71 2 Inborn Errors of Metabolism in Adults: A Diagnostic Approach to Neurological and Psychiatric Presentations Fanny Mochel, Frédéric Sedel 2.1 Differences Between Paediatric and Adult Phenotypes – 72 2.2 General Approach to IEM In Adulthood – 72 2.3 Specific Approaches to Neuro metabolic Presentations in Adults – 76 References – 89 J.-M. Saudubray et al. (Eds.), Inborn Metabolic Diseases, DOI 10.1007/978-3-662-49771-5_2, © Springer-Verlag Berlin Heidelberg 2016 72 Chapter 2 · Inborn Errors of Metabolism in Adults: A Diagnostic Approach to Neurological and Psychiatric Presentations Late-onset forms of IEM presenting initially in adulthood are of- In addition, some clinical signs are highly suggestive of a ten unrecognised, so that their exact prevalence is unknown [1]. particular IEM or of a particular group of IEM. Some of these Most often they have psychiatric or neurological manifestations, ‘red flags’ are listed in . Table 2.2. 2 including atypical psychosis or depression, unexplained coma, Unfortunately, in many circumstances, highly specific peripheral neuropathy, cerebellar ataxia, spastic paraparesis, de- signs or symptoms are lacking and the presentation is that of mentia, movement disorders and epilepsy [2][3][4][5]. a less specific neurological or psychiatric disorder (epilepsy, Physicians caring for adult patients with IEM are also involved in cognitive decline, psychiatric signs). In such situations, the the management of those with early onset forms who reach diagnostic approach is based on the type of clinical signs, their adulthood. The transfer of such patients from paediatric to adult clinical course (acute, acute-relapsing, with diurnal variations, care raises a number of medical, dietetic and social concerns. progressive, static), brain MRI findings, eye findings and elec- A further important issue is the diagnosis of adult patients who troneuromyography. Some matching between clinical, imag- had their first clinical signs in childhood but for whom the ing, ophthalmological and electrophysiological findings and diagnosis was missed, either because IEM were not considered IEM is shown in the text and tables below. or because the disease or its mild clinical form had not been Metabolic diseases involving the nervous system can be described at that time. divided into five main categories, all of which display some similarities in clinical presentation, diagnostic methods and treatment strategies. 2.1 Differences Between Paediatric and Adult Phenotypes 2.2.1 Disorders of Energy Metabolism Adults’ physicians who want to specialise in IEM are faced with the fact that, with the exception of several review arti- Disorders of energy metabolism include respiratory chain dis- cles, most if not all existing books and diagnostic algorithms orders (that can be primary or secondary, as can occur in or- refer to paediatric forms of these diseases. Late-onset forms ganic acidurias), pyruvate dehydrogenase deficiency, Krebs of IEM tend to display attenuated phenotypes, which in some cycle deficiencies, GLUT1 deficiency, β-oxidation defects and instances are associated with one or more clinical manifesta- disorders involving co-factors such as ETF deficiency, vitamin tions that differ from the classic clinical picture described in E deficiency, biotinidase deficiency, biotin-responsive basal children. Table 2.1 gives some examples of differences be- ganglia disease, creatine deficiency syndromes and coenzyme tween childhood and adult onset presentations. Although the Q synthesis defects. Acute manifestations are often triggered limited information available about adult forms of IEM by infections and encompass Leigh syndrome, acute optic makes the specialty new and quite exploratory, the diagnostic neuropathy, acute cerebellar ataxia, pseudo-strokes or status approach in adults is facilitated by the fact that the nervous epilepticus. Chronic presentations often involve muscles, system is already mature. Therefore, clinical presentations are cere bellum, basal ganglia (parkinsonism, dystonia), cortex more homogeneous than in children, in whom clinical signs (epilepsy, myoclonus) or the peripheral nervous system (axo- usually differ depending on their stage of maturation (7 nal polyneuropathy). In adults, the brain white matter is less Chapter 1). involved and spastic paraparesis is uncommon. 2.2 General Approach 2.2.2 Disorders of Lipid Metabolism to IEM in Adulthood Disorders of lipid metabolism include sphingolipidoses As stated above, adult-onset presentations of IEM are essen- (Krabbe disease, metachromatic leukodystrophy, Niemann tially neurological or psychiatric. The typical situation is that Pick A and B, Fabry disease and Gaucher disease), peroxiso- of a patient with an unexplained and bizarre neurological or mal disorders (adrenomyeloneuropathy, Refsum disease, dis- psychiatric problem in whom the usual aetiologies have been orders of pristanic acid metabolism, peroxisome biogenesis excluded by appropriate tests. The diagnostic approach in disorders), sterols disorders (cerebrotendinous xanthomato- such a situation is always based on the two questions of when sis, Niemann-Pick C, spastic paraplegia type 5 and Tangier to suspect an IEM and, when an IEM is suspected, what type disease) and the newly described group of metabolic diseases of metabolic investigations must be performed [6]. affecting the synthesis and remodelling of phospholipids (mu- Some general clinical features are highly suggestive of an tations in PLA2G6, DDHD1, DDHD2, NTE, CYP2U1, IEM: when clinical signs or symptoms are fluctuating, espe- ABHD12) and sphingolipids (mutations in FA2H, GBA2, cially when triggered by fasting, exercise, fever, catabolic B4GALNT1) [7][8] (7 Chapter 34, 7 Chapter 38, 7 Chapter 40). circumstances or post-partum; when clinical signs suggest a Given the great proportion of lipids in the nervous system, diffuse disease including neurological signs plus systemic these diseases can produce almost all kinds of symptoms but signs (eye or skin problems, organomegaly etc.) or involve- spastic paraparesis is very common. Leukodystrophy and de- ment of different parts of the nervous system (optic nerves and myelinating polyneuropathy are hallmarks of disorders inter- cerebellum; leukoencephalopathy and polyneuropathy). fering with myelin formation or maintenance. A past history 73 2 2.2 · General Approach to IEM in Adulthood . Table 2.1 Phenotypic differences between childhood-onset and adult-onset forms of inborn errors of metabolism Disease Classic presentation in childhood Adult-onset forms AGAT deficiency Psychomotor delay, severe language impairment, Mild mental retardation with myopathy failure to thrive and autistic-type behaviour AMACR deficiency Neonatal cholestasis, mental retardation, retinitis Recurrent encephalopathy, epilepsy, psychiatric pigmentosa disorders, polyneuropathy α-Mannosidosis Mental retardation, deafness, upper airways Episodes of psychosis, confusion, cerebellar ataxia, infections, dysmorphic features posterior leukoencephalopathy Biotinidase deficiency Muscular hypotonia, lethargy, grand mal and Bilateral optic atrophy, spastic paraparesis, motor myoclonic seizures, ataxia, stridor, skin lesions neuropathy Cerebral glucose trans- Epilepsy, psychomotor delay, dystonia, ataxia, Isolated seizures, exercise-induced dystonia, porter (GLUT1) deficiency acquired microcephaly lethargy triggered by fasting, dystonic tremor Cobalamin C disease Progressive encephalopathy, abnormal move- Psychiatric problems, confusion, subacute my- ments, epilepsy, comas, multisystem pathology elopathy, peripheral neuropathy, thromboembolic (renal failure, hepatic dysfunction, cardiomyo- events. MRI: normal or leukoencephalopathy, pathy), retinopathy, macrocytosis macrocytic anaemia is rare Coenzyme Q10 deficiency Leigh syndrome, myoglobinuria, encephalopathy Cerebellar ataxia, myopathy Cerebrotendinous Mental retardation, chronic diarrhoea, epilepsy, Tendon xanthomas, cerebellar ataxia, spastic xanthomatosis juvenile cataract, neonatal cholestasis paraparesis, dementia, psychiatric signs Cystathionine β-synthase Mental retardation, marfanoid habitus, epilepsy, Strokes (internal carotid dissection), deep vein deficiency autism, lens dislocation, scoliosis thrombosis, psychiatric disorders Fatty acid β-oxidation Non-ketotic hypoglycaemia, cardiomyopathy, Encephalopathy (MCAD), rhabdomyolysis, defects liver disease, rhabdomyolysis, peripheral proximal myopathy neuropathy, retinitis pigmentosa (LCHAD) Fabry disease Crises of acroparaesthesia Strokes, vertigo, cardiomyopathy, hearing loss, proteinuria GAMT deficiency Epilepsy, movement disorders, mental retarda- Isolated myopathy tion, behavioural problems Glutaric aciduria type 1 Encephalopathy or movement disorders with Leukoencephalopathy with subependymal bilateral lesions of basal ganglia, dystonia pre- nodules, spastic paraparesis, cephalalgia, dy- dominates sexecutive syndrome, peripheral neuropathy Glycogenosis type IV Neuromuscular form, combined hepatic and Polyglucosan body disease: spastic paraparesis, (glycogen branching myopathic form peripheral neuropathy, leukoencephalopathy with enzyme deficiency) spinal cord atrophy GM1 gangliosidosis Dysmorphic features, organomegaly, macular Generalised dystonia, parkinsonism, dysarthria, cherry red spot, progressive spasticity, seizures, kyphoscoliosis, vertebral and hip dysplasia. MRI: decerebrate posturing high signal of posterior putamen GM2 gangliosidosis Motor weakness, visual loss, progressive spastic- Psychosis, lower