher' enzyme53 andglycogen deposits occur in the hepatic, myocardialand skeletal muscle cells. Hepatomegaly, cardio-megaly, macroglossia, fasting hypoglycaemia andsometimes generalized progressive muscular weak-ness are apparent clinically. In some cases thelatter feature may be so prominent that the diseaseresembles amyotonia congenita.57

In the fourth type of glycogen-storage diseasethe glycogen molecules have abnormally longchains of glucose residues between the branchpoints;15 this is believed to be due to a deficiencyof the ' brancher' enzyme. The physical pro-perties of this abnormal glycogen resemble thoseof amylopectin (a starch polysaccharide); itaccumulates in the liver parenchyma and the cellsof the reticuloendothelial system. The mani-festations of diffuse hepatic cirrhosis dominatethe clinical picture, the blood sugar is normal,there is no ketosis and the response to adrenalineis sub-normal. Chemical investigation of theglycogen isolated from a liver biopsy specimenhas been used to confirm the diagnosis.54 59The disease progresses at a variable rate and itseems that patients may survive to the age ofabout ten years; it may be that some cases whichhave been labelled ' familial hepatic cirrhosis'have been examples of Type 4 glycogen-storagedisease.

Although cases of glycogen-storage disease canbe conveniently classified into these four groups,'5Calderbank, Kent, Lorber, Manners and Wright'2have encountered two sibs, one with glucose-6-phosphatase deficiency, the other with ' de-brancher ' enzyme (amylo-i : 6-glucosidase) de-ficiency.

DISORDERS OF LIPID METABOLISMIdiopathic hyperlipaemia is characterized by

gross elevation of the neutral fat and fatty acidfractions of the serum lipids, the cholesterol andphospholipid fractions being only slightly raised.

The al, a2 and p,i-globulin fractions of theserum proteins are elevated.

Beurger and Grutz" described the juvenilevariety of the disease as a syndrome of acuteattacks of abdominal pain, with cutaneous xantho-matosis and milky whiteness of the serum underfasting conditions. The yellowish pink ' eruptive 'xanthomata are surrounded by an inflammatory-looking red halo; they occur most commonly onthe buttocks, back and limbs, but may be general-ized, and the oral mucosa may be involved.Hepatosplenomegaly may be present and feverwith a polymorphocytosis accompanies the acuteepisodes. The occurrence of the latter cannot becorrelated with changes in the blood lipid level.A low fat diet or long-term heparin administra-tion diminish the serum turbidity, restore theplasma protein electrophoretic pattern to normaland cause the gradual disappearance of thecutaneous xanthomata. Buerger-Griutz's diseasehas a recessive pattern of inheritance, some of thepresumably heterozygous subjects have slightlyincreased serum lipid levels.9

Thannhauser85 has described an adult variantof the disease in which there may be few abnor-malities apart from the hyperlipaemia, and deniesthat these cases suffer from angina or myocardialinfarction at an unusually early age. The co-existence of cutaneous xanthomata and someimpairment of glucose tolerance in adult idio-pathic hyperlipaemia sometimes results in thesecases being confused with examples of xanthomadiabeticorum.

Familial hypercholesterolaemic xanthomatosis ap-pears to be due to excessive cholesterol synthesis.The serum cholesterol level is greatly elevated,but the other plasma lipids are normal or onlyslightly increased. It is unrelated to normo-cholesterolaemic xanthomatosis (eosinophilic xan-thomatous granuloma, lipid granuloma, Schiiller-Christian's syndrome), whichis probably notgenetically determined except in the acutegeneralized form (Letterer-Siwe's disease).85

In familial hypercholesterolaemic xanthomatosisthe cutaneous lesions (' xanthoma tuberosum etplanum ') have an orange-yellow colour, a ' vel-vety' consistency and vary in diameter from afew millimetres to several centimetres. Theyoccur mainly on the eyelids, on the extensorsurfaces of the limbs and on the buttocks. Non-pigmented subcutaneous xanthomatous depositsalso occur. Tendon-xanthomata, which are afeature of this disease, occur most commonly inthe tendo Achilles, the patella tendon and theextensor tendons of the fingers. Death due to thecardiovascular complications of extensive atheromamay occur at an early age. Hypercholesterolaemiais the constant and may be the only feature of the

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disease, the cutaneous and cardiovascular mani-festations being variable.The genetic analysis of familial hypercho-

lesterolaemia is rendered difficult by the normal,but variable, rise in the serum cholesterol withage. It appears to be transmitted in a dominantfashion, and it has been suggested that patientswith extensive cutaneous lesions or markedatheroma at an early age are homozygous for theabnormal gene.

The Disorders in which Cerebrosides,Sphingomyelins and GangliosidesAccumulateThe ceramides are the amides of sphingosine

(an amino-alcohol) with a higher fatty acid; thesphingomyelins are choline or ethanolamine phos-phoric acid esters of the ceramides, and theydiffer from one another in respect of the fattyacid component of the ceramide moiety. Thecerebrosides consist of a ceramide, the fatty acidof which is linked to a galactose or glucoseresidue. The cerebrosides of normal tissue con-sist almost entirely of galactocerebrosides andonly small amounts are present in cells other thanthose of the nervous system. The ceramidesappear to be intermediate in the biosynthesis ofboth the sphingomyelines and the cerebrosides:

SPHINGOMYELINSI t

Phosphoryl choline or phosphorylethanolamine

CERAM IDES

Glucose or galactoseI -if

CEREBROSIDESThe gangliosides are related compounds, the exactstructures of which are not known. They containa ceramide linked to glucose, galactose, chondro-samine and neuraminic acid (a polyhydroxyamino-acid), and have been isolated from somenormal tissues.

In both the adult and infantile forms ofGaucher's disease, either glucocerebrosides aloneor a mixture of galactocerebrosides and gluco-cerebrosides accumulate in the reticuloendothelialcells. This is attributed to imbalance of theintracellular enzymes which effect the intercon-version of the ceramides and cerebrosides.85 Theadult form of Gaucher's disease usually presentsin late childhood or early adult life, and may becompatible with relatively little disability. Inthis type Gaucher cells (cerebroside-containing

reticuloendothelial cells) are found mainly in thespleen, which is usually very large, the liver andbone marrow; bone pain and deformities, blooddyscrasias and brown pigmentation (most com-monly involving the face, backs of the hands andanterior aspects of the legs) are characteristicclinical findings. In the relatively rare infantiletype the child usually seems normal at birth, buthepatosplenomegaly, cyanotic attacks, neurologicalmanifestations and poor mental development are-soon apparent, and death is usual during the firstyear of life. Numerous Gaucher cells are demon-stable in the thymus, adrenal, intestinal lymphfollicles and lungs, as well as in the organs whichare involved in the adult varietv. Gaucher cellshave not been found in the nervous tissue asopposed to the meninges of these patients. Theganglion cells of the brain are distended, but donot contain abnormal amounts of cerebrosides.Pedigrees suggesting both dominant and recessivepatterns of inheritance for Gaucher's disease havebeen described.47 85 These apparent geneticdifferences have not been correlated with possibleminor chemical differences in the cerebrosides.There is a suggestion that infantile and adultforms of the disease may be genetically distinct.47

Niemann-Pick's disease in which sphingo-myelin accumulates in the reticuloendothelialcells is attributed to imbalance of the intracellularenzymes which effect the metabolic turnover ofphospholipids. Clinical abnormalities usuallybecome apparent when the infant is about threemonths old, hepatosplenomegaly results in grossabdominal distension with wasting, anaemia,muscle hypotonia, mental retardation, yellowish-brown cutaneous pigmentation, generalized lymph-adenopathy and progressive blindness and deaf-ness. The macula lutea shows a cherry-red spotin about 50% of cases. ' Foam cells' (sphingo-myelin-containing histiocytes) are often presentin the peripheral blood (cf. the invariable absenceof Gaucher cells from this situation) and theplasma phospholipid level is low. Foam cellshave been detected histologically in virtuallyevery organ except the central nervous systemand the skin. The ganglion cells of the brain andretina are swollen and degenerate, but this is notdue to an abnormal accumulation of sphingo-myelin within them. The sphingomyelin contentof the brain is normal although differences be-tween the fatty acid composition of specimensprepared from normal brain and specimens pre-pared from the brains of patients with Niemann-Pick's disease have been reported. The ganglio-side content of the brain is increased and it seemsthat this is responsible for the apparent distensionof the ganglion cells. Patients with the rareadult form of the disease are usually unaware of

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WATTS: A Suirvey of some Hereditary Metabolic Diseases

their disease until it is detected during a routineexamination. The lungs, liver and spleen are themost extensively involved organs, and pulmonaryinfiltration may cause diffuse pulmonary fibrosiswith cor pulmonale. It has been suggested thatNiemann-Pick's disease has a recessive patternof inheritance, patients with the infantile formbeing homozygous for the gene concerned, thosewith the adult variant being the correspondingheterozygous individuals; further genetic studiesof this disease are, however, needed.Tay-Sachs disease (infantile amaurotic familial

idiocy) occurs mainly in Jews and has a recessivepattern of hereditary transmission. It is charac-terized chemically by the accumulation of verylarge amounts of gangliosides in the centralnervous system in the absence of visceral sphingo-myelin accumulation. The possibility that theganglioside content of the brain may be increasedin other genetically-determined degenerative dis-eases of the nervous system has not been investi-gated.85 Cases of Tay-Sachs disease appearnormal at birth, but delayed mental development,fits, amaurosis and the classical ' cherry-red ' spotin the region of the macula lutea are apparentby the age of six months; and they usually dieduring the first two years of life.

The PorphyriasThe porphyrias are primary disorders of por-

phyrin synthesis, and they should be distinguishedfrom the porphyrinurias in which the increasedurinary and faecal porphyrin excretion is asecondary phenomenon (e.g. when there is ab-normally active erythropoesis). Porphyrin bio-synthesis takes place according to the followingsimplified scheme:

Stage i: One molecule of glycine and onemolecule of succinate combine to form 8-amino-laevulic acid. This reaction only occurs if thesuccinate has been activated by Coenzyme-A('succinyl Coenzyme-A').

Stage 2: Twvo molecules of 8-aminolaevulicacid combine to form one molecule of porpho-bilinogen. This compound contains the fivemembered ' pyrrole' ring which occurs in theporphyrins.

Stage 3: Four molecules of porphobilogen com-bine to form uroporphyrin. Two isomeric uro-porphyrins can result at this stage and are de-scribed as belonging to ' Series I ' and ' Series III.'The physiologically important porphyrins belongto Series III and normally only small traces ofSeries I porphyrins are formed.

Stage 4: Uroporphyrin III forms copropor-phyrin III by loss of the carboxyl groups fromfour of its eight side chains.

Stage 5: Partial dehydrogenation of two of the

side chains converts coproporphyrin III to proto-porphyrin III.

Stage 6: Haem is formed from protopor-phyrin III by the insertion of one atom of ferrousiron per molecule.

Acute Intermnittent PorphyriaAttacks of severe intestinal colic, constipation

and episodic neurological manifestations (pain',hypoaesthesia, paresis, fits, coma and psychiatricsymptoms) sometimes accompanied by fever andhypertension, and beginning at puberty, arecharacteristic of this disease. The onset of anacute attack can sometimes be traced to bar-biturate administration; pregnancy also appearsto affect the disease adversely. The urine is darkred (port-wine coloured) during the acute episodesand contains large amounts of porphobilinogenand 8-aminolaevulic acid; small amounts of thezinc complexes of Series I and III uroporphyrinsand coproporphyrins are also present. There isno urinary abnormality until the first attack andrelatively low levels of porphobilinogen and8-aminolaevulic acid excretion are found betweenthe attacks. It is suggested that the uroporphyrinsand coproporphyrins are formed secondarily fromexcreted porphobilinogen when this reaches veryhigh levels. Necropsy shows patchy demyelinationof the peripheral nerves and in the central nervoussystem.The biochemical lesion has not been identified,

it may be that the conversion of porphobilinogento uroporphyrin III is blocked, or there may bea defect in the balance of synthesis and utilizationof 8-aminolaevulic acid via other metabolic path-ways so that it accumulates and is converted toporphobilinogen in the liver. The clinical mani-festations cannot be accounted for by the knownpharmacological properties of porphobilinogen or8-aminolaevulic acid.34 50 Affected individualsand asymptomatic porphobilinogen excretors arebelieved to be heterozygous for the gene con-cerned.33, 87, 88, 89 Only symptomatic treatmentis available for the acute attacks, although Gold-berg33 has suggested that corticotrophin or cor-tisone may be helpful if given early in the attack.

Contgenital PorphyriaLarge amounts of Series I porphyrins, which

cannot be utilized or metabolized in the normalway, are synthesized in this disease. They accu-mulate in the bones, teeth, erythrocytes and skinand are excreted in the urine and bile; the urinedoes not contain porphobilinogen or 8-amino-laevulic acid. The bones and teeth, which arereddish-brown, and the urine fluoresce in ultra-violet- light. The skin is abnormally photo-sensitive and bullous eruptions (hydroa aestivale),




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which heal slowly and leave considerable scarringand deformity, occur on the exposed skin sur-faces. A chronic haemolytic anaemia possiblydue to erythocyte-photosensitivity is usuallypresent and there may be splenomegaly. Por-phyria congenita is thought to be due to theoperation of a rare recessive gene for which thepatients are homozygous.75 These investigatorsalso make the novel suggestion that two series oferythrocytes and erythrocyte-precursors exist inthe same patient, porphyrin synthesis being ab-normal in one series and normal in the other.

Porphyria Cutanea TardaThe clinical manifestations of porphyria cLu-

tanea tarda are intermediate between those ofacute intermittent porphyria and porphyria con-genita, but they are less disabling. Attacks ofintestinal colic and cutaneous photo-sensitivityvith vacciniform lesions of the exposed skinareas begin in early adult life, but neurologicalmanifestations are rare and less severe than thosewhich occur in acute intermittent porphyria.During remissions, large amounts of protopor-phyrin and coproporphyrins are excreted in thefaeces; this diminishes during the acute exacerba-tions of the clinical manifestations when largeamounts of Series I and Series III uroporphyrinsand coproporphyrins appear in the urine. Por-phobilinogen is absent from the urine exceptpossibly terminally. It has been suggested thatthe metabolic lesion in porphyria cutanea tardainvolves the step:

Protoporphyrin III--haemand that the acute manifestations are related toepisodic disturbances of hepatic function whichinhibit the biliary excretion of the abnormal pig-ments.35, 36 71 It seems likely that the caseswhich have been described under this title maycomprise more than one entity.89 Adequategenetic studies require faecal as well as uriinaryporphyrin analyses in order to detect asympto-matic cases. Where this has been done the resultshave suggested a dominant pattern of inherit-ance.44

Hereditary CoproporphyriaLarge amounts of coproporphyrin III are ex-

creted in the urine and faeces in this apparentlyrecessively-inherited anomaly.8 There are nosymptoms such as occur in the other porphyrias,although it has been suggested that there may bea predisposition to riboflavine deficiency.

The Congenital MethaemoglobinaemiasIn these conditions the iron of an appreciable

proportion of the circulating haemoglobili istrivalent (methaemoglobin or ferrihaemoglobini).

They -have to be distinguished from secondarymethaemoglobinaemia due to phenacetin, anti-pyrine, acetanilide and nitrates.

Gibson-Harrison Type (' Congenital IdiopathicMethaemoglobinaemia')

This condition results from an inborn deficiencyof the enzyme system which normally keeps theiron of haemoglobin in the divalent state (ferro-haemoglobin). The chemical conditions withinthe erythrocyte, particularly on the venous sideof the circulatory system, are such as to favour theconversion of ferrohaemoglobin to ferrihaemo-globin and a small proportion (about o.4°)) ofthe total circulating haemoglobin is in this physio-logically inert form. 68 Ferrihaemoglobin accountsfor between io and 450O of the total circulatinghaemoglobin in congenital, idiopathic methaemo-globinaemia, the patients have life-long historiesof cyanosis and there may be slight compensatorypolycythaemia.4 Apart from an inconstant asso-ciation with mental defect,96 there is usually nodisability associated with the condition. Intra-venous injection of ascorbic acid or of methylene-blue temporarily relieves the cyanosis; these twosubstances appear to act in different ways.28 29Trhe oxygen dissociation curve is shifted to theleft; a similar shift is observed in haemoglobinsolutions containing methaemoglobin in vitro, andhas been attributed to interaction betweenhaemoglobin and methaemoglobin. If this ex-planation is correct, the observation suggests thatmethaemoglobin is present in all the erythro-cytes rather than being segregated in some ofthem. If the two pigments were segregated intodifferent cells there could be no interactionbetween them and the oxygen dissociation curvewould have a normal shape.

Tl"he data of Gibson and Harrison341 arc com-patible 'vith a recessivc pattern of inheritance,but Codounis14 studied a family whose pedigrecsuggested dominant transmission. The enzymicdefect xvas not investigated in the latter familyso it is uncerta n wvhether these cases vere of theGibson-Harrison type, although the cyaniosis wvasrelieved by ascorbic acid and by methylene-bluc.

Horlein- Weber Tvpe46This variety is due to an abnormality of the

globin moiety of haemoglobin which is thoughtto make the iron atom unduly easily oxidizableso that the rate of production of ferrihaemoglobinexceeds the capacity of the erythrocyte-reducingsystems. Between I 5 and 2500/ of the haemo-globini is in the form of ferrihaemoglobin, andthis is uinaffected by vitamin C and methylene-blue. 'The pattern of inheritance is dominiant;

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the abnormal haemoglobin (' haemoglobin M')has characteristic electrophoretic properties.

The Congenital HyperbilirubinaemiasCrigler-Najjar Type'9, 74

Glucuronide synthesis, including the formationof bilirubin glucuronide (conjugated or directreacting bilirubin) is grossly defective in thesepatients due to a recessively inherited deficiencyof glucuronyl transferase. The patients, who aredeeply icteric by the second day of life, becomespastic and choreoathetotic and die in earlychildhood. Their serum bilirubin consists vir-tually entirely of unconjugated (indirect reacting)bilirubin. Subjects (the parents and some sibs),who may be presumed to be heterozygous forthe abnormal gene but are not jaundiced, showsome impairment of their ability to make glucuro-nide conjugates.Gilbert Type 3, 31, 63This is a benign condition in which inter-

mittent jaundice is usually first noticed duringthe second or third decades. There is a smallincrease in the circulating unconjugated bilirubin,and the mode of inheritance appears to bedominant. Impaired glucuronide synthesis hasbeen demonstrated, and the Gilbert and Criger-Najjar types of congenital hyperbilirubinaemiaare presumably closely related to one another.

Dubin-Johnson Type 22Patients with this condition suffer no disability

apart from intermittent icterus which is usuallyfirst noted in early life. The hyperbilirubinaemiais due to the presence of increased amounts ofconjugated bilirubin so there is bilirubinuria.The aetiology of this condition is uncertain, itappears to be familial; the liver looks greenish-black on macroscopic examination and the livercells contain brown iron-free and bile-free pig-ment of uncertain composition.52

GoutThe purine moieties of the nucleic acids are

synthesized in the body from glycine and othersmall molecules (formate, CO2 and NH3) via4-amino-5-imidazole-carboxamide ('AIC '), thestructure of which is:

H1N- 0-o

L -NH

CH

H2N C--- NNormally, the endogenous urinary uric acid isderived mainly from nucleic acid catabolism and

to a lesser extent via an alternative (' shunt ')pathway which appears to leave the main routeafter the 4-amino-5-imidazole-carboxamide stage:

+ NH3Glycine -j AIC-..+ Purine moeties of

+ CO. t nucleic acids-) II

Shunt'Pat hwayv Catabolism

"Uric acid

The underlying abnormality in gout appears toinvolve excessive uric acid production via the' shunt' pathway, but the precise nature of themetabolic lesions has not been elucidated.7' 78, 83, 97In contradistinction to this, the increased uricacid production which may give rise to goutymanifestations in patients suffering from suchdiseases as polycythaemia rubra vera and myeloidleukaemia results from increased nucleic acidturnover. 98The occurrence of multiple cases of gout in a

given family is well recognized, but except for apreponderance of male cases the pedigrees, asjudged by the clinical manifestations, are usuallyirregular, and apparently sporadic cases arecommon. The distribution of plasma urate levelsamong the relatives of gouty patients has beenstudied by several groups of workers. Smyth,Cotterman and Freyburg80 concluded that hyper-uricaemia was an inherited character whichappeared in subjects who were heterozygous forthe gene and about io% of these develop clinicalgout, for some, as yet, unexplained reasons. Ifthis is correct the rare cases in which very severegout develops in early life might be homozygousfor the abnormal gene concerned. The data ofHauge and Harvald42 do not, however, fit thisrelatively simple hypothesis.

HypophosphatasiaPatients with this disease, which resembles

rickets clinically and radiologically, have lowserum and tissue alkaline phosphatase activities,and excrete large amounts (IOO-200 mg./l.) ofethanolamine phosphate in the urine. Ethanol-amine phosphate occurs in the cells of manytissues, but only trace amounts which could bederived from the breakdown of cephalins arenormally present in the urine, and there is noevidence that it normally has any specific functionin connection with bone formation.The clinical severity of the disease appears to

be very variable, ranging from skeletal abnor-malities which are sufficiently severe to beapparent radiologically in utero to minor de-formities which are only detected in later child-




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496 POSTGRADUATE MEDICAI, JOURNAL, Auiguist 196o

hood or adult life.24 6' It appears that the overtcases of hypophosphatasia are homozygous for arare abnormal gene; the heterozygous individualshave been identified by their small but signi-cantly raised ethanolamine phosphate excretion.The wide variation in the normal serum alkalinephosphatase level makes this parameter unsuit-able as a means of identifying the heterozygotes,although the average values for groups of thesesubjects have been found to be lower than thoseof control subjects.4'

Cusworth and Dent20 reported that an adultpatient with hypophosphatasia had a low. plasmathreonine level, a small excretion of proline andincreased excretions of taurine, threonine andserine. The relationship of these resuLlts to theother chemical features of the syndrome is notapparent.

Congenital Serum PseudocholinesteraseDeficiencySome otherwise normal individuals have ab-

normally low levels of serum pseudocholinesteraseactivity and are therefore unduly sensitive to themuscle-relaxant drug, suxamethonium.60 Thistrait has a recessive pattern of inheritance and isdue to the formation of an enzyme protein withcatalytic properties wvhich differ from those of itsnormal counterpart.39

Congenital Adrenal HyperplasiaThere is a failure to complete the synthesis of

cortisol (hydrocortisone) in congenital adrenalhyperplasia and cases of this condition can beclassified clinically into three groups:

i. Those wvith virilization only.2. Those with virilization and inability to retain

sodium.3. Those with virilizationi and hypertension.Progesterone is hydroxylated at carbon atoms

numbers 17, 2I and ii to form hvdrocortisone;1'0although not necessarily in this order. 94 Theexcretion products of the adrenocortical steroidshave either 2I or I9 carbon atoms. The latter(the ' adrenal I7-ketosteroids ') are androgenic.Failure of progesterone hydroxylation preventsthe synthesis of hydrocortisone, the level of cir-culating adrenocorticotrophic hormone is in-creased and the gland is stimuilated to produceabnornmal amounts of the incompletely hydroxy-lated precursor substances wNhich are degradedin part to I 7-ketosteroids. A high circulating levelof these androgens beginning during intrauterinelife produces pseudohermaphroditism in girls andmacrogenitosomia praecox with hypoplastic testesin boys.

In the commonest type of congenital adrenalhyperplasia, virilization is the only manifestation,

an-d the urinary excretions of i7-ketosteroids anid3x, 170, 20oc-pregnantriol (a derivative of 170-hydroxy-progesterone) are high. The anatomicalabnormalities are apparent in the affected girls atbirth, but boys do not usually slow clinical evi-dence of virilization until they are about one yearold. Untreated patients grow rapidly in earlychildhood but are of less than average height inadult life, due to premature epiphyseal fusion.The costal cartilages calcify at an unusually earlyage. The continued parenteral administration ofcortisone to suppress the abnormal adrenocortico-trophin output brings about normal somaticgrowth and secondary sexual development pro-vided that it is begun in early infanicy. Th'liedosage should be such as to maintaini a 17-keto-steroid excretion level which is normal for thiepatient's age. Some treated male patienits hiaefathered apparenitly normal children, but treate(dfemales have very low fertility (although fewv ofthose who have been treated with cortisone frominfancy have yet reached puberty). The patterniof inheritance is recessive and females appear tobe more commonly affected than males, althoughthis may only reflect the fact that the genitalabnormalities are more striking in females. Somepresumably heterozygous members of the familieshave been shown to excrete somewhat largeramounts of 30x, 17x, 20x-pregnantriol afterthe administration of adrenocorticotrophin thannormals.The patients who are unable to retain sodium

develop an Addisonian crisis-like state when theyare about two weeks old and soon die, unless theyare treated with desoxycorticosterone or fludro-cortisone as well as with cortisone. This acuteepisode may be precipitated by an intercurrentinfection or by surgery as may similar episodesin the children who have survived infancy. Thereis evidence that it is the hydroxylation of carboniatom number 2I wvhich is defective in both ofthese groups of cases, although the severities ofthe virilizing and sodium-losing syndromes donot parallel one another.

In the third group, the hypertensioni begins inthe first years of life, there appears to be iniabilityto hydroxylate carbon atom number i i, anldabnormal amounts of powerful salt-retainingsteroids (e.g. I7x-desoxycorticosterone) are pro-duced. Treatment with cortisone acetate byinjection abolishes the hypertensioni anid restoresnormal development.

REFERENCESALLEN, J. D., CUSWORTH, D. C., DENT, C. E, andWILSON, V. K. (I958), Lancet, i, i82.

2. ARCHER, I. E., DORMER, A. E., SCOWEN, E. F., andLWATTS, R. W. E. (I958), Brit. med. Y., i, 175.

3. ARIAS, 1. NI., and LONDON, 1. M. (957), Science, 126, sh6.

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August 1960 WVATTS: A Survey' of some Hereditary, Metabolic Diseases 497

4. BARCROFT, H., GIBSON, Q. H., HARRISON, D. C., andMcMURRAY, J. (1945), C'lin. PSO'CS.5,145-

1.3ARON, D. N., DENT, C. E., HARRIS, H., HARI', r. w.,and JEPSON, J. B. (1956), Lanicet, ii, 421.

6. BAYNE, S. (1958), Antni. Rep. (hemt. Soc., 55, 353.7. BENEDICT, J. D., YU, T. F., BIEN, E. J., GJU'1'MI\LN,

A. B., and STET"I'EN, E \XV. (19i3), 7. clin. inVest., 3Z, 775.S. BERGER, H., and GOLBERG, A. (t95s), Brit. siied. 7.,

ii, 85.9. BOGGS, J. D., HSIA, D. Y. Y., MAIS, R., anl BI(;GLER,

J. A. (1957), New Eng. 7. Mled., 257, 1101.io. BONGIOVANNI, A. M., anJ] EBERLEIN, XX'. R. (tr.,8),

Pediatrics, I6, 628.ii. BUERGER, M., and GRUTZ, 0. (1932), Arch. demi-piatol. ii.

S,yph., i66, 542.12. CALDERBANK, A., KENT, P. XX., LORBER, J., MAN-

NERS, D. J., and WRIGH r, A. ( 19'o), B3iochenl. 7., 74, 223.13. CHILDS, B., ZINKHAM, XVT., BROWNE, E. A., KIMBRO,

E. L., and TORBERT, J. v. (1958),.7ohns Hopk. Iolsp. Bull.,102, 21.

14. CODOUNIS, A. (1952), Brit. suted. 7., ii, 36S.I5. CORI, G. 1. (1954), fHarvey Lect., 48, 145.i6. CORI, G. T., and CORI, C. F. (1952), .7. biol. ('hem., i99, 66i.17. CRAWHALL, J. C., SCOXWEN, E. F., an] XWATTI.-, R. \V. E'.

(1959), Lancet, ii, 8o6.i8. CRAXN'HALL, J. C., and XX'ATT'S, R. \XX. E. (196o), linpUb-

lished data.19. CRIGLER, J. F., and NAJJAR, '. A. (1952), Pediatrics,

IO, I 69.20. CUSXVORTH, D. C., and DENT, C. E1. (1960), Bis)chemn. Y.,

74, 550.21. DENT, C. E. (1959), Proc. Roev. Soc. Med., 52, 885.22. DUBIN, 1. N., and JOIINSON, F. B. (1954), M1edicine, 33, 155.23. FOLLING, A. (1934), Hoppe-SeYl. Z., 227, 169.24. FRASER, D. (1957), Amier.7. Mled., 22, 730.25. GARROD, A. E. (1902), Lancet, ii, i6i6.26. (;ARROD, A. E. (1908), Ibid, ii, i and 73.27. GARROD, A. E. (1923), ' Inborn Errors of Metabolism,'

2nd edition. London: Frowde and Hocider & Stoughton.28. GIBSON, Q. H. (19i3), Biochemn. Y7., 37, 615.29. GIBSON, Q. H. (1948), Ibid., 42, 13.30. GIBSON, Q. H., and HARRISON, D. C. (1947), Lantcet,

ii, 941.3 1. GILBERT, A., and LEREBOULLET, P. (1901), Sent. mned.

(Paris), 21, 241.32. GODWIN, J. T., FOWLER, M. F., DEMPSEY, E. F., and

HENNEMAN, P. H. (1958), New Eng. Y. Med., 259, 1ogg.33. GOLDBERG, A. (0959), Qluart. Y7. Med., N.S., 28, 183.34. GOLDBERG, A., PATON, W. D. M., and THOMPSON,

J. W. (1954), Brit. Yt. Pharnitacol., 9, 91.35. GRANICK, S. (I954), 'Metabolism of HIaem and Chloro-

phyll.' In 'Chemical Pathways of Metabolism,' v-ol. 2. ed.(;REENBERG, D. M. New York: Academic Press Inc.

36. GRAY, C. H., RIMINGTON, C., and THOMPSON, S.(1948), Quiart. 7. Med., N.S., 17, 123.

37. HALL, E. G., SCOWEN, E. F., and XX'ATTS, R. XV. E.(1960), Arc/i. Dis. Child., 35, io8.

38. HAMIL'T'ON, J. G., SOLEY, MI. H., REILLY, XV. A., anidEICtHORN, K. B. ('943), Anmer. 7. D)is. ('ild., 66, 495.

39. HARRIS, H. (1959), Human Biochem--ical Genetics.' Cati-bridge: 'I'he University Press.

40. HIARRIS, H., PENROSE, L. S., and 'I'HOMIAS, D. H. H.(1959), Anti. humiolat Cetnet., 23, 442.

41. HIARRIS, H., and ROBSON, E. B. (0959), Ibid., 23, 421.42. HAUGE, M., anId HIARN'ALD, B. ('955), Acta nsed. Scamd.,

152, 247.43. HOGBEN, L., XXWORRALL, R. L., an' ZIEVE, 1. (1932),

Proc. Roy. Soc. Edinb., 52, 264.44. HOLTI, G., RIMINGTON-,C. TATE, 13. C., and 'ITHOMAS,

G. (1958), Quiart. Y7. Med., N.S., 27, 1.45. HOLZEL, A., KOMROWER, G. M\1., and SCHXX'AR'TZ, X'.

(1957), Amer. .Y. Med., 22, 703.46 HORLEIN, H., and WEBER, G. (1948), D)tsch. sued. Wschr.,

73, 476.47. I-ISIA, D. Y. Y. ('959), Inborn Errors of M'letabolisml.'

Chicago: The Year Book Publishers Inc.48. HSIA, D. Y. Y., DRISCOLL, K. XX'., TROLL, X_., and

KNOX, XXV. E. (1956), NTature (Lond.), 178, I239.49. I-IUTCHINSON, J. H., and N/IcGIR1R, E. M'V. (1956), Laicet,

i, 1035.50. JARRETI', A., RINIINGTON, C., anid XX'ILLOUGHBY,

D. A. (1956), Ibid., i, 125.5i. JERVIS, G. A. (1954), Res, Puibl. Ass. nlerv. snetnt. Dis., 33, 259.

52. JOHN, G. CG., and KNUDT)SON, K. P. (1956), Amer. 7. M;Ied.,21, I38.

53. ILLIN(GWORTH, B., CORI, (J. '., and CORI. C. F. (1956),7. biol. (hen,., 2i8, 123.

54. ILLINGXVORTH, B., LARtNER, J., and CORI, (;. T. (1952),Ibid., I99, 631.

55. KNOX, W. T'. (1i,8), Amer. 7. humian Genet., 10, 95.56. K9NOX, XV. E., anl HSIA, D. Y. Y. (1957), Amer. 7. fed.,

22, 687.57. KRIV'Fr, WN., POLGLAI;E, XV. J., GUNN, F. D., and

'T'YLER, F. H. (1953), Pediatrics, I2, i65.58. LA DUE, B. N., ZANNONI, XT. C., LASTE:R, L., and

SEEGMILLER, J. E. (1958), 7. biol. Chem., 230, 251.59. LARNER, J., ILLINGXVORTH, B., and CORI, G. r. (1952),

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