Letter to the Editor

Multiple Sclerosis, Porphyria-Like Symptoms, and aHistory of Iron Deficiency Anemia in a Family ofScottish Descent

To the Editor:

During the establishment of a molecular diagnosticservice for variegate porphyria (VP) [Warnich et al.,1996], one of the common founder-related diseases inSouth Africa [Dean, 1972], many subjects were previ-ously misdiagnosed due to clinical and biochemicalvariability of this disease [Kotze et al., 1998]. This find-ing prompted further investigation to define the fac-tor(s) underlying the condition in molecularly unchar-acterized families.

In a family of Scottish descent, a patient was diag-nosed with a porphyria-like disease and multiple scle-rosis (MS). Because the acute porphyrias may mimicMS [Macy et al., 1991], it is noteworthy that a historyof iron deficiency anemia coinciding with symptomssuggestive of porphyria was documented in this familyover many years. The purpose of this report is to docu-ment the condition of the index patient, together withthe family history of these symptoms, as a first steptoward the possible elucidation of the genetic and/orenvironmental factors underlying this familial associa-tion.

At age 30, this now 47-year-old woman developedrelapsing neurological symptoms, including visual loss,diplopia, weakness, incoordination, and sensory loss.In 1985 a diagnosis of MS was suggested on the basis ofhistory and cerebrospinal fluid (CSF) findings (oligo-clonal bands and increased IgG-index). However, find-ings of cranial magnetic resonance imaging (MRI) werenormal. She had a past history of intermittent iron-deficiency anemia. Neurological relapses were accom-panied by cramping abdominal pain, constipation, lightflashes in the peripheral vision, discolored urine, andsun-inducible skin rash (Table I), not attributable tomedication intake. Because these symptoms are sug-gestive of acute porphyria, the patient was re-

examined and numerous additional tests were per-formed in different laboratories. Results, while fre-quently abnormal, were not diagnostic of any knownporphyria or other putative mimic of MS. The highestporphyrin values were measured in urine during exac-erbations (Table II). The index patient was examinedin 1996 by J. A. C., who concluded that her neurologicalsymptoms and findings on examination, the initiallyrelapsing course evolving into a secondary progressivecourse, and the demonstration of intrathecal antibodysynthesis on CSF examination were diagnostic of MS.Cranial and cervical MRI findings, demonstrating mul-tifocal lesions characteristic of those of MS, and asym-metric bilateral slowing of conduction on visual evokedpotentials supported the diagnosis.

Family history showed that at least one individual ineach generation had some of the symptoms describedby the index case (Table I). The grandmother waswheelchair-dependent and was the earliest knownrelative with a sun-induced skin rash. The proposita’sfather, who died of heart failure at age 68, had experi-enced leg weakness and abdominal pain following sul-fonamide or alcohol intake. An aunt and cousin sharedarm weakness with the index case, recognized as anearly symptom of MS, which was diagnosed as “Cush-ing syndrome” in the aunt (who died at age 42 years,autopsy excluded this diagnosis) and remained undiag-

Contract grant sponsor: University of Stellenbosch; Contractgrant sponsor: Harry and Doris Crossley Foundation.

*Correspondence to: Maritha J. Kotze, Division of Human Ge-netics, Faculty of Medicine, University of Stellenbosch, P.O. Box19063, Tygerberg 7505, South Africa. E-mail: mjk@gerga.sun.ac.za

Received 23 December 1998; Accepted 30 April 1999

TABLE I. Symptoms in the Index Case

TypicalVisual loss with bilateral optic neuropathiesDiplopiaSpastic triparesisSensory lossNeurogenic bladderAppendicular/truncal/gait ataxia

AtypicalOverall pallor and local cyanosis (bluish nail beds)Sun-induced skin rash following exacerbationsDark, reddish urine during exacerbationsSevere to mild abdominal distress during exacerbationsConstipation or diarrhea during exacerbationsWeight loss during exacerbationsExacerbation and/or frequent vomiting during last trimester

of pregnancyAbnormally strong craving for saltTendency to low blood pressureBright flashes of light in the peripheral vision

American Journal of Medical Genetics 86:194–196 (1999)

© 1999 Wiley-Liss, Inc.

nosed in the cousin despite extensive investigations.The anemic 21-year old daughter of the proposita wasalso tested for porphyria (Table II) due to unexplainedabdominal distress and skin rash. Unaffected relativesincluded the son and sister of the index case, as well as2 aunts and their 7 children.

This family report highlights the similarities be-tween MS and some of the manifestations of acute por-phyria that are probably due to CNS dysfunction inboth conditions, although the acute porphyrias also af-fect the peripheral nervous system (PNS). Both dis-eases can lead to limb weakness and autopsy findings,although limited in the case of the acute porphyrias,demonstrate similar changes [Denny-Brown andSciarra, 1945; Goldberg and Remington, 1962]. No pub-lished data could be found on MRI findings in por-phyria patients of a similar age to the index case, ex-cept for the case report by Macy et al. [1991]. However,it remains uncertain whether the patient described bythese authors had MS or coproporphyria, because al-teration of the initial MS diagnosis (based on the pres-ence of three oligoclonal bands in the CSF and MRIfindings) to coproporphyria was challenged by Pierach[1993]. He argued that it is “far more plausible that thepatient suffered from a demyelinating disease such asMS, and at the same time excreted slightly increasedamounts of two porphyrins.” The MS patient of Scot-tish descent described in this study had no evidence ofPNS involvement, which may distinguish MS from theacute porphyrias and many of the other genetic dis-eases that masquerade as MS [Natowicz and Bejjani,1994].

A history of intermittent anemia and porphyrinuriain the family may be of significance, because iron defi-ciency (or an excess of iron) is likely to affect hemebiosynthesis and precipitate porphyria [Fargion et al.,1999; Grabczynska et al., 1996]. Iron is a cofactor ofheme proteins and a regulator of heme synthesis[Ponka, 1997]. Notably, the index case responded fa-vorably to a daily supplement of 65 mg iron, togetherwith a multivitamin tablet to enhance absorption. Shehas had no acute relapses or progression of pre-existingdeficits since 1995 while supplementing her diet withiron. A recent neurological examination and cranialMRI (March 1999) confirmed that her MS remainsstable (data not shown) in the absence of any othermedication. Since initiation of iron supplementation inaffected relatives, none of the aforementioned MS- andporphyria-like symptoms have reappeared.

In light of increasing evidence of a genetic predispo-

sition to MS among the Scottish [Rothwell and Charl-ton, 1998], we suspect that the apparently hereditarydisease phenotype described in the index family mayrepresent a “partially expressed” form of MS in undi-agnosed relatives exhibiting symptoms suggestive ofan acute porphyria. The fact that these symptoms arepresent in the absence of porphyrin levels raised suffi-ciently as to be characteristic of a specific type of por-phyria supports our view that the disease phenotyperesembling MS in the index case may be related to asecondary porphyria, possibly as a consequence of irondeficiency, and not to a defect in one of the genes en-coding an enzyme involved in heme biosynthesis. Al-though linkage studies have suggested that suscepti-bility to MS is largely determined by multiple loci [Belland Lathrop, 1996], this phenotype may represent amajor gene (possibly inherited in a dominant fashionwith incomplete penetrance) that accounts for a smallproportion of disease. Downey [1992] independentlyproposed that MS may be caused by a disturbance inheme biosynthesis, after appropriate environmentalexposure (e.g., virus infection or heavy metal intoxica-tion) of genetically susceptible individuals. A multidi-ciplinary approach is needed to investigate our hypoth-esis that the MS phenotype in a subgroup of patients[Kotze and Rooney, 1997; Reich et al., 1998] is relatedto iron deficiency during heme synthesis, causing CNSdamage and/or triggering an immune response. Futurestudies may lead to a clearer definition of diseasemechanisms, improved management of MS [Rudick etal., 1997] and ultimately, the development of noveltherapy to treat this major cause of neurologic disabil-ity.

ACKNOWLEDGMENTS

The authors thank Prof. H. Will and B. Reich forhelpful discussion and Dr. C Heesen, Department ofNeurology, University Hospital Eppendorf, Germanyfor critical reading of the manuscript.

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TABLE II. Representative Porphyria Test Results in the Index Case (1) and her Daughter (2)†

1 2 Reference values

24-hr Urine Porphyrin MeasuresUroporphyrins (MCG/TV) 251* 149* 10–50Coproporphyrins (MCG/TV) 609* 296* 60–280Uroporphyrins (MCG/24 hr) 17 12 #22Coproporphyrins (MCG/24 hr) 129* 120* #60Coproporphyrin 1 (MCG/24 hr) 46* ND 2–27Coproporphyrin 3 (MCG/24 hr) 93* ND 2–48

Enzyme activity in BloodUroporphyrinogen decarboxylase activity 116%* 109%* % of normal

†Asterisks denote elevated levels; ND, not determined.

Letter to the Editor 195

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Roberta N. RooneyMaritha J. Kotze*J. Nico P. de VilliersRenate HillermannDivision of Human GeneticsFaculty of MedicineUniversity of StellenboschTygerberg, South Africa

Jeffrey A. CohenMellen Center for MS Treatment and ResearchDepartment of NeurologyCleveland Clinic FoundationCleveland, Ohio

196 Rooney et al.