Leukoencephalopathies associated with inborn errors of metabolism in adults

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1 J Inherit Metab Dis (2008) 31: DOI /s REVIEW Leukoencephalopathies associated with inborn errors of metabolism in adults F. Sedel & A. Tourbah & B. Fontaine & C. Lubetzki & N. Baumann & J.-M. Saudubray & O. Lyon-Caen Received: 23 September 2007 / Submitted in revised form: 17 December 2007 / Accepted: 31 December 2007 / Published online: 23 February 2008 # SSIEM and Springer 2008 Summary The discovery of a leukoencephalopathy is a frequent situation in neurological practice and the diagnostic approach is often difficult given the numerous Communicating editor: John Walter Competing interests: None declared F. Sedel : B. Fontaine : C. Lubetzki : O. Lyon-Caen Federation of Nervous System Diseases, Hôpital de la Salpêtrière and Université Pierre et Marie Curie (Paris VI), Assistance Publique-Hôpitaux de Paris, Paris, France F. Sedel (*) Neurometabolic Unit and National Reference Center for Lysosomal Diseases, Pitié-Salpêtrière Hospital, Paris, France frederic.sedel@psl.aphp.fr A. Tourbah : B. Fontaine Unité mixte de recherche INSERM U-546, Pitié-Salpêtrière Hospital, Paris, France C. Lubetzki : N. Baumann Unité mixte de recherche INSERM U-711, Pitié-Salpêtrière Hospital, Paris, France A. Tourbah Service de Neurologie, Centre hospitalier universitaire de Reims et Faculté de médecine de Reims, Reims, France J.-M. Saudubray National Reference Center for Metabolic Diseases, Necker-enfants malades Hospital and Université René Descartes (Paris V), Assistance Publique-Hôpitaux de Paris, Paris, France possible aetiologies, which include multiple acquired causes and genetic diseases including inborn errors of metabolism (IEMs). It is now clear that IEMs can have their clinical onset from early infancy until late adulthood. These diseases are particularly important to recognize because specific treatments often exist. In this review, illustrated by personal observations, we give an overview of late-onset leukoencephalopathies caused by IEMs. Abbreviations ALDc adult cerebral adrenoleukodystrophy ALDP adrenoleukodystrophy protein AMN adrenomyeloneuropathy ARSA arylsulfatase A HMG hydroxymethylglutaryl IEM inborn error of metabolism MTHFR methylene tetrahydrofolate reductase Introduction The term Fleukoencephalopathies_ means disorders that selectively or predominantly involve the white matter of the brain. It is associated with a group of diseases that affect the myelin itself, oligodendrocytes, astrocytes or even axons. The main acquired causes of leukoencephalopathies include inflammatory diseases, vascular diseases, infections, neoplasias and toxic causes (reviewed in Filley and Kleinschmidt-DeMasters 2001). Hereditary leukoencephalopathies can be separated into three categories (Baumann and Turpin 2000; Schiffmann and van der Knaap 2004; Sedel et al 2005): (1) leukoencephalopathies characterized clinically, radiologically or pathologically but for which the gene causing the leukoencephalopathy is still

2 296 J Inherit Metab Dis (2008) 31: Table 1 Leukoencephalopathies caused by IEMs in adults Disease Inheritance Clinical signs Striking MRI and MRS features a Treatment Biological signs Complex molecule metabolic disorders Metachromatic AR Psychiatric troubles, pyramidal signs, ataxia, leukodystrophy epilepsy, dementia, optic atrophy Krabbe disease AR Spastic paraparesis, ataxia, tongue hemiatrophy, dysarthria Adrenoleukodystrophy X linked AMN: Spastic paraparesis, sensory signs, vesicle dysfunction, adrenal insufficiency Peroxisome biogenesis disorders Cerebrotendinous xanthomatosis Polyglucosan body disease Cerebral ALD: psychiatric signs, epilepsy, dementia, optic atrophy, pyramidal signs AR Retinitis pigmentosa, mental retardation, deafness, polyneuropathy, pyramidal signs AR Mental retardation, tendon xanthomata, chronic diarrhoea, presenile cataract cerebellar ataxia, spastic paraparesis, dementia, psychiatric signs AR Dementia, upper and lower motor neuron disease, bladder dysfunction, parkinsonism Sjögren Larsson AR Ichthyosis, mental retardation, macular dystrophy with retinal white dots, spastic paraparesis Mucolipidosis type IV AR Retinal dystrophy, optic atrophy, mental retardation Fabry disease X linked Acroparaesthesias, strokes, cornea verticillata, proteinuria, cardiomyopathy, angiokeratomas, hearing loss Intermediary metabolism disorders MTHFR deficiency AR Psychiatric signs, cognitive deficits, coma, thromboembolic events, polyneuropathy, spastic paraparesis Periventricular leukodystrophy sparing U fibres None or bone marrow transplantation Pyramidal tract involvement None or bone marrow transplantation AMN: normal or pyramidal tract involvement Cerebral ALD: Periventricular leukodystrophy, corpus callosum and pyramidal tracts involvement, gadolinium enhancement Lorenzo_s oil and diet poor in VLCFA? Low arylsulfatase A in leukocytes, high urinary excretion of sulfatides Low galactocerebrosidase in leukocytes Increased plasma VLCFA Nonspecific None (docosahexaenoic acid?) High VLCFA, phytanic, pristanic, peroxisomal bile acids, low plasmalogen synthesis Abnormal signals of cerebellar dentate nuclei Chenodeoxycholic acid High serum cholestanol Nonspecific Symptomatic Presence of polyglucosan bodies on axillary skin biopsy Periventricular leukodystrophy, increased peak at 1.3 ppm corresponding to fatty acids Periventricular leukoencephalopathy, corpus callosum atrophy Strokes, vascular leukoencephalopathy, high signals of pulvinars on T1-weighted images (pulvinar sign) Periventricular leukoencephalopathy Possible involvement of U fibres Potentially reversible Zyleuton to decrease the itch Low fatty aldehyde dehydrogenase activity (fibroblasts), mutations in the ALDH gene Symptomatic Iron depletion, hypergastrinaemia, ubiquitous lysosomal inclusions (skin biopsy), mucolipin gene mutations Enzyme replacement therapy Low!-galactosidase activity (leukocytes) Folinic acid, betaine, vitamin B 12, riboflavin Hyperhomocysteinaemia >100 2mol/L, hypomethioninaemia, low folates

3 J Inherit Metab Dis (2008) 31: Table 1 Continued Disease Inheritance Clinical signs Striking MRI and MRS features a Treatment Biological signs Cobalamin C disease AR Psychiatric signs, confusion, combined degeneration of the spinal cord, peripheral neuropathy, retinitis pigmentosa, glomerular nephritis, thromboembolic events Phenylketonuria AR Optic atrophy, cognitive deficits, pyramidal signs, parkinsonism 3-Methylglutaconic aciduria type I AR Cognitive deficits, pyramidal signs, cerebellar syndrome, urinary incontinence 3-OH-HMG-CoA lyase AR Episodes of hypoglycaemia, mental retardation, epilepsy, pyramidal signs Glutaric aciduria type I AR Macrocephaly, cephalalgia, cognitive deficits, oculomotor paresis, pyramidal signs, epilepsy, tremor l-2-oh-glutaric aciduria Energy production Respiratory chain disorders AR Mental retardation, epilepsy, parkinsonism, pyramidal signs, ataxia Any Myopathy, hearing loss, cerebellar ataxia, ophthalmoplegia, retinitis pigmentosa, stroke-like episodes, chronic intestinal peudo-obstruction, myoclonic epilepsy, diabetes Periventricular leukoencephalopathy, high signal of spinal pyramidal tracts and posterior columns Potentially reversible Periventricular leukoencephalopathy potentially reversible with a low-phenylalanine diet Variable periventricular leukoencephalopathy involving U fibres Patchy confluent periventricular and subcortical white matter hyperintensities Periventricular leukoencephalopathy Involvement of U fibres Hydroxocobalamin, folic acid; betaine Hyperhomocysteinaemia >100 2mol/L, hypomethioninaemia, methylmalonic aciduria Low-phenylalanine diet Hyperphenylalaninaemia, hypotyrosinaemia Low-leucine diet High urinary excretion of 3-methylglutaconic acid, 3-methylglutarate and 3-hydroxyisovalerate l-carnitine, avoidance of fasting High urinary excretion of 3-OH-3- methylglutarate, 3-methylglutaconate, 3-hydroxyisovalerate and 3-methylglutarate l-carnitine, low-protein diet High urinary excretion of glutaric acid and 3-OH-glutaric acid Diffuse involvement of U fibres Symptomatic High urinary excretion of l 2-OHglutaric acid Mutations in the gene coding l-2-oh-glutarate dehydrogenase Involvement of basal ganglia, calcifications, high lactate peak on MRS Symptomatic High lactate in CSF, ragged red fibres (muscular biopsy), search for mitochondrial or nuclear DNA specific mutations ALD, adrenoleukodystrophy; AMN, adrenomyeloneuropathy; AR, autosomal recessive; MTHFR, methylenetetrahydrofolate reductase; VLCFA, very long chain fatty acids. a In addition, nonspecific features observed in many leukoencephalopathies include increased choline, decreased N-acetylaspartate and increased myoinositol.

4 298 J Inherit Metab Dis (2008) 31: Table 2 Diagnostic orientation according to clinical examination, ophthalmology and electroneuromyography With episodes of confusion/coma/strokes With cutaneous signs With visceral signs With abnormal visual findings With macrocephaly With polyneuropathy Inborn errors of metabolism CblC, MTHFR, mitochondrial disorders (MELAS), 3-HMG CoA lyase deficiency, Fabry disease CTX (xanthomata), Sjögren Larsson (ichthyosis), ALD/AMN (melanoderma), angiokeratoma (Fabry disease) CTX (chronic diarrhoea), ALD (adrenal insufficiency), MNGIE (chronic diarrhoea, cachexia, pseudo-obstructions), RCD (diabetes and other endocrine problems) Retinitis pigmentosa: cblc, RCD, PBD Optic nerve atrophy: cblc, ALD, RCD, metachromatic leukodystrophy, Krabbe disease, organic acidurias, phenylketonuria, mucolipidosis type IV Cataract: CTX, PBD, RCD Macular dystrophy: Sjögren Larsson, mucolipidosis type IV Glutaric aciduria type I l-2-hydroxyglutaric aciduria CTX, MTHFR deficiency, CblC, Krabbe disease, metachromatic leukodystrophy, RCD, AMN/ALD, peroxisomal biogenesis disorders, polyglucosan body disease Other genetic leukoencephalopathies CACH syndrome, CADASIL Amenorrhoea (CACH) ADLD, Adult-onset autosomal dominant leukodystrophy caused by lamin B1 duplications; ALD, adrenoleukodystrophy; AMN, adrenomyeloneuropathy; CACH, childhood ataxia with CNS hypomyelination; CADASIL, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, cblc, cobalamin C disease; CTX, cerebrotendinous xanthomatosis; MLC, megalencephalic leukodystrophy with cysts; MTHFR, methylenetetrahydrofolate reductase; PBD, peroxisome biogenesis disorders; RCD, respiratory chain disorders. Table 3 Diagnostic orientation according to brain and spinal cord MRI and MRS Specific signs on MRI IEM Other genetic leukoencephalopathies Involvement of AMN/ALD, Krabbe disease, RCD, CTX ADLD pyramidal tracts Involvement of CTX, RCD, l-2oh-glutaric aciduria dentate nuclei Involvement of basal ganglia CTX, RCD, organic acidurias Alexander disease Involvement of U fibres early in disease course Organic acidurias (including l-2-oh glutaric aciduria), homocysteine remethylation defects, RCD, polyglucosan body disease Involvement of FXTAS, ADLD, LBSL cerebellar peduncles High signal of the Cbl, MTHFR deficiency, RCD, CTX Alexander disease spinal cord Cystic degeneration of the white matter RCD CACH syndrome, Alexander disease Strokes or MTHFR, Cbl, Fabry, RCD CADASIL stroke-like lesions Areas of contrast Cerebral ALD Alexander disease enhancement Specific signs on MRS Lactate doublet at 1.3 ppm RCD LBSL Single peak at 1.3 ppm Sjögren Larsson ADLD, Adult-onset autosomal dominant leukodystrophy caused by lamin B1 duplications; ALD, adrenoleukodystrophy; AMN, adrenomyeloneuropathy; CACH, childhood ataxia with CNS hypomyelination; CADASIL, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, cblc, cobalamin C disease; CTX, cerebrotendinous xanthomatosis; FXTAS, fragile X tremor ataxia syndrome; LBSL, leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation; MRS, proton magnetic resonance spectroscopy; MTHFR, methylenetetrahydrofolate reductase; PBD, peroxisome biogenesis disorders; RCD, respiratory chain disorders.

5 J Inherit Metab Dis (2008) 31: unknown; (2) leukoencephalopathies caused by genes coding for proteins not directly involved in metabolic pathways and for which the diagnosis relies directly on gene analysis; and (3) leukoencephalopathies caused by genes coding for enzymes or proteins involved in the cell metabolism and for which the diagnosis relies mostly on biochemical analysis of plasma and urines samples. The third category corresponds to inborn errors of metabolism (IEMs) which are important to recognize because specific treatments often exist (Sedel et al 2007). Most IEMs causing leukoencephalopathies begin in childhood and have been described by neuropaediatricians. However, late-onset forms also exist that display different clinical and radiological features, sometimes very far from the classical paediatric description. With the exception of some leukoencephalopathies caused by certain lysosomal or peroxisomal disorders, neurologists are usually poorly familiar with IEMs. The aim of this review is to describe clinical and radiological features of late-onset forms of leukoencephalopathies caused by IEMs that can be diagnosed in an adult neurology department This includes diseases with onset in adolescence or adulthood as well as mild forms with premonitory signs in childhood. Importantly, the distinction between late-onset (adolescence to adulthood) and childhoodonset leukoencephalopathies will certainly change in the future as new late-onset cases are described. The main clinical and radiological characteristics of leukoencephalopathies in adults are summarized in Table 1. In Tables 2 and 3, we propose diagnostic orientations to help neurologists_ reasoning in a patient with a leukoencephalopathy. Leukoencephalopathies caused by disorders of complex molecule metabolism Metachromatic leukodystrophy Metachromatic leukodystrophy is caused by a deficiency in lysosomal arylsulfatase A (ARSA) which catabolizes sulfatides (Von Figura et al 2001). Sulfatides accumulate in multiple tissues including oligodendrocytes and Schwann cells, provoking demyelination in both the central and peripheral nervous system. The incidence of the disease is around 1/ and adult forms represent about 20% of cases. Clinical onset can be as late as the seventh decade of life (Bosch and Hart 1978; Von Figura et al 2001). In adults, first symptoms are usually psychiatric, mimicking schizophrenia with delusion, hallucinations, disorganized behaviour and social dysfunction (Baumann et al 1991). The clinical picture is completed after several years or decades by cognitive deficits as well as motor signs (spastic paraparesis, cerebellar ataxia, mild demyelinating polyneuropathy). Motor onset forms of the disease are preferentially associated with the homozygous mutation P426L, whereas psychiatric forms are linked to the I179S mutation (Rauschka et al 2006). MRI shows a bilateral periventricular leukoencephalopathy with frontal predominance and cerebral atrophy. Importantly U-fibres are relatively spared at least at early stages of the disease (Fig. 1). The only treatment which can be proposed to date is bone marrow transplantation, with few successes obtained in late-onset forms of the disease (Kidd et al 1998). Diagnosis of metachromatic leukodystrophy is based on the measurement of ARSA activity on leukocytes. However, about 15% of people in Europe and the United States display low ARSA activity without clinical symptoms and no tissue or urine accumulation of sulfatides (Von Figura et al 2001). These pseudodeficiencies are caused by certain polymorphism within the ARSA coding gene (Von Figura et al 2001). Thus the diagnosis of metachromatic leukodystrophy in a patient with low ARSA activity requires the demonstration of high urinary excretion of sulfatides or molecular analysis of the ARSA gene. Reciprocally, deficiency in saposin B, an activator necessary to activate sulfatides degradation, can cause metachromatic leukodystrophy despite normal ARSA activity (Deconinck et al 2007). Although such deficiency has not been described in adults to our knowledge, it should be suspected in patients with leukodystrophy and high urinary excretion of sulfatides. Krabbe disease Krabbe disease is caused by a deficiency in the lysosomal enzyme cerebroside "-galactocerebrosidase that catabolizes galactocerebrosides. Accumulation of galactocerebrosides and of "-galactosylsphingosine provokes oligodendrocyte cell death. The frequency of the disease is around 1/ and the percentage of late-onset forms is around 10% (Wenger et al 2001). Onset can be as late as 60 years of age (Wenger et al 2001). In the adult form of the disease, the clinical picture is that of a long-standing spastic paraparesis associated with a motor demyelinating polyneuropathy which can be asymmetric and can involve bulbar muscles (Bataillard et al 1997; Farina et al 2000; Fontaine et al 2003; Harzer et al 2002; Henderson et al 2003; Sabatelli et al 2002). Brain MRI demonstrates a quite specific pattern with high signal of the pyramidal tracts, eventually with involvement of the splenium of the corpus callosum and

6 300 J Inherit Metab Dis (2008) 31: Fig. 1 Metachromatic leukodystrophy in a 43-year-old woman. Her first pregnancy at the age of 31 years was followed by psychiatric signs mimicking postpartum psychosis. Psychiatric signs became permanent, resembling schizophrenia, and cognitive deficits appeared with a frontal syndrome and severe attention deficit. Brain MRI with an axial T2-weighted spin echo sequence shows a diffuse high signal (arrows) of the periventricular white matter spreading to the subcortical areas but sparing U fibres. It is associated with cortical and subcortical atrophy optic radiations (Farina et al 2000; Fontaine et al 2003; Fig. 2). Rarely, brain MRI can be normal (Bajaj et al 2002). Cerebrospinal fluid analysis can reveal high protein concentration. Although bone marrow transplantation has been proposed in children, it remains to be evaluated in adults (Krivit et al 1998). Adrenoleukodystrophy and related peroxisomal disorders Adrenoleukodystrophy is an X-linked disorder due to a deficiency in adrenoleukodystrophy protein (ALDP), which plays a role in the catabolism of very long-chain fatty acids (Moser et al 2007). In adult males, the predominating clinical form is adrenomyeloneuropathy (AMN), a distal axonopathy predominantly affecting pyramidal tracts and posterior columns of the spinal cord. This clinical phenotype, which manifests with a progressive spastic paraparesis represents around 40% of all clinical forms of adrenoleukodystrophy (Moser et al 2007). Brain MRI can show signs of leukoencephalopathy in about 50% of cases. Signal abnormalities are usually localized to pyramidal tracts but may also involve the corpus Fig. 2 Krabbe disease in a 63-year-old woman. From adolescence the patient exhibited walking instability and urinary incontinence. At 39 years of age, she visited a neurologist who noted a bilateral lower limb pyramidal syndrome and pes cavus. The evolution was then progressive, associating a progressive spastic paraparesis, vesical instability, tongue amyotrophy, swallowing difficulties and a demyelinating sensorimotor polyneuropathy. Brain MRI with an axial T2-weighted spin echo sequence shows bilateral and symmetrical high signal of the corticospinal tracts (arrows). (From Fontaine et al 2003, with permission.)

7 J Inherit Metab Dis (2008) 31: callosum (splenium or genu) or the periventricular white matter (Aubourg et al 1992; Eichler et al 2007; Tourbah et al 1997). Around 20% of patients with an AMN phenotype will develop, after 10 years of disease evolution, a more severe phenotype called adult cerebral adrenoleukodystrophy (ALDc; Van Geel et al 2001). ALDc is a progressive inflammatory demyelinating disease which often starts with psychiatric signs and which progresses rapidly with motor signs, optic atrophy, epilepsy and death within several years. The brain MRI shows more diffuse signal abnormalities (Fig. 3). Importantly, there might be contrast enhancement at the periphery of these signal abnormalities suggesting increased blood brain barrier permeability caused by inflammation (Fig. 3). In addition, some adult patients can present directly with an ALDc phenotype. This kind of presentation is exceedingly rare and accounts for less than 5% of all cases of ALD (Moser et al 2007; Fig. 3). Infantile and adult cases of ALD can occur in the same family (Turpin et al 1985). In addition, focal forms of ALDc mimicking a brain tumour have occasionally been described (Sakakibara et al 2001). Heterozygous women are usually asymptomatic or exhibit only brisk tendon reflexes and mild decreased in proprioception. In 15% of cases however, they present a progressive spastic paraparesis which begins around 40 years of age (Menage et al 1993). The brain MRI is often normal or can show the same abnormalities as in AMN. The cerebral ALDc phenotype has exceptionally been observed in women (Moser et al 2007). Biological adrenal insufficiency may be present in around 70% of males and less than 1% of females. Dietary therapy with Lorenzo_s oil (composed of glutaryl trioleate and glutaryl trierucate) normalizes the concentration of very long-chain fatty acids and recent open studies suggest that it could slow the disease progression in adults with adrenomyeloneuropathy, although the latter finding warrants further controlled studies (Moser et al 2007). Late-onset leukoencephalopathies have also been described in patients with peroxisome biogenesis disorders. Although these diseases rarely present in adulthood, isolated case reports of adults with various combination of cognitive deficits, deafness, retinitis pigmentosa, polyneuropathy, cerebellar ataxia and leukoencephalopathy involving the periventricular white matter and pyramidal tracts have been published (Baumgartner et al 1998; Moser et al 1995). Cerebrotendinous xanthomatosis Cerebrotendinous xanthomatosis is a treatable disease due to a deficiency in the mitochondrial enzyme sterol 27-hydroxylase (CYP27) involved in the synthesis of bile acids from cholesterol (Bjorkhem et al 2001; Kuriyama et al 1991; Verrips et al 2000). The incidence of the disease has been suggested to be as Fig. 3 Adult cerebral adrenoleukodystrophy in a 53-year-old man. The patient_s personal history was remarkable for episodes of depression over the previous ten years leading to several suicide attempts. At the age of 53 he exhibited a severe frontal syndrome with urinary incontinence leading to dementia within 4 months. Electroneuromyography revealed a subclinical axonal polyneuropathy. (A) Brain MRI with a T2-weighted spin echo sequence shows symmetric high signal of the frontal periventricular white matter (arrow). (B) T1-weighted sequence with gadolinium injection showing diffuse contrast enhancement (arrow) surrounding demyelinating zones

8 302 J Inherit Metab Dis (2008) 31: high as 1/ and thus should represent one of the main causes of leukoencephalopathies in adults (Lorincz et al 2005; our personal experience). The enzymatic block leads to the accumulation in several tissues of cholesterol and of cholestanol, a poorly soluble compound and potentially toxic against oligodendrocytes. Storage compounds can form xanthomata in various tissues including the nervous system. Clinical presentations of the disease are quite variable. Initial symptoms often begin in childhood with epilepsy, nonspecific mental retardation, juvenile cataract or chronic diarrhoea. Progressive neurological deterioration follows in adolescence or adulthood with psychiatric signs, progressive spastic paraparesis, cerebellar ataxia, polyneuropathy, epilepsy and cognitive deficits. These neurological signs can be accompanied by the appearance of tendon xanthomata (mainly visible at the level of the Achilles tendon), although the last are only found in 30% to 70% of cases (Verrips et al 2000). The clinical picture can be mild with apparent monosymptomatic forms consisting of presenile cataract, pure polyneuropathy, isolated spastic paraparesis of psychosis (Tészas et al 2006; references above; personal observations and Fig. 4). MRI shows a specific pattern with high signals of dentate nuclei of the cerebellum on T2-weighted sequences (Barkhof et al 2000; Fig. 4). Other structures involved include pyramidal tracts, cerebral peduncles, the periventricular white matter, the corpus callosum and basal ganglia (Barkhof et al 2000; Fig. 4). Low signals on T1- and T2-weighted sequences corresponding to lipid xanthomata can also be observed in advanced stages, particularly in cerebellar dentate nuclei. Treatment with chenodeoxycholic acid, which suppresses the formation of cholestanol by restoring the negative feedback on cholesterol 7-!-hydroxylase (the enzyme at the origin of cholestanol synthesis) is very efficient both on biological, clinical and spectroscopic abnormalities but must be given at early stages before the appearance of irreversible brainstem lesions (Bjorkhem et al 2001; our personal observations). Polyglucosan body disease Polyglucosan body disease is defined neuropathologically by the presence of periodic acid Schiff (PAS)- positive inclusions containing glycogen in the central and peripheral nervous system. The mode of transmission is usually autosomal recessive and in certain cases mutations were found in the gene coding for the glycogen branching enzyme (Ziemssen et al 2000). The phenotype associates signs of pyramidal degeneration (progressive spastic paraparesis) with signs of lower motor neuron involvement, urinary disturbance, progressive dementia or parkinsonism. The diagnosis is suggested by the demonstration of polyglucosan accumulation in a peripheral nerve or an axillary skin biopsy. Brain MRI can show a diffuse periventricular leukoencephalopathy which involves the mesencephalon and the cerebellum together with diffuse cerebral, cerebellar and spinal cord atrophy (Berkhoff et al 2001). Fig. 4 Cerebrotendinous xanthomatosis in a 59-year-old woman. The patient presented a spastic paraparesis from the age of 44 followed during the last 7 years by a progressive dementia with urinary incontinency. She did not exhibit xanthomata, cataract or polyneuropathy. Brain MRI with an axial FLAIR sequence shows high signals of cerebellar dentate nuclei (arrow) with a periventricular leukoencephalopathy involving the splenium of the corpus callosum

9 J Inherit Metab Dis (2008) 31: Sjögren Larsson syndrome Sjögren Larsson syndrome is caused by deficiency in fatty aldehyde dehydrogenase, involved in the catabolism of fatty aldehydes. Clinical symptoms usually appear in early infancy with ichthyosis, spastic paraparesis, mental retardation and macular dystrophy with retinal dots. In certain cases, neurological signs can appear in adulthood (Willemsen et al 2001). Brain MRI typically shows a diffuse periventricular leukoencephalopathy. Proton magnetic resonance spectroscopy (MRS) shows a characteristic narrow lipid peak at 1.3 ppm at short and long echo times (Willemsen et al 2004). Mucolipidosis type IV Mucolipidosis type IV is a rare lysosomal storage disease defined neuropathologically by the presence of diffuse lysosomal lipidic inclusions (reviewed in Bach 2001). It has been almost exclusively reported in the Ashkenazi Jewish population. The underlying genetic abnormalities lie in the gene encoding mucolipin, a cationic channel (Kiselyov et al 2007). Clinical signs include mental retardation, spastic paraparesis and ophthalmological abnormalities (corneal dystrophy, retinal degeneration, optic atrophy). Mild forms that remain poorly symptomatic until adolescence or adulthood have been observed rarely (Reis et al 1993). Brain MRI shows hypoplastic corpus callosum with periventricular leukoencephalopathy and cerebellar atrophy (Frei et al 1998). The diagnosis is suggested by hypergastrinaemia that occurs in all the patients (thus far), while iron deficiency occurs in about half cases. Thus elevated blood gastrin is very useful as a screening and diagnostic test of this disease (Schiffmann et al 1998). Fabry disease Fabry disease is an X linked multisystemic lysosomal disorder caused by!-galactosidase deficiency which is responsible for globotriaosylceramides accumulation mainly in endothelial cells. The diffuse vasculopathy can be responsible for cerebral strokes in adulthood (mainly in small-artery territories or in the vertebrobasilar circulation) and can lead to a vascular leukoencephalopathy. The latter can be observed in hemizygous males as well as in heterozygous women (Fellgiebel et al 2005; Mitsias and Levine 1996). Specific signs of the disease include crises of acroparaesthesia, angiokeratoma, cornea verticillata, proteinuria and cardiomyopathy (Brady and Schiffmann 2000). Leukoencephalopathies caused by intermediary metabolism disorders Homocysteine remethylation defects Homocysteine remethylation defects comprise a group of enzymatic deficiencies that disrupt the remethylation of homocysteine into methionine. These disorders are responsible for a deficiency in methionine regeneration and consequently in S- adenosylmethionine, which is the methyl donor for most methylation reactions including that of myelin basic protein (Hörster et al 2005). The two main disorders that have been reported in adults are methylenetetrahydrofolate (MTHFR) deficiency and cobalamin C disease. Both diseases can manifest with leukoencephalopathy at any age (Boxer et al 2005; Walk et al 1994; Fig. 5). In adults, main symptoms include psychiatric signs (psychosis or depression), cognitive deficits, spastic paraparesis caused by subacute degeneration of the spinal cord, peripheral neuropathy, strokes and, eventually, transient episodes of confusion or coma. The leukoencephalopathy is usually periventricular, with a posterior predominance, and can involve U fibres (Fig. 5). It can also involve the spinal cord with increased signal of the posterior columns. Importantly, this leukoencephalopathy is reversible with specific medications (usually betaine, folic acid and vitamin B 12 ; Ogier de Baulny et al 1998). Phenylketonuria Phenylketonuria can be responsible for a diffuse periventricular leukoencephalopathy in adults. This has been described in adults who escaped neonatal screening programmes and who exhibited the first signs of the disease in adulthood, usually spastic paraparesis, dementia and/or optic atrophy (Kasim et al 2001; Weglage et al 2000). This has also been observed in patients who interrupted their low-phenylalanine diet and who displayed high levels of phenylalanine (McCombe et al 1992; Thompson et al 1993; Fig. 6). The mechanism of white-matter changes is not completely understood but could correspond to white-matter oedema since it is reversible after reintroduction of the diet (Thompson et al 1993; Fig. 6). Organic acidurias It has been hypothesized that high intracellular contents of organic acids could be toxic for oligodendrocytes (Hörster et al 2005). In adults, leukoence-

10 304 J Inherit Metab Dis (2008) 31: Fig. 5 Methylenetetrahydrofolate reductase (MTHFR) deficiency in a 56-year-old woman (Michot et al, submitted). A 56-yearold woman was admitted for confusion and walking problems. She had exhibited psychiatric signs for the previous 3 years and a diagnosis of late-onset schizophrenia was proposed. During hospitalization, she exhibited complete paraplegia and her vigilance status rapidly worsened, leading to coma. Biological investigations disclosed high homocysteine (192 2mol/L, normal<15), and MTHFR deficiency was confirmed by molecular analysis and enzyme activity assay. (A) Brain MRI: FLAIR sequence shows leukoencephalopathy (arrow) involving periventricular and deep subcortical white matter. (B) A 3-month treatment with betaine, folinic acid and vitamin B 12 led to a complete disappearance of the leukoencephalopathy and of psychiatric and cognitive disturbances, but the patient remained paraplegic phalopathies have been observed in patients with glutaric aciduria type I (Kulkens et al 2005), l-2-ohglutaric aciduria (Owens and Okun 2004), 3-methylglutaconic aciduria type I (Eriguchi et al 2006) or 3-HMG-CoA lyase deficiency (Bischof et al 2004). Except in glutaric aciduria type 1 and l-2-oh-glutaric aciduria, where macrocephaly is a distinctive but inconstant feature, in other organic acidurias clinical signs are poorly specific (cephalalgia, epilepsy, supranuclear gaze palsy, cognitive deficits, optic atrophy, ataxia, pyramidal signs). Brain MRI can show signal abnormalities involving U fibres, a feature rarely encountered in other genetic leukoencephalopathies (with the exception of diseases responsible for diffuse hypomyelination), as well as involvement of basal ganglia. The involvement of U fibres is striking in l-2-oh-glutaric aciduria, where U fibres can remain the only tracts involved (Fig. 7). Fig. 6 Phenylketonuria in a 25-year-old woman. This patient was diagnosed as having phenylketonuria from birth. She followed a low-phenylalanine diet until the age of 5 years. Her psychomotor development was normal. At the age of 25 years, a brain MRI was performed because she complained of vertigo and anxiousness. Her phenylalanine level was mol/L. (A) Brain MRI with an axial FLAIR sequence showed bilateral and symmetric periventricular leukoencephalopathy. (B) Six months after reintroduction of the diet, the leukoencephalopathy disappeared

11 J Inherit Metab Dis (2008) 31: Fig. 7 l-2-oh-glutaric aciduria in an 18-year-old woman. This patient exhibited only mild mental retardation and few tonicclonic epileptic seizures that led to neurological investigations. Brain MRI with an axial FLAIR sequence shows a diffuse high signal of the juxtacortical white matter (U fibres), whereas periventricular white matter is spared. Very high urinary excretion of l-2-oh-glutaric acid was found Mitochondrial respiratory chain disorders Leukoencephalopathies have been observed in several syndromic mitochondrial disorders including Leber hereditary optic neuropathy (LHON), mitochondrial encephalomyopathy with lactic acidosis and strokelike episodes (MELAS), chronic external ophthalmoplegia (CPEO) and Kearns Sayre syndrome (KSS) (Lerman-Sagie et al 2005; Wray et al 1995). Leukoencephalopathy is also a cardinal feature of mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) caused by mutations in the thymidine phosphorylase gene and associated with a severe digestive disease leading to cachexia, polyneuropathy, external oculomotor paralysis and retinitis pigmentosa (Hirano et al 1994). Leukoencephalopathy can also be observed in nonsyndromic mitochondrial disorders with different combinations of clinical symptoms including myopathy, seizures, stroke-like episodes, dementia, ataxia, optic neuropathy, retinopathy, sensorineural hearing loss, peripheral neuropathy, and cardiac, gastrointestinal, renal or endocrine dysfunction. Overall, leukoencephalopathies in the context of mitochondrial disorders can involve any brain areas including the periventricular white matter, cerebellar white matter, U fibres, brainstem and spinal cord (Jaros et al 2007; Lerman-Sagie et al 2005). Other radiological findings include cerebral atrophy, calcifications or signal abnormalities of deep grey matter (basal ganglia, cerebellar dentate nuclei), small foci of abnormal signal of the white matter and stroke-like lesions (Finsterer 2006). Proton resonance spectroscopy often shows a high lactate doublet at 1.3 ppm, especially in brain regions damaged on MRI (Bianchi et al 2003). However this technique fails to detect weak increased lactate concentrations and can be normal even in cases of definite mitochondrial disease (Lin et al 2003). Diagnostic approach in a patient with an unexplained leukoencephalopathy The discovery of a leukoencephalopathy is often a diagnostic challenge. The first step in the diagnostic approach is to search for acquired, potentially treatable causes. These causes are numerous and include inflammatory, infectious, metabolic, neoplastic, paraneoplastic, toxic or vascular diseases (Filley and Kleinschmidt-DeMasters 2001). In genetic leukoencephalopathies, lesions are usually bilateral and symmetric and involve specific white-matter tracts (pyramidal tracts, cerebellar peduncles, U fibres, etc.). The diagnostic approach to genetic leukoencephalopathies should be guided by the clinical examination, the MRI aspect, electroneuromyographic studies and ophthalmological examination (Tables 2 and 3). Proton magnetic resonance spectroscopy is rarely specific of a given cause (Tables 1 and 3). Metabolic investigations leading to treatable diseases should be implemented in order of priority and include cholestanol, homocysteine, amino acids and organic acids analysis. It is probable that certain leukoencephalopathies only described in children such as Canavan disease (Janson et al 2006), ribose phosphate isomerase deficiency

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