Therapy Insight: inborn errors of metabolism in adult neurology—a clinical approach focused on treatable diseases

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<ul><li><p></p><p>Therapy Insight: inborn errors of metabolism in adult neurologya clinical approach focused on treatable diseases Frdric Sedel*, Olivier Lyon-Caen and Jean-Marie Saudubray</p><p>INTRODUCTIONInborn errors of metabolism (IEMs) repre-sent a subgroup of genetic disorders character-ized by dysfunction of an enzyme or other protein involved in cellular metabolism. With around 350 different diseases identified to date, IEMs as an entity represent about one-third of genetic diseases.1 In contrast with other genetic dis orders, the diagnosis of which relies predominantly on specific molecular analysis, diagnosis of IEMs can often be accomplished by bio chemical analysis of blood and urine samples, which can be rapidly obtained in specialized metabolic labora tories. IEMs can affect many organs, including liver, kidney, heart and muscle, but in most cases they involve the nervous system and can present as neuro-logical disorders. The first clinical symptoms usually manifest in infancy or childhood, but in a proportion of cases they can appear in adoles-cence or adulthood.2,3 The prevalence of IEMs in adulthood is unknown, and most of these diseases are probably underdiagnosed. </p><p>Many IEMs are amenable to specific treat-ments, including direct administration of the missing enzyme (e.g. enzyme replacement therapy for Gaucher disease), stimulation of the residual enzymatic activity or alternative pathways through cofactors (e.g. vitamin B6 in homocystinuria) or substrate loading (e.g. folic acid in methylene tetrahydrofolate reductase [MTHFR] deficiency). Another approach is to decrease the concentration of a toxic compound by prescription of a specific diet (e.g. diet poor in phenylalanine in phenylketonuria), by inhibiting synthesis of the toxic compound (e.g. miglustat in Gaucher disease) or by the use of cleansing drugs (e.g. chelators like sodium benzoate in urea cycle disorders, d-penicillamine in Wilsons disease). Finally, certain IEMs can be treated through the replacement of a deficient meta-bolic compound (e.g. coenzyme Q10, serine). A comprehensive list of treatments is provided in Supplementary Table 1. In all cases, treatments are more efficient if given at early stages, before </p><p>Inborn errors of metabolism (IEMs) are genetic disorders characterized by dysfunction of an enzyme or other protein involved in cellular metabolism. In most cases, IEMs involve the nervous system. The first clinical symptoms of IEMs usually present in infancy, but in an unknown proportion of cases they can appear in adolescence or adulthood. In this Review, we focus on treatable IEMs, presenting acutely or chronically, that can be diagnosed in an adult neurology department. To make our presentation readily usable by clinicians, the Review is subdivided into eight sections according to the main clinical presentations: emergencies (acute encephalopathies and strokes), movement disorders, peripheral neuropathies, spastic paraparesis, cerebellar ataxia, psychiatric disorders, epilepsy and leukoencephalopathies. Our aim is to present simple guidelines to enable neurologists to avoid overlooking a treatable metabolic disease.</p><p>KEYWORDS enzyme replacement therapy, genetic disorders, inborn errors of metabolism, late-onset, neurological disorders</p><p>F Sedel is a Hospital Practitioner in the Department of Neurology at Salptrire Hospital , O Lyon-Caen is Head of the Department of Neurology at Salptrire Hospital and Professor of Neurology at the Pierre et Marie Curie University, Paris VI, and J-M Saudubray is Full Professor of Pediatrics and Genetics at the Necker Enfants Malades Hospital and the Ren Descartes University Paris V, Paris, France.</p><p>Correspondence *Federation of Nervous System Diseases, Salptrire Hospital, 47 Boulevard de lHpital, 75651 Paris Cedex 13,</p><p>Received 19 January 2007 Accepted 13 March 2007</p><p></p><p>REVIEW CRITERIAReferences for this review were identified by searches of PubMed from 1966 to November 2007, with the terms inborn errors of metabolism, adult and late-onset. Articles were also identified through searches of the authors own files. Only papers published in English or French were reviewed.</p><p>SUMMARY</p><p>MAY 2007 VOL 3 NO 5 NATURE CLINICAL PRACTICE NEUROLOGY 279</p><p>ncpneuro_2007_011.indd 279ncpneuro_2007_011.indd 279 18/4/07 12:19:23 pm18/4/07 12:19:23 pm</p></li><li><p>REVIEW</p><p>280 NATURE CLINICAL PRACTICE NEUROLOGY SEDEL ET AL. MAY 2007 VOL 3 NO 5</p><p></p><p>the occurrence of irreversible neurological lesions. Sometimes treatments can be life-saving, such as in the case of ornithine trans-carbamylase (OTC) deficiency or B6-responsive homocystinuria. Even when irreversible damage has occurred, treatments can still be partially effective in avoiding progression to additional neurological or systemic symptoms, or in slowing the disease course. Focusing on treat-able diseases, therefore, constitutes a necessary and pragmatic approach to the complex field of metabolic diseases.3 </p><p>In this article, drawing on our personal expe-rience in metabolic and neurological diseases in children and adults, and the results of a comprehensive literature analysis, we review treatable IEMs that can be diagnosed in an adult neurology department. This includes mild clin-ical forms of IEM with onset in late childhood or adolescence, as well as IEMs that truly begin in adulthood. The main diagnostic features and treatments are detailed in Tables 13, in which IEMs are categorized patho physiologically as intoxications (Table 1), defects of energy metabolism and complex molecule metabolism (Table 2), and neurotransmitter defects and vitamin metabolism disorders (Table 3). Inborn errors of intermediary metabolism (intoxica-tions and energy defects) are frequently triggered by inter current illnesses, food intake, catabolism or drugs, or postpartum. We excluded from this Review myopathies and IEMs that are not readily treatable, including many mitochondrial, lysosomal and peroxysomal diseases.4,5</p><p>To make our presentation readily usable by clinicians faced with a given situation, this Review is subdivided into eight sections: emer-gencies (acute encephalopathies and strokes), movement disorders, peripheral neuropathies, spastic paraparesis, cerebellar ataxia, psychiatric disorders, epilepsy and leukoencephalopathies. Diagnostic approaches for acute and chronic situations are proposed.</p><p>CLINICAL PRESENTATIONS OF INBORN ERRORS OF METABOLISM IN ADULTSEmergenciesAcute or subacute encephalopathies Acute alteration of consciousness is a common problem in patients with IEMs. All types of confusion or coma, including those presenting with focal neurological signs, can be indica-tive of an IEM. The apparent initial acute manifestations are frequently preceded by </p><p>other premonitory symptoms, which might be un recognized or misinterpreted. Metabolic attacks are often set off by specific situations or triggers such as benign febrile illness, certain drugs or foods, prolonged exercise, surgery, or post-partum, and can mimic encephalitis, poisoning, iatrogenic effects, postpartum psychosis or complications of surgery. </p><p>Urea cycle disorders can present at any age, with episodes of confusion or coma, often preceded by digestive signs (nausea, diar-rhea, vomiting and anorexia) and cephalalgia. Clinical symptoms can be apparently spon-taneous or triggered by conditions of high protein intake (protein-rich foods, enteral or parenteral nutrition), high protein cata bolism (prolonged exercise, postpartum period, surgery, infections or corticoids), or treat-ment with valproate. Metabolic crisis might be accompanied by focal neurological signs or epilepsy, making it difficult to rule out differen-tial diagnoses such as ischemic stroke (venous or arterial), cerebral tumor, encephalitis or status epi lepticus. Diagnosis is suggested by the increased ammonia concentration in blood. OTC deficiency is by far the most frequent urea cycle defect. Transmission of this IEM is X-linked, and both adult heterozygous women and hemizygous men can be affected.610 Adult-onset presentations have also been reported in carbamoyl phosphate synthase,11 arginase and argininosuccinate synthetase deficiencies,12,13 all of which are autosomal recessive disorders. Treatment, if introduced at the beginning of the metabolic attack, prevents disease progression towards coma and ultimately death or definitive neurological lesions. </p><p>Homocysteine remethylation defects such as MTHFR deficiency and cobalamin metabolism defects (mainly cobalamin C [CblC] disease) can also present as a subacute encephalopathy, which might be precipitated by a surgical inter-vention or appear spontaneously. Mild mental retardation and chronic or subacute psychiatric signs often precede alteration of consciousness and motor signs.1418 Treatments are very effi-cient if introduced early. In MTHFR deficiency, treatment is based on folinic acid, vitamin B12 and betaine, whereas in CblC disease it depends on parenteral hydroxocobalamin. </p><p>Acute attacks of porphyrias are often trig-gered by certain drugs, infectious disorders or alcohol.19,20 They usually begin with behavioral changes, digestive symptoms, pain in extremities </p><p>ncpneuro_2007_011.indd 280ncpneuro_2007_011.indd 280 18/4/07 12:19:26 pm18/4/07 12:19:26 pm</p></li><li><p>REVIEW</p><p>MAY 2007 VOL 3 NO 5 SEDEL ET AL. NATURE CLINICAL PRACTICE NEUROLOGY 281</p><p></p><p>Table 1 Treatable neurological inborn errors of metabolism in adults: intoxications.</p><p>Disease Mode of inheritance</p><p>Age at onset</p><p>Major clinical and radiological signs (late-onset forms)</p><p>Major biological disturbances</p><p>Treatment Screening tests (mandatory tests in bold)</p><p>Urea cycle disorders</p><p>X-linked (OTC deficiency), AR </p><p>Any Metabolic crisis triggered by high protein intake or catabolism: nausea, vomiting, cephalalgia, confusion, psychiatric problems, ataxia, stroke-like episodes, epilepsy, coma. MRI: normal or cerebral edema. Subacute paraplegia in arginase deficiency</p><p>High ammonemia (&gt;80100 M) and high glutamine. Other abnormalities depend on the metabolic block</p><p>Protein restriction, sodium benzoate or phenylbutyrate, L-arginine, dialysis</p><p>Ammonemia,AAC, urinary orotic acid</p><p>CBS deficiency</p><p>AR Any Mental retardation, psychiatric problems, epilepsy, strokes, dystonia, thromboembolic events, Marfan-like appearance, lens dislocation, myopia</p><p>Hyperhomocysteinemia &gt;100 M, hypermethioninemia</p><p>Vitamin B6, protein restriction diet </p><p>Homocysteinemia, AAC</p><p>MTHFR deficiency</p><p>AR Any Psychiatric problems, confusion, coma, paraplegia, thromboembolic events, polyneuropathy. MRI: leukoencephalopathy </p><p>Homocysteine &gt;100 M, low methionine, low folates</p><p>Folinic acid, betaine, cobalamin</p><p>Homocysteinemia,AAC, blood folates</p><p>Cobalamin C disease</p><p>AR Any Psychiatric problems, confusion, subacute combined degeneration of the spinal cord, peripheral neuropathy, optic atrophy, thromboembolic events, macrocytosis. MRI: brain and spinal cord leukopathy</p><p>Homocysteine &gt;100 M, methionine low, high methylmalonic aciduria</p><p>Hydroxocobalamin, folic acid, betaine</p><p>Homocysteinemia, AAC, OAC</p><p>PKU AR Any Spastic paraparesis, optic atrophy, dementia, leukoencephalopathy, parkinsonism</p><p>Hyperphenylalaninemia, hypotyrosinemia</p><p>Diet low in phenylalanine</p><p>Guthrie test,AAC</p><p>NKH AR Any Acute: paroxysmal movement disorders, confusion, supranuclear gaze palsy. Chronic: mental retardation, behavioral problems</p><p>Hyperglycinemia, hyperglycinuria, CSF:blood glycine ratio &gt;0.04</p><p>Sodium benzoate dextromethorphan, ketamine</p><p>AAC </p><p>MSUD AR Any Episodes of nausea, vomiting, encephalopathy and coma triggered by high protein intake or circumstances of high protein catabolism </p><p>High levels of leucine, valine, isoleucine, 2-oxo and 2-hydroxy organic acids. Ketosis</p><p>Diet low in branched chain amino acids </p><p>AAC,OAC</p><p>Triple H syndrome</p><p>AR Any Episodes of nausea and vomiting triggered by high protein intake, spastic paraparesis, cerebellar ataxia, mild mental retardation</p><p>High ornithine, ammonemia, homocitrulline, orotic acid</p><p>Protein restriction, ornithine, arginine or citrulline</p><p>Ammonemia,AAC, urinary orotic acid</p><p>Glutaric aciduria type 1 </p><p>AR Any Cephalalgia, orofacial dyskinesias, supranuclear ophthalmoparesis, epilepsy, cognitive disorders, macrocephaly. MRI: leukoencephalopathy</p><p>High urinary glutaric acid and 3-hydroxyglutaric acid</p><p>L-Carnitine OAC, acylcarnitine profile</p><p>Propionic aciduria</p><p>AR Any Chorea, dementia, mental retardation, acute episodes of nausea or lethargia</p><p>High urinary methylcitrate, hydroxypropionate, propionyl glycine and propionyl carnitine</p><p>Diet low in branched chain amino acids, L-carnitine </p><p>OAC, acylcarnitine profile</p><p>Acute porphyrias</p><p>AD Adult Acute: digestive signs, acute peripheral neuropathy, psychiatric problems, confusion, epilepsy, dysautonomia, hyponatremia, dark urine. Chronic: cutaneous signs (coproporphyria, porphyria variegata)</p><p>High urinary excretion of -aminolevulinate and porphobilinogen </p><p>Avoid triggering factors, glucose and heme perfusion</p><p>Urinary -amino-levulinate and porphobilinogen </p><p>Wilsons disease</p><p>AR Any Psychiatric signs, tremor, parkinsonism, dystonia, dysarthria, KayserFleischer ring, chronic liver disease, abnormal brain MRI (see text)</p><p>High urinary copper, low plasma copper and ceruloplasmin</p><p>D-penicillamine, zinc, trientine</p><p>Ceruloplasmin,urinary and plasma cooper</p><p>Abbreviations: AAC, amino acid chromatography (plasma); AD, autosomal dominant; AR, autosomal recessive; CBS, cystathionine synthase; CSF, cerebrospinal fluid; MSUD, maple syrup urine disease; MTHFR, methylene tetrahydrofolate reductase; NKH, nonketotic hyperglycinemia; OAC, organic acid chromatography (urine); OTC, ornithine transcarbamylase deficiency; PKU, phenylketonuria.</p><p>ncpneuro_2007_011.indd 281ncpneuro_2007_011.indd 281 18/4/07 12:19:27 pm18/4/07 12:19:27 pm</p></li><li><p>REVIEW</p><p>282 NATURE CLINICAL PRACTICE NEUROLOGY SEDEL ET AL. MAY 2007 VOL 3 NO 5</p><p></p><p>and sympathetic signs. These symptoms can be followed by alteration of consciousness, diffuse muscle weakness and respiratory distress. </p><p>Isolated case reports have also been described in adolescents or adults with acute encephalo pathies revealing branched-chain </p><p>Table 2 Treatable neurological inborn errors of metabolism in adults: defects of energy metabolism and metabolism of complex molecules.</p><p>Disease Mode of inheritance</p><p>Age at onset</p><p>Major clinical and radiological signs (late-onset forms)</p><p>Major biological disturbances</p><p>Treatment Screening tests (mandatory tests in bold )</p><p>Defects of energy metabolism</p><p>Coenzyme Q10 deficiency</p><p>AR Any Myopathic form: myoglobinuria, exercise intolerance, CNS disorders. Ataxic form: cerebellar ataxia, epilepsy, pyramidal signs, mental retardation. Leighs syndrome</p><p>Low respiratory chain activity restored by coenzyme Q10. Low levels of coenzyme Q10 (muscle biopsy) </p><p>Coenzyme Q10 Muscular biopsy with measurement of coenzyme Q10</p><p>PDH de...</p></li></ul>