American Journal of Medical Genetics 86:194–196 (1999)
Letter to the Editor
Multiple Sclerosis, Porphyria-Like Symptoms, and a
History of Iron Deficiency Anemia in a Family of
Scottish Descent
To the Editor:
During the establishment of a molecular diagnostic
service for variegate porphyria (VP) [Warnich et al.,
1996], one of the common founder-related diseases in
South Africa [Dean, 1972], many subjects were previ-
ously misdiagnosed due to clinical and biochemical
variability 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 mimic
MS [Macy et al., 1991], it is noteworthy that a history
of iron deficiency anemia coinciding with symptoms
suggestive of porphyria was documented in this family
over many years. The purpose of this report is to docu-
ment the condition of the index patient, together with
the family history of these symptoms, as a first step
toward the possible elucidation of the genetic and/or
environmental factors underlying this familial associa-
tion.
At age 30, this now 47-year-old woman developed
relapsing neurological symptoms, including visual loss,
diplopia, weakness, incoordination, and sensory loss.
In 1985 a diagnosis of MS was suggested on the basis of
history and cerebrospinal fluid (CSF) findings (oligo-
clonal bands and increased IgG-index). However, find-
ings of cranial magnetic resonance imaging (MRI) were
normal. She had a past history of intermittent iron-
deficiency anemia. Neurological relapses were accom-
panied by cramping abdominal pain, constipation, light
flashes in the peripheral vision, discolored urine, and
sun-inducible skin rash (Table I), not attributable to
medication intake. Because these symptoms are sug-
gestive of acute porphyria, the patient was re-
Contract grant sponsor: University of Stellenbosch; Contract
grant sponsor: Harry and Doris Crossley Foundation.
*Correspondence to: Maritha J. Kotze, Division of Human Ge-
netics, Faculty of Medicine, University of Stellenbosch, P.O. Box
19063, Tygerberg 7505, South Africa. E-mail: mjk@gerga.sun.
ac.za
Received 23 December 1998; Accepted 30 April 1999
© 1999 Wiley-Liss, Inc.
examined and numerous additional tests were per-
formed in different laboratories. Results, while fre-
quently abnormal, were not diagnostic of any known
porphyria or other putative mimic of MS. The highest
porphyrin values were measured in urine during exac-
erbations (Table II). The index patient was examined
in 1996 by J. A. C., who concluded that her neurological
symptoms and findings on examination, the initially
relapsing course evolving into a secondary progressive
course, and the demonstration of intrathecal antibody
synthesis 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 evoked
potentials supported the diagnosis.
Family history showed that at least one individual in
each generation had some of the symptoms described
by the index case (Table I). The grandmother was
wheelchair-dependent and was the earliest known
relative with a sun-induced skin rash. The proposita’s
father, 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 shared
arm weakness with the index case, recognized as an
early 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-
TABLE I. Symptoms in the Index Case
Typical
Visual loss with bilateral optic neuropathies
Diplopia
Spastic triparesis
Sensory loss
Neurogenic bladder
Appendicular/truncal/gait ataxia
Atypical
Overall pallor and local cyanosis (bluish nail beds)
Sun-induced skin rash following exacerbations
Dark, reddish urine during exacerbations
Severe to mild abdominal distress during exacerbations
Constipation or diarrhea during exacerbations
Weight loss during exacerbations
Exacerbation and/or frequent vomiting during last trimester
of pregnancy
Abnormally strong craving for salt
Tendency to low blood pressure
Bright flashes of light in the peripheral vision

TABLE II. Representative Porphyria Test Results in the Index Case (1) and her Daughter (2)†
24-hr Urine Porphyrin Measures
Uroporphyrins (MCG/TV)
Coproporphyrins (MCG/TV)
Uroporphyrins (MCG/24 hr)
Coproporphyrins (MCG/24 hr)
Coproporphyrin 1 (MCG/24 hr)
Coproporphyrin 3 (MCG/24 hr)
Enzyme activity in Blood
Uroporphyrinogen decarboxylase activity
†
Asterisks denote elevated levels; ND, not determined.
nosed in the cousin despite extensive investigations.
The anemic 21-year old daughter of the proposita was
also tested for porphyria (Table II) due to unexplained
abdominal distress and skin rash. Unaffected relatives
included the son and sister of the index case, as well as
2 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 in
both 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 and
Sciarra, 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 by
these 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 MRI
findings) to coproporphyria was challenged by Pierach
[1993]. He argued that it is “far more plausible that the
patient suffered from a demyelinating disease such as
MS, and at the same time excreted slightly increased
amounts of two porphyrins.” The MS patient of Scot-
tish descent described in this study had no evidence of
PNS involvement, which may distinguish MS from the
acute porphyrias and many of the other genetic dis-
eases that masquerade as MS [Natowicz and Bejjani,
1994].
A history of intermittent anemia and porphyrinuria
in the family may be of significance, because iron defi-
ciency (or an excess of iron) is likely to affect heme
biosynthesis and precipitate porphyria [Fargion et al.,
1999; Grabczynska et al., 1996]. Iron is a cofactor of
heme proteins and a regulator of heme synthesis
[Ponka, 1997]. Notably, the index case responded fa-
vorably to a daily supplement of 65 mg iron, together
with a multivitamin tablet to enhance absorption. She
has had no acute relapses or progression of pre-existing
deficits since 1995 while supplementing her diet with
iron. A recent neurological examination and cranial
MRI (March 1999) confirmed that her MS remains
stable (data not shown) in the absence of any other
medication. Since initiation of iron supplementation in
affected relatives, none of the aforementioned MS- and
porphyria-like symptoms have reappeared.
In light of increasing evidence of a genetic predispo-
Letter to the Editor 195
1 2 Reference values
251* 149* 10–50
609* 296* 60–280
17 12 ⱕ22
129* 120* ⱕ60
46* ND 2–27
93* ND 2–48
116%* 109%* % of normal
sition to MS among the Scottish [Rothwell and Charl-
ton, 1998], we suspect that the apparently hereditary
disease phenotype described in the index family may
represent a “partially expressed” form of MS in undi-
agnosed relatives exhibiting symptoms suggestive of
an acute porphyria. The fact that these symptoms are
present 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 phenotype
resembling MS in the index case may be related to a
secondary porphyria, possibly as a consequence of iron
deficiency, 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 [Bell
and Lathrop, 1996], this phenotype may represent a
major gene (possibly inherited in a dominant fashion
with incomplete penetrance) that accounts for a small
proportion of disease. Downey [1992] independently
proposed that MS may be caused by a disturbance in
heme biosynthesis, after appropriate environmental
exposure (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 related
to iron deficiency during heme synthesis, causing CNS
damage and/or triggering an immune response. Future
studies may lead to a clearer definition of disease
mechanisms, improved management of MS [Rudick et
al., 1997] and ultimately, the development of novel
therapy to treat this major cause of neurologic disabil-
ity.
ACKNOWLEDGMENTS
The authors thank Prof. H. Will and B. Reich for
helpful discussion and Dr. C Heesen, Department of
Neurology, University Hospital Eppendorf, Germany
for critical reading of the manuscript.
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