18ournal ofNeurology, Neurosurgery, and Psychiatry 1995;59:318-321

SHORT REPORT

Hereditary haemochromatosis: a case of ironaccumulation in the basal ganglia associated witha parkinsonian syndrome

J E Nielsen, L Neerup Jensen, K Krabbe

AbstractHereditary haemochromatosis is charac-terised by excessive parenchymal irondeposition, particularly in the liver.Usually hereditary haemochromatosis isnot associated with neurological symp-toms and iron deposition in the brain hasnot previously been described as a patho-logical phenomenon. A patient isreported with hereditary haemochro-matosis and a syndrome of dementia,dysarthria, a slowly progressive gait dis-turbance, imbalance, muscle weakness,rigidity, bradykinesia, tremor, ataxia,and dyssynergia. The findings on MRI ofa large signal decrease in the basal gan-glia, consistent with excessive iron accu-mulation, indicate a causal relation tothe symptoms. Although the neurologicalsymptoms did not improve in ourpatient, hereditary haemochromatosisshould be considered in the differentialdiagnosis of parkinsonian syndromes,because complications of iron inducedorgan injury may be prevented by phle-botomy.

percentage saturation of transferrin andserum ferritin concentration, increasedamounts of stainable iron in hepatocytes andan increased hepatic iron concentration. Mostpatients present with symptoms at the age of40-50, but some may present earlier, in thesecond or third decade. There is a sex differ-ence and the frequency of male to femalehaemochromatosis ranges from 2:1 to 18:1 .2Neurological features associated with heredi-tary haemochromatosis are rare. Lethargy,psychomotor retardation, fatigue, confusion,hearing loss, and polyneuropathy have beendescribed.3To the best of our knowledge, there have

been no reports of excessive iron depositionin the CNS in hereditary haemochromatosis,an otherwise well known pathological featureof the Hallervorden-Spatz syndrome andfamilial hypoceruloplasminaemia.We report on a patient with hereditary

haemochromatosis with a parkinsonian syn-drome, most likely caused by excessive ironaccumulation in the basal ganglia and cere-bellum.

University Clinic ofNeurology, HvidovreHospital, Copenhagenand Institute ofMedical Biochemistryand Genetics,Laboratory ofMedicalGenetics, Section ofNeurogenetics,University ofCopenhagen,DenmarkJ E NielsenDepartment ofPediatrics, Hiller0dHospital, DenmarkL Neerup JensenDanish ResearchCenter ofMagneticResonance, HvidovreHospital, DenmarkK KrabbeCorrespondence to:Dr J E Nielsen, Institute ofMedical Genetics, Sectionof Neurogenetics, ThePanum Institute, Building24.4, Blegdamsvej 3, DK-2200 Copenhagen N,Denmark.

Received 21 January 1995and in revised form8 May 1995Accepted 11 May 1995

(J Neurol Neurosurg Psychiatry 1995;59:318-321)

Keywords: hereditary haemochromatosis; basal gan-glia iron; parkinsonian syndrome

Hereditary (or genetic) haemochromatosis isan autosomal recessive inherited iron over-load disease, localised to chromosome 6p inproximity to the HLA-A3 locus. If theaccumulation of excess iron is due to otherconditions-for example, thalassaemia orsideroblastic anaemia-the term secondaryiron overload syndrome is used. The geneticdefect and the underlying metabolic error ofhereditary haemochromatosis are unknown.Cellular accumulation of iron is thought toinduce lipid peroxidation with the conse-

quence of cell damage and cell death.' Theclinical manifestations are the result of thespecific pattern of organs affected, and mostoften seen are weakness and weight loss,arthralgiae, abdominal pain, skin pigmenta-tion, hepatomegaly, hepatic cirrhosis, dia-betes mellitus, arthropathy, cardiacmanifestations, and hypogonadism. The mostcommon laboratory abnormalities are raised

Case reportThe patient, a 50 year old man with a normalpsychomotor development, without knownpredisposition of any kind and no family his-tory of hereditary haemochromatosis, hadbeen admitted to a neurology departmentwhen 29 years old, because of a slowly pro-gressive gait disturbance with episodes ofunsteadiness and imbalance since the age of26. He noticed muscular weakness, rigidity,and slowness of voluntary movement of theleft arm and leg. His gait was described asreeling with a deviation towards the left, drag-ging his left foot. Tendon reflexes were nor-mal, except for a very brisk right sided bicepsreflex. Otherwise the neurological examina-tion was normal. A pneumoencephalogramshowed slight central atrophy of the cere-brum. Cervical pneumomyelography was nor-mal, as were radiographs of the chest, spine,and skull. Blood tests, examination of CSF,and EEG were all reported to be within thenormal range. He was discharged without anydefinite diagnosis.

Subsequently he was referred for a special-ist opinion concerning his application for adisablement pension. For 18 years he had

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Hereditary haemochromatosis: a case of iron accumulation in the basal ganglia associated with a parkinsonian syndrome

Figure 1 Coronal (A)and transverse (B,C)MRI, (T2 weighted) of thebrain, performed at highfield strength of 1 5 Teslawith a double spin echotechnique. There is apronounced signal decreasein the caudate nucleus, theinner segment of the globuspallidus, the red nucleus,and substantia nigra,consistent with excessiveiron accumulation. Thedentate nucleus (notshown) was similar. Therewas no atrophy orfocalabnormality seen.

been working as an airport tractor driver.Four years ago he was transferred to an

administrative job because of difficulties inmotor function, a job he was now intellectu-ally incapable of maintaining. The symptomshad been slowly progressive over the years,

gradually also encompassing the right limbs,in such a way that using cutlery and dressinghad become difficult. He also complained offatigue, headache, a monotonous voice, andan impaired short-term memory. He had no

cardiac complaints or arthralgiae, and no

weight loss, abdominal pain, impotence, or

episodes of alcohol misuse.He was slightly impaired intellectually with

a poor memory. His speech was monotonous,slow, and slurred with dysarthria and dys-prosody, but with normal volume. His facewas expressionless and mask-like and heblinked infrequently. A difference in the

degree of pigmentation in the irides, the cen-tres being brownish and hyperpigmented, wasstriking, but no Kayser-Fleischer ring wasseen on slit lamp examination. Other cranialnerve functions were normal. Examination ofthe heart and the abdomen was normal, andthere was no testicular atrophy.A slight muscle atrophy was evident in the

lower limbs, mainly distally on the left side.Muscular strength was moderately impairedin the upper limbs and in the lower limbs onthe left in a pyramidal distribution. The mus-cular tone was increased in both upper andlower limbs in the form of rigidity, mainly onthe left side, where there was also a discretecogwheel phenomenon. Cutaneous sensation,joint position, and vibration senses were nor-mal. Tendon reflexes were easily obtained inthe upper limbs and were very brisk in thelower limbs, particularly on the left, withclonus at the ankle. The right plantar reflexwas normal, whereas a Babinski's reflex wasfound on the left. Coordination was influ-enced by ataxia and severe dysdiadochokine-sia. A combined static and postural tremorwas noted, as well as truncal instability, witha tilting to the left. The gait was characterisedby spasticity with circumduction of the leftleg, holding the left arm in an adducted,flexed position; the step length and pace wasnormal. No involuntary movements werenoted, but bradykinesia was seen. The skinwas bronzed. The patient started treatmentwith levodopa. This resulted in an immediateimprovement.Normal findings included an ECG, blood

cell counts, haemoglobin, erythrocyte sedi-mentation rate, serum concentrations of crea-tinine, carbamide, sodium, potassium,calcium, albumin, carbon dioxide, transami-nase, alkaline phosphatase, total bilrubin,IgA, IgG, IgM, urate, a negative serumantinuclear antibody titre, and iron, plasmaconcentrations of fasting glucose and cerulo-plasmin, and plasma prothrombin time.Urinary copper excretion was normal and thecopper content in the liver (5.2 mg/kg) wasalso within the normal range (5-15 mg/kg).Serum ferritin (1313 pmol/I (normal 33-666pmol/l) and transferrin saturation (53% (nor-mal <50%) were high. Serum transferrin (25umol/l (normal 31-57 ,umol/l)) was low. Aliver biopsy showed a heavy iron overload,but liver architecture was normal. Brain MRI(fig 1) showed a pronounced signal decreasein the caudate nucleus, the inner segment ofthe globus pallidus, the red nucleus, substan-tia nigra, and the dentate nucleus, consistentwith excessive iron accumulation. No atrophyor focal abnormalities were seen. Liver MRI(fig 2) showed a pronounced signal intensitydecrease, corresponding to a hepatic ironconcentration of 70 umol/g wet weight (nor-mal range 1-9 ,umol/g). HMA typing showedheterozygosity for the HLA system (HLA-A2,3,B7,44).

Phlebotomy was started. After eight treat-ments the fatigue, the headache, and the skinbronzing had disappeared. There were noother improvements.

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320Nielsen, _Jensen, Krabbe

Figure 2 T2 weightedMRI of the liver with spinecho and gradient echosequences, showed apronounced signal intensitydecrease. There are nofocal abnormalities and thespleen is normal.

DiscussionThe diagnosis of hereditary haemochromato-sis was based on the presence of biopticallyconfirmed excessive parenchymal iron accu-mulation without any indication of secondaryiron overload, the increased percentage satu-ration of transferrin, and the increased serumferritin concentration. In accordance with therecessive mode of inheritance, and maybe thesex difference also, his parents as well as histwo sisters and half-brother had no symptomsof hereditary haemochromatosis. The cur-rently applied definition of hereditaryhaemochromatosis also requires homozygos-ity for the haemochromatosis alleles.2 Ourpatient is heterozygous for the HLA-A and Bhaplotypes, but presumably homozygous forthe haemochromatosis allele, which, owing tofamily relations is not accessible for investiga-tion. The two most common HLA allelesassociated with hereditary haemochromatosisin Denmark are A3 and B7,4 alleles whichwere both found in our patient. HLA-A3occurred in about 75% of patients withhereditary haemochromatosis compared with28-30% in controls in Europe, the UnitedStates, and Australia.5 Usually those who areheterozygous for the haemochromatosis alleledo not present with clinical disease or developmassive body iron overload, but a proportionmay display biochemical abnormalities (mostcommonly increased transferrin saturation).6

Excessive metal accumulation in the CNSis known to cause neurological symptoms.Wilson's disease (hepatolenticular degenera-tion) is an autosomal recessive condition,located on chromosome 13q with abnormalcopper deposition in the brain (particularlythe basal ganglia), liver, cornea, and otherorgans. Usually the neurological onset is inadolescence, with symptoms such as clumsi-ness, personality change, reduced mental per-formance, tremor, rigidity, bradykinesia,dystonia, chorea, incoordination, ataxia,dysathria and, rarely, seizures.7 Almost alwaysa Kayser-Fleischer ring at the edge of thecornea is seen. Confirmation of the diagnosisby DNA analysis is possible. Biochemicallythe diagnosis is confirmed by a low plasmaceruloplasmin, a low serum copper, a highurinary copper excretion, and a high concen-tration of copper in the liver. Thus this condi-tion was ruled out in our patient.

Locally increased iron concentration in thebasal ganglia, not related to any abnormalityin the general iron metabolism, with axonalswellings and neuronal degeneration, ispathognomonic for the Hallervorden-Spatzsyndrome; characterised by onset in child-hood, progressive dementia, bradykinesia,rigidity, spasticity, dystonia, and involuntarymovements.8 The inheritance is recessive, anda genetic localisation is not established.Eidelberg et al reported on three adult onsetsingle cases, all mentally retarded women, inwhom symptoms started between 31 and 42years of age.9 Three sibs, with late age ofonset from early adolescence to 55 years ofage, with Hallervorden-Spatz disease present-ing as familial parkinsonism, were describedby Jankovic et al'0 A biochemical analysis ofthe brain of the oldest man affected showedconsiderable loss of dopamine in the nigro-striatal areas, a feature which may explain thebeneficial effect of levodopa seen in ourpatient.

Miyajima et al described a 52 year oldwoman with familial hypoceruloplasmin-aemia, blepharospasm, and retinal degenera-tion. This disorder is dominantly inherited,located on chromosome 3q, and caused byapoceruloplasmin deficiency, which isthought to be causally linked to the irondeposition in the basal ganglia and otherorgans, shown by kinetics, CT, and histo-chemical studies."

Parkinson-like syndromes have also beenreported after chronic manganese and thal-lium intoxication, but never in associationwith hereditary haemochromatosis. Dementia,ataxia, rigidity, and myoclonic jerks weredescribed in two patients with idiopathichaemochromatosis. 12 Both exhibited slightabnormalities of liver function. Patient 1 hadnormal brain CT. A postmortem micronodu-lar cirrhosis was found, but no specificchanges were noted on neuropathologicalinvestigation. A small amount of iron inastrocytes and in the basal ganglia was notthought to represent a pathognomonicchange. Patient 2 had a history of alcoholabuse. Cerebrum CT and postmortem exam-ination were not performed. The authorsconcluded that cirrhosis of the liver, althoughclinically occult, were the cause of the syn-drome of chronic hepatocerebral degenera-tion.

Furthermore, it has been proposed that aselective increase of iron in the substantianigra might be linked to the neurodegenera-tive aspects of Parkinson's disease, involvingiron and iron-melanin induced membranelipid peroxidation,'3 but this issue stillremains to be solved.

Brain MRI showed pronounced signaldecrease in the caudate nucleus, the innersegment of the globus pallidus, the rednucleus, substantia nigra, and the dentatenucleus. Several MR studies performed inextrapyramidal movement disorders includingParkinson's disease, multiple system atrophy,Huntingtons disease, and Hallervorden-Spatzdisease have shown a close correlation

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Hereditary haemochromatosis: a case of iron accumulation in the basal ganglia associated with a parkinsonian syndrome

between brain iron concentration and T2relaxation time within these regions.14 15A recent study by Chen et al on post-

mortem brain tissue from patients withParkinson's disease and Huntington's diseaseshowed a trend towards T2 shortening withincreasing iron concentration within both theputamen and the globus pallidus in Parkin-son's disease and within the globus pallidusin Huntington's disease. In Huntington's dis-ease the highest iron concentration and thelongest T2 values were in the putamen, and itwas concluded that signal intensity of thebasal ganglia on T2 weighted images may bedetermined by several factors; however, thefact that iron deposition causes a reduction inT2 relaxation was not disputed.'6

In the present patient extremely low signalintensity was found in the liver on gradientecho MRI consistent with the finding of biop-tically confirmed excessive iron accumulationin the liver. A strong correlation has previ-ously been shown between signal intensityand iron concentration in the liver.'7 Thisfinding and that of reduced signal intensitywithin the mentioned brain areas in ourpatient suggests that increased iron accumu-lation may take place in the brain of patientswith hereditary haemochromatosis.

In conclusion, it is therefore likely thatexcessive iron deposition in the basal gangliaand cerebellum, as shown on MRI, is causallylinked to the parkinsonian syndrome in ourpatient. Although he has presently notimproved neurologically on the phlebotomytreatment there is still a possibility that hemay do so, because serum ferritin is not yetwithin the normal range. Hereditaryhaemochromatosis is not usually consideredin the differential diagnosis of parkinsoniansyndromes, but because complications of ironinduced organ injury may be prevented byphlebotomy, we draw attention to hereditaryhaemochromatosis as a possible explanationwhen facing an otherwise "idiopathic"extrapyramidal syndrome.

We thank Dr Lennart Gram and Dr Sven Asger S0rensenwho critically reviewed the manuscript. We are grateful to DrMargrethe Herning who placed the MRI at our disposal.

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2 Edwards CQ. Hemochromatosis and other iron storagedisorders. In: Lee GR, Bithell TC, Foerster J, AthersJW, Lukens JN, eds. Wintrobe's Clinical hematology. 9thed. Philadelphia: Lea and Febiger 1993;872-84.

3 Milder MS, Cook JD, Stray S, Finch CA. Idiopathichemochromatosis, an interim report. Medicine 1980;59:34-49.

4 Milman N, Graudal N, Nielsen LS, Fenger K. An HLAstudy in 74 Danish haemochromatosis patients and 21of their families. Clin Genet 1992;41:6-1 1.

5 Simon M, Le Mignon L, Fauchet R, et al. A study of 609HLA haplotypes marking the hemochromatosis gene:(1) mapping of the gene near the HIA-A locus andcharacters required to define a heterozygous populationand (2) hypothesis concerning the underlying cause ofhemochromatosis-HLA association. Am J7 Hum Genet1987;41:89-105.

6 Edwards CQ, Dadone M, Skolnick MH, Kushner JP.Hereditary haemochromatosis. Clin Haematol 1982;11:411-35.

7 Scheinberg IH, Sternlieb I. Wilson's disease. In: SmithLH Jr, ed. Major problems in internal medicine. VolXXIII. Philadelphia: WB Saunders Co, 1984.

8 Hallervorden J, Spatz H. Eigenartige Erkrankung imextrapyramidalen System mit besonderer Beteiligungdes Globus pallidus und der Substantia nigra. Z NeurolPsychiat 1922;79:254-302.

9 Eidelberg D, Sotrel A, Joachim C, et al. Adult onsetHallervorden-Spatz disease with neurofibrillary pathol-ogy. A discrete clinicopathological entity. Brain 1987;110:993-1013.

10 Jankovic J, Kirkpatrick JB, Blomquist KA, Langlais PJ,Bird ED. Late-onset Hallervorden-Spatz disease pre-senting as familial parkinsonism. Neurology 1985;35:227-34.

11 Miyajima H, Nishimura Y, Mizoguchi K, Sakamoto M,Shimizu T, Honda N. Familial apoceruloplasmindeficiency associated with blepharospasm and retinaldegeneration. Neurology 1987;37:761-7.

12 Jones HR Jr, Hedley-Whyte ET. Idiopathic hemochro-matosis (IHC): dementia and ataxia as presenting signs.Neurology 1983;33:1479-83.

13 Youdim MBH, Ben-Shachar D, Riederer P. IsParkinson's disease a progressive siderosis of substantianigra resulting in iron and melanin induced neuro-degeneration? Acta Neurol Scand 1989;126:47-54.

14 Drayer BP. Magnetic resonance imaging and extrapyramidalmovement disorders. Eur Neurol 1989;29(suppl 1):9-12.

15 Savoiardo M, Halliday WC, Nardocci N, et al.Hallervorden-Spatz disease: MR and pathologic find-ings. AJNRAm Jf Neuroradiol 1993;14: 155-62.

16 Chen JC, Hardy PA, Kucharczyk W, et al. MR of humanpostmortem brain tissue: correlative study between T2and assays of iron and ferritin in Parkinson's andHuntington's disease. AJNR Am J Neuroradiol 1993;14:275-81.

17 Thomsen C, Wiggers P, Ring-Larsen H, et al.Identification of patients with hereditary haemochro-matosis by magnetic resonance imaging and spectro-scopic relaxation time measurements. Magn ResonImaging 1992;10:867-79.

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