33 Disorders of Copper, Zinc, and Iron Metabolism
Eve A. Roberts
33.1 Introduction
Metabolic diseases associated with abnormal disposition of metals are generally rare, with the exception of hereditary hemochromatosis (HFE1) in northern European populations. They are highly disparate disorders.
I 33.1 Wilson disease
Wilson disease (hepatolenticular degeneration) is an autosomal recessive dis- order of copper disposition in the liver and certain other organs, notably the brain, kidneys, mammary glands, and placenta. It is associated with copper overload in the liver and secondary accumulation of copper in certain parts of the brain, cornea (Kaiser-Fleischer ring), and in the kidneys, heart, and synovia.
Wilson disease can present as liver disease, progressive neurological disease, or psychiatric illness (Roberts and Schilsky 2003). The hepatic presentation usually occurs at younger ages. Wilson disease is fatal if not treated, but with ef- fective treatment, especially if commenced early (ideally in the presymptomatic stage), the outlook for a normal healthy life is excellent. If a specific treatment must be discontinued because of adverse side-effects, alternate treatment must be substituted. Treatment should be continued through pregnancy. Dietary management by itself is inadequate, but foods containing very high concen- trations of copper (shellfish, nuts, chocolate, mushrooms, and organ meats) should be avoided, especially in the 1st year of treatment. Liver transplantation is indicated for patients unresponsive to medical treatment and for those with fulminant hepatic failure.
I 33.2 Menkes disease
Menkes disease is a rare (1:250,000) complex disorder of copper disposition leading to systemic copper insufficiency. The major features of Menkes disease involve neurodegeneration, vascular (usually arterial) abnormalities, and ab- normal hair structure (pili torti: occasioning the disease’s alternative name of
“kinky hair” syndrome). Detailed examination of the hair shaft reveals typical changes. Treatment with copper supplementation provided as subcutaneous in-
jections of copper-histidine (Sarkar et al. 1993; Christodoulou et al. 1998) must be started before 3 weeks of age if severe neurological disease is to be avoided.
Preemptive treatment of male sibs subsequent to the proband in a family may produce the best clinical outcome. Life expectancy in Menkes disease is reduced, usually to less than 10 years.
A mild variant of Menkes disease has been reported with later onset of symptoms and relative sparing of the central nervous system. Although these children may have the same facies, typical skin and hair abnormalities, their neurological disease is often limited to ataxia and dysarthria. The biological basis for this milder form of Menkes disease is not known.
I 33.3 Occipital Horn syndrome
This is a mild allelic form of Menkes disease, whose phenotypic mechanism is unknown.
I 33.4 Acrodermatitis enteropathica
This rare autosomal recessive disorder presents clinically with a constellation of findings: typical rash involving the perineum and perianal region, hands, and feet; diarrhea, alopecia, and visual disorders (photophobia). Poor growth and recurrent infections, associated with immunodeficiency, may occur. Most patients do not have all the possible clinical features. The disorder typically becomes evident at the time of weaning. The diagnosis is usually confirmed by finding very low concentrations of serum zinc; urinary zinc excretion is also very low. Classic acrodermatitis enteropathica is due to mutations in the ZIP4 gene implicated in zinc uptake (Dufner-Beattie et al. 2003). Treatment is with zinc replacement and is life-long and may need to be increased in times of increased growth demands, such as during adolescence or pregnancy.
A skin disorder resembling acrodermatitis enteropathica has been associ- ated with the urea cycle defect involving ornithine transcarbamylase (Lee et al.
2002).
I 33.5 Congenital cholestasis with hepatic zinc accumulation
An infantile cholestatic liver disease with hepatic zinc accumulation has been described in North American Indians mainly from Ontario, Canada, most of whom belonged to a single extended kindred. Two unrelated North American Indian children appeared to have extrahepatic biliary atresia clinically and at laparotomy (Phillips et al. 1996). The pathogenesis of this zinc-overload liver disease is not known. Treatment is general management of chronic cholestatic liver disease and orthotopic liver transplantation if indicated.
Introduction 355
I 33.6 Hemochromatosis
The term “hemochromatosis” refers to iron accumulation in parenchmyal cells of the liver and other tissues. Approximately 90% of primary hemochromatosis is due to mutations in the HFE gene. Other types of primary hemochromatosis are rare. Secondary hemochromatosis is usually related to congenital hemolytic anemia requiring chronic transfusion or to dietary excess in a genetically sus- ceptible individual (Bantu siderosis).
G 33.6.1 Hereditary hemochromatosis, classic form
Classic hereditary hemochromatosis with abnormal iron uptake from the in- testinal tract is due to mutations in the gene HFE on chromosome 6 near the HLA-A region (Feder et al. 1996). Classic hereditary hemochromatosis usually becomes symptomatic in men at 40–50 years of age, somewhat later in women.
Arthropathy, cardiac disease, and pituitary dysfunction (with loss of libido) are important early extrahepatic manifestations; skin pigmentation and diabetes mellitus tend to be later features. Liver disease is common and may lead to cir- rhosis and hepatocellular carcinoma. Early diagnosis (based on elevated fasting transferrin saturation and serum ferritin, abnormal serum aminotransferases, and positive genetic testing) permits reduction of total body iron load by phle- botomy (Tavill 2001). Treatment is indicated even if cirrhosis has developed, and symptoms relating to extrahepatic disease may improve on treatment. Vitamin C supplements should be avoided.
G 33.6.2 Juvenile hemochromatosis
This iron-accumulation disease usually becomes symptomatic in adolescence (Camaschella et al. 2002). Although the liver is involved as in classic heredi- tary hemochromatosis, affected individuals usually have severe cardiac disease which dominates the clinical presentation. Arthropathy and hypogonadism may also be present. The typical biochemical profile includes extremely high serum ferritin and transferrin saturation. The genetic basis HFE2 is on chro- mosome 1q21 (Papnikolaou et al. 2004). Its gene product, hemojuvelin, may affect hepcidin expression. A clinically indistinguishable disease has recently been described in two kindred with mutations in hepcidin, a protein that plays a role in regulating intestinal iron absorption (Roetto et al. 2002). Treatment with phlebotomy is indicated.
G 33.6.3 TFR2 deficiency
This rare form of hemochromatosis is due to mutations in the transferrin receptor-2 gene (on 7q22). Clinical features are similar to those found with mutations in HFE (Roetto et al. 2002).
G 33.6.4 Ferroportin deficiency
This is an important cause of hereditary hemochromatosis not related to the HFE locus. The disorder is inherited in an autosomal dominant pattern (Mon- tosi et al. 2001; Njajou et al. 2001). Patients present with anemia, diabetes, and arthritis. The serum ferritin is elevated but transferrin saturation is normal. Di- agnosis depends on genetic sequencing. Treatment is by phlebotomy is difficult because of anemia.
G 33.6.5 Perinatal hemochromatosis
Perinatal hemochromatosis (also known as neonatal hemochromatosis or neona- tal iron-storage disorder) comprises a group of disorders with similar clinical appearance: neonatal liver failure accompanied by iron overload in the liver, pancreas, heart, and other organs except the reticuloendothelial system (Gold- fischer et al. 1981; Knisely et al. 2003). The extent of organ damage indicates prenatal injury. The disease mechanism is not known. In some cases congenital infection with parvovirus B19 may be the etiology; nevertheless, when possi- ble etiologies have been excluded, a group of cases remains with an apparent genetic, or at least familial, basis. Mutations in HFE are not implicated.
Most affected infants present shortly after birth, although a few have been diagnosed later in the neonatal period (Kelly et al. 2001), with classic chronic- pattern neonatal liver failure. The liver and certain other organs (pancreas, kidneys, adrenal glands, and heart – not the reticuloendothelial system) show marked iron accumulation. Histologically apparent iron deposition in salivary glands on buccal biopsy or evidence of iron overload by magnetic resonance imaging of the liver and pancreas supports the diagnosis.
Supportive treatment in a neonatal intensive care unit is essential; liver trans- plantation is usually required. A multiple-drug regimen, called the “antioxidant cocktail” (Shamieh et al. 1993), has been used extensively with some success.
Not all infants respond to this regimen (Sigurdsson et al. 1998), but early in- stitution of treatment may favor success. Monitoring subsequent pregnancies closely appears critically important. Surviving infants appear to stabilize clin- ically; they may develop cirrhosis or have no residual liver disease. Incidental hepatocellular carcinoma has been reported in three infants. Recurrent iron accumulation in the liver graft occurred in one infant after transplantation.
G 33.6.6 Perinatal hemochromatosis with renal tubular dysgenesis
This condition is not necessarily a separate disorder from perinatal hemochro- matosis. In addition to neonatal liver failure with characteristics of perinatal hemochromatosis, proximal convoluted tubules are abnormal (Bale et al. 1994).
The prognosis is even more guarded than for perinatal hemochromatosis.
Introduction 357
G 33.6.7 Trichohepatic-enteric syndrome
This constellation of hair abnormalities, hepatic dysfunction with iron overload, and intractable diarrhea has been reported in one or two families (Verloes et al.
1997). This syndrome may be related to perinatal hemochromatosis, but its basis has not been determined.
G 33.6.8 GRACILE syndrome (Fellman syndrome)
GRACILE syndrome was first reported in Finnish kindreds but has since been identified in Turkish and British patients. The classic clinical features include growth retardation, cholestatic liver disease, hepatic iron overload, severe lactic acidosis, and early death (Fellman et al. 1998). This rare disorder is due to mutations in the BCS1L gene, which encodes a protein in the mitochondrial inner membrane essential for assembly of complex III in the mitochondrial respiratory chain (Visapaa et al. 2002). Treatments used thus far have proven ineffective.
I 33.7 Aceruloplasminemia
Defective ceruloplasmin production is inherited as an autosomal recessive dis- order; the ceruloplasmin gene is on 3q25. Ceruloplasmin is a ferroxidase; in its absence copper disposition remains normal, but iron accumulation occurs in the liver and in other organs. Patients with aceruloplasminemia develop ane- mia, retinal degeneration, diabetes mellitus, and neurodegeneration involving the cortex and basal ganglia, manifested as ataxia (most common), involun- tary movement disorders, parkinsonism, and dementia (Miyajima et al. 2003).
Symptoms typically begin in the third and fourth decades. Treatment of the iron overload is difficult, in part because ceruloplasmin is involved in the mecha- nism by which iron exits tissues, and aceruloplasminemia may be refractory to chelating agents such as desferroxamine.
33.2 Nomenclature
Disease Defect Gene OMIM No.
33.1 Wilson disease (hepatolenticular degeneration)
Hepatic Cu overload; defective synthesis of holoceruloplasmin and inefficient biliary excretion of Cu
ATP7B 277900
33.2 Menkes disease Systemic Cu deficiency; defective intestinal up- take of Cu; decreased synthesis of Cu-containing enzymes
ATP7A 309400
1. “Classic” form –
2. “Mild” form (atypical) –
33.3 Occipital Horn syndrome Defective extrahepatic Cu disposition as for Menkes disease
ATP7A 304150 33.4 Acrodermatitis
enteropathica
Systemic Zn deficiency due to abnormal intestinal absorption of Zn
ZIP4 201100
33.5 Congenital
cholestasis with hepatic zinc accumulation
Unknown – –
33.6 Hemochromatosis 33.6.1 1. Classic form,
HFE-deficient (HFE1)
Systemic Fe overload due to excess intestinal absorption of Fe
HFE 235200
33.6.2 2. Juvenile form (HFE2) Systemic Fe overload, mechanism uncertain HFE2 602390 33.6.3 Transferrin receptor-2
deficiency (HFE3)
Systemic Fe overload due to transferrin receptor dysfunction
TFR2 604250
33.6.4 Ferroportin deficiency (HFE4)
Systemic Fe overload with defective cellular export
SLC11A3 606069 33.6.5 Perinatal
hemochromatosis
Hepatic/extrahepatic Fe overload sparing reticu- loendothelial system, mechanism unknown
– –
33.6.6 Perinatal hemochromato- sis with renal tubular dys- genesis
Unknown – –
33.6.7 Trichohepato-enteric syndrome
Unknown – 222470
33.6.8 GRACILE syndrome Hepatic Fe overload with mitochondrial dysfunction
BSC1L 603358 33.7 Aceruloplasminemia Greatly decreased production of ceruloplasmin Cp 604290
Treatment 359 33.3 Treatment
33.1 Wilson disease d-Penicillamine: 1000–1500 mg per day in two or three divided doses initially, with 750 or 1000 mg used for maintenance therapy. Tolerability may be en- hanced by beginning with incremental doses, 250–500 mg per day, increased by 250 mg increments every 4–7 days to a maximum of 1000–1500 mg per day in 2–4 divided dosages. Dosing in children is 20 mg/kg per day rounded off to the nearest 250 mg and given in two or three divided doses. Food inter- feres with efficacy.aNeurological disease may deteriorate, usually transiently, when treatment is commenced. Adverse effects occur in 20–30% of patients necessitating discontinuing penicillamine and substituting trientine or zinc:
early sensitivity reaction with fever/rash/proteinuria; leukopenia, thrombo- cytopenia, aplastic anemia; late nephrotoxicity with proteinuria; lupus-like syndrome; various dermatological abnormalities (Roberts and Schilsky 2003) Trientine: 750–1500 mg per day in two or three divided doses initially, with 750 or 1000 mg used for maintenance therapy. Dosing in children is 20 mg/kg per
day rounded off to the nearest 250 mg and given in two or three divided doses.
Food interferes with efficacy.aNeurological disease occasionally deteriorates transiently when treatment is commenced. Adverse reactions are rare: anemia, extremely rare aplastic anemia, gastritis, loss of taste, rashes.
Zinc salts (sulphate; gluconate; acetate) to provide 50 mg elemental Zn tid.
Children’s dose is 25 mg elemental Zn tid. Minimal dosing frequency is bid.
Food interferes with efficacy.aAdverse reactions are uncommon, mainly gas- tritis with nausea.
33.2 Menkes disease
1. “Classic” form Copper-histidine subcutaneous injection: 50–150µg/kg per day. Typical dosage is 100µg/kg per day in newborns and 1 mg/day in older children.
2. “Mild” form (atypical) Copper-histidine subcutaneous injection as above 33.3 Occipital Horn syndrome Copper-histidine subcutaneous injection as above 33.4 Acrodermatitis
enteropathica
Zinc salts (sulphate; gluconate; acetate) to provide initially 5–10 mg elemental Zn/kg per day. Response is usually rapid, with improvement in skin lesions beginning within 24–48 h of starting treatment. Complete resolution and restoration of normal hair growth may take 2–4 weeks. Thereafter mainte- nance does is 1–2 mg elemental Zn/kg per day by mouth.
33.5 Congenital cholestasis with hepatic zinc accumulation
Standard treatment for chronic cholestatic liver disease, then orthotopic liver transplantation if indicated
33.6 Hemochromatosis 33.6.1 1. Classic form,
HFE-deficient (HFE1)
Phlebotomy to remove 500 mL of blood weekly or biweekly until serum ferritin
< 50µg/l, then decrease frequency to once every 2–4 months to maintain serum ferritin in 25–50µg/l range
33.6.2 2. Juvenile form (HFE2) Same as for HFE1 33.6.3 Transferrin receptor-2
deficiency (HFE3)
Same as for HFE1 33.6.4 Ferroportin deficiency
(HFE4)
Phlebotomy as for HFE1 except that interval should be extended to every 3–4 weeks or as tolerated
33.6.5 Perinatal hemochromatosis
“Antioxidant cocktail”: N-acetylcysteine (140 mg/kg by mouth or nasogas- tric tube as a loading dose then 70 mg/kg every 4 h to a total of 17–21 doses); selenium 2–3µg/kg per day intravenously over 24 h for∼ 4 weeks;
α-tocopheryl polyethylene glycol succinate 20–30 IU/kg per day given by mouth in two equally divided doses for∼ 4 weeks or longer; prostaglandin E1
as a continuous intravenous infusion (0.4–0.6µg/kg per hour) for 2–4 weeks;
desferroxamine (30 mg/kg per day) by continuous intravenous infusion over 8 h daily until the serum ferritin is < 500µg/l. Note that prostaglandin E1
cannot be administered if the ductus arteriosus is patent.
Orthotopic liver transplantation, if indicated 33.6.7 Perinatal hemochromato-
sis with renal tubular dysgenesis
No specific treatment
33.6.7 Trichohepato-enteric syndrome
No specific treatment 33.6.8 GRACILE syndrome No specific treatment
33.7 Aceruloplasminemia Phlebotomy as for HFE1 or as tolerated; hematocrit should be checked before each phlebotomy and it should be no lower than 20% below its starting value;
desferroxamine
aBest if taken 1 h before or 2 h after meals but closer proximity to meals (with possible dose adjustment) is acceptable if required for adequate compliance.
Alternative Therapies/Experimental Trials 361 33.4 Alternative Therapies/Experimental Trials
33.1 Wilson disease Tetrathiomolybdate, alone or in combination with zinc
(Brewer et al. 2003) – note significant risk of bone marrow, hepatotoxicity and brain toxicity
Vitamin E (α-tocopherol) 33.2 Menkes disease
1. “Classic” form None
2. “Mild” form (atypical) None
33.3 Occipital Horn syndrome None
33.4 Acrodermatitis enteropathica None
33.5 Congenital cholestasis with hepatic zinc ac- cumulation
None; liver transplantation may be necessary 33.6 Hemochromatosis
33.6.1 1. Classic form, HFE-deficient (HFE1) None
33.6.2 2. Juvenile form (HFE2) None
33.6.3 Transferrin receptor-2 deficiency (HFE3) None
33.6.4 Ferroportin deficiency None
33.6.5 Perinatal hemochromatosis Gamma-globulin infusions to mother during latter half of pregnancy
33.6.6 Perinatal hemochromatosis with renal tubular dysgenesis
Antioxidant cocktail; combined liver + kidney transplantation 33.6.7 Trichohepato-enteric syndrome Antioxidant cocktail; combined liver + intestinal transplanta-
tion
33.6.8 GRACILE syndrome Intravenous administration of apotransferrin followed by ex- change transfusion; antioxidant cocktail
33.7 Aceruloplasminemia Vitamin E (α-tocopherol)
33.5 Follow-up/Monitoring
33.1 Wilson disease Clinical review and physical examination every 6–12 months; serum AST, ALT, ALP, GGT, conjugated bilirubin, albumin, International Normalized Ratio (INR), serum Cu and ceruloplasmin, complete blood count, urinalysis every 6–12 months
Twenty-four-hour urinary copper excretion every 12–18 months if on stable dose of medication: for patients taking d-pencillamine or trientine, it should be 3–8µmol (200–500µg) per day, and for patients on any zinc salt it should be no more than 1.2µmol (75µg) per day
For patients taking zinc serum zinc or 24-h urinary zinc excretion every 12 months
33.2 Menkes disease
1. “Classic” form Clinical follow-up relates to major features of the disease: seizures, neurode- generation, arterial abnormalities, bone and joint disorders. Efficacy of treat- ment is determined by normalization of serum copper and ceruloplasmin and 24-h urinary copper excretion. Exceptionally: measurement of hepatic parenchymal copper concentration may be required to assess efficacy of treat- ment
2. “Mild” form (atypical) As for classic Menkes disease
33.3 Occipital Horn syndrome As for classic Menkes disease 33.4 Acrodermatitis
enteropathica
Clinical examination to ensure normal skin and hair. Serum Zn concentrations should be measured every 6–12 months; 24-h urinary excretion of Zn should be measured every 1–2 years. Serum Cu should be measured every 6–12 months, and the complete blood count should be monitored regularly to check for development of a Cu-deficiency anemia. Zn supplementation expected to be life-long; pregnancy or use of oral contraceptive pill may increase Zn demands
33.5 Congenital cholestasis with hepatic zinc accumulation
Routine surveillance for progressive liver disease 33.6 Hemochromatosis
33.6.1 1. Classic form, HFE-deficient (HFE1)
Clinical examination to monitor hepatic and extrahepatic disease; serum ferritin, fasting transferrin saturation, and complete blood count every 3–4 months or more often depending on maintenance phlebotomy requirements;
screening for hepatocellular carcinoma mandatory in any patient with cir- rhosis
33.6.2 2. Juvenile form (HFE2) Same as HFE1 33.6.3 Transferrin receptor-2
deficiency (HFE3)
Same as HFE1 33.6.4 Ferroportin deficiency
(HFE4)
Same as HFE1 33.6.5 Perinatal
hemochromatosis
Clinical review and physical examination every 3–12 months; serum AST, ALT, ALP, GGT, conjugated bilirubin, albumin, INR, complete blood count, urinalysis, serum iron, transferrin saturation and ferritin at each visit. Liver sonogram every 2–4 years
33.6.6 Perinatal hemochromato- sis with renal tubular dys- genesis
As for perinatal hemochromatosis, if infant survives
33.6.7 Trichohepato-enteric syndrome
As for perinatal hemochromatosis, if infant survives 33.6.8 GRACILE syndrome As for perinatal hemochromatosis, if infant survives
33.7 Aceruloplasminemia Regular clinical review and physical examination for neurological disease;
regular ophthalmologic examination of retina; serum ferritin and transferrin saturation; complete blood count to monitor anemia; serum AST, ALT, ALP, GGT, albumin
References
1. Bale PM, Kan AE, Dorney SF (1994) Renal proximal tubular dysgenesis associated with severe neonatal hemosiderotic liver disease. Pediatr Pathol 14:479–489
2. Brewer GJ, Hedera P, Kluin KJ, et al. (2003) Treatment of Wilson disease with ammonium tetrathiomolybdate: III. Initial therapy in a total of 55 neurologically affected patients and follow-up with zinc therapy. Arch Neurol 60:379–385
3. Camaschella C, Roetto A, De Gobbi M (2002) Juvenile hemochromatosis. Semin Hematol 39:242–248
4. Christodoulou J, Danks DM, Sarkar B, et al. (1998) Early treatment of Menkes disease with parenteral copper-histidine: long-term follow-up of four treated patients. Am J Med Genet 76:154–164
5. Dufner-Beattie J, Wang F, Kuo YM, Gitschier J, Eide D, Andrews GK (2003) The acro- dermatitis enteropathica gene ZIP4 encodes a tissue-specific, zinc-regulated zinc trans- porter in mice. J Biol Chem 278:33474–33481
References 363
6. Feder JN, Gnirke A, Thomas W, et al. (1996) A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet 13:399–408
7. Fellman V, Rapola J, Pihko H, Varilo T, Raivio KO (1998) Iron-overload disease in infants involving fetal growth retardation, lactic acidosis, liver haemosiderosis, and aminoaciduria. Lancet 351:490–493
8. Goldfischer S, Grotsky HW, Chang CH, et al. (1981) Idiopathic neonatal iron storage involving the liver, pancreas, heart, and endocrine and exocrine glands. Hepatology 1:58–64
9. Kelly AL, Lunt PW, Rodrigues F, et al. (2001) Classification and genetic features of neonatal haemochromatosis: a study of 27 affected pedigrees and molecular analysis of genes implicated in iron metabolism. J Med Genet 38:599–610
10. Knisely AS, Mieli-Vergani G, Whitington PF (2003) Neonatal hemochromatosis. Gas- troenterol Clin North Am 32:877–889
11. Lee JY, Chang SE, Suh CW, et al. (2002) A case of acrodermatitis enteropathica-like der- matosis caused by ornithine transcarbamylase deficiency. J Am Acad Dermatol 46:965–
967
12. Miyajima H, Takahashi Y, Kono S (2003) Aceruloplasminemia, an inherited disorder of iron metabolism. Biometals 16:205–213
13. Montosi G, Donovan A, Totaro A, et al. (2001) Autosomal-dominant hemochromatosis is associated with a mutation in the ferroportin (SLC11A3) gene. J Clin Invest 108:619–623 14. Njajou OT, Vaessen N, Joosse M, et al. (2001) A mutation in SLC11A3 is associated with
autosomal dominant hemochromatosis. Nat Genet 28:213–214
15. Papanikolaou G, Samuels ME, Ludwig EH, et al. (2004) Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis. Nat Genet 36:77–82 16. Phillips MJ, Ackerley CA, Superina RA, Roberts EA, Filler RM, Levy GA (1996) Excess
zinc associated with severe progressive cholestasis in Cree and Ojibwa-Cree children.
Lancet 347:866–868
17. Roetto A, Daraio F, Alberti F, et al. (2002) Hemochromatosis due to mutations in trans- ferrin receptor 2. Blood Cells Mol Dis 29:465–470
18. Roetto A, Papanikolaou G, Politou M, et al. (2003) Mutant antimicrobial peptide hepcidin is associated with severe juvenile hemochromatosis. Nat Genet 33:21–22
19. Roberts EA, Schilsky ML (2003) A practice guideline on Wilson disease. Hepatology 37:1475–1492
20. Sarkar B, Lingertat-Walsh K, Clarke JT (1993) Copper-histidine therapy for Menkes disease. J Pediatr 123:828–830
21. Shamieh I, Kibort PK, Suchy FJ, Freese DK (1993) Antioxidant therapy for neonatal iron storage disease (NISD) (abstract). Pediatr Res 33:109 A
22. Sigurdsson L, Reyes J, Kocoshis SA, Hansen TW, Rosh J, Knisely AS (1998) Neonatal hemochromatosis: outcomes of pharmacologic and surgical therapies. J Pediatr Gas- troenterol Nutr 26:85–89
23. Tavill AS (2001) Diagnosis and management of hemochromatosis. Hepatology 33:1321–
1328
24. Verloes A, Lombet J, Lambert Y, et al. (1997) Tricho-hepato-enteric syndrome: further de- lineation of a distinct syndrome with neonatal hemochromatosis phenotype, intractable diarrhea, and hair anomalies. Am J Med Genet 68:391–395
25. Visapaa I, Fellman V, Vesa J, et al. (2002) GRACILE syndrome, a lethal metabolic disorder with iron overload, is caused by a point mutation in BCS1L. Am J Hum Genet 71:863–876
