An insight into the biochemistry of inborn errors of metabolism for a clinical neurologist

Abstract

Neurological dysfunction is an important manifestation of inherited metabolic disorders. Although these are more common in childhood, adult onset forms with a different clinical presentation are often encountered. Recent advances in the diagnosis and treatment of these conditions have substantially improved the outcome in many of these conditions. This makes it essential that the practicing physician be familiar with the clinical presentation and diagnosis of these disorders. For the evaluation of a patient with a possible inborn error of metabolism, simple screening tests may aid in the diagnosis and provide direction for more comprehensive laboratory analysis. In this review, we present a practical approach to diagnosis of neurometabolic disorders. Establishing a specific diagnosis in these disorders will enable the clinician in offering a definitive long-term treatment, prognosis and genetic counselling.

Keywords: Biochemical tests; diagnosis; inborn errors.

Figure 1

An approach to inherited metabolic disorders with chronic encephalopathy.[3] GM2: GM2 gangliosidosis, GM1: GM1 gangliosidosis, NCL: neuronal ceroid lipofuscinosis, MELAS: mitochondrial encephalopathy lactic acidosis syndrome, X-ALD: X-adrenoleukodystrophy, MLD: metachromatic leukodystrophy, MPS: mucopolysaccharidosis, MSD: multiple sulfatase deficiency

Figure 2

Biochemical evaluation of hypoglycaemia Pl: Plasma, HFI: Hereditary fructose intolerance, FAO: Fatty acid oxidation, GSD: Glycogen storage disorder, FBP: Fructose-1,6-bisphosphatase deficiency, GH: Growth hormone, IGF-1: insulin-like growth factor-1

Figure 3

Evaluation of metabolic acidosis

Figure 4

Evaluation of metabolic acidosis with increased anion gap L/P: Lactate/pyruvate ratio, N: Normal, ↓: Decreased, ↑: Increased, GSD I: glycogen storage disorder type I, FBP: fructose-1, 6-bisphosphatase deficiency, PEPCK: phosphoenolpyruvate carboxykinase deficiency, PDH: Pyruvate dehydrogense deficiency, PC: pyruvate carboxylase deficiency

Figure 5

An approach to diagnosis of hyperammonemia in older children OA: organic acidurias, FAO: fatty acid oxidation defects, PC: pyruvate carboxylase deficiency, PDH: pyruvate dehydrogenase deficiency, ASA: argininosuccinic acid, AS: argininosuccinic aciduria, NAGS: N-acetylglutamate synthetase deficiency, CPS I: carbamoyl phosphate synthetase I deficiency, OTC: ornithine transcarbamoylase deficiency, HHH: hyperornithinemia hyperammonemia homocitrullinuria syndrome, LPI: lysinuric protein intolerance

Figure 6

MRI (FLAIR) in a 20 months old girl with phenylketonuria. Note the periventricular hyperintensities

Figure 7

MRI (T2W) in a 14 days- old baby with classic maple syrup urine disease. Note the diffuse symmetrical white matter hyper intensity of white matter. In addition, note involvement of globus pallidi and thalami

Figure 8

MRI (T2 W) in a 15 months old baby with glutaric aciduria type 1. Note the widened sylvian fissures, bilateral symmetrical signal changes in the basal ganglia. and widened subarachnoid spaces

Figure 9

MRI (T2W) in a 12- year old boy with methylmalonic acidemia. Note the bilateral symmetrical hyperintensities involving the medial globus pallidi