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 It involves cellular organelles and includes lysosomal, peroxisomal, collectively numerous. The term was coined by Archibald Garrod, glycosylation and cholesterol synthesis defects. who in 1927 presented the Huxley lecture at Charing Cross Hospital.1 • Mucopolysaccharidosis (Hurler, Hunter, Sanfilippo, Morquio, Until recently, IEMs were considered a specialty of pediatricians. Maroteaux, Sly, etc.) Indeed, the term “inborn” has meant for a long time, a disease which • Sphingolipidosis (gangliodosis, Tay-Sachs, Sandhoff) starts in the newborn period or at least in childhood. Although • Lactosylceramidosis (Gaucher, Farber, Niemann-Pick, Krabbe, most IEMs can have mild forms starting in adolescence or late in sulfatase deficiency) adulthood, this concept of “adult onset IEMs” has not reached the • Glycoproteinases (fucosidosis, manosidosis, sialidosis, aspartyl- medical community until recently. glucosaminuria) They refer to single gene disorders wherein loss of function of a • Defects in membrane transport (cystinosis, succinic semialdehyde single enzyme results in abnormalities in synthesis or catabolism dehydrogenase, Salla disease) of proteins, carbohydrates or fats, which results in a disruption in a • Peroxisomal biogenesis defects (Zellweger syndrome, adreno- metabolic pathway. This results in toxic accumulations of substrates leukodystrophy, Refsum’s disease, hyperoxaluria Type I) before the disruption, intermediates from alternative pathways, • Fabry’s disease, Shindler, Canavan disease, Pompe disease, acid and/or defects in energy production and utilization. Nearly every lipase deficiency, acid maltase deficiency, cerebrotendinous metabolic disease has several forms that vary in age of onset, clinical xanthomatosis, Juvenile Batten’s disease, Kuf’s disease, etc. severity and mode of inheritance. The mode of inheritance determines the male to female ratio of Group 2 affected and many IEMs have multiple forms that differ in their mode It includes IEMs that give rise to an acute or chronic intoxication. of inheritance. • Disorders of amino acids: Cystinuria, phenylketonuria (PKU), tyrosinemia, homocystinuria, alcaptonuria, maple syrup urine CLASSIFICATION disease, Hartnup’s disease, hyperornithinemia with gyrate A simple method classifies IEMs into disorders involving protein atrophy metabolism, carbohydrate metabolism, lysosomal storage, fatty acid • Organic acidurias: Beta-ketothiolase deficiency, methyl- oxidation defects, mitochondrial disorders, peroxisomal disorders. glutaconic academia, isovaleric academia, glutaric academia A detailed and widely used classification which categorizes IEMs Type I, propionic academia, multiple car boxylase deficiency, from a pathophysiological perspective is as follows (Flow chart 1):2 methyl malonic academia Flow chart 1: Classification of IEMs Metabolic Disorders Section 18 • Urea cycle defects: Citrullinemia, argininemia, argino succinic Group II aciduria, carbomyl phosphate synthase deficiency, ornithine They do not interfere with the embryofetal development and transcarbamylase deficiency they present with a symptom-free interval and clinical signs of • Sugar intolerance: Galactosemia, epimerase deficiency, heredi- “intoxication”, which may be acute (vomiting, coma, liver failure, tary fructose intolerance, galactokinase deficiency thromboembolic complications etc.) or chronic (failure to thrive, • Others: Porphyrias, Wilson’s disease, aceruloplasminemia, developmental delay, ectopia lentis, cardiomyopathy etc.). Circum- Lesch-Nyhan syndrome, Sjogren-Larsson syndrome. stances that can provoke acute metabolic attacks include fever, intercurrent illness and food intake. Clinical expression is often both Group 3 late in onset and intermittent. It includes IEMs that affect the cytoplasmic and mitochondrial energetic processes. Mitochondrial defects are the most severe and Group III are generally untreatable (except ketone body defects and coenzyme Common symptoms in this group include hypoglycemia, hyper- q10 defects). Cytoplasmic energy defects are generally less severe. lactatemia, hepatomegaly, hypotonia, myopathy, car diomyopathy, • Fatty acid oxidation defects: carnitine palmitoyl trans ferase I, cardiac failure, circulatory collapse, and brain involvement. Some II deficiency, short-chain acyl-CoA dehydrogenase deficiency, of the mitochondrial disorders and pentose phosphate pathway medium-chain acyl-CoA dehydrogenase defi ciency, very defects can interfere with the embryofetal development and give rise long chain acyl CoA dehydrogenase deficiency, long-chain to dysmorphism, dysplasia and malformations. 3-hydroxyacyl-CoA dehydrogenase deficiency, glutaric academia In general, clinicians should consider the possibility of an IEM in Type II, carnitine uptake deficiency, hy droxymethylglutaryl CoA any patient with an unexplained neurological disorder. Some brain lyase regions like basal ganglia are highly vulnerable to energy metabolism • Mitochondrial disorders: pyruvate dehydrogenase com plex defects and metals. In an adult patient with an unexplained deficiency, pyruvate carboxylase deficiency, myoclonic epilepsy encephalopathy or an unexplained coma, certain features are highly with ragged red fibers, mitochondrial encephalopathy with suggestive of an IEM: (1) when the encephalopathy is triggered by an lactic acidosis and stroke, phospho enolpyruvate carboxykinase extrinsic factor—surgery, fasting, exercise, treatments, high-protein deficiency, Leber’s hereditary optic atrophy, neuropathy ataxia intake, new medication (Table 1), etc.; and (2) when specific brain and retinitis pigmentosa (NARP) lesions are present on brain magnetic resonance imaging (MRI). • Glycogen storage disorders: von Gierke’s disease (Type I), Two main groups of IEMs are responsible for encephalopathies Pompe’s disease (Type II), Cori’s or Forbes’ disease (Type III), in adults: intoxications (mainly, urea cycle disorders, homocysteine Anderson’s disease (Type IV), McArdle’s disease (Type V), Her’s remethylation defects and acute porphyrias) and energy metabolism disease (Type VI), Tarui’s disease (Type VII), Type IX, Fanconi defects (respiratory chain disorders, pyruvate dehydrogenase Bickel syndrome (Type XI), red cell aldolase deficiency (Type deficiency and biotine responsive basal ganglia disease). XII), Type XIII, Type 0. In the first group, MRI is usually normal or can show poorly specific features whereas in the second group, MRI is almost always CLINICAL MANIFESTATIONS abnormal, showing bilateral lesions of basal ganglia (Leigh syndrome) Inborn errors of metabolism (IEMs) can affect any organ system and or pseudo-strokes (mainly in the case of respiratory chain defects). manifestations vary from those of acute life-threatening disease to subacute progressive degenerative disorder. Progression may be DIAGNOSIS AND MANAGEMENT unrelenting with rapid life-threatening deterioration over hours, Inborn errors of metabolism may present in adolescence or adulthood episodic with intermittent decompensations and asymptomatic as a psychiatric disorder. In some instances, an IEM is suspected intervals, or insidious with slow degeneration over decades. All because of informative family history or because psychiatric three groups of IEMs can manifest in adults, more so with Group I symptoms form part of a more diffuse clinical picture with systemic, disorders. cognitive or motor neurological signs. In neonates and children, manifestations are nonspecific and There are 3 important steps in the diagnosis and management of very similar to that of septicemia, a major reason why IEMs go an IEM. undetected. There may be dysmorphic features present at birth (generally when fetal energy is affected), or develop during the first 1. Suspicion year of life (lysosomal disorders). The symptoms and signs for an IEM are very common and nonspecific; In adults, the symptoms may include mild-to-profound mental therefore, one should think of IEM as an etiology in unexplained/ retardation, autism, learning disorders, behavioral disturbances, peculiar cases and try to rule out the possibility. muscle weakness, progressive paraparesis, hemiparesis, dystonia, chorea, ataxia, ophthalmoplegia, visual deficit, epileptic crisis, hepatosplenomegaly and hypoglycemia. TABLE 1 │ Drugs which aggravate inborn errors of metabolism Some manifestations may be intermittent, precipitated by the Disease Drugs Mechanism stress of illness, or progressive, with worsening over time. Disorders Urea cycle disorders Valproate Blockage of urea cycle manifested by subtle neurologic or psychiatric features often go undiagnosed until adulthood. Porphyrias Imipramine, Porphyrogenic meprobamate Group I Wilson’s disease Neuroleptics Blockage of D2 dopamine receptors Onset in adulthood (upto > 70 years). Among the organs impacted, the nervous system is by far most common. Thus, late onset forms GM2 gangliosidosis Tricyclic ?Increased lipid storage of IEMs often display psychiatric or neurological presentations. antidepressants, phenothiazines These include atypical psychosis or depression, unexplained coma, peripheral neuropathy, cerebellar ataxia, spastic paraparesis, Respiratory chain Valproate Blocks the respiratory dementia, movement disorders, epilepsy, etc. disorders chain 614 Section 18 Chapter 135 Inborn Errors of Metabolism: Disorder of Adults? 2.