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Section 18 Metabolic Disorders Chapter 135 Inborn Errors of Metabolism: Disorder of Adults? Kothiwale VA, Varun Kumar B INTRODUCTION Group 1 Inborn errors of metabolism (IEMs) are individually rare, but collectively numerous. The term was coined by Archibald Garrod, who in 1927 presented the Huxley lecture at Charing Cross Hospital.1 Until recently, IEMs were considered a specialty of pediatricians. Indeed, the term “inborn” has meant for a long time, a disease which starts in the newborn period or at least in childhood. Although most IEMs can have mild forms starting in adolescence or late in adulthood, this concept of “adult onset IEMs” has not reached the medical community until recently. They refer to single gene disorders wherein loss of function of a single enzyme results in abnormalities in synthesis or catabolism of proteins, carbohydrates or fats, which results in a disruption in a metabolic pathway. This results in toxic accumulations of substrates before the disruption, intermediates from alternative pathways, and/or defects in energy production and utilization. Nearly every metabolic disease has several forms that vary in age of onset, clinical severity and mode of inheritance. The mode of inheritance determines the male to female ratio of affected and many IEMs have multiple forms that differ in their mode of inheritance. It involves cellular organelles and includes lysosomal, peroxisomal, glycosylation and cholesterol synthesis defects. • Mucopolysaccharidosis (Hurler, Hunter, Sanfilippo, Morquio, Maroteaux, Sly, etc.) • Sphingolipidosis (gangliodosis, Tay-Sachs, Sandhoff ) • Lactosylceramidosis (Gaucher, Farber, Niemann-Pick, Krabbe, sulfatase deficiency) • Glycoproteinases (fucosidosis, manosidosis, sialidosis, aspartylglucosaminuria) • Defects in membrane transport (cystinosis, succinic semialdehyde dehydrogenase, Salla disease) • Peroxisomal biogenesis defects (Zellweger syndrome, adrenoleukodystrophy, Refsum’s disease, hyperoxaluria Type I) • Fabry’s disease, Shindler, Canavan disease, Pompe disease, acid lipase deficiency, acid maltase deficiency, cerebrotendinous xanthomatosis, Juvenile Batten’s disease, Kuf’s disease, etc. CLASSIFICATION A simple method classifies IEMs into disorders involving protein metabolism, carbohydrate metabolism, lysosomal storage, fatty acid oxidation defects, mitochondrial disorders, peroxisomal disorders. A detailed and widely used classification which categorizes IEMs from a pathophysiological perspective is as follows (Flow chart 1):2 Group 2 It includes IEMs that give rise to an acute or chronic intoxication. • Disorders of amino acids: Cystinuria, phenylketonuria (PKU), tyrosinemia, homocystinuria, alcaptonuria, maple syrup urine disease, Hartnup’s disease, hyperornithinemia with gyrate atrophy • Organic acidurias: Beta-ketothiolase deficiency, methyl glutaconic academia, isovaleric academia, glutaric academia Type I, propionic academia, multiple carboxylase deficiency, methyl malonic academia Flow chart 1: Classification of IEMs Metabolic Disorders • Urea cycle defects: Citrullinemia, argininemia, arginosuccinic aciduria, carbomyl phosphate synthase deficiency, ornithine transcarbamylase deficiency • Sugar intolerance: Galactosemia, epimerase deficiency, hereditary fructose intolerance, galactokinase deficiency • Others: Porphyrias, Wilson’s disease, aceruloplasminemia, Lesch-Nyhan syndrome, Sjogren-Larsson syndrome. Group 3 It includes IEMs that affect the cytoplasmic and mitochondrial energetic processes. Mitochondrial defects are the most severe and are generally untreatable (except ketone body defects and coenzyme q10 defects). Cytoplasmic energy defects are generally less severe. • Fatty acid oxidation defects: carnitine palmitoyl transferase I, II deficiency, short-chain acyl-CoA dehydrogenase deficiency, medium-chain acyl-CoA dehydrogenase deficiency, very long chain acyl CoA dehydrogenase deficiency, long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency, glutaric academia Type II, carnitine uptake deficiency, hydroxymethylglutaryl CoA lyase • Mitochondrial disorders: pyruvate dehydrogenase complex deficiency, pyruvate carboxylase deficiency, myoclonic epilepsy with ragged red fibers, mitochondrial encephalopathy with lactic acidosis and stroke, phosphoenolpyruvate carboxykinase deficiency, Leber’s hereditary optic atrophy, neuropathy ataxia and retinitis pigmentosa (NARP) • Glycogen storage disorders: von Gierke’s disease (Type I), Pompe’s disease (Type II), Cori’s or Forbes’ disease (Type III), Anderson’s disease (Type IV), McArdle’s disease (Type V), Her’s disease (Type VI), Tarui’s disease (Type VII), Type IX, Fanconi Bickel syndrome (Type XI), red cell aldolase deficiency (Type XII), Type XIII, Type 0. CLINICAL MANIFESTATIONS Inborn errors of metabolism (IEMs) can affect any organ system and manifestations vary from those of acute life-threatening disease to subacute progressive degenerative disorder. Progression may be unrelenting with rapid life-threatening deterioration over hours, episodic with intermittent decompensations and asymptomatic intervals, or insidious with slow degeneration over decades. All three groups of IEMs can manifest in adults, more so with Group I disorders. In neonates and children, manifestations are nonspecific and very similar to that of septicemia, a major reason why IEMs go undetected. There may be dysmorphic features present at birth (generally when fetal energy is affected), or develop during the first year of life (lysosomal disorders). In adults, the symptoms may include mild-to-profound mental retardation, autism, learning disorders, behavioral disturbances, muscle weakness, progressive paraparesis, hemiparesis, dystonia, chorea, ataxia, ophthalmoplegia, visual deficit, epileptic crisis, hepatosplenomegaly and hypoglycemia. Some manifestations may be intermittent, precipitated by the stress of illness, or progressive, with worsening over time. Disorders manifested by subtle neurologic or psychiatric features often go undiagnosed until adulthood. Group I 614 Onset in adulthood (upto > 70 years). Among the organs impacted, the nervous system is by far most common. Thus, late onset forms of IEMs often display psychiatric or neurological presentations. These include atypical psychosis or depression, unexplained coma, peripheral neuropathy, cerebellar ataxia, spastic paraparesis, dementia, movement disorders, epilepsy, etc. Section 18 Group II They do not interfere with the embryofetal development and they present with a symptom-free interval and clinical signs of “intoxication”, which may be acute (vomiting, coma, liver failure, thromboembolic complications etc.) or chronic (failure to thrive, developmental delay, ectopia lentis, cardiomyopathy etc.). Circum stances that can provoke acute metabolic attacks include fever, intercurrent illness and food intake. Clinical expression is often both late in onset and intermittent. Group III Common symptoms in this group include hypoglycemia, hyper lactatemia, hepatomegaly, hypotonia, myopathy, cardiomyopathy, cardiac failure, circulatory collapse, and brain involvement. Some of the mitochondrial disorders and pentose phosphate pathway defects can interfere with the embryofetal development and give rise to dysmorphism, dysplasia and malformations. In general, clinicians should consider the possibility of an IEM in any patient with an unexplained neurological disorder. Some brain regions like basal ganglia are highly vulnerable to energy metabolism defects and metals. In an adult patient with an unexplained encephalopathy or an unexplained coma, certain features are highly suggestive of an IEM: (1) when the encephalopathy is triggered by an extrinsic factor—surgery, fasting, exercise, treatments, high-protein intake, new medication (Table 1), etc.; and (2) when specific brain lesions are present on brain magnetic resonance imaging (MRI). Two main groups of IEMs are responsible for encephalopathies in adults: intoxications (mainly, urea cycle disorders, homocysteine remethylation defects and acute porphyrias) and energy metabolism defects (respiratory chain disorders, pyruvate dehydrogenase deficiency and biotine responsive basal ganglia disease). In the first group, MRI is usually normal or can show poorly specific features whereas in the second group, MRI is almost always abnormal, showing bilateral lesions of basal ganglia (Leigh syndrome) or pseudo-strokes (mainly in the case of respiratory chain defects). DIAGNOSIS AND MANAGEMENT Inborn errors of metabolism may present in adolescence or adulthood as a psychiatric disorder. In some instances, an IEM is suspected because of informative family history or because psychiatric symptoms form part of a more diffuse clinical picture with systemic, cognitive or motor neurological signs. There are 3 important steps in the diagnosis and management of an IEM. 1. Suspicion The symptoms and signs for an IEM are very common and nonspecific; therefore, one should think of IEM as an etiology in unexplained/ peculiar cases and try to rule out the possibility. TABLE 1 │ Drugs which aggravate inborn errors of metabolism Disease Drugs Mechanism Urea cycle disorders Valproate Blockage of urea cycle Porphyrias Imipramine, meprobamate Porphyrogenic Wilson’s disease Neuroleptics Blockage of D2 dopamine receptors GM2 gangliosidosis Tricyclic antidepressants, phenothiazines ?Increased lipid storage Respiratory chain disorders Valproate Blocks the respiratory chain Chapter 135 Inborn Errors of Metabolism: Disorder of Adults? Section 18 2. Evaluation Once the possibility of an IEM is suspected, how should it be evaluated? There are four parts to the evaluation of an IEM: A. History, family history: One of the most important clue is a history of deterioration after an initial period of apparent good health ranging from hours to weeks. Developmental delay, particularly missing milestones may be present. Another key feature is change in the diet and unusual dietary preferences particularly protein or carbohydrate aversion. The family history is very important. Most IEM are autosomal recessive, so there may have been siblings with similar illnesses or deaths from “sepsis” or “sudden infant death syndrome (SIDS)”. The parents may be consanguineous or come from a genetic isolate. There are also X-linked, and mitochondrial inherited IEM, so a family history must include information about the mother’s siblings, their children, etc. B. Physical examination: The physical examination of patients with IEM is usually normal except for nonspecific findings. Physical findings that are important include: facial dysmorphism, cataracts, hepatosplenomegaly and myopathy. C Initial screening tests: The initial evaluation of an IEM should begin with simple urine and blood analysis. The first step is checking for unusual odors in urine (Table 2), some of which are not specific, but a positive result can direct toward one or more specific tests. The blood tests encompass complete blood count, blood gases and blood electrolytes. The panel of tests should also include lactate, liver function test, cholesterol, pyruvate, urea, creatinine and uric acid. A low neutrophil count may be indicative of organic acidemias. The lactate/pyruvate ratio of less than 25 cancels the possibility of lactic acidosis, organic acidurias, urea cycle defects and fatty acid metabolism. High levels of lactate and pyruvate are symbolic of mitochondrial defects.3 An elevated ammonia level in blood points to urea cycle abnormalities and some organic acidemias. Serum and urine amino acid analyses reveal hyperalaninemia. A value above 16 for the anion gap is suggestive of organic acidurias. Glucose level is checked to rule out hypoglycemia, which is a common feature of many IEMs. D. Advanced screening tests: There are numerous biomarkers used in many laboratories that specialize in biochemical genetics. TABLE 2 │ Urine odor in different inborn errors of metabolism Disorder Odor Compound Phenylketonuria Musty Phenyl acetate Tyrosinemia Cabbage Rancid butter Hydroxybutyric acid Oxomethylbutyric acid Maple syrup urine disease Maple syrup Burnt sugar Oxoisocaproic acid oxomethyl valeric acid Isovaleric acidema, glutaric academia type II Sweaty feet Isovaleric acid Methylcrotonyl-CoA Carboxylase deficiency Cat urine Hydroxyisovaleric acid Multiple carboxylase deficiency Cat urine Hydroxyisovaleric acid Methylmalonic academia Acid smell Methylmalonic acid Cystinuria Sulfurus Hydrogen sulfide Hydroxy methyl glutaric acidurias Cheesy Cheesy These include carnitine, acylcarnitines, lysosomal enzymes, etc (Table 3).4 These tests are key to exclusion or inclusion of an IEM. Magnetic resonance spectroscopy of brain shows high lactate levels in individuals with mitochondrial disorders.5 3. Treatment The basic principle for treatment of the acute inborn errors is reduction of the substrate that accumulates due to catabolic enzyme deficiency. The specific treatment of individual metabolic disease is too vast to be described in detail. The treatment strategies commonly employed are discussed. In general, Group III are considered untreatable, and the following strategies apply on most part to Groups I and II. The brief approaches are as follows: Prevent catabolism: Administration of calories is used in acute episodes to slow down the catabolism. Limit the intake of the offending substance: Simple restriction of certain dietary components such as galactose and fructose form the basis of treatment in galactosemia and fructose intolerance. Neonates with PKU should be given a protein substitute that is phenylalanine-free. Patients with Group I are commonly considered for this line of treatment. Increase excretion of toxic metabolites: Rapid removal of toxic metabolites (in IEM’s Group II) can be achieved by exchange transfusion, dialysis, forced diuresis, using alternative pathways for the excretion of toxic metabolites.6 For example, carnitine is useful in elimination of organic acids in the form of carnitine esters, sodium benzoate and phenylacetate are useful in treating hyperammonemia, etc. Enzyme replacement therapy: Patients with Group I IEMs have various forms of enzyme deficiencies and are considered for enzyme replacement. For example, human alphaglucosidase enzyme is safe and effective in Pompe’s disease.7 Laronidase is developed as a treatment strategy for mucopolysaccharidoses I,8 recombinant alpha-Gal A for Fabry’s disease,9 imiglucerase in management of Gaucher disease,10 etc. Increase the residual enzyme activity: People with Group II IEMs can benefit by increasing the residual enzyme activity. This is done by administration of pharmacologic doses of the vitamin cofactor for the defective enzyme (Table 4). If the enzyme is reasonably functional, increasing the vitamin concentration will increase enzyme activity via a mass action effect. A study showed that B12 decreases the urinary levels of methyl malonate by enhancing activity of transcobalamin II.11 Reduce substrate synthesis: In glycolipid lysosomal storage disease, glycohydrolase that catalyzes glycosphingolipid (GSL) is defective leading to accumulation of GSL in lysosome and precipitation of the disease. The imino sugar N-butyldeoxynojirimycin (NB-DNJ) inhibits the first step in GSL synthesis12 and balances the rate of GSL synthesis with the impaired rate of GSL breakdown. Replacement of the end product: Hypoglycemia is a frequent finding in patients with glycogen storage diseases, and can be prevented by frequent feeds. Raw cornstarch (2 g/kg every 6 hours) has been shown to be effective in preventing hypoglycemia in glycogen storage disease Type I as also decreasing hyperlipidemia, hyperuricemia and lactic acidemia.13 Transplantation and gene therapy: Hematopoietic cell transplantation (HCT) has been used as effective therapy for IEMs, mainly lysosomal storage diseases and peroxisomal disorders. The main rational for HCT in IEMs is based on the provision of correcting enzymes by donor cells within and outside the blood compartment.14 615 Metabolic Disorders Section 18 TABLE 3 │ Inborn errors of metabolism according to symptom groups Disease Clinical symptoms Investigation Fatty acid oxidation defects Cardiomyopathy, hypoglycemia, liver disease, myoglobinuria Urine organic acids (fasting) Glycolytic pathway disorders Anemia, liver disease, muscle weakness, cardiomyopathy, endocrinological disorders, ptosis Red cells or muscle biopsy for enzyme assays Respiratory difficulties due to diaphragmatic weakness Lymphocyte acid á-glucosidase (b) Type III (Cori’s disease) History of early hypoglycemia and hepatomegaly Leukocyte glycogen debrancher enzyme assay (c) Type V (McArdle’s disease) Myoglobinuria, exercise intolerance, cramps Ischemic exercise test (d) Phosphorylase b kinase deficiency Cardiomyopathy, liver disease Erythrocyte or liver phosphorylase b kinase assay Muscle weakness or exercise intolerance Glycogen storage disease (a) Type II (acid maltase deficiency) Motor neuron disease Adult polyglucosan storage disease Dementia, neurogenic bladder, sensory loss Leukocyte glycogen brancher assay Tay-Sach’s and Sandhoff’s disease Slow progressive disorder, pyramidal signs, cerebellar degeneration Leukocyte total hexosaminidase and hexosaminidase A Chorea and/or dystonia Glutamic aciduria type 1 Reye’s syndrome Hypoglycemia, slow progressive disorder, gait, disturbance, dysarthria Urine organic acids Blood spot for acyl carnitines Lesch-Nyhan syndrome Renal stones, gout Plasma urate and urine, urate/creatinine ratio Methylmalonic aciduria with homocystinuria Anemia Urine organic acids and amino acids, urine, and plasma homocystine Niemann-Pick disease type C Supranuclear ophthalmoplegia, ataxia, psycho-motor retardation, dementia, splenomegaly Bone marrow aspirate fibroblast cholesterol incorporation and staining Wilson’s disease Cataracts, Kayser-Fleischer rings, liver disease, dementia, renal failure, parkinsonian features, dysarthria, loss of coordination of voluntary movement Plasma copper and ceruloplasmin, urine, copper, liver copper Leukodystrophy Krabbe’s leukodystrophy Pes cavus, hemiparesis, spastic tetraparesis Leukocyte â-galactocerebrosidase X-linked adrenoleukodystrophy In males, gait disturbance, spastic paraparesis, rarely dementia, Addison’s disease. In females, onset >30 y, spastic paraparesis, vibration sense loss, long tract signs, peripheral neuropathy Plasma very long chain fatty acids Ataxia Abetalipoproteinemia Muscle weakness, fat malabsorption, retinitis pigmentosa Plasma cholesterol and triglycerides, blood film (acanthocytes), lipoproteins Aceruloplasminemia Presenile dementia, diabetes mellitus, retinal dystrophy Plasma and urine copper Cerebrotendinous xanthomatosis Spasticity, cataracts, tendon xanthomas Urine cholesterol Hartnup disease Skin lesions, dementia Plasma and urine amino acids Pyruvate dehydrogenase deficiency (X-linked) Episodes in males triggered by carbohydrate feeding Pre and postprandial blood lactate, CSF lactate, fibroblast pyruvate dehydrogenase Sialidosis (mucolipidosis type I) Type I: Visual defect with lens or corneal opacity, ataxia, myoclonus, generalized seizures sometimes with nystagmus, ataxia, dementia, cherry red spot Type II: Mycoclonus, blindness, cherry red spot, dysmorphic features, angiokeratoma Urine oligosaccharides fibroblast alphaneuraminidase Febry’s disease Angiokeratoma, renal disease, development delay Leukocyte alfa-galactosidase A Homocystinuria Lens dislocation, occlusive cerebrovascular disease, osteoporosis, skeletal deformities, mental retardation Urine and plasma homocystine and methionine Strokes and stroke-like episodes Contd... 616 Chapter 135 Inborn Errors of Metabolism: Disorder of Adults? Section 18 Contd... Disease Clinical symptoms Investigation Mitochondrial myopathy, encephalopathy with lactic acidemia and stroke-like episodes (MELAS) Seizures, developmental delay, sensorineural hearing loss, diabetes mellitus Blood of mtDNA analysis Urea cycle defects Postprandial vomiting, coma, confusion Blood ammonia, plasma, and urine amino acids Epilepsy Electron transport chain disorders Any combination of symptoms CSF and blood lactate, blood mtDNA analysis, muscle biopsy for enzyme assay Juvenile Batten’s disease Visual loss, retinitis pigmentosa Skin or rectal biopsy for histological analysis, DNA for the common mutation Myoclonic epilepsy with ragged red fibers (MERRF) Myoclonus Blood for mtDNA analysis Pyridoxine dependent seizures Persistent seizures responsive to pyridoxine Pyridoxine response trial (primary defect not known) Gaucher’s disease type III Horizontal supranuclear gaze defect, developmental delay, hydrocephalus, skeletal abnormalities, psychosis Leukocyte b-glucosidase, bone marrow aspirate Ornithine transcarbamylase deficiency Episodic symptoms (often postprandial), sleep disorders, comatose episodes Plasma ammonia (1 h postprandial), plasma amino acids, urine amino acids and orotic acid Porphyrria Limb, neck, or chest pain, muscle weakness, abdominal pain, photosensitivity Urine and fecal porphyrins, urine delta aminolevulinic acid and porphobilinogen Galactokinase deficiency Cataracts Postprandial urine sugar, chromatography Hyperornithinemia with gyrate atrophy of the retina Optic atrophy Plasma and urine amino acids (ornithine) Gaucher’s disease type III Horizontal supranuclear gaze defect, developmental delay, hydrocephalus, skeletal abnormalities, psychosis Leukocyte b-glucosidase Juvenile Batten’s disease Seizures, visual loss, retinitis pigmentossa, dementia Skin or rectal biopsy for histological analysis, blood for DNA analysis for the common mutation Leber’s hereditary optic atrophy Bilateral optic atrophy (may be alcohol or tobacco triggered) Blood for mtDNA analysis Neuropathy ataxia and retinitis pigmentosa Retinitis pigmentosa, ataxia, neuropathy Blood for mtDNA analysis Niemann-Pick disease type C Psychomotor retardation leading to dementia ataxia with dystonia, vertical supranuclear ophthalmoplegia Bone marrow aspirate, fibroblast cholesterol uptake and staining Refsum’s disease Peripheral neuropathy, retinitis pigmentosa, cerebellar ataxia Plasma phytanic acid Sialidosis Cherry red spot Urine oligosaccharides, fibroblast alfa-neuraminidase Tyrosinemia type II Cataracts, skin lesions, slight development delay Plasma and urine amino acids Wilson’s disease Cataract, Kayser-Fleischer rings, liver disease, dementia, renal failure, parkinsonian features, dysarthria, loss of coordination of voluntary movement Plasma copper and ceruloplasmin, urine copper, liver copper Behavioral and/or psychiatric disorders and/or dementia Eye disorders CONCLUSION The most common mistake made in the management of IEM is delayed diagnosis or misdiagnosis. In unexplained cases, the possibility of an IEM should be entertained, as many disorders are treatable and, in most cases, successful outcome is dependent on rapid diagnosis and early instigation of therapy. Even with untreatable disorders, it is important to establish the diagnosis in the index case in order to allow prenatal diagnosis in subsequent pregnancies. 617 Metabolic Disorders Section 18 TABLE 4 │ Vitamins in treatment of inborn errors of metabolism Disorder Vitamin used in the treatment Maple syrup urine disease Thiamine Homocystinuria Pyridoxine, folic acid and vitamin B12 Propionic academia Biotin Methylmalonic academia Hydroxycobalamin Glutaric academia Riboflavin Biotinidase deficiency Biotin Hartnup disease Nicotinic acid Pyruvate dehydrogenase deficiency/Leigh’s disease Thiamine Respiratory chain disorders Riboflavin 618 REFERENCES 1. Garrod AG. Inborn errors of metabolism. Oxford: Oxford University Press; 1909. 2. Saudubray JM, Ogier H, Charpentier C (Eds). Clinical approach to inherited metabolic diseases. Inborn Metabolic Diseases: Diagnosis and Treatment. Springer-Verlag; 1995. 3. Cleary MA, Green A. Developmental delay: when to suspect and how to investigate for an inborn error of metabolism. Arch Dis Child. 2005;90(11):1128-30. 4. Gray RGF, Preece MA, Green SH, et al. Inborn errors of metabolism as a cause of neurological disease in adults: an approach to investigation. J Neurol Neurosurg Psychiatry. 2000;69:5-12. 5. Lin DD, Crawford TO, Barker PB. Proton MR Spectroscopy in the diagnostic evaluation of suspected mitochondrial disease. Am J Neuroradiol. 2003;24(1):33-41. 6. Low LCK. Inborn errors of metabolism: clinical approach and management. HKMJ. 1996;2(3):274-81. 7. Van den Hout JM, Kamphoven JH, Winkel LP, et al. Long-term intravenous treatment of Pompe disease with recombinant human alpha-glucosidase from milk. Pediatrics. 2004;113(5):e448-57. 8. Wraith EJ, Hopwood JJ, Fuller M, et al. Laronidase treatment of mucopolysaccharidosis I. Bio Drugs. 2005;19(1):1-7. 9. Desnick RJ, Banikazemi M. Fabry disease: clinical spectrum and evidence-based replacement therapy. Nephrol Ther. 2006;2 Suppl 2:S172-85. 10. Wenstrup RJ, Kacena KA, Kaplan P, et al. Effect of enzyme replacement therapy with imiglucerase on BMD in type 1 Gaucher disease. J Bone Miner Res. 2007;22(1):119-26. 11. Miller J, Ramos MI, Garrod MG, et al. Transcobalamin II 775G>C polymorphism and indices of vitamin B12 status in healthy older adults. Blood. 2002;100:718-20. 12. Platt FM, Jeyakumar M, Andersson U, et al. Inhibition of substrate synthesis as a strategy for glycolipid lysosomal storage disease therapy. J Inherit Metab Dis. 2001;24(2):275-90. 13. Chen YT, Cornblath M, Sidbury JB. Cornstarch therapy in type1 glycogen storage disease. N Engl J Med. 1984;310:171-5. 14. Boelens JJ. Trends in haematopoietic cell transplantation for inborn errors of metabolism. J Inherit Metab Dis. 2006;29(2-3):413-20.