J Neurol Neurosurg Psychiatry 2000;69:5–12 5 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.69.1.5 on 1 July 2000. Downloaded from REVIEW Inborn errors of metabolism as a cause of neurological disease in adults: an approach to investigation R G F Gray, M A Preece, S H Green, W Whitehouse, J Winer, A Green In 1927 Archibald Garrod presented the Hux- LYSOSOMAL STORAGE DISEASES ley Lecture at Charing Cross Hospital1 Out of The lysosome is an intracellular organelle this lecture emerged the concept of an “inborn involved in the degradation of various complex error of metabolism” whereby an inherited lipids, glycoproteins, and mucopolysaccha- defect may lead to the accumulation in cells or rides. Defects in specific enzymes lead to the body fluids of a metabolite which in itself may accumulation of complex catabolic intermedi- predispose to disease. The disorders cited as ates. Although the process occurs in utero the examples were all adult onset disorders. age of onset of clinical symptoms can vary sub- Today there are over 200 known inborn stantially. Alleles are known which are associ- errors of metabolism; however, the vast major- ated with a milder, later onset phenotype. This ity of cases reported are of childhood onset may be related to the presence of significant (<16 years of age). In part this may reflect the residual functional enzyme activity resulting in fact that the paediatric forms of the disease are a lower rate of accumulation of the intermedi- more severe and hence more easily recognis- ate metabolite. The clinical symptoms of the able. However, in some cases it may be due to adult onset forms of these diseases can diVer a lack of awareness by physicians treating substantially from the childhood onset forms. adults of the possibility of inborn errors of This disparity between the text book descrip- metabolism being a cause of disease. Certainly, tion of the “classic” phenotype and the reality current experience of inborn errors of metabo- of the presentation in adults can cause consid- lism leads us to think that, potentially, every erable diagnostic diYculty. disorder has a milder form with a later onset. West Midlands Tay-Sach’s and SandhoV’s diseases are http://jnnp.bmj.com/ Regional Metabolic In an attempt to increase awareness of adult gangliosidoses which present in the infantile Disease Service, onset inborn errors of metabolism this article period with seizures, blindness, hypotonia, and Birmingham reviews the disorders which can present at or developmental delay. The adult onset forms Children’s Hospital older than 16 years of age with CNS or neuro- present with a much wider clinical range vary- NHS Trust, Steelhouse muscular disease. We have included disorders Lane, Birmingham ing from atypical forms of motor neuron B4 6NH, UK in which the patient may present with mild or disease2 to dystonia3 and bulbospinal R G F Gray “soft” signs before that age, which are likely to neuronopathy.4 M A Preece be overlooked or mistaken for other disorders. Metachromatic leukodystrophy presents (in on September 30, 2021 by guest. Protected copyright. A Green This is not intended to be an in depth review of its severe form) in the first 2 years of life with each disorder but rather to be a practical guide spastic paraparesis and developmental delay Department of to the initial diagnosis of these disorders for Neurology, Diana, whereas in the adult form it is associated with Princess of Wales neurologists outside specialist centres for the dementia and behavioural problem.5 Children’s Hospital investigation of inborn errors of metabolism. Acid maltase deficiency (glycogen storage NHS Trust, disease type II) usually presents in the first Birmingham, UK S H Green The disorders weeks of life with hypotonia and hypertrophic W Whitehouse We have prepared two tables listing inborn cardiomyopathy. The adult onset forms may errors of metabolism presenting in adulthood. present with muscle weakness but without Department of Table 1 lists the disorders reported in the lit- obvious cardiomyopathy.6 Neurology, University erature together with the main clinical symp- Some of the lysosomal enzymes show a Hospital NHS Trust, “pseudodeficiency” state. Enzyme activity, Birmingham, UK toms, primary defect (if known), and diagnos- J Winer tic tests for their detection. although reduced to as little as 5% of normal, Table 2 lists the disorders associated with does not produce clinical symptoms. In any Correspondence to: specific symptom groups together with any patient who does not show the typical pheno- DrRGFGray type but who shows a gross enzyme deficiency George.Gray@bhamchildrens. specific neurological signs and characteristic wmids.nhs.uk non-neurological features. Diseases are catego- this state needs to be excluded by demonstra- rised in a specific group based on the tion of the accumulating metabolite or by Received 12 February 1999 symptom(s) which is the major feature of the analysis of the relevant gene. This is particu- and in revised form 26 November 1999 disorder, and may in some cases be the initial larly a problem with metachromatic leukodys- Accepted 5 January 2000 presenting symptom. trophy, where 1/50 -1/100 of the population are 6 Gray, Preece, Green, et al J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.69.1.5 on 1 July 2000. Downloaded from Table 1 Inherited metabolic disorders with adult onset forms Disease Clinical symptoms Tests Lysosomal storage diseases Acid maltase deficiency Muscle weakness, respiratory diYculty Lymphocyte á-glucosidase Fabry’s disease Peripheral nerve pain (±renal Leucocyte á-galactosidase A failure±angiokeratoma±cardiomyopathy), stroke-like episodes Gaucher’s disease type III Horizontal supranuclear gaze defect, developmental Leucocyte â-glucosidase, bone marrow aspirate delay, hydrocephalus, skeletal abnormalities, psychosis GM1 gangliosidosis (i) Extra pyramidal signs, flattening of vertebral Leucocyte â-galactosidase, urine oligosaccharides bodies, normal cognitive function. sometimes with psychosis GM2 gangliosidosis (Tay Sach’s and SandhoV’s (i) Lower motor neuron disease with onset 20–40 y, Leucocyte total, hexosaminidase, and disease) pyramidal signs, and cerebellar degeneration hexosaminidase A (ii) Atypical amyotropic lateral sclerosis Krabbe’s leukodystrophy Pes cavus, hemiparesis, spastic tetraparesis, Leucocyte â-galactocerebrosidase leukodystrophy Metachromatic leukodystrophy Loss of cognitive function or behavioural Leucocyte arylsulphatase A (the pseudodeficiency abnormalities, neuromuscular weakness with state must be excluded) impaired nerve conduction, leukodystrophy Sialidosis (mucolipidosis type I) Type I Urine oligosaccharides, fibroblast á-neuraminidase Visual defect with lens or corneal opacity, ataxia, myoclonus, generalised seizures sometimes with nystagmus, ataxia Type II Dementia±cherry red spot Myoclonus, blindness, cherry red spot, dysmorphic features, angiokeratoma. Niemann-Pick’s disease type C Psychomotor retardation leading to dementia, ataxia Bone marrow aspirate, fibroblast cholesterol uptake with dystonia and staining. Amino acid disorders Arginase deficiency Disorientation, coma Plasma and urine amino acids, plasma ammonia (1 h postprandial). Citrullinaemia Disorientation, restlessness, coma Plasma and urine amino acids, plasma ammonia (1 h postprandial). Hartnup’s disease Dementia, ataxia ±skin lesions. Plasma and urine amino acids Homocystinuria (cystathionine Occlusive cerebrovascular disease, dislocated lenses, Urine homocystine, plasma homocystine and http://jnnp.bmj.com/ synthasedeficiency: classic form) osteoporosis, psychiatric disturbances methionine Homocystinuria (methylene Parasthaesia, hallucinations, tremor, withdrawal, Urine homocystine, plasma homocystine and tetrahydrofolatereductase deficiency remethylation mental retardation, limb weakness, memory loss methionine defect). Hyperornithinaemiawith gyrate atrophy of the Gyrate atrophy of choroid and retina Plasma and urine amino acids (ornithine) retina Ornithine transcarbamylase deficiency Behavioural disturbances, comatose episodes, sleep Plasma ammonia (1 h postprandial)plasma amino disorders acids, urine amino acids and orotic acid on September 30, 2021 by guest. Protected copyright. Organic acid disorders Fatty acid oxidation defects Muscle weakness, easy fatigability ±liver disease Urine organic acids (fasting) ±cardiomyopathy ±hypoglycaemia Glutaric aciduria type 1 Dystonia±hypoglycaemia, may present with a Urine organic acids, blood spot acyl carnitines Reye-like syndrome Propionic acidaemia Chorea and dementia, recurrent vomiting Urine organic acids, blood spot acyl carnitines Peroxisomal disorders X linked adrenoleukodystrophy (i) Onset 20–30 y in males, gait disturbance, spastic Plasma very long chain fatty acids. paraparesis, intellectual function usually intact, impotence±Addison’s disease, occasionally cerebral symptoms may occur, eg dementia and psychosis. (ii) Onset >30 y in females, spastic paraparesis, vibratory sense loss, long tract signs, peripheral neuropathy Lactic acidaemias Electron transport chain disorders (i) mtDNA encoded NARP, MELAS, MERRF, Kearns-Sayre syndrome, Blood or tissue mtDNA analysis LHON (ii) Nuclear DNA encoded Muscle weakness, multisystem disease CSF/plasma lactate, muscle biopsy for respiratory chain assays Inborn errors of metabolism as a cause of neurological disease in adults 7 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.69.1.5 on 1 July 2000. Downloaded from Table 1 Inherited metabolic disorders with adult