Handbook of Clinical Neurology, Vol. 120 (3rd series)Neurologic Aspects of Systemic Disease Part IIJose Biller and Jose M. Ferro, Editors© 2014 Elsevier B.V. All rights reserved

Chapter 57

Disorders of heavy metals

FRANCE WOIMANT* AND JEAN-MARC TROCELLO

French National Wilson’s Disease Centre (CNR Wilson), Lariboisi�re Hospital, Paris, France

INTRODUCTION

Heavy metals and trace elements play an important rolein relation to the physiology and pathology of the ner-vous system. Metals are present in air, water, and diet.Input sources in humans are mainly respiratory anddigestive and rarely dermal. Some metals have no bio-logic function but are toxic where there is excessiveexposure (e.g., cadmium, lead, aluminum, mercury,manganese). The main features of these metal toxicitiesare summarized in Table 57.1. Other metals, such as ironand copper, are involved in biologic processes as cofac-tors of numerous enzymes. Disorders of metabolism ofthese metals will lead to various neurologic diseases.

COPPER DISORDERS

Copper is an essential trace element, necessary for theactivity of many key enzymes including superoxidedismutase, lysyloxidase, dopamine b-hydroxylase,cytochrome oxidase, and ceruloplasmin.

Copper disorders can be divided into two groups:

● ATP7A- or ATP7B-related inherited copper trans-

*Co

Pari

port disorders

● acquired diseases associated with copper deficiency

or copper excess.

Copper metabolism

Themain regulators of cellular coppermetabolism are thecopper-transporting P-type ATPases: ATP7A andATP7B.Their transport activity is crucial for central nervous sys-tem (CNS) development, liver function, connective tissueformation, and many other physiologic processes (Barneset al., 2005). The physiologic importance of Cu-ATPasesis illustrated by the deleterious consequences of muta-tions or deletions in the gene encoding these proteins,

rrespondence to: Dr France Woimant, Neurology Department, C

s, France. Tel: þ33-1-49-95-65-27, Fax: þ33-1-49-95-65-34, E-m

essentiallyMenkes disease forATP7AandWilson diseasefor ATP7B. Both Cu-ATPases have two main roles incells, namely to provide copper to essential cuproenzymesand tomediate the excretion of excess intracellular copper(Lutsenko et al., 2007). They are expressed inmost tissues.Their roles are probably not the same in all organs. Inintestine where the two Cu-ATPases are expressed,ATP7Bdoes not compensate for the deficiency ofATP7Afunction (Menkes disease). In contrast, in the cerebellumof ATP7B�/� mice, ATP7A appears to substitute formissing ATP7B (Barnes et al., 2005).

The daily intake of copper is about 3 mg. Copper isabsorbed by the intestinal cells and stored with metal-lothioneins in a nontoxic form (Fig. 57.1). It is exportedfrom the enterocytes into the blood byCu-ATPaseATP7Aand transported via the portal vein to the liver, which is themain organ responsible for copper homeostasis. Inhepatocytes and other cells, copper is absorbed by coppertransporter 1 (CTR1) (Vulpe et al., 1993). In the cytoplasm,it is bound to metallothionein or to copper-specific chap-erone proteins (CCS, ATOX 1, and COX17). Thus, cellsare protected from the toxic effects of free copper.CCS and COX17 guide copper to mitochondria andATOX1 to the trans-Golgi network (TGN). Under basalconditions, ATP7A and ATP7B are essentially localizedwithin the TGN. Under increased copper concentrations,ATP7A is translocated to the vesicles or to the plasmamembranes, allowing excretion of excess intracellularcopper; in hepatocytes, ATP7B is relocalized toward can-alicular membrane allowing excretion of copper into thebile and subsequently to feces (deBie et al., 2007). In liver,ATP7Bmediates also the incorporation of copper into thecopper-dependant ferroxydase ceruloplasmin (CP), whichis subsequently secreted into the blood. CP is the majorcopper-containing protein; however, it does not seem toplay an essential role in copper metabolism. (Valentineand Gralla, 1997).

NRWilson, Lariboisiere Hospital, 2 rue Ambroise Pare. 75010

ail: france.woimant@lrb.aphp.fr

Table 57.1

Main features of excessive exposure to heavy metals

Metal Mode of intoxication General features Neurological features Diagnosis

Cadmium (Sethiand Khandelwal,2006)

Inhalation of fumes NephropathyDecreased bone density

Neuropsychiatricmanifestations,polyneuropathy

Urinary cadmiumlevel

Lead (Brodkin et al.,2007)

Occupationalexposure,(manufacturingof batteries,

pigments,solder . . .)

Diet

Abdominal pain,anorexia, nausea andconstipation,nephropathy, anemia

with basophilicstippling

Headache,concentration andmemorydifficulties, sleep

disturbances,peripheralneuropathy

Blood lead level

Mercury (Brodkinet al., 2007)

Dental amalgamFish consumption

Gingivitis, stomatitis,hypersalivation,metallic taste,

nephropathy

Irritability,concentration andmemory

difficulties, sleepdisturbances,sensory peripheral

neuropathy

Blood and urinemercury levels

Aluminum (Letzelet al., 2000; Yonget al., 2006)

Occupationalexposure

Dialysis

Intravenous boiledmethadone

Bone pain, ostemalacia,pathologicalfractures, microcytic

anemia

Seizures, myoclonus,personalitychanges, tremor,

ataxia

Serum aluminiumlevel

Manganese (Jog

and Lang, 1995;Stepens et al.,2008)

Intravenous

methcathinoneInhalation of fumesAcquired

hepatocerebraldegeneration(CAHD)

Weakness Personality changes,

irritability, sleepdisturbances,Parkinsonism,

chorea, dystonia,ataxia, tremor,myoclonus

Serum manganese

levelHypersignal onT1-weighted brain

MRI in globuspalidus

Copper from Diet

Metallothionein

Metallothionein

Vesicle

Hepatocyte

CTR1

ATP7 A

ATP7 B

ATP7 B

Cp

Cp Ferroxydasic activity

- Menkes disease- Occipital horn syndrome- ATP7A-related distal motorneuropathy (DMN)

- Acute copper poisoning- chronic copper toxicosis

- Malabsorption- Inflammatory disease- Drugs- Zinc excess

Wilson’s disease

ATP7A-related copper transportdisorders

Acquired copper toxicosis

Acquired copper deficiency

Excretion of copper into the bile

Atox 1

Atox 1

Nucleus

Nucleus

Enterocyte

Portal vein

CTR: copper transporter; ATOX 1: copper specific chaperone protein; ATP7: copper-transporting P-type ATPases; Cp:ceruloplasmin (Apoceruloplasmin, without copper, holoceruloplasmin with copper)

AceruloplasminemiaCTR1

Fig. 57.1. Copper metabolism and disorders.

852 F. WOIMANT AND J.M. TROCELLO

DISORDERS OF H

ATP7A- or ATP7B-related inheritedcopper transport disorders

ATP7A-RELATED COPPER TRANSPORT DISORDERS

Menkesdisease (MD), occipital horn syndrome (OHS), andATP7A-related distal motor neuropathy are caused bymutations in the ATP7A gene, which is located on the longarmof theXchromosome (Xq13.1-q2).Over200mutationshave been identified, among which are small deletions/insertions, nonsense mutations, missense mutations, andsplice site mutations. In one-third of cases, MD is causedby de novo mutations. Splice site mutations appear to beover-represented in patients with OHS (de Bie et al.,2007). ATP7A-related distal motor neuropathy involvesunique missense mutations (Kennerson et al., 2010).

Menkes disease (MD), also known as kinky hair dis-ease, was first described by Menkes in 1962 (Menkeset al., 1962). Some 10 years later, Danks et al. (1972) foundserum copper and ceruloplasmin levels to be reduced andsuggested that the primary defect in Menkes diseaseinvolved copper metabolism. In 1993, three teams isolatedthe gene that encodes Cu-ATPase, the ATP7A gene(Chelly et al., 1993; Mercer et al., 1993; Vulpe et al., 1993).

Defective ATP7A function results in:

● dysfunction of several copper-dependant enzymes,

Tab

Cup

Seru

UrinSeru

Cu:

due to inability to load these enzymes with copper

● reduction of elimination of copper from cells, and

almost all the tissues except for liver and brain willaccumulate copper to abnormal levels. As intestinalcopper absorption is impaired, the copper level doesnot reach a toxic state (T€umer and M�ller, 2010). Inthe liver, low levels of copper are explained by the factthat ATP7A is not the main liver copper transporter.

The incidence of MD is estimated to range between1:40000 and 1:350000. (M�ller et al., 2009). Clinical fea-tures include progressive neurologic deterioration andmarked connective tissue dysfunction. As in linked-Xdisease, MD typically occurs in males. Usually, patientsare born at term. Developmental regression appearswithin the first 2 months of life as axial hypotonia,

le 57.2

ric tests in copper disorders

Menkes

disease

Occipital horn

disease

ATP7A related

neuropathy

m Cu & NI / & NI

ary Cu & NI / & NIm Cp & NI / & NI

copper; Cp: ceruloplasmin

seizures, and psychomotor retardation. The appearanceof the hair is often remarkable, being sparse, hypopig-mented, and kinky (pili torti). Ligamentous hyperlaxity,skin hyperelasticity, and bladder and ureter diverticulaare often associated. Skeletal findings are metaphysealspurs and long bone fractures. Autonomic dysfunction,including temperature instability and hypoglycemia,may be present in the neonatal period. Because of abnor-mal development of the vessel walls (fragmentation ofthe internal elastic lamina and thickening of the intima),arterial tortuosities and aneurysms are frequent, leadingto cerebral infarcts and intracranial and intestinal bleeds(Horn et al., 1992). There is important variability in theseverity of clinical expression of MD. Mild MD formswith later onset, moderate symptoms, and longer sur-vival are observed in 5–10% of the patients.

Diagnosis of MD can be established by detecting lowlevels of copper (and ceruloplasmin) in the serum, and highlevels in cutaneous fibroblasts (Table 57.2). However, intheneonatalperiodserumcopperandceruloplasminshouldbe interpretedwith caution, as their levels are low in healthynewborns. In this period, plasma catecholamine analysis(ratio of dihydroxyphenylalanine to dihydroxyphenylgly-col) indicative of dopamine b-hydroxylase deficiencyallows a rapid diagnosis (T€umer and M�ller, 2010). Thediagnosis can be confirmed by identification of the genemutation, but because of the large size of the gene andthe high number of mutations, genetic analysis may taketime. Genetic analysis also allows screening of carrierfemales and antenatal diagnosis through chorionic villussampling.

Parenteral administration of histidine-copperimproves the neurologic outcome and increases lifespan.The prognosis remains inevitably poor. The age atwhich treatment is started, the severity of the disease,and the presence of at least partially functionalATP7A seem to be among the main determinants forthe prognosis. Death usually occurs by 3 years of age,but some patients survive to 10 years or even more(T€umer and M�ller, 2010).

Occipital horn syndrome (or X-linked cutis laxa, orEhlers–Danlos syndrome type 9) is a less severe allelic

EAVY METALS 853

Wilson’s

disease

Copper

deficiency Aceruloplasminemia

& & &% & NI& & &&

D J.M. TROCELLO

variant of the MD syndrome (Kaler, 1998). Its incidenceis unknown. Individuals typically live to at least mid-adulthood. Its principal clinical features are related toconnective tissue, with bladder diverticula, inguinal her-nias, skin laxity and hyperelasticity. Neurologic abnormal-ities are far less severe or even absent. Characteristic is theformation of occipital exostoses resulting from calcifica-tion of the trapezius and sternocleidomastoid muscles attheir attachments to the occipital bone (Peltonen et al.,1983). The symptoms result from alterations in the func-tion of copper-dependant enzymes, in particular that oflysyloxidase. Serum copper and ceruloplasmin levelsare normal or low (Table 57.2).

A newly discovered allelic variant associated withATP7A is ATP7A-related distal motor neuropathy(DMN). It is an adult-onset distal motor neuropathyresembling Charcot–Marie–Tooth disease, and charac-terized by atrophy and weakness of distal muscles inhands and feet. There is no sign of systemic copperdeficiency. Serum copper and ceruloplasmin levels arenormal (Table 57.2) (Kaler, 2010).

854 F. WOIMANT AN

ATP7B-RELATED COPPER TRANSPORT DISORDERS

Wilson disease (WD) is caused by mutations in theATP7B gene, located on chromosome 13 (q14.3.-q21.1).Although missense mutations are most frequent, dele-tions, insertions, nonsense, and splice site mutationshave been reported. More than 400 mutations and 100polymorphisms have been documented. In the US andnorthern Europe, two mutations, His1069Gln andGly1267Arg, represent 38% of identified mutations(Thomas et al., 1995). The worldwide prevalence ofWD is estimated in the order of 30 per 1 million, witha carrier frequency of approximately 1 in 90.WD ismorefrequent in countries in which consanguineous mar-riages are common (Figus et al., 1995).

In 1912, in a doctoral thesis published in Brain, S.A.Kinner Wilson gave a very detailed description of boththe clinical and pathologic characteristics of “Progressivelenticular degeneration: a familial nervous diseaseassociated with cirrhosis of the liver” (Wilson, 1912;Walshe, 2006). The therapeutic area of WD began withCumings in 1948; he suggested an etiologic role forcopper and proposed chelating therapy with British anti-Lewisite (BAL or dimercaptopropanol) (Cumings, 1948).In 1956, Walshe proposed the use of D-penicillamine(Walshe, 1956), and in 1961, Schouwink the use of zincsalts as decoppering agents (Hoogenraad, 2001). In1985, Frydman reported that the WD gene was locatedon chromosome 13 (Frydman et al., 1985). The identifica-tion of the gene, ATP7B, was realized by three separateteams during year 1993 (Bull et al., 1993; Tanzi et al.,1993; Yamaguchi et al., 1993).

Physiopathology

Defective ATP7B function leads a reduction of conver-sion of apoceruloplasmin into ceruloplasmin and of cop-per release into the bile, resulting in important copperaccumulation in the liver, very low levels of copper-bound ceruloplasmin in the serum, and low biliary cop-per. When the hepatic copper storage capacity intometallothioneins is exceeded, unbound copper spillsout of the liver and is deposited in other organs and tis-sues (Trocello et al., 2010a).

Clinical features

WD begins with a presymptomatic period during whichthere is accumulation of copper in the liver that willcause hepatitis and, without treatment, will progress toliver cirrhosis and development of extrahepatic symp-toms. In our series of 385 patients, the initial manifesta-tions are hepatic dysfunction in 44% of cases, andneurologic or neuropsychiatric symptoms in 39%. Otherpatients present with Kayser–Fleischer rings, hemato-logic or renal syndromes. The mean age of first hepaticsymptoms is 17 years and for initial neurologic symp-toms 23 years. It is rare that the first symptoms appearbefore 5 years, but WD has been diagnosed as early as 2years (Beyersdorff and Findeisen, 2006), and as late as72 years in a patient with Kayser–Fleischer rings(Czonkowska et al., 2008).

WD can be asymptomatic with abnormal serum ami-notransferases or hemolytic anemia found incidentally.Isolated splenomegaly or thrombopenia due to clinicalunapparent cirrhosis with portal hypertension or detec-tion of Kayser–Fleischer rings can also reveal the dis-ease. Nonspecific symptoms are often the firstmanifestations: nausea, anorexia, fatigue, abdominalpain, amenorrhea, or repeated miscarriages. Diseasemay also present as acute transient hepatitis that canmimic autoimmune hepatitis, as chronic liver diseaseand cirrhosis either compensated or decompensated,or as fulminant hepatic failure with an associatedCoombs-negative hemolytic anemia and acute renal fail-ure (Ala et al., 2007).

First neurologic symptoms of WD include changes inbehavior, deterioration in school or professional work, inhandwriting, dysarthria, drooling, tremor, or dystonia.The main neurologic manifestations can be roughly dis-tinguished in three movement disorder syndromes(Trocello and Woimant, 2008):

● dystonic syndrome characterized by choreoathetosis

and dystonic postures (Lorincz, 2010). It starts withfocal signs or functional dystonia and may progressto generalized dystonia. It often affects facial mus-cles, resulting in a fixed sardonic smile. Dystonic

Fig.

HEAVY METALS 855

dysarthria affects laryngeal or pneumophonatorymuscles. Choreic movements are often associated.

DISORDERS OF

● parkinsonian syndrome with rigidity and akinesia.

Hypomimia is present, as well as dysarthria withhypophonia, tachylalia. Gait is unsteady with smallsteps, reduced postural reflexes, festination, andfreezing. Rest tremor is rarely isolated.

● postural and action tremor with high amplitude and

low frequency. Its proximal component can be wellobserved when a patient’s arms are outstretched,showing the “wing-beating tremor.” It is sometimesassociated with cerebellar syndrome.

Behavioral abnormalities are common at diagnosis, par-ticularly in case of neurologic presentation. Symptomsare apathy, irritability, aggressive behavior, obsession,and disinhibition. A recent study reported psychiatricdisorders in 24% of patients: bipolar affection (18%),major depression (4%), and dysthymia (2%)(Shanmugiah et al., 2008). The frontier between subcor-tical disorders and psychiatric disease is imprecise.Many patients suffer from a dysexecutive syndromelinked to subcorticofrontal lesions. Corneal Kayser–Fleischer (KF) rings are detected by slit-lamp examina-tion (Fig. 57.2). They are, in our experience, invariablypresent in patients with neurologic symptoms. Theyare detected in 42–62% of the hepatic forms (Robertsand Schilsky, 2008). They are very suggestive of WD,even if they are also seen in other chronic hepatopathies(Suvarna, 2008). Other ophthalmic findings are sun-flower cataracts that do not impair vision and oculomo-tor abnormalities; vertical eye movements, in particularvertical pursuits, are often impaired (Ingster-Moatiet al., 2007). Other extrahepatic features include renalmanifestations (as lithiasis), osteoarticular disorders,myocardial abnormalities, endocrine disturbances(Hoogenraad, 2001).

57.2. Corneal Kayser–Fleischer ring (Wilson disease).

Wilson disease diagnosis

There is no single test for the diagnosis ofWD; its assess-ment should include history, clinical, biologic, radiologicand sometimes histologic data. WD is characterized bylow serum ceruloplasmin and total copper concentra-tions and increased urinary copper excretion(Table 57.2). Normal serum ceruloplasmin concentrationdoes not exclude the diagnosis, since about 10% of WDpatients and up to 50% of patients with severe liver dis-ease have normal serum ceruloplasmin (Steindl et al.,1997). The level of serum ceruloplasmin is low in healthynewborns, and in Menkes disease, aceruloplasminemia,nephritic syndrome, copper deficiencies, and severechronic liver disease of any cause (Pfeiffer, 2007). Some20% of subjects heterozygous for the Wilson diseasegene have reduced levels. In contrast, serum ceruloplas-min concentrations are elevated by inflammation states,by estrogen supplementation, and during pregnancy.Therefore, the interpretation of serum ceruloplasminis often difficult (Chappuis et al., 2005). Serum copperlevel measures bound and free serum copper. Copperbound to ceruloplasmin normally represents about90% of total serum copper. In WD, the total serum cop-per is usually decreased in proportion to the decreasedceruloplasmin. In cases of acute hepatitis or hemolysis,however, the total serum copper concentration can beincreased due to important release of copper from liveror red blood cells. It has been proposed that the level offree copper should be calculated using the following for-mula: nonbound ceruloplasmin copper (mmol/L)¼ totalserum copper (mmol/L)� 0.047� serum holoceruloplas-min (mg/L). The result is dependent on the adequacy ofthe methods for measuring both serum copper and ceru-loplasmin (Twomey et al., 2008) and so thismethod is notof great value inWD diagnosis or in monitoring therapy.Relative exchangeable copper (REC) (exchangeablecopper/total serum copper) is probably the most usefulscreening method (El Balkhi et al., 2011). The majorityof patients withWD have a level of urinary copper above100 mg by 24 hours. Increased urinary copper levels arenot specific for WD; they can be found in disorders withsevere proteinuria and in heterozygotes for the Wilsondisease gene. A provocative test for urinary copperexcretion using D-penicillamine can be a useful diagnos-tic adjunctive test (Foruny et al., 2008). In suspectedWD,if the clinical and biochemical parameters are not sup-portive, a hepatic biopsy with a measurement of its cop-per content can be carried out. The hepatic copper valuein untreatedWD patients is above 250 mg by gram of dryweight. Interpretation can be difficult because increasedliver copper concentrations can be seen in long-term cho-lestasis, and hepatic copper concentrations can be falselylow inpatientswith extensive fibrosis (Ferenci et al., 2005).

D

ATP7B mutation analysis makes an important contribu-tion to the diagnosis. Unfortunately, the sequencing ofthe complete coding sequence and of the intron-exon junc-tion of the gene allows confirmation of the diagnosis ofWD in only 80% of the cases (Trocello et al., 2009).

In our experience, brain magnetic resonance imaging(MRI) is always abnormal in patients with neurologicsymptoms. It reveals widespread atrophy and on T2-weighted, FLAIR, and diffusion sequences shows bilat-eral, symmetric high-signal intensitymainly in the globuspallidus, putamen, thalamus, mesencephalon, pons, anddentate nucleus (Fig. 57.3) (Sener, 2003). A characteristicfeature is the “face of the giant panda” sign on FLAIRand T2-weighted images of the midbrain. White matterchanges are observed in about 25–40% of patients, oftenasymmetric with frontal predilection; when these lesionsare extensive, they are associated with worse prognosis(Mikol et al., 2005). Abnormalities in the posterior partof the corpus callosum are frequent, observed in 23% ofcases (Trocello et al., 2010b). Cortical lesions are infre-quent. In patients with hepatic symptoms, a decreaseof the apparent diffusion coefficient in the putamencan be detected before the occurrence of neurologicmanifestations (Favrole et al., 2006). Patients withhepatic insufficiency may have high-signal intensitylesions in the basal ganglia on T1-weighted images(van Wassenaer-van Hall et al., 1996).

856 F. WOIMANT AN

Wilson disease treatment

Wilson disease was fatal before the use of the firstchelating agents. Low copper diet is recommended;chocolate, liver, nuts, and shellfish containing highconcentrations of copper should be avoided, as shouldalcohol because of its liver toxicity. The drug treatmentis particularly effective if it is administered at anearly stage of the disease and followed for life. It isbased on the use of copper chelators to promotecopper excretion from the body (D-penicillamine and

A B

Fig. 57.3. Wilson disease, FLAIRMRI. Hypersignals in lenticular

tate nuclei (C), and mesencephal aspect of the “face of the giant

triethylenetetramine or Trientine) and zinc salts (Wil-zin®) to reduce copper absorption. The improvementis not immediate and may appear only after 3–6 monthsof therapy. Furthermore, at the institution of treatmentthere is a risk of a worsening of the hepatic and/or neu-rologic disease (Woimant et al., 2006). This deteriorationis observed with all treatments, more frequently underD-penicillamine (13.8%) than under triethylenetetramine(8%) or zinc salts (4.3%) (Merle et al., 2007). A gradualinstitution of treatment might prevent this. Initial neuro-logic worsening could be due to the mobilization ofhepatic copper into the circulation and its redistributionin the brain. It can also be observed in very acute formsas treatmentmight act too slowly. In rare cases, this dete-rioration is not reversible, the disease continuing toevolve under treatment. Tetratiomolybdate could havea lower risk of neurologic deterioration since it acts byforming a tripartite complex with copper and protein,either in the intestinal lumen where it prevents copperabsorption or in the circulation where it makes the cop-per unavailable for cellular uptake (Brewer et al., 2006).This drug remains an experimental agent and is unavail-able for general use.

The usual daily dose of D-penicillamine is750–1500 mg/day. Regular monitoring of full bloodcount and urinary protein is recommended because ofpossible side-effects which occur in 30% of patients.Most of them are reversible when the drug is withdrawn.Early sensitivity reactions, with fever, rash, lymphade-nopathy, proteinuria, or bone marrow depression withneutropenia, and thrombocytopenia, may occur duringthe first weeks. Later adverse effects include lupus-likesyndrome, Goodpasture’s syndrome, and myastheniagravis. Long-term use of D-penicillamine induceschanges in elastic tissues and in collagen andmight causeskin lesions including elastosis perforans serpiginosa.The usual daily dose of triethylenetetramine is 750–1500 mg/day. Side-effects are rare but include lupus-likereactions and reversible sideroblastic anaemia (Pfeiffer,

J.M. TROCELLO

C D

and caudate nuclei (A), thalami and corpus callosum (B), den-panda” sign (D).

H

2007). The dose of zinc for adults is 150 mg/day of ele-mental zinc. Zinc is generally well tolerated althoughdyspepsia may occur; elevation in serum amylase andlipase, without clinical and radiologic evidence of pan-creatitis, has been reported.

These treatments aremonitored bymeasuring 24 hoururinary copper excretion: high during D-penicillamineand Trientine therapy, and less than 2 micromoles perday during zinc therapy.

The best therapeutic approach remains controversialbecause no controlled trials have compared these treat-ments. A recent systematic review showed no obviousdifferences in clinical efficacy of D-penicillamine andzinc as initial therapy in WD. The two drugs controlledthe disease effectively in a majority of patients, withthe best results being in presymptomatic patients(Wiggelinkhuizen et al., 2009). Therefore, the choiceof drug varies from center to center, based on theopinion of the physicians and on drug availability andcosts. When the disease is stabilized after several yearsof treatment, the initial treatment with chelator may becontinued on a lower dosage or shifted to treatment withzinc salts because they are better tolerated. During preg-nancy, the treatment by chelating agents or zinc saltsmustbe maintained; however, dosages of drugs should bereduced and adapted to copper urinary excretion.

Themost difficult question is how tomanage patientswho deteriorate despite medical therapy. Liver trans-plantation is the treatment for acute fulminant liver fail-ure and for decompensated cirrhosis unresponsive tomedical treatment. In cases of neurologic deterioration,the decision onwhether to continuewith the chosen treat-ment or change to adding another agent is difficult. Indi-cation of liver transplantation is still a matter ofcontroversy in cases of neurologic worsening withoutliver failure. In the study by Medici and colleagues,70% of these patients improved after transplantation(Medici et al., 2005).

The follow-up of WD patients is essential to makesure of observance, efficiency, and tolerance of thetreatment. A clinical or biologic deterioration may pro-voke poor compliancewith treatment. In the longer term,patients may develop hepatocellular carcinoma (Walsheet al., 2003).

Family screening is essential in this autosomal reces-sive disease; indeed, early diagnosis ofWD is essential astreatment is more effective if initiated early. The prob-ability of finding a homozygote in siblings is 25%. Theinterpretation of cupric analysis can be difficult inWD heterozygotes and therefore molecular genetic ana-lyses are very important. For families in which bothmutations have been detected in the index patient, thesemutations are researched in siblings. In the absence ofindications on the mutations, haplotype analysis of

DISORDERS OF

markers around the ATP7B gene on chromosome 13 isused (Chappuis et al., 2005).

Acquired diseases associated with copperdeficiency or copper excess

ACQUIRED COPPER DEFICIENCY

Copper deficiency is exceptional in developed countriesbecause copper is present in numerous foods. However,nutritional copper deficiency is well documented in pre-mature newborns and in patients maintained on paren-teral nutrition for long periods of time without coppersupplementation. Copper malabsorption is observed inother conditions such as upper gastrointestinal surgeryor inflammatory bowel disease. An unusual cause ofacquired copper deficiency is excess zinc intake, forexample chronic use of denture cream containing zinc(Nations et al., 2008; Trocello et al., 2011).

Manifestations of acquired copper deficiency arealmost always neurologic and hematologic (Madsen andGitlin, 2007). Patients present with a spastic gait and prom-inent sensory ataxia related to amyelopathy, similar to sub-acute combined degeneration observed in vitamin B12

deficiency. Associated peripheral neuropathy is common.Spinal MRI typically shows a longitudinal high T2 signallesion in the dorsal cervical and thoracic cord. Cytopeniasare found in 78%of cases, particularly anemia. Low serumcopper and ceruloplasmin levels confirmed the diagnosisand, in contrast toWD, urinary copper levelswere typicallylow (Table 57.2). Copper supplementation resolves the ane-mia and neutropenia promptly and completely. But,improvement of neurologic deficits is slight and often sub-jective (Jaiser and Winston, 2010).

ACQUIRED COPPER TOXICOSIS

The first case of fatal copper intoxication was reported byPercival in 1785. Acute copper poisoning may occur acci-dentally or intentionally with suicidal objective, althoughthe lethal dose is about 1000 times normal dietary intakes(Bremner, 1998). It manifests by a metallic taste, vomit-ing, diarrhea, gastrointestinal bleeding, hemolysis, oli-guria, hematuria, seizures, coma, and death.

The low incidence of chronic copper toxicosis reflectsthe efficiency of the copper homeostatic control mecha-nisms. Nevertheless, copper poisoning can developunder certain conditions. Liver copper accumulationhas been observed in Indian childhood cirrhosis, non-Indian disease termed idiopathic copper toxicosis, andTyrolean childhood cirrhosis. D-penicillamine, if givenearly, reduces mortality. The excess copper found inthese childhood types of cirrhosis was believed to bedue to increased dietary intake of copper associated withan autosomal recessive inherited defect in copper

EAVY METALS 857

D

metabolism; this genetic disorder is as yet uncharacter-ized (Haywood et al., 2001).

858 F. WOIMANT AN

IRON DISORDERS

Iron is essential in multiple functions in CNS, includingDNA synthesis, gene expression, myelinization, neuro-transmission, and mitochondrial functions. Either brainaccumulation or depletion of intracellular iron may impairnormal function and promote cell death (Benarroch, 2009).

Iron brain disorders can be divided into:

● genetic neurodegeneration with brain iron

Fig.

accumulation

● genetic systemic iron accumulation with neurologic

features (hemochromatosis)

● acquired neurodegenerative disorders such as

Alzheimer disease and Parkinson disease

● acquired diseases associated with iron excess (super-

ficial siderosis) or iron deficiency (restless legsyndrome).

Iron metabolism

(Fig. 57.4)Dietary iron (Fe3þ) is first reduced to Fe2þ by duode-

nal cytochrome B (DcytB), a ferrireductase present onthe apical membranes of enterocytes. Fe2þ then entersthe enterocytes by divalent metal transporter-1 (DMT1)expressed on the apical membrane. Once inside, Fe2þ

can be stored as ferritin or can leave the enterocytethrough ferroportin (Fpn, Ireg1, MTP1), expressed onthe basolateral membrane. Prior to the transport of ironoutside the cell, intracellular iron must be converted toFe3þ via either hephaestin or ceruloplasmin, both ofwhich have ferroxidase activity (Mills et al., 2010).

Intracellular iron is regulated by the IRE (iron regula-tory element)–IRP (iron regulatory proteins) system. So,in case of elevation of intracellular iron, and particularly

57.4. Brain iron metabolism.

of the LIP (labile iron pool), the synthesis of ferritin isincreased (allowing the storage of the overload iron)and the expression of the receptor for transferrin(RTf1) reduced (limiting the entrance of iron to the cell).Hepcidin produced by hepatocytes is an importantregulator of cellular iron export by controlling the amountof ferroportin that is the primary determinant of gastro-intestinal absorption and iron release from reticuloendo-thelial stores. Ceruloplasmin is a major copper-containingprotein in the serum (Lutsenko et al., 2007). This a-2-glycoprotein is synthesized in the hepatic microsomes,as apoceruloplasmin. Loaded with six copper atoms permolecule, it is excreted into the circulation as holocerulo-plasmin. Its essential function is a ferroxidase activitywhich is necessary to release iron from storage.

The cellular and intercellular iron transportmechanisms in the CNS are still poorly understood.Blood–brain barrier limits iron entry to the brain fromthe blood, so disturbances of systemic iron homeostasisexhibit minimal effects on CNS iron content or metabo-lism (Moos and Morgan, 2004). Molecular mechanismsof iron transport seem similar to those described in theperipheral tissues; ferritine, DMT 1, ferroportine,hephaestine, and ceruloplasmin are all expressed in theCNS. Brain endothelial cells express the transferrin recep-tor 1 in their luminal membrane; this receptor bindsiron-loaded transferrin and internalizes this complex inendosomes. Then ceruloplasmin, which acts as a ferroxi-dase, oxidizes ferrous iron to ferric iron, which binds tothe transferrin in brain interstitial fluid (Benarroch, 2009).

Disorders

INHERITED NEURODEGENERATION WITH BRAIN

IRON ACCUMULATION

Inherited neurodegeneration with brain iron accumula-tion (NBIA) includes neurologic progressive disorderswith basal ganglia iron accumulation and axonal dystro-phy (spheroid bodies).

J.M. TROCELLO

Fig. 57.5. PKAN disease. T2-weighted brain MRI. Aspect of

the “eye of the tiger” sign (Grabli© 2010, Elsevier Masson

SAS).

DISORDERS OF HEAVY METALS 859

NBIA type 1: pantothenate kinase-associatedneurodegeneration

In 1922, Hallervorden and Spatz described theHallervorden–Spatz disease (HSD) (Hallervorden andSpatz, 1922). Since the discovery of the PANK2 gene,the eponymHSD is no longer used. Classic pantothenatekinase-associated neurodegeneration (PKAN) beginswith gait abnormalities, usually before 6 years of age.Dystonia, often asymmetric, is the major feature. Otherssymptoms include dysarthria, extrapyramidal syndrome,cognitive deterioration, or psychiatric disorder. Abouttwo-thirds of patients have clinical or electroretinographicevidence of retinopathy (Gregory et al., 2009). Deathoccurs about 30 years of age, related to decubitus compli-cations. Approximately 25% of affected individuals havean atypical presentation with later onset (teenage) andslower progression. Presenting features include speechdifficulties and extrapyramidal syndrome; psychiatric dis-orders are more prominent than in the classic form of thedisease, including depression, emotional lability andimpulsivity (Gregory et al., 2010). PKAN gene mutationshave also been described in the HARP syndrome (hypo-b-lipoproteinemia, acanthocyosis, retinitis pigmentosa andpallidal degeneration) (Ching et al., 2002). Iron tests arenormal. Classic and atypical PKAN patients show thesame brain MRI findings. In globus pallidus, the “eyeof the tiger” sign consists of bilateral areas of hyperinten-sity (corresponding to necrosis tissue) surrounded by aring of hyposignal (high iron) on T2*-weighted sequences(Fig. 57.5) (Angelini et al., 1992; Grabli et al., 2011).Hypointensity of the substantia nigria and dentate nucleusare also described.

PKAN is a recessive autosomal disease caused by amutation of the gene (20p13-p12.3) encoding panthote-nate kinase 2 (PANK2), an essential mitochondrialenzyme involved in coenzyme A biosynthesis (Zhouet al., 2001). Pantothenate kinase deficiency is thoughtto cause accumulation of N-pantothenoyl-cysteine andpantetheine, which may cause cell toxicity directly orvia free radical damage as chelators of iron (Yoonet al., 2000). PANK2 mutations (essentially missense)are present in all patients with the classic form of the dis-ease and in one-third of those with atypical disease andlate onset (Hayflick et al., 2003).

NBIA type 2: classic infantile neuroaxonal dys-trophy and atypical neuroaxonal dystrophy

Infantile neuroaxonal dystrophy (INAD), sometimescalled Seitelberger disease, was considered for a longtime as an early form of Hallervorden–Spatz disease.The classic form begins generally in early childhood,before the age of 2 years, mostly with a regression of

psychomotor acquisitions, delayed walking, or gait dis-turbance. Other presenting signs are cerebellar syn-drome with ataxia, pyramidal signs, and bulbardysfunction. Disease progression is rapid with axialhypotonia and severe spastic tetraparesis. Strabismus,nystagmus, and optic atrophy are common. Deathoccurs generally during the first decade, but somepatients can survive up to the age of 20 years (Aicardiand Castelein, 1979; Kurian et al., 2008). In the atypicalform of INAD (ANAD), the onset is often later and theevolution slower. Ataxia remains the main symptom(Kurian et al., 2008).

Denervation atrophy is seen on the electromyogram(Johnson et al., 2004). T2-weighted MRI demonstratescerebellar cortical atrophy, white matter abnormalities,and corpus callosum changes. T2*-weighted MRI canshow hypointense globus pallidus and substantia nigra(indicating iron accumulation). These abnormalitiesare more severe with increasing age (Kurian et al.,2008). Biological investigations do not indicate the pres-ence of a metabolic disorder.

Before the finding of the PLA2G6 gene, thediagnosis of INADwas established by tissue biopsy (suralnerve, skin, muscles, rectal). Indeed, unlike the neurode-generation associated with pantothenate-kinase deficit,typical dystrophic axons are not limited to the CNS.

D

INAD is inherited in an autosomal recessive mannerrelated to mutations in the PLA2G6 gene (22q13.1) encod-ing a calcium-independent phospholipase A2 group VIthat is thought to play a key role in cell membrane homeo-stasis. The sequencing of the gene allows detectingapproximately 85%of themutations. The less severe atyp-ical NAD phenotype is caused by compound heterozygos-ity for missense mutations (Gregory et al., 2008).

860 F. WOIMANT AN

Idiopathic neurodegeneration with brain ironaccumulation

In recent years, progress has been made in the discoveryof gene mutations and phenotypes. However, a largepopulation of idiopathic cases caused by undiscoveredgenes remains to be investigated.

Neuroferritinopathy

Neuroferritinopathy was described for the first time in2001 in a family from the north of England; it resultsfrom mutations in the ferritin light polypeptide gene(FTL) encoding the light chain of ferritin (Curtis et al.,2001). Clinical onset is around 40–50 years of age, withchorea, dystonia, and extrapyramidal syndrome. A cer-ebellar syndrome is sometimes associated (Ory-Magneet al., 2009). The evolution of the disease is slowly pro-gressive; themajority of patients develop a characteristicorofacial dystonia leading to dysarthrophonia,and thegait is generally lost more than 20 years after the firstsymptoms.

Serum ferritin concentrations are low (<20 mg/L) inthe majority of males and postmenopausal females butwithin normal limits for premenopausal females. Serumiron concentrations are usually normal (Chinnery et al.,2007). All affected individuals have evidence of excessbrain iron accumulation. In presymptomatic patients,T2* MRI demonstrates hyposignals of substantia nigraand red nuclei related to iron deposits. In symptomaticpatients, T2* hyposignals are described in caudate, glo-bus pallidus, putamen, thalami, and dentate nuclei. Cor-tical cerebellar atrophy is sometimes present. At a laterstage, cystic cavitation in the caudate and putamenappears on T2-weighted sequences as a hypersignal sur-rounded with a hypointense ring and on T1-weightedsequences as a hyposignal (Chinnery et al., 2007). Thisimage is very close to “the eye of tiger” described inPKAN.

Neuroferritinopathy is an autosomal dominant dis-ease. FTL, located on chromosome 19, is the only genecurrently known to be associated with neuroferritinopa-thy. FTLmutations are known to alter the structure of E-helices, thereby leading to the release of free iron andexcessive oxidative stress (Harrison and Arosio, 1996).

Iron depletion therapy by iron chelation in symptomaticpatients has not been shown to be beneficial.

Aceruloplasminemia

Miyajima et al. described in 1987 the first case of aceru-loplasminemia (Miyajima et al., 1987). Since then, about40 families have been reported. This disease is clinicallycharacterized by the triad of retinal degeneration, diabe-tes mellitus, and neurologic symptoms, including dysto-nia, chorea, blepharospasm, tremor, cerebellar ataxia,and cognitive deterioration (Miyajima, 2003). Anemiais often present, prior to onset of diabetes mellitus.The age at diagnosis ranged from 16 to 71 years with amean of 51. Prognosis depends on heart disease due tocardiac iron overload, control of diabetes, and severityof neurologic impairment. Treatment is based on ironchelators (deferiprone or deferasirox). Heterozygouspatients have a partial CP deficiency; some develop a lesssevere disease with cerebellar ataxia, tremor, or chorea-athetosis (McNeill et al., 2008a).

Diagnosis is based on the absence of serum cerulo-plasmin and low serum copper concentration, low serumiron concentration, high serum ferritin concentration, aswell as hepatic iron overload (Table 57.2). MRI findingsare abnormal T2* hyposignals reflecting iron accumula-tion in the brain (striatum, thalamus, dentate nucleus)and liver (McNeill et al., 2008b).

Genetic testing can confirm the diagnosis. Acerulo-plasminemia is a rare autosomal recessive disordercaused by mutations in the CP gene (3q23-q24). Theabsence of ceruloplasmin and its ferroxidase activityleads to pathologic iron overload in the brain and otherorgans (McNeill et al., 2008a).

GENETIC SYSTEMIC IRON ACCUMULATION WITH

NEUROLOGIC FEATURES

Hereditary hemochromatosis (HH) is an autosomalrecessive condition in which excessive intestinal ironabsorption leads to iron deposition in systemic tissues.The most common form, especially in populations ofNorthern European origin, is caused by mutations inHFE. Presenting features are chronic asthenia, arthrop-athies, impotence, hyperpigmentation, liver abnormali-ties (hepatomegaly, slight hypertransaminasemia),diabetes, cardiomyopathy, and hyperferritinemia. Neu-rologic manifestations are rarely described in HH.Tremor, myoclonus, cerebellar ataxia, cervical dystonia,or parkinsonism have occasionally reported. Brain MRIsuggests excessive iron in the basal ganglia of thesepatients. However, the CNS damage in hemochromatosisremains a subject for discussion and Russo suggests thatsuch patients should be thoroughly investigated foranother cause of neurologic disorders (Russo et al., 2004).

J.M. TROCELLO

HEAVY METALS 861

Restless legs syndrome (RLS) in patients with hemo-chromatosis occurred predominantly in patients withserum ferritin levels below 50 ng/mL. The emergenceof RLS symptoms was most likely when ferritin fellbelow 25 ng/mL and indicates that iron removal has beenexcessive in such patients. Nevertheless, RLS can occurin patients with iron overload, as prior to diagnosis andtreatment of HH (Shaughnessy et al., 2005). Polyneuro-pathy has also been reported (Hermann et al., 2002).

ACQUIRED NEURODEGENERATIVE DISORDERS SUCH AS

ALZHEIMER DISEASE AND PARKINSON DISEASE

Iron accumulates in the brain as a function of age, pri-marily in the form of ferritin, particularly in the micro-glia and astrocytes, but also in oligodendrocytes.Imbalance in iron homeostasis leading to either excessiveaccumulation of free cytosolic iron or decreased ironavailability for critical enzymes is suggested as a precur-sor to the neurodegenerative processes. Increased ironconcentrations are reported in the cortex and cerebellumfrom cases of preclinical Alzheimer disease (AD) andmild cognitive impairment (Smith et al., 2010). Ironmay have a direct impact on plaque formation throughits effects on amyloid precursor protein. Parkinson dis-ease (PD) is characterized by iron accumulation in dopa-minergic neurons of the substantia nigra (Benarroch,2009). This iron accumulation is probably not causalbut secondary to the disease process.

ACQUIRED DISEASES ASSOCIATED WITH IRON EXCESS

OR IRON DEFICIENCY

Superficial siderosis (SS) of the CNS is caused byrepeated slow hemorrhage into the subarachnoid spacewith resultant hemosiderin deposition in the subpiallayers of the brain and spinal cord. It is characterizedby deafness and cerebellar ataxia. Less frequently, itis also associated with bladder disturbance, anosmia,ocular palsies, anisocoria, dementia, or myelopathy.Gradient-echo T2-weighted MRI shows a rim of hypoin-tensity (due to hemosiderin deposition) around thecerebellum, brainstem, and spinal cord; it may alsoinvolve the cortical sulci, sylvian fissure, and interhemi-spheric fissure. Cerebrospinal fluid analysis may showxanthochromia and an increased number of red bloodcells (Kumar, 2007). The causes of SS include historyof trauma, aneurysms, or other vascular malformations,CNS tumors, and cerebral amyloid angiopathy (Vernooijet al., 2009). In most cases, however, despite extensiveinvestigations, the cause of bleeding remains undeter-mined. Therapy is treatment for of the cause of thebleeding when this is possible. In the absence of a curablecause, medical treatments are proposed (copper or ironchelators) but their effectivenes remains low.

DISORDERS OF

RESTLESS LEGS SYNDROME

All studies of CNS iron have consistently shown ironinsufficiency in restless legs syndrome (RLS) (Allenet al., 2001). Autopsy analysis revealed that the immu-nostaining for iron management proteins was alteredin the substantia nigra of RLS brains and the profileof proteins responsible for iron management in the neu-romelanin cells indicated iron deficiency (Connor et al.,2003). Iron supplementation improves the symptoms(Allen et al., 2001).

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