Tall stature Marfan syndrome See b p.940. 25_McClure_25.indd 948 11/14/2012 3:33:37 PM GENETIC DISORDERS OF GROWTH 949 Obesity Bardet \200\223Biedl syndrome (BBS) \200 \200 Rare condition; incidence in the UK population <1/100 000. Genetically heterogeneous with a t least 8 genes identi \201 ed to date. In the majority of families inheritance is autosom al recessive. Features include: cognitive impairment; renal defects. pigmentary retinopathy; postaxial polydactyly; obesity; Prader \200\223Willi syndrome (PWS) \200 71/10 000 individuals. \200 Affects Caused by disruption to the paternally derived imprinted domain on 15q11 \200\22313 . Babies are \202 oppy with feeding dif \201 culties and may fail to thrive in infancy. There is rapid weight gain between the ages of 1 and 6yrs. Older children have truncal obes ity, mild/moderate learning dif \201 culties, and short stature. Typically children have a n insatiable appetite with food-foraging and other behavioral problems. Diagnosis is by mol ecular genetic analysis ( SNRPN methylation assay). Overgrowth Beckwith \200\223Wiedemann syndrome \200 71/14,000. \200 Incidence Genetic basis is complex; it is caused by disruption of the imprinted region on c hromosome 11p15. Usually presents in the perinatal period with macrosomia. Birth weight is usually >97th centile and length is usually > +2SD. Polyhydramnios or preterm delivery comm only occur. There may be associated congenital anomalies: exomphalos/umbilical hernia; dysm orphic features (e.g. ear lobe creases, port wine stain, macroglossia (large tongue)); visc eromegaly; hemihypertrophy. Neonates are at risk for severe hypoglycaemia and should be mon itored closely. Macrosomia continues through early childhood and then becomes less dramatic with increasing age. Some children with BWS are at increased risk for Wilms \200\231 tumor . 750% diagnosis can be con \201 rmed by molecular genetic testing. In Uniparental disomy 11p15 analysis requires blood testing of child and both parents. \200 Sotos syndrome \200 Incidence \200 Due to mutation or deletion in the Most are isolated de novo mutations but familial cases do occur. 71/15 000 children. NSD1 gene on chromosome 5q35. Characterized by prenatal overgrowth (birth weight 74200g in males; 74000g in females), whi ch persists in childhood, especially through the pre-school years. Final adult height is of ten in the upper normal range. OFC is also increased and bone age is advanced. Affected chi ldren typi- cally have a tall skull with a prominent broad forehead and pointed chin. Devel opmental delay is almost always present, but varies from mild to severe. Some children have seizures. 25_McClure_25.indd 949 11/14/2012 3:33:37 PM 2 5 _ M c C l u r e _ 2 5 . 9 5 0 i n d d 9 S e e T a b e M i s c e l l a n e o u s 5 Table 25.1 Miscellaneous genetic conditions 0 C H A P T E R Syndrome Features Inheritance Chromosome Gene l Achondroplasia Short limbs, large head, \200\230trident \200\231 hand, \202 at midface, lumbar lordosis AD 4p16 FGFR3 2 5 1 2 5 G e n e t i c s Apert Craniostenosis, beaked nose, cleft palate, severe syndactyly ( \200\230mitten hand \200\231 ), d IQ Coloboma, congenital Heart disease, choanal Atresia, Retarded growth (short stature ), hypoGenitalism, external Ear abnormality and deafness AD 10q26 FGFR2 . CHARGE (see b pp.373, 846) AD (usually de novo) 8q12 CHD7 g e n e t i c 5p- (Cri du chat) Hypoplastic larynx (cat-like cry), small stature, microcephaly, micrognathia, low-set ears, hypertelorism, d IQ Craniostenosis, brachycephaly, prominent forehead, proptosis, beaked n ose Hypoplastic thumbs 9 radius, ASD, VSD Sloping forehead, OFC << 0.4th centile (< 4SD), m oderate mental retardation Sporadic 5p deletion (5p \200\223) FGFR2 Crouzon AD 10q26 TBX5 Holt \200\223Oram AD 12q MCPH1-7 c o n d i t i o n s Primary AR microcephaly AR Various DHCR7 Smith \200\223Lemli \200\223 Opitz (SLO) Ptosis, anteverted nostrils, narrow frontal region, hypospadias, toe syndactyly, d IQ Large head, small thorax, short limbs, lethal AR 11q12 \200\22313 Thanatophoric dysplasia Sporadic 4p16 FGFR3 Treacher \200\223Collins Malar hypoplasia, micrognathia, down-slanting eyes, ear malformations, deafness, lower eyel id coloboma AD 5q32 TCOF1 Zellweger Prominent forehead, large fontanelles, \202 at facies, hypotonia, stippled epiphyses, nys tagmus, hepatomegaly AR Various PEX1-14 1 1 / 1 4 / 2 0 1 2 3 : 3 3 : 3 7 P M 2 5 _ M c C l u r e _ 2 5 . i n d d 9 S e e T a b e M i s c e l l a n e o u s 5 Table 25.2 Miscellaneous congenital malformations 1 Condition Features Cause l Amniotic bands Congenital facial clefts, limb constrictions, amputations, syndactyly or talipes Annular amniotic bands 2 5 2 Diabetic embryopathy Macrosomia, organomegaly (particularly heart and liver), polycythaemia, caudal regression s yndrome (sacral and femoral agenesis or hypoplasia), transient hypertrophic cardiomyopathy, neural tube defects Maternal diabetes mellitus . M I S C E L L A N E O U S Fetal compression syndrome Joint contractions/dislocation, talipes, micrognathia, cleft palate, skull deformity In utero compression, e.g. maternal pelvic abnormality c o n g e n i t a l Fetal alcohol syndrome IUGR, hirsutism, microcephaly, mid-face hypoplasia, short palpebral \201 ssures, long smo oth philtrum, d IQ, low weight for height. Excessive maternal alcohol ingestion in pregnancy 2 \200\2233x increase in major malformations, growth retardation, midface hypoplasia, d IQ. Maternal valproate causes a 10x increased incidence of neural tube defects Fetal anticonvulsant syndrome Maternal anticonvulsant therapy in pregnancy C O N G E N T A L M A L F O R M A T O N S Goldenhar syndrome Asymmetric facial hypoplasia, eye coloboma/dermoid, ear hypoplasia, preauri- cular skin tag s, vertebral defects, cardiac defects (Fallot \200\231s tetralogy, VSD) Unknown. Usually sporadic m a l f o r m a t i o n s Klippel \200\223Feil syndrome Cervical vertebral fusion, low hair line, webbed neck, torticollis, kyphoscoliosis, deafnes s Usually sporadic I Moebius syndrome Immobile face, strabismus, limb defects, syndactyly Unknown, usually sporadic Pierre \200\223Robin sequence(see b p.847) Potter \200\231s sequence Micrognathia, glossoptosis, cleft palate Unknown (need to exclude del22q11). Usually sporadic Depressed nasal bridge, crumpled low set ears, talipes equinovarus, joint contractures, lun g hypoplasia and respiratory failure. Lethal Severe oligohydramnios due to renal or urethral abnormalities I VATER association(see b pp.373, 848) Vertebral defects, Anal atresia, Tracheo-oEsophageal \201 stula, Renal defects. (VACTERL = additional cardiac and radial limb defects) Unknown. Usually sporadic 1 1 / 1 4 9 5 1 / 2 0 1 2 3 : 3 3 : 3 8 P M This page intentionally left blank 953 Chapter 26 Inherited metabolic disease General principles 954 Metabolic syndromes: neurological 956 Metabolic syndromes: metabolic acidosis 958 Metabolic syndromes: storage dysmorphism 959 Metabolic syndromes: hepatic syn dromes 960 Metabolic syndromes: cardiac syndromes 962 Urea cycle disorders 964 Disorders of amino acid metabolism 965 Disorders of organic acid metabolism 966 Disorders of carbohydra te metabolism 967 Disorders of lipoprotein metabolism 967 Lysosomal storage diseases 968 Di sorders of fatty acid oxidation 970 Mitochondrial disorders 971 Peroxisomal disorders 972 D isorders of nucleotide metabolism 973 Disorders of porphyrin metabolism 974 Disorders of me tal metabolism and transportation 976 26_McClure_26.indd 953 11/14/2012 3:34:53 PM CHAPTER 26 Inherited metabolic disease 954 General principles Inherited metabolic disease (IMD) may present at any age and the signs a nd symptoms may result from: \200 \200 \200 s \200 Accumulation of substrate that leads to a toxic effect. Accumulation of a minor metabolite that in excess is toxic. De \201 ciency of a product of a speci \201 c reaction. metabolic phenomena. The commonest error in managing infants and children with IMD is a delay in diagnosis, and therefore a delay in starting treatment. Failure to recognize an IMD may occur because its clinical features are confusing because of: \200 \200 \200 Genetic heterogeneity. A presenting intercurrent illness. similarity with other common, acq uired conditions where the differential diagnosis has not been fully explored. A useful approach is to consider certain \200\230syndromes \200\231 and use this as a fram ework for investigation (Table 26.1).1 This approach is widely used and should serve the pu rpose. Table 26.1 Differential diagnosis of inherited metabolic syndromes IMD syndrome Neurology (b p.956) Encephalopathy Non-metabolic differential Infections: enterovirus, herpes Drug reaction: CNS depressants, antihistamines, anticonvulsants Metabolic acidosis (b p.958) Lactic acidosis Drug reaction: alcohol, methanol, ethylene glycol, salicylates (see b p.104) De \201 cienc y: thiamine Storage or dysmorphism (b p.959) Infections: congenital CMV, congenital toxoplasmosis Hematological disorders (see b p.626) Infections: hepatitis, enterovirus, infectious mononucleosis Hepatic (b p.960) Drug reaction Hematological disorders (see b p.632) Infections: enterovirus Cardiac (b p.962) Drug reaction Reference 1 Clarke JTR (2006). A clinical guide to inherited metabolic diseases. Cambridge: Cambridge University Press. 26_McClure_26.indd 954 11/14/2012 3:34:53 PM GENERAL PRINCIPLES 955 26_McClure_26.indd 955 11/14/2012 3:34:53 PM CHAPTER 26 Inherited metabolic disease 956 Metabolic syndromes: neurological There are 7 presentations of IMD with neurological featur es. Chronic encephalopathy Gray matter: developmental delay, psychomotor retardation Developmen tal delay is a common problem (see b pp.557, 562), but the features that warrant investigat ion for IMD include: \200 Global delay affecting all areas of development. \200 Progres sive course with loss of developmental milestones. \200 Objective evidence of neurologica l dysfunction (e.g. special senses, pyramidal tract, extrapyramidal, cranial nerves). Sever e behaviors including irritability, impulsiveness, aggressiveness, and hyperactivity. Seizu res (complex partial or myoclonic) originating early in life that are resistant to usual th erapy. Causes include vitamin B6 dependency; biotinidase de \201 ciency; neuronal ceroid-lipofusc inosis; GM2 gangliosidosis; cherry-red spot \200\223myoclonus syn- drome (sialidosis type I ); Leigh disease; Alper \200\231s disease; MELAS (mitochon- drial encephalopathy \200\223la ctic acidosis and stroke-like episodes syndrome). White matter: gross motor delay, weakness, and incoordination \200 Canavan disease; Alexander disease; GM2 Central involvement only: gangliosidosis; GM1 gangl iosidosis; X-linked adrenoleucodystrophy (ALD); amino acidurias, organic acidurias. Central and peripheral involvement: (MLD); Krabbe leucodystrophy; peroxisomal disorders. metachromatic leucodystrophy Chronic encephalopathy with abnormalities outside the CNS \200 \200 mitochondrial myopathy (b p.971). Muscle: Hepatosplenomegaly +/ \200\223 bone: disease, mucopolysaccharidosis (MPS) I \200 \223IV (Hurler disease, Hunter disease, San \201 lippo disease, Sly disease), GM1 ganglios idosis, sialidosis II, Zellweger. Skin +/ \200\223 connective tissue: sulphatase de \201 c iency; galactosialidosis; prolidase de \201 ciency. Gaucher disease, Niemann \200\223Pick homocystinuria; Menkes; fucosidosis; multiple Investigations for chronic encephalopathy See also b pp.536 \200\223537, 942, 960 \200 \200 \200 \200 Clinical: Imaging: Blood: Urine: oligosaccharide screen Electrophysiology: potentials; soma tosensory-evoked potentials; nerve conduction; EMG; EEG developmental assessment and neurological examination MRI of head; X-rays of hands, chest, lateral spine plasma amino acids; ammonia; lactate amino acids, organic acids, and mucopolysaccharide and auditory brainstem re \202 exes; visual-evoked 26_McClure_26.indd 956 11/14/2012 3:34:53 PM METABOLIC SYNDROMES: NEUROLOGICAL 957 Acute encephalopathy Deterioration in level of consciousness resulting from IMD: \200 \200 \200 \200 The likely causes are: hyperammonaemia (urea cycle; b p.964); amino aci - dopathy (b p.965); organic aciduria (b p.966); fatty acid oxidation defect (b p.970); mit ochondrial defect (b p.971); hypoglycaemia (b p.96). may occur in a previously healthy child; usually shows no focal features, but ataxia may be present; may start with unusual behavior; progresses rapidly, even to the stage of coma. Stroke The IMD associated with stroke or stroke-like episodes are: \200 \200 \200 b p.965). Homocystinuria ( Fabry disease ( Organic acidopathy: isovaleric acidaemia; glutaric aciduri a I and II (b p.966). Ornithine transcarbamoylase de \201 ciency ( MELAS ( Congenital diso rder of glycosylation type 1A. Familial hemiplegic migraine. Movement disorder (b p.524) \200 b p.968). methylmalonic acidaemia; propionic acidaemia; \200 \200 \200 b p.964). b p.956) Ataxia: Friedreich ataxia; abetalipoproteinaemia. Choreoathetosis triose phosphate isomeras e de \201 ciency. Parkinsonism: maple syrup urine disease; pyruvate dehydrogenase de \201 ciency; and dystonia: glutaric aciduria I; Lesch \200\223Nyhan disease; Wilson disease; tyrosine hydroxylase de \201 ciency. Myopathy \200 Acute paramyotonia congenita; hypokalaemic periodic paralysis. Progressive disease); GSD III. Exercise de \201 ciency, carnitine palmitoyltransferase II. Myopathy my opathies. intermittent muscle weakness: hyperkalaemic periodic paralysis; muscle weakness: glycogen storage disease II (GSD, Pompe intolerance with cramps and myoglobinuria: myophosphorylase as a manifestation of multisystem disease: mitochondrial Autonomic dysfunction The causes include: dopamine B-hydroxylase de \201 ciency; neurovisc eral porphyrias; Fabry disease; MPS I \200\223III; occipital horn syndrome; mitochondrial n eurogastrointestinal encephalomyopathy. Psychiatric problems The causes include the following: \200 \200 Child: Adolescent: Wilson disease; Wolfram syndrome; cerebrotendinous xanthomatosis; urea c ycle defect; homocystinuria; adult onset neuronal ceroid lipofuscinosis. MPS II; MPS III; X-linked ALD; Lesch \200\223Nyhan syndrome. late-onset MLD; late-onset GM2 gangliosidosis; porphyria; 26_McClure_26.indd 957 11/14/2012 3:34:53 PM CHAPTER 26 Inherited metabolic disease 958 Metabolic syndromes: metabolic acidosis The emergency care of acid \200\223base problems is discussed on b p.104. Metabolic acidosis may occur as a result of: \200 \200 Abnormal loss of bicarbonate. Abnormal accumulation of hydrogen ions in association with a non- volatile organic anion. These two states can be differentiated by calculating the anion gap (i.e. the difference be tween plasma [Na+] and the sum of plasma [Cl \200\223] and [HCO3 \200\223 ]). The normal anion gap is 10 \200\22315mmol/L. Abnormal bicarbonate loss When metabolic acidosis is due to bicarbonate loss from either th e gut or kidney: \200 \200 The anion gap is normal. Hyperchloraemia is usually present. To distinguish bicarbonate loss from the gut or from the kidney: \200 A history of diarrhea will distinguish between hyperchloraemia due to GI losses from that d ue to renal tubular losses. Urine net charge (UNC), calculated as [Na estimate urine ammoni um (NH4+) when there is no accumulated organic acid. A negative UNC implies the presence of adequate or increased urinary ammonium; therefore the acidosis results from abnormal GI lo ss of bicarbonate. (Note: Urine ammonium is low in renal tubular disorders.) ++ K+] \200\223 [Cl \200\223], is used to IMDs associated with RTA include \200\224galactosaemia; hereditary fructose intolerance; he patorenal tyrosinaemia; cystinosis; glycogen storage disease I; Fanconi \200\223Bickel synd rome; congenital lactic acidosis; Wilson disease; vita- min D dependency; osteopetrosis wit h RTA; Lowe syndrome. Accumulation of organic anion When metabolic acidosis is due to accumulated organic anion: \200 \200 s \200 \200 \200 b p.308). It is associated with failure to thrive ( Tachypnoea may be present. hypoglycaemia leads to a neurological syndrome (b p.96). Organic anion may lead to distinct smell of sweat or urine. The anion gap is raised. The causes include the following: \200 Lactic de \201 ciency, pyruvate carboxylase de \201 ciency, multiple carboxylase de \201 ciency); NADH accumulation (e.g. defect of mitochondrial electron chain). Ketoacidosis: pa thies, glycogen storage disease, disorders of gluconeogenesis; rare p disorders of ketone u tilization, e.g. B-ketothiolase de \201 ciency, succinyl- CoA: 3-ketoacid transferase de \201 ciency. Organic aciduria: acidosis: pyruvate accumulation (e.g. pyruvate dehydrogenase s to IMD (e.g. maple syrup urine disease, organic acido- a large spectrum of disorders (see b p.966). 26_McClure_26.indd 958 11/14/2012 3:34:53 PM METABOLIC SYNDROMES: STORAGE DYSMORPHISM 959 Metabolic syndromes: storage dysmorphism IMDs associated with signi \201 cant dysmorphic features Lysosomal disorders (b p.968) \200 \200 \200 Peroxisomal disorders (b p.972) \200 \200 Mitochondrial disorders ( b p.971) Glutaric aciduria type II (b p.966) Mucopolysaccharidoses Glycoproteinoses Sphingolipidoses Zellweger syndrome Rhizomelic chondrodysplasia punctata Other \200 \200 \200 b p.976) b p.965) Menkes disease ( Homocystinuria ( Familial hypercholesterolaemia ( b p.963) Lysosomal disorder The characteristic features of this storage dysmorphic syndrome are: \200 \200 \200 \200 coarse facies; bone changes (dysostosis multiplex); short stature; organomegaly (hepatosple nomegaly). Peroxisomal disorder The characteristic features of the Zellweger phenotype are: \200 \200 \200 \200 \200 psychomotor retardation; hypotonia and weakness; seizures; hepatocellular dysfunction; impa ired special senses. Investigations The initial investigation should include the following. \200 \200 Urine: Plasma: amino acids; isoelectric focusing of transferrin. mucopolysaccharide and oligosaccharide screen; organic acids. lactate; pyruvate; very long- chain fatty acids; phytanic acid; 26_McClure_26.indd 959 11/14/2012 3:34:53 PM CHAPTER 26 Inherited metabolic disease 960 Metabolic syndromes: hepatic syndromes There are four possible ways in which IMD may presen t with hepatic involvement. Jaundice See b pp.130 \200\223131, 314 \200\223315 Hepatomegaly See b p.967. The liver enlargement associated with IMD is usually persis- tent and not tender. The causes include: \200 Glycogen storage disease (GSD) type I: hypoglyc aemia. GSD type III: hyperlipidaemia, ketosis during fasting, and deranged liver function. GSD VI: Hereditary tyrosinaemia type I. presents in infancy with presents in early infancy with failure to thrive, \200 Hypoglycaemia See b pp.96 \200\22397, 132, 412, 967 Hepatocellular dysfunction See b pp.342 \200\223345 IMD with characteristic, severe liver involvement may present at differ ent ages. \200 hepatic phosphorylase de \201 ciency. Infancy: hypoglycaemia; hyperammonaemia; deranged LFTs; bleeding; oedema; ascites. Children : hyperbilirubinaemia, tender hepatomegaly), cirrhosis (oedema, gynaecomastia, ascites, clu bbing, spider naevi), or neuropsychiatric disease. failure to thrive; mild to severe hyperbilirubinaemia; presentation with chronic active hepatitis (fatigue, anorexia, Some causes with distinguishing features in infancy \200 Galactosaemia: (see b p.967). Hepatorenal hyperbilirubinaemia; haemolytic anemia; coagulopathy \200 tyrosinaemia: coagulopathy 1-antitrypsin de \201 ciency: jaundice; failure to thrive; intracranial and other hemorrhages. Congenital and diarrhea; seizures; developmental delay. disorders of glycosylation: failure to thrive; chronic vomiting Some causes with distinguishing features in childhood \200 type III: skeletal myopathy (s ee b p.967). \200 GSD disease type III: massive hepatosplenomegaly; failure to thrive; Gaucher abdominal prot uberance; anemia; ascites; bleeding diathesis (see b p.969). Niemann \200\223Pick Wilson ne uropsychiatric disturbance (see b p.976). \200 disease, type C: neurodegeneration; hepatosplenomegaly. disease: onset in adolescence with hepatitis, haemolysis, 26_McClure_26.indd 960 11/14/2012 3:34:54 PM METABOLIC SYNDROMES: HEPATIC SYNDROMES 961 Investigation of liver function Tests of cholestasis \200 \200 \200 \200 Bilirubin (conjugated and unconjugated) Alkaline phosphatase Gamma-glutamyltranspeptidase B ile acids (urine) Blood tests of active liver disease: \200 Aspartate aminotransferase \200 Alanine amino transferase Tests of synthetic function \200 \200 \200 \200 Albumin Prothrombin and partial thromboplastin time Clotting factor levels VII, V Ammonium Speci \201 c tests for IMD \200 \200 \200 \200 \200 \200 \200 \200 Copper and caeruloplasmin (Wilson disease) Alpha-fetoprotein (tyrosinaemia) Alpha-1-antitry psin (PI phenotype, ZZ for de \201 ciency) Plasma amino acids Urinary organic acids Red ce ll galactose-1-phosphate uridyltransferase (galactosaemia) Lysosomal enzymes Liver biopsy 26_McClure_26.indd 961 11/14/2012 3:34:54 PM CHAPTER 26 Inherited metabolic disease 962 Metabolic syndromes: cardiac syndromes Cardiomyopathy may be the dominant or only clinical problem in a variety of IMDs. Glycogen metabolism (hypertrophic cardiomyopathy) Pompe disease (GSD II) \200\224presents i n early infancy with marked skeletal myopathy, mas- sive cardiomegaly (large QRS, left axis deviation, shortened PR, T-wave inversion). Fatty acid metabolism (dilated cardiomyopathy) \200 presents with skeletal myopathy, hypotonia Systemic carnitine de \201 ciency: encephalopathy, hepatic syndrome (hepatomegaly, hypogly caemia, hepatocellular dysfunction). Long or very long chain acyl-CoA dehydrogenase de \201 ciency: with myopathy, exercise intolerance with myoglobinuria, hypotonia, encephalopa thy, hepatic syndrome 9 hyperammonaemia. presents Organic acidopathy (dilated cardiomyopathy) Propionic acidaemia \200\224 intermittent metab olic acidosis; ketosis; hyperammonaemia; neutropenia. Mitochondrial cardiomyopathy (hypertrophic or dilated) Sphingolipidoses (hypertrophic cardiomyopathy) Fabry disease \200\224 chronic neuritis pain in hands and feet; angiokeratomata; corneal opacities; pro- gressive renal failure; cardia c arrhythmias (intermittent SVT); cerebrov- ascular disease. Mucopolysaccharidosis (hypertrophic cardiomyopathy) Investigation Initial studies \200 Plasma: ammonium; liver function tests; urea, creatinine, and electr olytes Urine: lactate; carnitine (free and total); acylcarnitine pro \201 le; organic acids Suspected fatty acid oxidation defect Fibroblast cultures; enzyme studies Suspected mitochondrial electron transportation defect \200 \200 \200 \200 \200 Plasma: CSF: Imaging: Electrophysiology: Tissue: lactate/pyruvate ratio lactate MRI evoked potentials muscle and skin biopsy studies Suspected lysosomal storage disease \200 \200 \200 Urine: Imaging: Blood: mucopolysaccharide and oligosaccharide screen, glycolipids skeletal radiology lysosomal enzyme studies 26_McClure_26.indd 962 11/14/2012 3:34:54 PM METABOLIC SYNDROMES: CARDIAC SYNDROMES 963 Arrhythmias IMD-related cardiomyopathy may be complicated by arrhythmias includ- ing: \200 Heart block: acylcarnitine translocase (CACT) de \201 ciency; propionic acidaemia. Tachyar rhythmia: mitochondrial cytopathy; Fabry disease; carnitine \200\223 fatty acid oxidation defects; CACT. Coronary artery disease (CAD) CAD occurs in Fabry disease, familial hyperlipidaemias, and f amilial hyper- cholesterolaemia (FH). FH affects 1/500 individuals with the following effects. Homozygotes: infancy or childhood; cholesterol accumulation in the skin (tuberous xanthomas, subcutaneous nodules); and arcus senilis. Heterozygotes: severe cholesterolaemia; ischaemic heart disease in fatal myocardial infarction in third decade. Familial hyperlipidaemias causing premature CAD include the following. \200 \200 Type IV: Type IIa, familial hypercholesterolaemia: hypercholesterolaemia (increased low-den sity lipoproteins) with tuberous xanthomas, tendinous xanthomas, and arcus senilis. Type II b: density lipoproteins). Type III, familial dysbetalipoproteinaemia: lipoproteins with eru ptive tuberous xanthoma, planar xanthomas, peripheral vascular disease. hyperlipidaemia (increased very low-density lipoproteins). combined hyperlipidaemia (increased low- and very low- B-very low-density 26_McClure_26.indd 963 11/14/2012 3:34:54 PM CHAPTER 26 Inherited metabolic disease 964 Urea cycle disorders The urea cycle disorders are a group of conditions in which enzyme def ects result in the accumulation of nitrogen in the form of ammonia, which is a highly toxic substance causing irreversible brain damage. Clinical presentation may be in the \201 rs t few days of life. Hyperammonaemia (usu- ally severe) results in: \200 \200 coma; convulsions and vomiting. Clinical confusion with septicaemia is common. In the older child, patients may present wit h: \200 \200 \200 \200 \200 psychomotor retardation; growth failure; vomiting; behavioral abnormalities; recurrent cere bellar ataxia and headache. It is essential to monitor the blood ammonia in any patient with unex- plained neurological symptoms. The urea cycle disorders \200 \200 \200 \200 \200 N-acetylglutamate synthetas Carbamyl phosphate synthetas Ornithine transcarbamylas Arginino succinic acid synthetas Argininosuccinase acid lyas ASA) Arginas e de \201 ciency (NAGS) e de \201 ciency (CPS) e de \201 ciency (OTC) e de \201 ciency (citrullinaemia; AS) e de \201 ciency (argininosuccinic aciduria; AL/ e de \201 ciency (arginaemia; AL/ASA) All are autosomal recessive except for ornithine transcarbamylase de \201 - ciency (X-link ed). Individuals with childhood or adult onset disease may have a partial enzyme de \201 c iency Diagnosis Plasma concentrations of ammonia are elevated, glutamine and alanine (the major n itrogen-carrying amino acids) are usually high, and arginine is low. Speci \201 c urea cyc le defects can be diagnosed by their characteristic plasma and urine amino acid pro \201 l es. Treatment Management of dietary protein intake with essential amino acids and restricti on of protein intake to suppress ammonia formation. 26_McClure_26.indd 964 11/14/2012 3:34:54 PM DISORDERS OF AMINO ACID METABOLISM 965 Disorders of amino acid metabolism Due to defects either in the synthesis of (or the breakd own of) amino acids or in the body \200\231s ability to transportation amino acids into cel ls. Most are autosomal recessive. Diagnosis is established by detecting abnormal plasma and urinary amino acid pro \201 les. Phenylketonuria (PKU) AR. Occurs in 1/10 000 \200\22315 000 live births. In its classical f orm it is due to a de \201 ciency in phenylalanine hydroxylase. Untreated, brain developme nt is impaired leading to progressive mental retardation and seizures, usually evident by 6 \200\22312mths of age. Many children have fair hair and blue eyes. In PKU phenylalanine ac cumulates and is converted into phenylketones, which are detected in the urine. \200 PKU can be managed entirely by a diet low in phenylalanine and high in tyrosine. Adherence to the diet will prevent neurological problems. PKU is detected early in a national neonata l biochemical screening program. Homocystinuria Due to de \201 ciency in cystathionine beta-synthase, resulting in increase d urinary homocystine and methionine excretion. Clinical manifestations resemble those of M arfan \200\231s syndrome (see b p.940). Treatment with high-dose pyridoxine and low-methionine diet, supple- mented with cysteine. Cardinal features of homocystinuria \200 \200 \200 Eyes: CNS: Skeleton: arachnodactyly Cardiovascular Thromboembolism lens subluxation (ectopia lentis); myopia; glaucoma seizures; neurodevelopmental delay; beh avior problems Marfanoid body habitus; high-arched palate; kyphoscoliosis; \200 system: mitral valve prolapse risk 26_McClure_26.indd 965 11/14/2012 3:34:54 PM CHAPTER 26 Inherited metabolic disease 966 Disorders of organic acid metabolism A large group of disorders characterized by a broad ra nge of clinical symptoms and signs varying in seriousness from trivial to lethal. Includes developmental delay, poor growth, and episodic illnesses with vomiting and metabolic acidos is. Some of these may be precipitated by prolonged fasting or minor viral infection. May be associated with hypoglycaemia and ketosis or ketoacidosis. \200 Characterized by urinary excretion of abnormal types and amounts of organic acids. Diagnosi s by urinary organic acid pro \201 le. Treatment: during illness. \200 avoid prolonged fasting, and administer extra carbohydrate Examples include the following. Methylmalonic acidaemia (MMA) Caused by methylmalonyl-CoA mutase de \201 ciency. Commonly presents in the newborn period with: \200 \200 \200 \200 severe metabolic acidosis; acute encephalopathy; hyperammonaemia; neutropenia and thrombocy topenia. 3-hydroxy-3-methyl-CoA (HMG-CoA) lyase de \201 ciency May present in the newborn period wi th severe metabolic acidosis, poor feeding and vomiting, lethargy, altered level of conscio usness, hypoglycae- mia, and hyperammonaemia. Glutaric aciduria \200 GluA type 1 is caused by de \201 ciency of mitochondrial glutaryl-CoA dehydrogenase. The c ondition presents in infancy with episodes of hypotonia, dystonia, opisthotonus, grimacing, \201 sting, tongue thrusting, and seizures. GluA type II is caused by de \201 ciency of mitochondrial electron transportation falvoprotein or dehydrogenase. It may present in the following ways. \200 Neonatal muscular defects of the abdominal wall, hypospadias in boy s, cystic kidneys); hypotonia; hepatomegaly; hypoketotic hypoglycaemia; metabolic acidosis; hyperammonaemia. Later-onset hypoglycaemia, hyperammonaemia, and encephalopathy. disease: with or without dysmorphism (abnormal facies, disease: episodic metabolic acidosis, failure to thrive, 26_McClure_26.indd 966 11/14/2012 3:34:54 PM DISORDERS OF CARBOHYDRATE METABOLISM 967 Disorders of carbohydrate metabolism Autosomal recessive conditions. Often presenting with one or more of the following \200\224episodic hypoglycaemia; lactic acidosis; poor growth a nd hypotonia; mental retardation/developmental delay; and vomiting; cramps, myoglobinuria, and muscle weakness. Glycogen storage disease (GSD) Speci \201 c enzyme defects preventing mobilization of gluc ose from glycogen, and resulting in abnormal storage in liver and/or muscle (see Table 26.2 ). Table 26.2 GSD types I \200\223V GSD type Enzyme defect Tissue Key clinical features I: Von Gierke Glucose-6- phosphatase Liver +++ Poor growth Hypoglycaemia Hepatomegaly II: Pompe Lysosomal A-glucosidase Glycogen debrancher (amylo- 1,6-glucosidase) Liver ++Muscle +++ Cardiac failure Hypotonia III: Corri Liver ++Muscle + Poor growth Muscle weakness Hypoglycaemia IV: Andersen Glycogen branching (amylo-1,4 \200\2231,6 transglucosidase Liver +++Muscle + Failure to thrive Liver failure Muscle weakness V: McArdle Phosphorylase Muscle ++ Muscle weakness Cramps Disorders of fructose metabolism Hereditary fructose intolerance Fructose-1-phosphate aldol ase de \201 cien- cy. Failure to thrive; hypoglycaemia; metabolic/lactic acidosis; vomitin g; GI bleeding. Galactosaemia Galactose-1-phosphate uridyltransferase de \201 ciency. Failure to thrive; c ata- racts; hepatomegaly; jaundice, vomiting and diarrhea; mental retardation (if untreated ). Treatment with galactose-free diet. Disorders of lipoprotein metabolism This is a heterogeneous group of disorders resulting in abnormalities of blood lipid pro \201 le. May predispose to cardiovascular disease (see b p.963). 26_McClure_26.indd 967 11/14/2012 3:34:54 PM CHAPTER 26 Inherited metabolic disease 968 Lysosomal storage diseases See also b p.959. This is a large group of disorders due to defe cts in lysosomal function. Mucopolysaccharidoses A group of IMD caused by de \201 ciency in lysosomal enzymes needed to break down glycosaminoglycans (long chain carbohydrate molecules for- merly called mucop olysaccharides). Affects bone, cartilage, tendons, eyes, skin, and connective tissue, leadi ng to accumulation of glycosaminoglycans and progressive cellular and tissue damage. Clinical features are not apparent at birth, but progress with time as storage of glycosami noglycans impacts on tissues and organs. Typical fea- tures include: \200 Neuropathy: \200 Neurodevelopmental delay; hearing loss (conductive/sensory); hydrocephalus. Visual lo ss: Coarsening of facial features. Short stature/skeletal deformities; joint stiffness. Val vular heart disease. peripheral/spinal. \200 \200 \200 corneal clouding/glaucoma/retinal degeneration. Sphingolipidoses Clinically the sphingolipidoses show variable severity. They cause progres - sive peripheral and CNS disease (psychomotor retardation, myoclonus, weakness, and spasti city). Variants of Gaucher and Niemann \200\223Pick disease that do not affect the nervous system are termed non-neuronopathic. Sphingolipidoses \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 Fabry \200\231s disease Gangliosidosis GM1 gangliosidoses GM2 gangliosidoses Tay \200\223Sa chs disease Sandhoff disease Gaucher \200\231s disease Krabbe disease Metachromatic leucody strophy Niemann \200\223Pick disease Fabry \200\231s disease X-linked recessive. Due to a de \201 ciency of alpha galactosidase A, result- ing in the accumulation of globotriaosylceramide within blood vessels and other tissues. Clinical features become evident in early childhood and increase in severity with age \200\224anhidrosis; fatigue; skin lesions (angiokera- tomas: tiny, painless papules); and burning pain of the extremities. Renal failure, heart disease, and stroke increase with age. Other symptoms include tinnitus, vertigo, nausea, and diarrhea. 26_McClure_26.indd 968 11/14/2012 3:34:55 PM LYSOSOMAL STORAGE DISEASES 969 Gaucher \200\231s disease AR. This is the most common lysosomal storage disorder. It is due to de \201 cient activity of beta-glucocerebrosidase and leads to intracellular accumulat ion of glucosylceramide (glucosylcerebroside) within cells of mononuclear phagocyte origin (producing characteristic \200\230Gaucher cells \200\231). Gaucher disease is categorized phenotypically into 3 main subtypes: Type I Gaucher disease: most common form of Gaucher di sease \200\224lacks p CNS involvement. Wide spectrum of severity, ranging from affected inf ants to asymptomatic adults. Usually presents in childhood with hepatosplenomegaly, pancyto penia, and bone marrow in \201 ltration. Severe orthopedic complications, including verteb ral compression, avascular necrosis of the femoral head, and pathological fractures of long bones. acute neuronopathic form of the disorder Type II acute neuronopathic: starts in inf ancy, and death is often by 2yrs of age. Patients are usually normal at birth, but develop hepatosplenomegaly, developmental regression, and growth arrest within a few months of age. Type III subacute neuronopathic: Gaucher disease, but has later age of onset and slower pr ogression. subacute form similar to type II Glycoproteinosis A heterogeneous group of disorders of glycoprotein storage. A spectrum of phenotypes include neurological deterioration, growth retardation, visceromegaly, and seizu res. Also coarse facial features, angiokeratoma corporis diffusum, spasticity, and delayed development. Types of glycoproteinosis \200 \200 \200 Mucolipidosi Mucolipidosi Defects in fucosidosis, mannosidosis, sialidosis (mucolipidosis I ) s II (I-cell disease) s III (pseudo-Hurler polydystrophy) glycoprotein degradation: aspartylglucosaminuria, 26_McClure_26.indd 969 11/14/2012 3:34:55 PM CHAPTER 26 Inherited metabolic disease 970 Disorders of fatty acid oxidation Disorders of fatty acid metabolism may be due to de \201 ciency in the acyl dehydrogenase enzyme complex, de \201 ciency in carnitine, or a defect in the carnitine transportation process. \200 Clinical presentation is with acute encephalopathy with recurrent vomiting, lethargy, drows iness, and seizures. Hypoglycaemia is usually observed, as well as hepatomegaly and hyperam monaemia. Episodes of acute encephalopathy are precipitated by periods of prolonged fasting or by intercurrent illness associated with poor feeding. Presentation is usually in the \201 rst 2yrs of life. Diagnosis depends on a high index of suspicion. A positive family hi story or a history of previous acute metabolic crisis during trivial intercurrent illness m ay be present. Diagnosis of a speci \201 c disorder of fatty acid metabolism is establishe d by demonstrating characteristic abnormalities in urinary organic acid excretion and in pl asma acyl carnitine pro \201 les. Abnormalities may not be present when child is well. Mol ecular genetic testing is also available for some disorders. Treatment successfully managed by avoidance of prolonged fasting, high carbohydrate diet, and carnitine supplements. Duri ng intercurrent illness, administration of high carbohydrate diet is required. \200 Medium chain acyl-CoA dehydrogenase de \201 ciency (MCAD) This is the commonest fatty acid oxidation disorder (1/13 000 births) and is due to mutations in the MCAD gene (1p31). Clin ical presentation may vary from asymptomatic to fulminant. Newborn screening programs, uti- lizing neonatal blood spot collection methods, are now in place in many countries for the early detection and management of this condition. 26_McClure_26.indd 970 11/14/2012 3:34:55 PM MITOCHONDRIAL DISORDERS 971 Mitochondrial disorders Disorders of mitochondrial function result in a wide of clinical pr oblems (see Box 24.1). Box 24.1 Disorders of mitochondrial function: clinical problems Common clinical features \200 \200 \200 \200 \200 Lactic acidosis Muscle weakness/hypotonia Poor growth/short stature Neurodevelopmental dela y Seizures Other recognized features \200 \200 \200 \200 \200 \200 \200 Eyes: Ears: Cardiovascular: Respiratory: Diabetes mellitus Stroke Renal tubular dysfunction ophthalmoplegia; retinal degeneration sensorineural deafness cardiomyopathy; arrhythmias periodic breathing Inheritance may be either autosomal dominant/recessive or X-linked or mitochondrial (i.e. m atrilineal), although most arise as de novo mutations. Diagnosis requires muscle biopsy, wi th histochemical studies, electron microscopy, and biochemical studies on isolated tissue. Presence of \200\230ragged-red \200\231 \201 bres in skeletal muscle biopsy is character istic of disorders presenting with myopathy. Leigh \200\231s syndrome Relapsing acute encephalopathy; lactic acidosis; hypot- onia; seiz ures; +/ \200\223 cardiomyopathy; +/ \200\223 hepatic or renal tubular dysfunction. Pearson \200\231s syndrome Failure to thrive; lactic acidosis; sideroblastic anemia; hypoparathyro idism; diabetes mellitus. 26_McClure_26.indd 971 11/14/2012 3:34:55 PM CHAPTER 26 Inherited metabolic disease 972