Metabolic
Overview
The porphyrias are a set of metabolic disorders, each representing a defect in one of the eight enzymes in the heme biosynthetic pathway that results in the accumulation of organic compounds called porphyrins. This leads to the clinical and biochemical profile typical for each porphyria.
Hepatic porphyrias are those in which the enzyme deficiency occurs in the liver:
- acute intermittent porphyria (AIP),
- variegate porphyria (VP),
- aminolevulinic acid dehydratase deficiency porphyria (ALAD),
- hereditary coproporphyria (HCP), and
- porphyria cutanea tarda (PCT).
The acute hepatic porphyrias clinically present with neurological attacks (seizures, psychosis, severe abdominal and back pain, and acute polyneuropathy) and, to a lesser extent, with cutaneous manifestations such as photosensitive blistering rash or hypertrichosis.
The worldwide prevalence of acute hepatic porphyrias ranges from one in 500 to one in 50,000 individuals; with all racial and ethnic groups affected by. In most regions, AIP is the most common, and ALAD is the least common. The prevalence of AIP presenting with clinical manifestations is reported to be 5 to 10 per 100,000 individuals, while the prevalence of genetic mutations of AIP is approximately one in 1675 individuals. VP, which is rarer, has a reported prevalence of 4 to 13 cases per million individuals.
The treatment goal for an acute attack of hepatic porphyria is to abate the attack as quickly as possible and to provide appropriate supportive care and symptomatic care until the acute attack resolves. Hospitalization is usually required. Therapy requires confirmation that the patient indeed has acute porphyria, based on the finding of elevated urinary porphobilinogen (PBG), either at present or previously.1
Diagnosis
The first step of AP diagnosis is to:2
- Measure urine porphobilinogen (PBG), total porphyrins and creatinine using a spot (random, single void) urine sample.
- PBG can be measured in plasma or serum in patients with advanced renal disease, but plasma levels are less elevated than in urine in patients with normal renal function.
Symptoms
Patients with AP may develop the following signs and symptoms, which can vary from one patient to another:2
- Severe abdominal pain is the most common and often the initial symptom of an attack.
- Peripheral neuropathy can be manifested as pain in multiple areas such as the back, buttocks, chest or limbs. Paresis may develop and progress, especially with an advanced attack.
- Central and autonomic nervous system involvement may cause mental status changes, seizures, psychosis, insomnia and anxiety.
Causes
Porphyrias are due to an absence of enzymes of the porphyrin pathway, causing abnormally elevated concentrations of these heme precursors, which are toxic to tissues at high levels. Porphyrins are the major precursors of heme, an important component of hemoglobin, myoglobin, catalase, peroxidase, and P450 liver cytochromes.1
Patient organisations
- A Worldwide Network | International Porphyria Network
References
- Kothadia JP et al.. [Updated 2023 May 1]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan.
- Anderson KE. Acute hepatic porphyrias: Current diagnosis & management. Mol Genet Metab. 2019 Nov;128(3):219-227.
Overview
Cystic fibrosis (CF) is an inherited disorder affecting the secretory glands, including those producing mucus and sweat. It primarily impacts the lungs, pancreas, liver, digestive tract, sinuses, and sexual organs. In CF, thick mucus accumulates in these organs, leading to clogged airways, trapped bacteria, recurrent infections, lung damage, and eventually respiratory failure. Mucus in the pancreas hinders the release of digestive enzymes, affecting food digestion and nutrient absorption.1
Advancements in treatment have significantly improved the life expectancy of people with CF. Many individuals now live into their 40s and beyond.2 Early diagnosis and personalized treatment plans are crucial for managing the disease effectively. Lifestyle changes play a vital role in managing CF:3
- Regular exercise: Helps to improve lung function and overall health
- Nutritional support: A high-calorie, high-protein diet with enzyme supplements aids digestion and nutrient absorption
- Airway clearance techniques: Daily routines to clear mucus from the lungs
- Avoiding infections: Minimizing exposure to germs through good hygiene practices and avoiding contact with sick individuals
By adhering to these lifestyle changes and working closely with healthcare providers, people with CF can lead healthier, more active lives.3
Diagnosis
CF is often detected shortly after birth through the newborn blood spot test, which involves collecting a blood sample from the baby’s heel. Additional tests to confirm CF include:3,4
- Sweat test: Measures salt levels in sweat, which are higher in CF patients
- Genetic test: Checks blood or saliva for the faulty CF gene2
These tests can also diagnose older children and adults with CF symptoms who were not previously screened.
Symptoms
CF symptoms and severity vary widely. Factors like specific gene mutations and age of diagnosis influence health outcomes. People with CF are prone to lung infections due to thick mucus that harbors bacteria. Minimizing germ exposure is crucial. Mucus buildup in the pancreas can lead to malnutrition and poor growth, while liver disease can result from blocked bile ducts. CF can also affect male fertility. Concretely, people with CF may experience:5
- Salty-tasting skin
- Persistent coughing with phlegm, shortness of breath, and wheezing
- Recurrent lung infections like pneumonia or bronchitis
- Poor growth and slow weight gain
- Frequent, greasy, bulky stools and occasional bowel movement difficulties
- Male infertility
Causes
CF is a genetic disease passed from parents to children through genes. Individuals with CF inherit two copies of the defective CF gene, one from each parent. Carriers, who have one copy of the defective gene, do not have the disease. When two carriers have a child, there is a 25% chance the child will have CF, a 50% chance they will be a carrier, and a 25% chance they will not be a carrier or have CF. Over 1,800 known mutations of the CF gene exist.6
Patient organisations
- A Worldwide Network | International Porphyria Network
References
- Shteinberg M, et al. Lancet. 2021;397(10290):2195-211
- Simmonds NJ, et al. Eur Respir J. 2010;36(6):1277-83
- Southern KW, et al. J Cyst Fibros. 2024;23(1):12-28
- De Boeck K, et al. Presse Med. 2017;46(6 Pt 2):e97-e108
- Ong T, et al. JAMA. 2023;329(21):1859-71
- Mathew A, et al. Cureus. 2021;13(2):e13526
Overview
Nephropathic cystinosis is a rare, monogenic autosomal-recessive disease belonging to the family of lysosomal storage disorders. It is caused by mutations in the CTNS gene encoding cystinosin, a lysosomal proton/cystine cotransporter.
Defective cystinosin is unable to export cystine out of the lysosome into the cytoplasm, leading to the formation of crystals. Given that cystinosin is expressed throughout the body, cystinosis is a systemic disease in which multiple organs are affected; however, the kidneys are most vulnerable.1,2
Cystinosis has a general incidence rate of 0.5–1 per 100,000 live births.2
Diagnosis
The diagnosis can be confirmed by performing the following tests:
- measurement of leukocyte cystine levels (LCL),
- demonstration of corneal cystine crystals by the slit lamp exam and
- genetic analysis of the CTNS gene.3
Symptoms
Cystine accumulation begins during fetal life and affects all tissues. Cell damage and organ dysfunction, however, are heterogeneous and vary in severity and progression.
At birth, renal tubular function appears well preserved. The renal Fanconi syndrome usually manifests by 4–6 months of age with polyuria, polydipsia, failure to thrive, vomiting, constipation, dehydration, growth retardation and/or rickets, in association with biochemical evidence of proximal tubular dysfunction. This includes substantial losses of electrolytes, low-molecular weight proteinuria and severe acidosis; hypophosphatemia and impaired calcitriol metabolism often cause severe rickets. Corneal cystine crystals are usually visible by a slit lamp exam after the first year of life.3
Causes
Cystinosis is caused by bi-allelic mutations in the CTNS gene (17p13.2) that encodes the lysosomal cystine transporter cystinosin. Current evidences indicate that cystinosis is a monogenic-recessive disease with complete penetrance. Severe truncating mutations cause infantile cystinosis, while milder mutations in at least one allele are usually observed in late-onset and ocular forms. More than 100 mutations have been reported. The most frequent mutation, affecting ∼76% of northern European alleles, is a large deletion of 57 257 base pairs involving the first 9 CTNS exons and part of exon 10.3
References
- Cherqui S, Courtoy PJ. The renal Fanconi syndrome in cystinosis: pathogenic insights and therapeutic perspectives. Nat Rev Nephrol. 2017 Feb;13(2):115-131.
- Jamalpoor A, Othman A, Levtchenko EN, Masereeuw R, Janssen MJ. Molecular Mechanisms and Treatment Options of Nephropathic Cystinosis. Trends Mol Med. 2021 Jul;27(7):673-686.
- Emma F, Nesterova G, Langman C, Labbé A, Cherqui S, Goodyer P, Janssen MC, Greco M, Topaloglu R, Elenberg E, Dohil R, Trauner D, Antignac C, Cochat P, Kaskel F, Servais A, Wühl E, Niaudet P, Van’t Hoff W, Gahl W, Levtchenko E. Nephropathic cystinosis: an international consensus document. Nephrol Dial Transplant. 2014 Sep;29 Suppl 4(Suppl 4):iv87-94.
Overview
Hyperammonemia is a metabolic condition characterised by raised levels of ammonia, a nitrogen-containing compound. Ammonia is a potent neurotoxin. Hyperammonemia most commonly presents with neurological signs and symptoms that may be acute or chronic, depending on the underlying abnormality.1
Diagnosis
The first step of hyperammonemia diagnosis is to quantify the ammonia blood level of the patient. Normal levels are mentioned below:
- Healthy term infants: 45±9 micromol/L; 80 to 90 micromol/L is the upper limit of normal
- Preterm infants: 71±26 micromol/L, decreasing to term levels in approximately seven days
- Children older than 1 month: less than 50 micromol/L
- Adults: less than 30 micromol/L1.
Symptoms
Early-onset hyperammonemia is seen in neonates at 24-72 hours of life. The neonate presents lethargy, irritability, and vomiting as ammonia levels rise above 100-150 micromol/L.
Late onset hyperammonemia presents later in with irritability, headache, vomiting, ataxia, until seizures, encephalopathy, coma, and even death.2
Patients may develop intellectual disability, behavioral and psychiatric symptoms in chronic hyperammonemia. This has been linked to glutamine levels in the brain.3
Causes
Inborn errors (genetic disorders) of metabolism inducing hyperammonemia, among the others, are N-Acetylglutamate Synthetase Deficiency (NAGSD), Propionic Acidemia (PA), Methylmalonic Acidemia (MMA) and Isovaleric Acidemia (IVA), all autosomal recessive.4
NAGSD is the rarest defect of the urea cycle, with an incidence of less than one in 2,000,000 live births.5
PA prevalence estimates rates of 0.29, 0.33, 0.33 and 4.24 in the Asia-Pacific, Europe, North America and the Middle East and North Africa (MENA) regions, per 100,000 newborns respectively.6
MMA prevalence worldwide is estimated 1.14 per 100,000 newborns.7
Prevalence of IVA is estimated to be 1 in 90,000–100,000 newborns worldwide.8
Patient Organisation
References
- Ali R, Nagalli S. Hyperammonemia. [Updated 2023 Apr 7]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK557504/
- aquero J, et al. Pathogenesis of hepatic encephalopathy in acute liver failure. Semin Liver Dis. 2003 Aug;23(3):259-69.
- Clay AS, Hainline BE. Hyperammonemia in the ICU. Chest. 2007 Oct;132(4):1368-78.
- Alfadhel M, Al Mutairi F, Makhseed N, Al Jasmi F, Al-Thihli K, Al-Jishi E, Al-Sayed M, Al-Hassnan ZN, Al Murshedi F, Häberle J, Ben-Omran T. Therapeutics and Clinical Risk Management 2016:12 479–487.
- Singh, R.H., et al. The efficacy of Carbamylglutamate impacts the nutritional management of patients with N-Acetylglutamate synthase deficiency. Orphanet J Rare Dis 19, 168 (2024).
- Almási, T. et al. Systematic literature review and meta-analysis on the epidemiology of propionic acidemia. Orphanet J Rare Dis 14, 40 (2019).
- Jin L, et al. Prevalence of methylmalonic acidemia among newborns and the clinical-suspected population: a meta-analyse. J Matern Fetal Neonatal Med. 2022 Dec;35(25):8952-8967.
- Reigstad H, et al. Normal Neurological Development During Infancy Despite Massive Hyperammonemia in Early Treated NAGS Deficiency. JIMD Rep. 2017;37:45-47.
Overview
Genetic homocystinurias are a group of inborn errors of metabolism that result in the massive excretion of homocysteine (Hcy) in the urine due to Hcy accumulation in the body, usually causing neurological and cardiovascular complications.
Diagnosis
Markedly high tHcy (>50 µmol/L in children; tHcy >100 µmol/L in adults) together with increased Met and low cysteine in plasma are the classical biochemical features of HCU. However, these biochemical abnormalities may be less pronounced in patients with milder forms of HCU or those taking vitamin supplements.
Confirmation can be made via the measurement of CBS activity in fibroblasts. Since this method is not broadly available, molecular genetic analysis is most often used for confirmation of the diagnosis.
Newborn screening has been performed, especially in countries with high incidences of HCU, such as Ireland and Qatar.
CblC should be suspected when both tHcy and MMA are markedly elevated. CblC is a disorder of intracellular cbl metabolism caused by homozygous or compound heterozygous mutations in the MMACHC gene on chromosome 1p34. This disorder results in the impaired delivery of intracellular cbl to its two metabolically active forms, Mecbl and Adocbl. The decreased activity of these two enzymes causes elevations of tHcy and MMA as well as low-normal or reduced Met.
More than 100 different mutations in over 170 patients with severe MTHFR deficiency have been reported. Most mutations in the MTHFR gene are restricted to one or two families. The c.665C>T (p.Ala222Val) is a polymorphism leading to a thermolabile MTHFR variant with a propensity for monomer dissociation and flavin adenine dinucleotide binding loss, showing a 70% and 35% reduction of enzyme activity in lymphocytes in homozygotes and heterozygotes, respectively, when compared with wild-type controls.
Symptoms
CBS deficiency or classical homocystinuria (HCU; OMIM +236200) is the most common type of homocystinuria. Four organ systems are primarily affected in HCU: ocular, vascular, central nervous (CNS) and skeletal. The hallmark study of Mudd et al. in 1985 concerns a cohort of over 600 patients. According to this survey, eye disease, particularly lens dislocation (ectopia lentis), was the main reason for HCU investigation (85% of the cases) and commonly the first symptom, manifesting after the age of two years old and affecting more than 50% of non-treated patients at the age of 10 years old. Other ocular abnormalities that might occur in HCU include high myopia, iridodonesis, glaucoma, optic atrophy, retinal degeneration, retinal detachment, cataracts and corneal abnormalities.
Individuals with cblC deficiency often suffer from a wide range of clinical complications, including developmental, metabolic, hematologic, neurologic, ophthalmologic and dermatologic findings.
Severe methylenetetrahydrofolate reductase (MTHFR) deficiency is associated with slow brain growth, severe neurological disability, and untimely death.
Causes
The three most frequent causes are classical homocystinuria [deficiency of cystathionine beta-synthase (CBS)], methylmalonic aciduria with homocystinuria, cblC type (cblC deficiency) and severe methylenetetrahydrofolate reductase (MTHFR) deficiency.
References
Weber Hoss GR. Et al. Journal of Inborn Errors of Metabolism & Screening 2019, Volume 7: e20190007.
Overview
Patent ductus arteriosus (PDA) is a congenital cardiac anomaly that may be associated with the onset of severe intraventricular and pulmonary hemorrhages after 72 h of birth, thereby impacting neurodevelopmental outcomes.
Persistent Patent Ductus Arteriosus (PDA) is prevalent among extremely preterm infants, with its occurrence inversely related to gestational age. A persistent PDA correlates with increased mortality and morbidities such as intraventricular hemorrhage, pulmonary hemorrhage, chronic lung disease, bronchopulmonary dysplasia, and necrotizing enterocolitis as observed clinically. Conversely, numerous randomized controlled trials have failed to demonstrate significant benefits from PDA treatment. One contributing factor to these conflicting findings is that PDA affects each individual differently depending on the cardiovascular decompensation and its hemodynamic impact. PDA management should be based on the hemodynamic significance, rather than just the presence or size of PDA.1
Diagnosis
Echocardiography remains the gold standard for diagnosing PDA. It confirms its presence and assesses the PDA shunt volume and downstream effects.
A comprehensive echocardiographic assessment of PDA and its hemodynamic significance typically encompasses the following aspects: (a) ductus arteriosus characteristics, (b) assessment of pulmonary hyperperfusion, (c) assessment of systemic hypoperfusion and (d) assessment of myocardial functions.1
Symptoms
Infants with a PDA may initially remain asymptomatic due to elevated pulmonary vascular resistance (PVR), impeding excessive blood flow between the aorta and the pulmonary artery across the PDA. The PDA becomes hemodynamically significant when blood shunting across the PDA increases, causing strain on the other organ systems. Pulmonary overcirculation occurs when PVR diminishes over subsequent days after birth, resulting in symptoms such as pulmonary edema, tachypnea, desaturations, or apnea. Increased pulmonary venous return may lead to cardiac manifestations, including a loud heart murmur, tachycardia, cardiomegaly, and a hyperactive precordium. The phenomenon of blood flow diversion from the systemic circulation, known as the “steal phenomenon,” results in bounding peripheral pulses, widened pulse pressure, lowered diastolic blood pressure, and systemic hypoperfusion, often characterized by oliguria and feeding intolerance. When myocardial adaptation to hemodynamic significant PDA (hsPDA) fails, heart failure may lead to severe hypotension and acidosis, necessitating cardioactive or vasopressor medications.1
Causes
Postnatal ductal closure is stimulated by rising oxygen tension and withdrawal of vasodilatory mediators (prostaglandins, nitric oxide, adenosine) and by vasoconstrictors (endothelin-1, catecholamines, contractile prostanoids), ion channels, calcium flux, platelets, morphologic maturity, and a favorable genetic predisposition. A persistently patent ductus arteriosus (PDA) in preterm infants can have clinical consequences. Decreasing pulmonary vascular resistance, especially in extremely low gestational age newborns, increases left-to-right shunting through the ductus and increases pulmonary blood flow further, leading to interstitial pulmonary edema and volume load to the left heart.2
References
Singh Y, Chan B, Noori S, Ramanathan R. Narrative Review on Echocardiographic Evaluation of Patent Ductus Arteriosus in Preterm Infants. J Cardiovasc Dev Dis. 2024 Jun 28;11(7):199. doi: 10.3390/jcdd11070199. PMID: 39057619; PMCID: PMC11277213.
Hamrick SEG, Sallmon H, Rose AT, Porras D, Shelton EL, Reese J, Hansmann G. Patent Ductus Arteriosus of the Preterm Infant. Pediatrics. 2020 Nov;146(5):e20201209.
Overview
Phenylketonuria (PKU) is an inherited disorder that increases the levels of phenylalanine in the bloodstream. Phenylalanine is an amino acid found in all proteins and some artificial sweeteners. Without treatment, phenylalanine can build up to harmful levels, causing intellectual disability and other serious health problems.1,2 The prevalence of PKU varies widely around the world. In Europe the prevalence is about one case per 10000 livebirths.1
With early diagnosis and proper management, individuals with PKU can lead healthy lives. Adhering to a strict low-phenylalanine diet is crucial for preventing complications. Regular monitoring and adjustments to the diet are necessary to ensure optimal health. Support from healthcare providers, family, and support groups can help individuals manage the challenges of the PKU diet and maintain a good quality of life.1,2
Diagnosis
Most cases of PKU are detected soon after birth through the newborn blood spot test, which involves collecting a drop of blood from the baby’s heel. Additional tests, such as plasma amino acid analysis, are needed to confirm the diagnosis. PKU occurrence varies among ethnic groups and geographic regions worldwide. Early detection through newborn screening programs has significantly reduced the incidence of severe PKU symptoms.1,3
Symptoms
PKU symptoms range from mild to severe:1-3
- Classic PKU: The most severe form, where infants appear normal until a few months old. Without treatment, children develop intellectual disability, seizures, delayed development, behavioral problems, and psychiatric disorders. Untreated children may have a musty odor due to excess phenylalanine. They often have lighter skin and hair than unaffected family members and may have skin disorders like eczema.
- Less severe forms: Variant PKU and non-PKU hyperphenylalaninemia have a lower risk of brain damage. People with very mild cases may not need treatment if they follow a low-phenylalanine diet.
- Maternal PKU: Babies born to mothers with uncontrolled phenylalanine levels are at significant risk of intellectual disability, low birth weight, slower growth, heart defects, microcephaly, and behavioral problems. Women with uncontrolled phenylalanine levels also have an increased risk of pregnancy loss.
Causes
PKU is caused by mutations in the PAH gene, which provides instructions for synthesizing an enzyme called phenylalanine hydroxylase. This enzyme is necessary to convert phenylalanine into thyroxine, which is then used for the synthesis of other substances needed by the body. When the PAH gene is mutated, phenylalanine accumulates in the blood and becomes toxic.4 Over 500 different mutations in the PAH gene have been identified, contributing to the variability in PKU severity.1
Patient organisations
- A Worldwide Network | International Porphyria Network
References
- Blau N, et al. Lancet. 2010;376(9750):1417-27
- Al Hafid N, et al. Transl Pediatr. 2015;4(4):304-17
- van Wegberg AMJ, et al. Orphanet J Rare Dis. 2017;12(1):162
- Elhawary NA, et al. Hum Genomics. 2022;16(1):22
Overview
Jaundice, a yellow discoloration of the skin, sclera, mucous membranes, and bodily fluids, is a common clinical finding in the first 2 weeks after birth, occurring in 2.4% to 15% of newborns. Most often, jaundice is of the indirect/ unconjugated bilirubin variety and resolves spontaneously without intervention. However, persistent jaundice is abnormal and can be the presenting sign of serious hepatobiliary and metabolic dysfunction. When jaundice persists beyond age 2 weeks, cholestasis or conjugated hyperbilirubinemia must be considered in the differential diagnosis. Cholestasis represents an impairment in bile flow and may be caused by either an intrahepatic or extrahepatic disorder. Reduced delivery of bile acids to the small intestine leads to decreased mixed micelle formation and subsequent fat and fat-soluble vitamin malabsorption, including vitamin E.1
Diagnosis
Any infant who remains jaundiced beyond age 2 to 3 weeks should have the serum bilirubin level fractionated into a conjugated (direct) and unconjugated (indirect) portion. Conjugated hyperbilirubinemia is never physiologic or normal. Evaluation of a jaundiced infant should begin with fractionation of serum bilirubin into total and direct (or conjugated) bilirubin. Infants who have cholestasis will generally have a direct (or conjugated) bilirubin greater than 2.0 mg/dL, which will be more than 20% of the total bilirubin concentration. The differential diagnosis of cholestasis is extensive, initial history and physical examination is useful to rapidly identify the underlying etiology.
Symptoms
The typical findings in an infant who has cholestasis are protracted jaundice, scleral icterus, acholic stools, dark yellow urine, and hepatomegaly. It should be noted that there may be a perception of decreasing jaundice over the first weeks after birth as the indirect bilirubin component (from human milk–associated jaundice) decreases, causing false reassurance that the jaundice is resolving and need not be evaluated further. Acholic stools in an infant should always prompt further evaluation. Some infants may have coagulopathy secondary to vitamin K malabsorption and deficiency and present with bleeding or bruising. Coagulopathy may also be caused by liver failure, indicating either severe metabolic derangement of the liver (as in respiratory chain deficiency disorders) or cirrhosis and end-stage liver disease (as in neonatal hemochromatosis). Splenomegaly can be observed in infants who have cirrhosis and portal hypertension, storage diseases, and hemolytic disorders.
Causes
Cholestatic jaundice affects approximately 1 in every 2,500 infants and has a multitude of causes. The number of unique disorders presenting with cholestasis in the neonatal period may be greater than at any other time in life and include infections, anatomic abnormalities of the biliary system, endocrinopathies, genetic disorders, metabolic abnormalities, toxin and drug exposures, vascular abnormalities, neoplastic processes, and other miscellaneous causes. Of the many conditions that cause neonatal cholestasis, the most commonly identifiable are biliary atresia (BA) (25%–35%), genetic disorders (25%), metabolic diseases (20%), and a1-antitrypsin (A1AT) deficiency (10%).
Patient Organisation
References
Feldman AG, Sokol RJ. Neonatal Cholestasis. Neoreviews. 2013 Feb 1;14(2):10.1542/neo.14-2-e63. doi: 10.1542/neo.
Overview
Wilson’s disease (WD) is a rare disorder of copper metabolism. The disease is inherited in an autosomal recessive manner. Its occurrence is due to a mutation in the ATP7B gene located on the long arm of chromosome 13. As a result, the function of ATPase 7B, encoded by ATP7B, an enzyme found mainly in liver cells and responsible for cellular copper transport, is impaired. It cannot cooperate with its partner, antioxidant protein 1 (ATOX1), which is necessary for the proper transport of copper in the cell; its enzymatic activity decreases, its half-life shortens, and/or it undergoes incorrect localization in the cell. The incorrect function of ATPase 7B leads to copper incorrectly binding to apoceruloplasmin, and the excretion of excess copper in bile is impaired, which leads to copper retention in cells, primarily in hepatocytes. After exceeding the capacity threshold of liver cells, they are damaged, and copper is released into the bloodstream, where it remains unbound with ceruloplasmin, and in this form it is very toxic, and it also easily accumulates in other organs, e.g., in the intestines, brain, kidneys, and cornea.1
WD is present all over the world. The incidence of this disease in the general population is estimated at approximately 1:30,000. The disease is more common in closed populations with low population migration and/or consanguineous marriages; this includes China, Japan, the Canary Islands, Corsica, and Sardinia.1
Diagnosis
Until the unequivocal proof or an autosomal recessive disorder of the hepatic copper transporter ATP7B has been ruled out, differential diagnoses must be examined. Laboratory-chemical parameters of copper metabolism can both be deviations from the norm not related to the disease as well as other copper metabolism disorders besides.2
Symptoms
Until puberty, gastrointestinal symptoms with hepatic or haemolytic findings are predominant. Consequently, an indistinct elevation of transaminases and bilirubin, icteric flare-ups, signs of a virus—negative acute hepatitis as well as hepatosplenomegaly should lead to the suspicion. Acute liver failure is also possible. Haematologically, the occurrence of a Coombs-negative haemolysis and unclear anaemia, leukopenia as well as thrombocytopaenia, are suspicious.
Without an exact age limit and after overcoming undetected bland gastrointestinal findings, symptoms affecting the central nervous system appear from puberty onwards with dysarthric, extrapyramidal and mental manifestations. Laboratory-chemical involvement of the liver (transaminases, synthesis parameters albumin and coagulation factors, cholinesterase, ammonia), change in the sonographic liver texture and a Kayser-Fleischer ring (KFR) can support the suspicion.2
Causes
Wilson’s disease fits into a broad spectrum of internal and neurological disease patterns with icterus, anaemia and EPS. Recently discovered disease patterns pertaining to manganese and copper metabolism are relevant after ruling out an ATP7B mutation.2
References
Gromadzka, G.; Czerwińska, J.; Krzemińska, E.; Przybyłkowski, A.; Litwin, T. Wilson’s Disease—Crossroads of Genetics, Inflammation and Immunity/Autoimmunity: Clinical and Molecular Issues. Int. J. Mol. Sci. 2024, 25, 9034.
Hermann W. Classification and differential diagnosis of Wilson’s disease. Ann Transl Med. 2019 Apr;7(Suppl 2):S63.
