therapy insight: inborn errors of metabolism in adult neurology—a clinical approach focused on...

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Therapy Insight: inborn errors of metabolism in adult neurology—a clinical approach focused on treatable diseases Frédéric Sedel*, Olivier Lyon-Caen and Jean-Marie Saudubray

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.

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 Wilson’s 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

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.

KEYWORDS enzyme replacement therapy, genetic disorders, inborn errors of metabolism, late-onset, neurological disorders

F Sedel is a Hospital Practitioner in the Department of Neurology at Salpêtrière Hospital , O Lyon-Caen is Head of the Department of Neurology at Salpêtrière 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 René Descartes University Paris V, Paris, France.

Correspondence *Federation of Nervous System Diseases, Salpêtrière Hospital, 47 Boulevard de l’Hôpital, 75651 Paris Cedex 13, [email protected]

Received 19 January 2007 Accepted 13 March 2007

www.nature.com/clinicalpracticedoi:10.1038/ncpneuro0494

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.

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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

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 1–3, 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

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.

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

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.

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.6–10 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.

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.14–18 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.

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


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Table 1 Treatable neurological inborn errors of metabolism in adults: intoxications.

Disease Mode of inheritance

Age at onset

Major clinical and radiological signs (late-onset forms)

Major biological disturbances

Treatment Screening tests (mandatory tests in bold)

Urea cycle disorders

X-linked (OTC deficiency), AR

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

High ammonemia (>80–100 μM) and high glutamine. Other abnormalities depend on the metabolic block

Protein restriction, sodium benzoate or phenylbutyrate, L-arginine, dialysis

Ammonemia,AAC, urinary orotic acid

CBS deficiency

AR Any Mental retardation, psychiatric problems, epilepsy, strokes, dystonia, thromboembolic events, Marfan-like appearance, lens dislocation, myopia

Hyperhomocysteinemia >100 μM, hypermethioninemia

Vitamin B6, protein restriction diet

Homocysteinemia, AAC

MTHFR deficiency

AR Any Psychiatric problems, confusion, coma, paraplegia, thromboembolic events, polyneuropathy. MRI: leukoencephalopathy

Homocysteine >100 μM, low methionine, low folates

Folinic acid, betaine, cobalamin

Homocysteinemia,AAC, blood folates

Cobalamin C disease

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

Homocysteine >100 μM, methionine low, high methylmalonic aciduria

Hydroxocobalamin, folic acid, betaine

Homocysteinemia, AAC, OAC

PKU AR Any Spastic paraparesis, optic atrophy, dementia, leukoencephalopathy, parkinsonism

Hyperphenylalaninemia, hypotyrosinemia

Diet low in phenylalanine

Guthrie test,AAC

NKH AR Any Acute: paroxysmal movement disorders, confusion, supranuclear gaze palsy. Chronic: mental retardation, behavioral problems

Hyperglycinemia, hyperglycinuria, CSF:blood glycine ratio >0.04

Sodium benzoate dextromethorphan, ketamine

AAC

MSUD AR Any Episodes of nausea, vomiting, encephalopathy and coma triggered by high protein intake or circumstances of high protein catabolism

High levels of leucine, valine, isoleucine, 2-oxo and 2-hydroxy organic acids. Ketosis

Diet low in branched chain amino acids

AAC,OAC

Triple H syndrome

AR Any Episodes of nausea and vomiting triggered by high protein intake, spastic paraparesis, cerebellar ataxia, mild mental retardation

High ornithine, ammonemia, homocitrulline, orotic acid

Protein restriction, ornithine, arginine or citrulline

Ammonemia,AAC, urinary orotic acid

Glutaric aciduria type 1

AR Any Cephalalgia, orofacial dyskinesias, supranuclear ophthalmoparesis, epilepsy, cognitive disorders, macrocephaly. MRI: leukoencephalopathy

High urinary glutaric acid and 3-hydroxyglutaric acid

L-Carnitine OAC, acylcarnitine profile

Propionic aciduria

AR Any Chorea, dementia, mental retardation, acute episodes of nausea or lethargia

High urinary methylcitrate, hydroxypropionate, propionyl glycine and propionyl carnitine

Diet low in branched chain amino acids, L-carnitine

OAC, acylcarnitine profile

Acute porphyrias

AD Adult Acute: digestive signs, acute peripheral neuropathy, psychiatric problems, confusion, epilepsy, dysautonomia, hyponatremia, dark urine. Chronic: cutaneous signs (coproporphyria, porphyria variegata)

High urinary excretion of δ-aminolevulinate and porphobilinogen

Avoid triggering factors, glucose and heme perfusion

Urinary δ-amino-levulinate and porphobilinogen

Wilson’s disease

AR Any Psychiatric signs, tremor, parkinsonism, dystonia, dysarthria, Kayser–Fleischer ring, chronic liver disease, abnormal brain MRI (see text)

High urinary copper, low plasma copper and ceruloplasmin

D-penicillamine, zinc, trientine

Ceruloplasmin,urinary and plasma cooper

Abbreviations: AAC, amino acid chromatography (plasma); AD, autosomal dominant; AR, autosomal recessive; CBS, cystathionine β 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.


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and sympathetic signs. These symptoms can be followed by alteration of consciousness, diffuse muscle weakness and respiratory distress.

Isolated case reports have also been described in adolescents or adults with acute encephalo pathies revealing branched-chain

Table 2 Treatable neurological inborn errors of metabolism in adults: defects of energy metabolism and metabolism of complex molecules.


Age at onset



Treatment Screening tests (mandatory tests in bold )

Defects of energy metabolism

Coenzyme Q10 deficiency

AR Any Myopathic form: myoglobinuria, exercise intolerance, CNS disorders. Ataxic form: cerebellar ataxia, epilepsy, pyramidal signs, mental retardation. Leigh’s syndrome

Low respiratory chain activity restored by coenzyme Q10. Low levels of coenzyme Q10 (muscle biopsy)

Coenzyme Q10 Muscular biopsy with measurement of coenzyme Q10

PDH deficiency

X-linked or AR

Any Acute signs: episodes of ataxia, dystonia, limb weakness, encephalopathy, coma triggered by fever or exercise. Chronic signs: mental retardation, axonal polyneuropathy, optic atrophy, movement disorders (dystonia, chorea, parkinsonism). MRI: normal or necrosis of putamina.

High lactate and pyruvate in blood and CSF with low lactate:pyruvate ratio. Low PDH activity in leucocytes or fibroblasts

Vitamin B1, ketogenic diet

Blood lactate and pyruvate (before and 1 hour after lunch), CSF lactate and pyruvate

Fatty acid β-oxidation defects

AR Any Acute signs: encephalopathy, coma, rhabdomyolysis, cardiac arrhythmias, liver dysfunction. Chronic signs: cardiomyopathy, proximal myopathy, (axonal polyneuropathy in trifunctional protein deficiency)

Nonketotic hypoglycemia, high urinary dicarboxylic acids, high blood acylcarnitines

Avoid prolonged exercise or fasting; MCTs in long chain fatty acid β-oxidation defects

Acylcarnitine profile (blood), OAC

Cerebral glucose transporter (Glut1) deficiency

AD (de novo mutations)

Child Epilepsy, movements disorders, confusion and lethargy, triggered by fasting (morning)

CSF:blood glucose ratio below 0.4 (normal >0.6)

Ketogenic diet, avoid fasting

Blood and CSF glucose (measured at the same time)

Disorders of complex molecule metabolism

Adult Refsum disease

AR Adult Retinitis pigmentosa, polyneuropathy, ataxia, anosmia, ichthyosis, hyperproteinorachia, cataract, hearing loss, skeletal abnormalities

High phytanic acid Diet low in phytanic acid

Plasma phytanic acid

CTX AR Any Juvenile cataract, xanthomas, cerebellar ataxia, spastic paraparesis, dementia, psychiatric signs, polyneuropathy, parkinsonism, chronic diarrhea

High cholestanol and sterol intermediates

Chenodeoxycholic acid

Plasma cholestanol

Fabry disease

AR Any Acroparesthesias, strokes, cornea verticillata, proteinuria, cardiomyopathy, angiokeratomas, hearing loss

Low α-galactosidase activity

Enzymotherapy α-Galactosidase(leucocytes)

Gaucher disease

AR Any Progressive myoclonic epilepsy, parkinsonism, asthenia, hepatosplenomegaly, thrombopenia, anemia, osseous manifestations

Low glucocerebrosidase activity

Enzymotherapy Glucocerebrosidase(leucocytes)

Others

Serine deficiency

Unknown Child Mental retardation, polyneuropathy, ichthyosis

Low serine in plasma and CSF

L-serine AAC

Abbreviations: AAC, amino acid chromatography (plasma); AD, autosomal dominant; AR, autosomal recessive; CSF, cerebrospinal fluid; CTX, cerebrotendinous xanthomatosis; MCTs, medium chain triglycerides; OAC, organic acid chromatography (urine); PDH, pyruvate dehydrogenase.


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Table 3 Treatable neurological inborn errors of metabolism in adults: defects in neurotransmitter and vitamin metabolism.


Age at onset



Treatment Screening tests (mandatory tests in bold)

Neurotransmitter metabolism defects

GTPCH1deficiency

AD Any Dystonia, parkinsonism, pseudo-spastic paraparesis, diurnal fluctuations

Low biopterins, neopterins, HVA and 5-HIAA in CSF. Mutations in the GTPCH1 gene

Levodopa, anticholinergic drugs, dopamine agonists

CSF neurotransmitters, trial with levodopa

Tyrosine hydroxylase deficiency

AR Child Dystonia, parkinsonism, pseudo-spastic paraparesis, pyramidal signs, mental retardation

Low HVA in CSF with normal biopterins, neopterins and 5-HIAA

Levodopa CSF neurotransmitters, trial with levodopa

PTPS AR Any Dystonia (generalized or paroxysmal), diurnal fluctuations with or without mental retardation, pyramidal signs, epilepsy

Hyperphenylalaninemia, low biopterin and high neopterins in CSF with low 5-HIAA and HVA

BH4, levodopa, levotonine, diet low in phenylalanine

AAC, CSF neurotransmitters, trial with levodopa

SR AR Child Mental retardation, dystonia, hypersomolence

High biopterins, low HVA, low 5-HIAA in CSF

Levodopa, levotonine

CSF neurotransmitters, trial with levodopa

DHPR AR Child Mental retardation, dystonia, parkinsonism, epilepsy, depression

Hyperphenylalaninemia, high biopterins, low HVA, low 5-HIAA in CSF

Levodopa, levotonine, diet low in phenylalanine

AAC, CSF neurotransmitters, trial with levodopa

Disorders of vitamin metabolism

Cerebral folate deficiency syndrome

Sporadic Child Spastic paraparesis, generalized dystonia, deafness, cerebellar ataxia, spinal amyotrophy

Low MTHF in CSF, normal folates in blood

Folinic acid MTHF in blood and CSF

Biotinidase deficiency

AR Child or adolescent

Bilateral optic atrophy, spastic paraparesis, cerebellar ataxia, motor neuropathy, deafness, alopecia, seborrheic dermatitis

High lactate, high urinary 3-hydroxy isovalerate, 3-hydroxypropionate, 3-methylcrotonyl glycine, low biotinidase activity (erythrocytes)

Biotin Lactates, OAC, therapeutic trial with biotin, biotinidase activity (blood)

Biotin responsive basal ganglia disease

AR Child Acute: encephalopathy, coma, epilepsy, rigidity. Chronic: dystonia. MRI: bilateral lesions of basal ganglia (head of caudate nuclei and putamen)

SLC19A3 gene mutations

Biotin Therapeutic trial with high doses of biotin

Vitamin E deficiency AR Any Ataxia, peripheral neuropathy, retinitis pigmentosa, pyramidal signs, deafness

Very low vitamin E Vitamin E Vitamin E (blood)

Abetalipoproteinemia and hypo beta-lipoproteinemia

AR Any Neurological signs of vitamin E deficiency, steatorrhea, acanthocytosis, anemia

Very low cholesterol, undetectable VLDL, LDL and HDL cholesterol

High doses of vitamin E and A

Serum lipids and lipoproteins,vitamin E

Abbreviations: AAC, amino acid chromatography (plasma); AD, autosomal dominant; AR, autosomal recessive; CSF, cerebrospinal fluid; DHPR, dihydropteridine reductase; GTPCH1, GTP-cyclohydrolase 1; 5-HIAA, 5-hydroxyindoleacetic acid; HVA, homovanillic acid; MTHF, methyltetrahydrofolate; OAC, organic acid chromatography (urine); PTPS, pyruvoyl tetrahydrobiopterin synthase; SR, sepiapterin reductase.


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organic acidurias,21 non-ketotic hyper glycinemia (NKH),22 pyruvate dehydrogenase (PDH) deficiency,23 medium-chain acyl-coenzyme A dehydrogenase deficiency24 or biotin-responsive basal ganglia disease.25 In addition, patients with urea cycle disorders, aminoacidopathies (maple syrup urine disease) or organic acid-urias (propionic, methyl malonic, isovaleric and biotin responsive multiple carboxylase deficiency) who were diagnosed in infancy and treated since diagnosis can present in adulthood with an acute metabolic attack, usually after nondeclared therapeutic interruption or in the postpartum period.

Cerebral strokesCerebral strokes in patients with IEMs are often accompanied by specific systemic signs. In some cases, however, strokes can be in augural symptoms. Besides truly cerebral infarctions, pseudostrokes—that is, acute focal central neurological signs—can be observed in urea cycle disorders (see above) and Wilson’s disease.26 Strokes and stroke-like episodes are also hallmarks of respiratory chain dis orders (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes) or congenital dis orders of glycosylation, neither of which are readily treatable.4,5

Homocystinurias, including cystathionine β synthase (CBS) deficiency, MTHFR deficiency, and cobalamin metabolism defects (mainly ClbC disease), all result in a substantial accu-mulation of homocysteine, which is responsible for thromboembolic events. Cerebral strokes can reveal these diseases in adulthood (Sedel F et al., unpublished data).27–29 In homocysteine remethylation defects, other neurological signs are often present (see above and Table 1). In CBS deficiency, thromboembolic complications can be venous or arterial, and affect around 50% of patients over 29 years of age, with cerebral strokes accounting for around one-third of thromboembolic events.27 Systemic signs are present in most but not all cases (Table 1).28 Treatment with vitamin B6 fully normalizes homocysteinemia in most cases presenting in adulthood.

In Fabry disease, small-vessel cerebral infarc-tions are characteristic features.30,31 They occur in the fourth decade of life in around one-third of patients, and might be equally frequent in hemizygous males and hetero zygous females. In most cases, they involve the vertebrobasilar

territory and are associated with dilatative arterio pathy. They can seem to be inaugural symptoms. In young patients with cryptogenic strokes (with no explained cause), mutations in α-galacto sidase were found in as many as 4.9% of men and 2.4% of women.31 Renal or cutaneous signs or pain in extremities were often already present but not reported. Enzyme replacement therapy can treat most signs of Fabry disease, but its role in preventing cerebral strokes is unproven.32

Movement disordersIn acute situations, movement disorders are usually accompanied by alteration of conscious-ness. Patients with NKH can exhibit mild mental retardation and acute episodes of choreic move-ments, usually triggered by nonspecific febrile illness. During these crises, patients also display confusion, ataxia or supranuclear gaze palsy, which might be efficiently treated by sodium benzoate and dextromethorphan.22,33

Biotin-responsive basal ganglia disease has been described in the Arabian popula-tion.25,34 Patients presented with subacute crisis of encephalopathy in late childhood or adolescence, triggered by a benign febrile disease. These crises were characterized by confusion, parkinsonism, dystonia and oculomotor abnormalities (ophthalmoplegia or oculogyric crisis). Brain MRI showed character istic bi lateral high signal on T2-weighted sequences of putamina and heads of caudate nuclei. With high doses of biotin, most patients recovered within a few days. Acute movement disorders can also be observed in Wilson’s disease.26

IEMs causing chronic movement disorders can be classified according to the presence or absence of basal ganglia lesions. In Wilson’s disease, MRI typically shows abnormal signal in basal ganglia, dentate nuclei, brainstem and cerebellar white matter on T2-weighted sequences.35 In PDH deficiency, brain MRI can show bilateral necrotic lesions of putamina similar to Leigh syndrome.36 Coenzyme Q10 deficiency has been described in two adult sisters with childhood-onset Leigh’s encephalo pathy characterized by developmental delay, lactic acidosis, pyramidal and extrapyramidal signs, ataxia, and deafness, with brain MRI showing high signals in the putamen and caudate nuclei on T2-weighted sequences. Both sisters responded to high doses of co enzyme Q10.37


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To date, at least two inborn errors affecting coenzyme Q10 synthesis have been elucidated in infants.38 We recently found a cerebral folate deficiency syndrome39 in a 26-year-old patient who had a 10-year history of generalized dystonia with diffuse brain calcifications. This patient is currently improving with high doses of folinic acid (Sedel F et al., unpublished data). Besides these treatable disorders, brain iron storage diseases (panthotenate kinase deficiency, acerulo plasminemia and neuroferritinopathy) can cause movement disorders with severe basal ganglia lesions.40

Chronic movement disorders without brain abnormalities are seen in disorders of the biosynthetic pathway of dopamine or tetra-hydrobiopterin. These disorders are mainly responsible for the so-called ‘dopa-responsive dystonias’—dystonia or parkinsonism that responds to low doses of levodopa. The most frequent cause is a partial defect in GTP cyclo-hydrolase (also known as Segawa disease), the first enzyme in the tetra hydrobiopterin synthetic pathway.41 Exceptional cases of tyro-sine hydroxylase deficiency,42 sepiapterin reduc-tase deficiency,43 pyruvoyl tetra hydrobiopterin synthase deficiency44 or di hydropteridine reductase deficiency45 have, however, been reported in adults. In addition to dystonia or parkinsonism, these patients might exhibit pyramidal signs, mental retardation and hyper-somnolence or depression related to serotonin deficiency.42,46 In cases of pyruvoyl tetra-hydrobiopterin synthase and dihydropteridine reductase deficiencies, hyperphenylalaninemia is also found. The diagnosis of defects in mono-amine biosynthesis relies mainly on the analysis of neurotransmitter metabolites in cerebro-spinal fluid (CSF), which should ideally be collected before a levodopa trial is commenced. Chronic dystonia can also be observed in CBS deficiency.47 In Gaucher disease type I, atyp-ical parkinsonism not improved by enzyme replacement therapy has been reported.48 In addition, movement dis orders (mainly dystonia) represent important features of other less readily treatable neuro lipidoses such as Niemann–Pick disease type C, and GM1 and GM2 ganglio sidosis.4,5

Peripheral neuropathies Peripheral neuropathies in the context of IEMs are usually part of a more complex clinical picture. This is the case in cerebro tendinous

xanthomatosis (CTX),49 homocysteine remethyla-tion defects,14 vitamin E deficiency,49,50 Wilson’s disease,51 and biotinidase deficiency.52 In some cases, however, peripheral neuro pathy can be apparently isolated at onset, thus mimicking acute Guillain–Barré syndrome or chronic Charcot–Marie–Tooth disease.

Acute peripheral neuropathy is a hallmark of attacks of porphyrias, which can be primary19,20 or secondary such as in tyrosinemia type 1 (Sedel F et al., unpublished data).53 Acute peripheral neuropathy can also be observed during the course of Refsum’s disease, or in the course of PDH deficiency (see below).

Chronic, apparently isolated, peripheral neuropathy can be observed in PDH deficiency, Refsum’s disease, and trifunctional protein deficiency.54–56 In PDH deficiency, axonal neuropathy usually associates with carbo-hydrate-induced or fever-induced episodes of ataxia or peripheral weakness.54 In Refsum’s disease, the neuropathy, mostly demyelina ting, is usually progressive with exacerbations character-ized by diffuse weakness and eventually cranial nerve involvement.55 Trifunctional protein deficiency might present with an axonal poly-neuropathy that begins in childhood (Sedel F et al., unpublished data).56 An unexplained serine deficiency syndrome was reported in a 15-year-old Iranian girl who presented with an axonal polyneuropathy.57 The patient’s condition improved markedly with serine supple mentation. In addition to these treatable diseases, patients with peroxysomal disorders (biogenesis defects and alpha-methylacyl-CoA racemase deficiency) can present with a Charcot–Marie–Tooth-like disorder.58,59

Spastic paraparesis and paraplegiaIEMs rarely cause pure progressive spastic para-paresis. Spastic paraparesis might, however, be the unique presenting sign of homocysteine remethyla tion defects.17,18,60 Hyper ornithinemia–hyperammoniemia–homocitrullinuria (triple H) syndrome can present at any age, from the neonatal period through to adulthood, with a progressive spastic paraparesis.61 Protein in tolerance, and acute episodes of vomiting, confusion or coma resulting from hyper ammonemia, are usually present. Arginase deficiency can be revealed by an isolated subacute paraplegia preceded by episodes of nausea and vomiting.12 A few adult patients with phenylketonuria who were born before neonatal screening programs or who had


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discontinued their low-phenylalanine diet were reported to have adult-onset spastic paraparesis or white matter abnormalities on brain MRI, which were in some cases reversible after normal-ization of phenylalaninemia.62,63 Cerebral folate deficiency was found in a 14-year-old girl with a progressive spastic paraparesis, mental retarda-tion and dystonia who improved after folinic acid supplementation.64 A spinal form of CTX characterized by isolated proprioceptive and pyramidal signs has also been reported.65 In all cases, bi lateral juvenile cataract was present, but tendon xanthomas were absent in most patients. A mild form of biotinidase deficiency has been described in a few adolescents with bilateral optic atrophy and paraplegia. The neuro logical signs partially resolved with biotin supple-mentation.52,66 In addition, GTP cyclohydrolase deficiency and tyrosine hydroxylase deficiency might be responsible for a dopa-responsive pseudo-paraparesis.67,68

Ataxia Acute episodes of cerebellar ataxia triggered by fever can be observed in patients with PDH deficiency.23 Chronic ataxia might be the presenting feature of vitamin E deficiency. Vitamin E deficiency can be caused by mutations in the gene encoding the α-tocopherol transfer protein (TTPA),49 abetalipo proteninemia (Bassen–Kornzweig disease)69 or hypobeta-liproteinemia.70 Clinically, the phenotype resembles Friedreich ataxia. Neurological signs can improve or stabilize after vitamin E supple-mentation. Chronic cerebellar ataxia is also a hallmark of CTX,71 co enzyme Q10 deficiency72 and Refsum’s disease.55 In addition, a unique and still-un explained case of a 30-year-old woman with hearing loss, cere bellar ataxia, pyramidal signs, action myoclonus, and epileptic seizures who improved on biotin supplementation has been reported.73

Psychiatric disorders Acute psychiatric signs sometimes reveal urea cycle disorders,6 homocysteine remethylation defects,15 CBS deficiency,74 porphyrias19,20 or NKH.33 Although chronic psychiatric signs are often integrated into a more diffuse clinical picture, they can remain isolated for years before the occurrence of organic signs. This phenom-enon has been reported in Wilson’s disease,75 CTX76 and homocystinurias.17,77 In addition, less readily treatable diseases, including lysosomal

and peroxysomal diseases (meta chromatic leuko-dystrophy, Niemann–Pick type C, GM2 ganglio-sidosis, adreno leukodystrophy), can present as pure psychiatric disorders.78

Epilepsy Glucose transporter (Glut-1) deficiency has been reported in adults with seizure-like episodes, impaired consciousness, and sudden loss of tone, which occurred predominantly before breakfast and improved after eating sweets, thereby mimicking hypoglycemia.79 Glut-1 deficiency has also been reported in patients with isolated tonic–clonic and myoclonic seizures not affected by fasting.80 This disorder is easily diagnosed by the simul-taneous measurement of glucose in blood and CSF, which shows a low CSF:blood glucose ratio. Seizures usually respond to a ketogenic diet. A few adult-onset cases of Gaucher disease type III have been reported with a clinical picture of progressive myoclonic epilepsy.81 Epileptic seizures can also be the presenting features of acute attacks of porphyrias82 and urea cycle disorders,8 and can be observed in patients with Wilson’s disease,83 CTX84 or homocystinurias.27 B6-responsive epilepsy, the molecular defects of which have been recently elucidated, has been described in infants but not in adults.85

LeukoencephalopathiesWith advances in brain imaging techniques, unexplained leukoencephalopathy became a major motif of consultation in neurology. After the elimination of classical causes of leuko encephalopathies,86 a metabolic leuko-dystrophy is often suspected. ‘Classical’ leuko dystrophies include metachromatic leukodystrophy, Krabbe’s disease and adreno-leukodystrophy, all of which can start in adult-hood. For these disorders, the preventive or curative effectiveness of therapeutic procedures such as bone marrow transplantation remains a matter of debate. CTX usually presents in childhood with nonspecific learning difficul-ties and juvenile cataract. Tendon xanthomas are present in only 50% of cases, and they usually appear between the second and fourth decades, accompanied by neurological signs.71 Brain MRI typically shows high signals on T2-weighted sequences involving dentate nuclei of the cerebellum, globus pallidus, corticospinal tracts and the periventricular white matter.


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Low signals corresponding to lipid storage can also be observed, especially in dentate nuclei.87 Treatment with chenodeoxycholic acid improves neurological signs and prevents disease progres-sion. Homocysteine remethylation defects can also manifest as potentially reversible supra-tentorial leuko encephalopathy.16,88 In CblC disease, high-signal abnormalities of the spinal cord can be observed. Glutaric aciduria type 1 has been described in few adults with headache, abnormal behavior and various neurological signs.89,90 Importantly, in all patients, MRI showed a supratentorial leuko encephalopathy. Clinical improvement could be obtained with oral l-carnitine and a moderate protein-restricted diet.90 Adult patients with phenyl-ketonuria can also exhibit diffuse periventricular white matter hyperintensities mimicking leuko-dystrophy with no apparent clinical symptoms. These hyperintensities resolve dramatically after normalization of phenylalanine concentrations in blood.60,61,91

CONCLUSIONS AND GENERAL DIAGNOSTIC STRATEGY Clinicians should consider the possibility of an IEM in any patient with an unexplained neurological disorder. Certain clinical condi-tions increase the probability of an IEM: when clinical signs or symptoms are fluctuating, espe-cially when triggered by fasting, exercise, fever, catabolic circumstances or postpartum; when clinical signs suggest a diffuse disease including incongruous neurological signs (for example neuropathy and leukoencephalopathy) together with systemic signs (including skin problems, visceromegaly, xanthomas, and deafness); when first symptoms of the disease have been present since childhood; or when the family history suggests a recessive or X-linked mode of inheri-tance. IEMs frequently present as sporadic cases, however, and they rarely display a dominant mode of inheritance.

Given the very large number of different IEMs, and because metabolic investigations are often

Table 4 Metabolic investigations in acute situations to avoid overlooking a treatable inborn error of metabolism.

Main clinical presentations

Treatable metabolic diseases Screening tests First-line treatmenta

Encephalopathy or coma

Urea cycle disordersHomocysteine remethylation defectsPorphyriasOrganic aciduriasβ-oxidation defectsAminoacidopathiesBiotin-responsive basal ganglia diseasePyruvate dehydrogenase deficiency

AmmonemiaHomocysteinemiaUrinary porphyrinsUrinary OACPlasma acylcarnitinesPlasma AACTherapeutic trial with biotinBlood lactate, pyruvate

NH3 chelatorsb, stop protein intake, arginineFolinic acid, vitamin B12, betaineHeme arginate, high glucose-infusion rateCarnitine, stop protein intakeCarnitine, high glucose-infusion rateStop protein intakeVery high doses of biotinKetogenic diet, vitamin B1

Strokes and pseudostrokes

Urea cycle disordersCystathionine β synthase deficiencyHomocysteine remethylation defectsWilson’s disease

AmmonemiaHomocysteinemiaHomocysteinemiaCopper metabolism

NH3 chelators, stop protein intake, arginineVitamin B6Folinic acid, vitamin B12, betaineCopper chelatorsc

Acute movement disorders

Nonketotic hyperglycinemiaBiotin responsive basal ganglia diseaseWilson’s disease

Plasma AACTherapeutic trial with biotinCopper metabolism

Sodium benzoate, dextromethorphanVery high doses of biotinCopper chelators

Acute polyneuropathy PorphyriasPyruvate dehydrogenase deficiency

Urinary porphyrinsBlood lactate, pyruvate

Heme arginate, high glucose-infusion rateKetogenic diet, vitamin B1

Acute or subacute paraplegia

Homocystein remethylation defectsArginase deficiencyBiotinidase deficiency

HomocysteinePlasma AACTherapeutic trial with biotin

Folinic acid, vitamin B12, betaineStop protein intake, ammonia chelatorsLow doses of biotin

Acute cerebellar ataxia

Pyruvate dehydrogenase deficiencyUrea cycle disorders

Blood lactate, pyruvateAmmonemia

Ketogenic diet, vitamin B1NH3 chelators, stop protein intake, arginine

Acute psychiatric problems

Urea cycle disordersCystathionine β synthase deficiencyHomocysteine remethylation defectsPorphyriasNonketotic hyperglycinemia

AmmonemiaHomocysteinemiaHomocysteinemiaUrinary porphyrinsPlasma AAC

NH3 chelators, stop protein intake, arginineVitamin B6Folinic acid, B12, betaineHeme arginate, high glucose-infusion rateSodium benzoate, dextromethorphan

aFor details, see Supplementary Table 1. In all situations, but mostly in urea cycle disorders, homocystinurias, organic acidurias and aminoacidopathies, it is important to stop protein catabolism. bSodium benzoate, sodium phenylbutyrate. In life-threatening situations, hemodialysis should be discussed. cD-penicillamine, zinc, trientine. Abbreviations: AAC, amino acid chromatography; OAC, organic acid chromatography (urine).


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expensive and time consuming, it is not realistic to propose a systematic metabolic screening.

The clinical approach to IEM is different in acute and chronic situations.3–5 In acute situa-tions (coma, strokes or pseudostrokes, psychi-atric signs, cerebellar ataxias or neuropathies), the most important message is ‘do not miss the opportunity to provide life-saving treatment’. Table 4 presents such acute situations with guidelines for first-line metabolic investigations and emergency treatments. Analysis of glucose, ammonia and lactate levels, electrolytes, blood gases, transaminases and prothrombin time are always mandatory and can be undertaken in all emergency departments. Plasma and urine must be collected and kept in the fridge for further specialized analysis. Plasma amino acids, acyl carnitines, homocysteine, urinary organic acids and porphyrins are the key factors that should be investigated within 48 hours in a specialized laboratory. As soon as an IEM is suspected, treatment should be undertaken without delay.

In chronic situations, the large diversity of metabolic disorders that could be hypothesized makes it difficult to propose a systematic meta-bolic protocol. We can, however, recommend three steps of investigation. First, common nonmetabolic causes need to be ruled out. Second, if the symptoms remain unexplained, a metabolic disorder should be considered, neces-sitating a search for subtle or infraclinical signs (complete clinical and ophthalmologic exami-nations, brain MRI, electrodiagnostic studies, audiogram, abdominal ultrasonography) to guide biological investigations, starting first with those leading to treatable diseases (see Tables 1–3). Last, along the way, specialists in meta-bolic departments should be asked for help in diagnosis, modes of sampling and transport.

Neurological disorders are often consider ed as progressive and handicapping diseases. Furthermore, despite important progress in classifications, a great number of diseases remain unclassified and unexplained. Neurologists should be aware that an ‘unexplained’ neuro-psychiatric disease could be a treatable IEM. The cost of metabolic investigations should be balanced by the potential consequences of missing a treatable disorder.

Supplementary information in the form of a table is available on the Nature Clinical Practice Neurology website.

KEY POINTS ■ Inborn errors of metabolism (IEMs) represent

an important group of genetic disorders, the diagnosis of which relies mostly on biochemical analysis of plasma and urines samples

■ IEMs can present at any age from fetal life to old age

■ Although most genetic metabolic errors are hereditary and transmitted as recessive disorders, most individual cases present in the absence of a notable family history

■ It is important to be aware that symptoms that persist after investigation and treatment for more common disorders might be attributable to an IEM

■ In acute situations, it is important not to miss a treatable disease including urea cycle disorders, homocystinurias and porphyrias, and life-saving treatments should be commenced as soon as possible

■ In chronic situations, it is important not to confuse a symptom or a syndrome with etiology—the underlying cause might be an IEM

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Competing interestsThe authors declared they have no competing interests.


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