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Headache as a presenting symptom in hereditary.

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We express our gratitude to the family for their participation in the
study. We also thank D. Rochefort for technical assistance and
Dr A. Toulouse for carefully reading the manuscript.
1
McGill University Health Centre Research Institute and
Centre for Research in Neuroscience, Montreal, Quebec;
2
Hospital for Sick Children and University of Toronto,
Toronto, ON; 3Neurogenetics Unit, Montreal Neurological
Hospital and Institute, McGill University, Montreal, Quebec;
4
Centre for Molecular Medicine and Therapeutics, Vancouver,
British Columbia; and Departments of 5Neurology and
Neurosurgery, 6Pediatrics, and 7Human Genetics, McGill
University, Montreal, Quebec, Canada
References
1. Hadano S, Hand CK, Osuga H, et al. A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2. Nat Genet 2001;29:166 –173.
2. Yang Y, Hentati A, Deng HX, et al. The gene encoding alsin,
a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral
sclerosis. Nat Genet 2001;29:160 –165.
3. Eymard-Pierre E, Lesca G, Dollet S, et al. Infantile-onset ascending hereditary spastic paralysis is associated with mutations
in the alsin gene. Am J Hum Genet 2002;71:518 –527.
4. Fontaine B, Davoine CS, Durr A, et al. A new locus for autosomal dominant pure spastic paraplegia, on chromosome
2q24 –q34. Am J Hum Genet 2000;66:702–707.
5. Esters H, Alexandrov K, Iakovenko A, et al. Vps9, Rabex-5 and
DSS4: proteins with weak but distinct nucleotide-exchange activities for Rab proteins. J Mol Biol 2001;310:141–156.
DOI: 10.1002/ana.10422
Headache as a Presenting Symptom in Hereditary
Anne McCune, Bsc (Hons), MBBS, MRCP and
Mark Worwood, PhD, FRCPath, FMed Sci
We read with interest the recent article by Hagen and colleagues.1 In this large population-based study from Norway,
51,282 (55%) unselected subjects completed a headache
questionnaire and were screened for hereditary hemochromatosis (HH). Women with phenotypic (increased fasting
transferrin saturation and serum ferritin) HH (n ⫽ 74) were
almost twice as likely to report migrainous and/or nonmigrainous headache as those women with normal iron studies
(odds ratio, 1.8; confidence interval 1.1–2.9).
We, like the authors, have recognized that unexplained
headaches can be a feature of HH. In a systematic review2 of
all patients treated with HH in two health authorities in
South Wales (population 1.3 million), we discovered 81 individuals with iron overload attributed to HH. Thirty-seven
(26 men, 11 women) presented clinically (excluding 7 with
porphyria cutanea tarda). Two of these women (18.2%) had
headache as the only presenting symptom. The first, C282Y
homozygous, presented at the age of 28 years with typical
migrainous headaches (frontal, throbbing pains with nausea
and mild photophobia) lasting up to 24 hours. She had no
other recognized symptom or sign of HH. Her iron indices
confirmed iron overload (transferrin saturation [ST], 89%;
ferritin, 263 ␮g/L). The second woman (aged 66 years) reported frequent headaches but no other features of HH. Her
ferritin level was 1,087 ␮g/L and liver biopsy confirmed tissue iron overload. She unfortunately has been lost to followup.
Hagen and colleagues suggest that the association between
hemochromatosis and headache may be a causal one, suggesting that iron in some way may alter neuronal excitability.
However, no relationship between iron load and headache
prevalence was found. If neuronal iron is responsible for
causing headache, it is disappointing that our first patient
did not improve after venesection therapy. Hagen and colleagues also found an association between C282Y homozygosity and headache, and, in women who had phenotypic
HH and C282Y homozygosity (n ⫽ 64), an even stronger
association with headache was found (odds ratio, 2.3; confidence interval 1.3–3.8). However, only women with increased iron indices were genotyped, and thus the association
in any nonexpressing homozygotes remains unknown. HH
screening studies have found that 40 to 81% of C282Y homozygotes have a normal ferritin level.3 Symptoms correlate
poorly with the presence of iron overload in HH, and morbidity in screening-detected HH does not differ from that in
controls.4 However, once diagnosed, HH is readily treatable,
and, provided complications have not arisen, life expectancy
is not reduced.5 Continued effort should be made to educate
all physicians in an attempt to increase awareness of HH and
lead to earlier diagnosis. Our experience, like Hagen and colleagues, suggests that headache can be the presenting symptom of HH.
Department of Haematology, University of Wales College of
Medicine, Cardiff, United Kingdom
References
1. Hagen K, Stovner LJ, Asberg A, et al. High headache prevalence
among women with hemochromatosis: the Nord-Trøndelag
Health Study. Ann Neurol 2002;51:786 –789.
2. McCune CA, Al-Jader LN, May A, et al. Only 1% of adults
homozygous for the C282Y mutation of the HFE gene have a
clinical diagnosis of iron overload: evidence from the South
Wales haemochromatosis study. Gastroenterology 2002;122:
M1471.
3. Adams PC. Non-expressing homozygotes for C282Y
hemochromatosis: minority or majority of cases? Mol Genet Metabolism 2000;71:81– 86.
4. Asberg A, Hveem K, Kruger Ø, Bjerve KS. Persons with
screening-detected haemochromatosis: as healthy as the general
population? Scand J Gastroenterol 2002;6:719 –724.
5. Niederau C, Fischer R, Purschel A, et al. Long-term survival in
patients with hereditary hemochromatosis. Gastroenterology
1996;110:1107–1119.
DOI: 10.1002/ana.10428
Reply
Knut Hagen, MD, PhD,1 Lars Jacob Stovner, MD, PhD,1
Arne Åsberg, MD,2 Ketil Thorstensen, PhD,2
Kristian S. Bjerve, MD, PhD,2
and Kristian Hveem, MD, PhD3
We thank McCune and Worwood for the relevant criticism
of our article and the interesting clinical observations. In our
population-based study, we found a high prevalence of head-
Annals of Neurology
Vol 53
No 1
January 2003
145
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