Low Ceruloplasmin Levels Research Articles

Low penetrance of frequent ATP7B mutations explains the low prevalence of Wilson disease. Lessons from real-life registries.

Background & AimsWilson disease (WD) is a copper metabolism disorder caused by mutations in ATP7B gene, with significant clinical variability. Several studies have analyzed the prevalence and penetrance of mutations. We evaluated both characteristics for our more frequent mutations. MethodsEvaluation of 260 patients from the National Registry: clinical, analytical and genetic data. Estimation of homozygotes and total cases according to Hardy-Weinberg equilibrium and comparison with Registry records. ResultsThe estimated number of homozygotes were higher than registered: p.Met645Arg (1949/6), p.His1069Gln (20/8), p.Leu708Pro (63/24) and p.Gly869Arg (147/0). p.Met645Arg homozygotes presented less cirrhosis at diagnosis, extrahepatic disease and Kayser-Fleischer ring (KFR) and more presymptomatic cases and diagnosis after 40 years of age than p.Leu708Pro and p.His1069Gln homozygotes. p.Met645Arg homozygotes presented more late diagnosis than p.Met645Arg compound heterozygotes. Compound heterozygotes carrying p.Met645Arg or p.Gly869Arg showed less cirrhosis at diagnosis, KFR and neurological symptoms and more hepatic and presymptomatic cases, despite clearly low ceruloplasmin levels. The estimated prevalence was 1:3.785, predicting more than 10.500 patients. ConclusionsThe widespread mutations p.Met645Arg and p.Gly869Arg show low penetrance. WD might be underdiagnosed in Spain due to less severe phenotype of the most frequent mutations, a crucial fact to avoid misdiagnosis and to offer early therapy.

Pili Torti: A Clue to Life-threatening Illness – A Rare Case Report

Menkes kinky hair disease (MKHD) is a rare inherent error of copper metabolism presenting during early infancy with multi-system involvement. It is associated with high morbidity and mortality in early childhood. Characteristic hair changes mirror internal metabolic alterations. Here, we report a case of 13-month-old male child who presented with peculiar changes of skin and hair along with convulsion and high-grade fever. Dermatoscopy and hair mount examination showing pili torti with pigmentary dilution pointed toward the diagnosis of MKHD, which was further enforced with blood investigations showing low copper and ceruloplasmin levels. Cutaneous findings play a crucial role in early diagnosis, thereby reducing morbidity with timely treatment.

Clinical signs and symptoms of Wilson disease in a real-world cohort of patients in the United States: a medical chart review study

IntroductionThere are limited data from the United States regarding the real-world signs and symptoms of Wilson disease (WD). This retrospective, observational medical chart review was conducted to identify real-world characteristics of patients with WD in the United States, as well as WD signs and symptoms at diagnosis and over time.MethodsDe-identified clinical data were abstracted from medical charts of US patients diagnosed with WD between January 1, 2012, and June 30, 2017. Hepatic, neurologic, and psychiatric biochemical findings, signs, and symptoms were characterized at diagnosis and follow-up/during treatment.ResultsIn total, 225 WD patients were included in the study. The mean (SD) age at diagnosis was 24.7 (9.8) years, and 65.3% were male. Median (Q1–Q3) follow-up after diagnosis was 39.5 (33.8–60.4) months. The most common disease presentation at WD diagnosis was combined neurologic/psychiatric and hepatic (52.9%), followed by neurologic/psychiatric (20.0%), hepatic (16.9%), and asymptomatic (10.2%). Common clinical characteristics at diagnosis were Kayser-Fleischer rings (77.2%), low ceruloplasmin levels (95.2%), high hepatic copper (97.8%), elevated 24-hour urinary copper excretion (90.2%), and abnormal liver function tests (38.7%–85.1%). At diagnosis, the most common biochemical findings or hepatic sign/symptoms were abnormal liver enzymes (50.7%), abdominal pain (16.6%), and fatigue (15.7%). The most common neurologic signs/symptoms were headache (18.3%), dysarthria (17.4%), and ataxia (17.0%). Common psychiatric signs/symptoms included anxiety/depression/other mood changes (36.2%), emotional lability (12.8%), and increased irritability/anger outbursts (9.2%). Prevalence of biochemical abnormalities or signs/symptoms among patients at diagnosis and after ~1-year follow-up were neurologic (60.1% and 44.0%), hepatic (69.6% and 37.8%), and psychiatric (53.7% and 37.6%), respectively. Common new onset symptoms at ~1-year post-WD diagnosis were abnormal liver enzymes (5.6%), headache (6.2%), and anxiety/depression/other mood changes (7.2%).ConclusionsThese real-world, descriptive data highlight the clinical complexity and heterogeneity of WD and the need for better education about diagnostic testing and multidisciplinary support. Although rare, the neurologic, psychiatric, and hepatic signs/symptoms of WD have a substantial clinical impact.

First application of next-generation sequencing in four families with Wilson disease in Morocco

BackgroundWilson disease is a rare autosomal recessive disorder characterized by toxic accumulation of copper in various organs, principally in the liver and brain. The disease can be manifested with hepatic, neurologic and ophthalmic signs and in a rare case with psychiatric, hematological, renal and skeletal signs; symptoms vary among and within families. Traditionally, Wilson disease was diagnosed on the basis of biochemical markers which include low ceruloplasmin levels and elevated urinary and hepatic copper. However, theses parameters are not specific and can been seen in other disorders. Genetic testing is now considering the most specific test allowing a precise diagnosis. In this study, we report the results of molecular analysis of four unrelated patients with Wilson disease from Morocco; we used a next-generation sequencing customized multigene panel to investigate the ATP7B gene for the four unrelated patients with Wilson disease.ResultsGenetic tests based on next-generation sequencing allow to the identification of four previously described variants. One in compound heterozygous state and three at homozygous state.ConclusionsOur results confirm the clinical diagnosis of Wilson disease in these reported families and have implications for their genetic counselling and clinical management. Diagnosis of Wilson disease is a major challenge in clinical practice, and Genetic testing of ATP7B gene should be recommended in patients with suspected Wilson disease.

Low ceruloplasmin levels exacerbate retinal degeneration in a hereditary hemochromatosis model.

In a previous report, a 39-year-old patient with high serum iron levels from hereditary hemochromatosis (HH) was diagnosed with a form of retinal degeneration called bull's eye maculopathy. This is atypical for patients with HH, so it was theorized that the low serum levels of ferroxidase ceruloplasmin (CP) of this patient coupled with the high iron levels led to the retinal degeneration. CP, by oxidizing iron from its ferrous to ferric form, helps prevent the oxidative damage caused by ferrous iron. To test this, a hepcidin knockout (KO) mouse model of HH was combined with Cp KO to test whether the combination would lead to more severe retinal degeneration. Monthly in vivo retinal images were acquired and, after 11 months, mice were euthanized for further analyses. Both heterozygous and homozygous Cp KO increased the rate and severity of retinal degeneration. These results demonstrate the protective role of CP, which is most likely owing to its ferroxidase activity. The findings suggest that CP levels may influence the severity of retinal degeneration, especially in individuals with high serum iron.

Clinical Characteristics, Genetic Features, and Long-Term Outcome of Wilson's Disease in a Taiwanese Population: An 11-Year Follow-Up Study.

ObjectiveaaWilson's disease (WD) is a rare genetic disorder of copper metabolism, and longitudinal follow-up studies are limited. We performed a retrospective analysis to determine the clinical characteristics and long-term outcomes in a large WD cohort. MethodsaaMedical records of WD patients diagnosed from 2006-2021 at National Taiwan University Hospital were retrospectively evaluated for clinical presentations, neuroimages, genetic information, and follow-up outcomes. ResultsaaThe present study enrolled 123 WD patients (mean follow-up: 11.12 ± 7.41 years), including 74 patients (60.2%) with hepatic features and 49 patients (39.8%) with predominantly neuropsychiatric symptoms. Compared to the hepatic group, the neuropsychiatric group exhibited more Kayser-Fleischer rings (77.6% vs. 41.9%, p < 0.01), lower serum ceruloplasmin levels (4.9 ± 3.9 vs. 6.3 ± 3.9 mg/dL, p < 0.01), smaller total brain and subcortical gray matter volumes (p < 0.0001), and worse functional outcomes during follow-up (p = 0.0003). Among patients with available DNA samples (n = 59), the most common mutations were p.R778L (allelic frequency of 22.03%) followed by p.P992L (11.86%) and p.T935M (9.32%). Patients with at least one allele of p.R778L had a younger onset age (p = 0.04), lower ceruloplasmin levels (p < 0.01), lower serum copper levels (p = 0.03), higher percentage of the hepatic form (p = 0.03), and a better functional outcome during follow-up (p = 0.0012) compared to patients with other genetic variations. ConclusionaaThe distinct clinical characteristics and long-term outcomes of patients in our cohort support the ethnic differences regarding the mutational spectrum and clinical presentations in WD.

Technical Study of Automated High-Throughput High-Sensitive Ceruloplasmin Assay on Dried Blood Spots-Reinstate the Potential Use for Newborn Screening of Wilson Disease.

In this study, we modified a fully automatic immunoassay on ceruloplasmin concentration on dried blood spots (DBS) to increase its analytical sensitivity in order to accurately differentiate newborns from true Wilson disease (WD) patients. Modifications to the assay parameters of the Roche/Hitachi Cobas c systems immunoturbidimetric assay are adjusted to lower the limit of quantitation to 0.60 mg/L from 30 mg/L. This enables sensitive measurement of ceruloplasmin in eluent after DBS extraction. In addition, reference intervals and receiver operating characteristic curve analysis for diagnostic cut-off were established using DBS of neonates and WD adult patients. After DBS whole blood calibration, the 95th percentile of the reference interval for newborns was 86-229 mg/L. The cut-off value of 54 mg/L was found to be the most optimal point for differentiating true adult WD from newborn controls. This test shows a high area under curve of 1.000 with 100% sensitivity and specificity in differentiating normal newborns from WD adult samples. However, the results should be further validated with true newborn WD patient samples together with the consideration of other factors that can also lead to low ceruloplasmin levels. This test shows application potential in newborn screening for WD, which can save lives through early identification and timely treatment.

Phenotypes and ATP7B gene variants in 316 children with Wilson disease

Objectives: To summarize the clinical phenotypes and the variation spectrum of ATP7B gene in Chinese children with Wilson's disease (WD) and to investigate their significance for early diagnosis. Methods: Retrospective analysis was performed on the clinical data of 316 children diagnosed as WD in Guangzhou Women and Children's Medical Center during the period from January 2010 to June 2021. The general situations, clinical manifestations, lab test results, imaging examinations, and ATP7B gene variant characteristics were collected. The patients were divided into asymptomatic WD group and symptomatic WD group based on the presence or absence of clinical symptoms at the time that WD diagnosis was made. The χ2 test, t test or Mann-Whitney U test were used to compare the differences between groups. Results: Among the 316 children with WD, 199 were males and 117 were females, with the age of 5.4 (4.0, 7.6) years at diagnosis; 261 cases (82.6%) were asymptomatic with the age of 4.9 (3.9, 6.4) years; whereas 55 cases (17.4%) were symptomatic with the age of 9.6 (7.3, 12.0) years. The main symptoms invloved liver, kidney, nervous system, or skin damage. Of all the patients, 95.9% (303/316) had abnormal liver function at diagnosis; 98.1% (310/316) had the serum ceruloplasmin lever lower than 200 mg/L; 97.7% (302/309) had 24-hour urine copper content exceeding 40 μg; only 7.4% (23/310) had positive corneal K-F rings, 8.2% (23/281) had abnormal MRI signals in the lenticular nucleus, and all of them had symptoms of damage in liver, kidney or nervous system. Compared with the group of symptomatic WD, asymptomatic group had higher levels of serum alanine aminotransferase and lower levels ceruloplasmin and 24-hour urine copper [(208±137) vs. (72±78) U/L, (55±47) vs. (69±48) mg/L, 103 (72, 153) vs. 492 (230, 1 432) μg; t=9.98, -1.98, Z=-4.89, all P<0.001]. Among the 314 patients completing genetic sequencing, a total of 107 mutations in ATP7B gene were detected, of which 10 are novel variants, and 3 cases (1.0%) had large heterozygous deletion (exons 10 to exon 11) in ATP7B gene. The percentage of missense mutation in asymptomatic WD children was significantly higher than that in symptomatic WD (81.5% (422/518) vs. 69.1% (76/110), χ²=8.47, P<0.05). WD patients carrying homozygous variant of c.2 333G>T had significantly low levels of ceruloplasmin than those not carrying this variant ((23±5) vs. (61±48) mg/L, t=-2.34, P<0.001). Conclusions: The elevation of serum ALT is an important clue for early diagnosis of WD in children, while serum ceruloplasmin and 24-hour urine copper content are specific markers for early diagnosis of WD. In order to confirm the diagnosis of WD, it is necessary to combine the Sanger sequencing with multiplex ligation-dependent probe amplification or other testing technologies.

S2755 Subclinical Liver Involvement in Wilson's Disease

Introduction: Wilson’s disease is an autosomal recessive disorder resulting in defective cellular copper transport. End-organ damage due to copper accumulation in the liver and brain disease (hepatolenticular degeneration) is the most common clinical manifestation. Case Description/Methods: A 29 year old woman was evaluated at the emergency department for a suicidal gesture. During the initial evaluation, she admitted she did not want to kill herself but was rather seeking immediate help for issues that she felt had been unattended to. Her complaints included bilateral leg pain associated with muscle cramps, stiffness, weakness, symmetric resting and intentional tremors, ataxia and depressed mood evolving over the previous six months. The patient had been diagnosed with a variety of psychiatric disorders. The patient stated she had moved to Indiana shortly after Hurricane Maria and returned to PR at the onset of the present illness. No family history of neurologic or liver disease. The physical exam revealed an unaltered mental status, flat affect, facial grimacing, cogwheel rigidity of the upper extremities with mild muscle weakness, bradykinesia, dystonia, fasciculations, muscle wasting, choreoathetosis and a Parkinsonian gait. Hepatomegaly or stigmata of cirrhosis were not found. Initial laboratories were negative for anemia, thrombocytopenia, coagulopathy or hyperbilirubinemia, as was serology for Lyme disease, syphilis, hepatitis and HIV. Moreover, transaminases, inflammatory markers, ANA, ASMA, ammonia and aldolase levels were also all normal. Brain MRI suggested encephalopathy. CSF revealed no pleocytosis. The working diagnosis was encephalitis, possibly infectious or autoimmune, and the patient was initially treated with antibiotics & intravenous glucocorticoids. An elevated AFP was reported which led to an abdominal CT scan that revealed hepatomegaly with heterogeneous enhancement throughout the liver parenchyma and surface nodularity. Ophthalmology evaluation showed Kaysher-Fleischer rings. Low ceruloplasmin levels, high urine copper levels and liver biopsy were all confirmatory of Wilson’s disease, and the patient was treated with penicillamine. Discussion: This case report emphasizes the importance of ruling out organic disease before diagnosing a psychiatric illness. A young patient with neurological symptoms in the absence of evident liver disease at presentation should prompt evaluation for uncommon disorders such as Wilson’s disease.

ATP7B variant spectrum in a French pediatric Wilson disease cohort

Background/aimThe spectrum of ATP7B variants varies significantly according to geographic distribution, and there is insufficient data on the variants observed in the French population. MethodsClinical data of 113 children included in the French WD national registry were gathered from March 01, 1995 to July 01, 2020. Data included epidemiological, clinical, laboratory, genetics. ResultsDiagnosis was made at a mean age of 11.0 ± 4.1 years (range 1–18 years). At diagnosis, 91 patients (79.8 %) had hepatic manifestations, 18 (15.8 %) presented neurological manifestations, and 4 patients (3.5 %) were asymptomatic. Only 29 patients (25 %) were homozygous for a variant. We have found a total of 102 different variants including 14 novel variants. Recurrent variant p.His1069Gln was the most prevalent, n = 31 alleles (14,2%), with only seven homozygous; in contrast 55% of variants are identified in only one family. 45% were truncating variants. In respect of mutated exon, the three most prevalent were exon 14 (16.5%), exon 8 (13.8%), and exon 3 (11.5%). When considering patients with two Nonsense / Frameshift variants as a group and those with two Missense variants, we found significantly lower ceruloplasmin for the former: 2.8 ± 0.7 mg/dl vs 8.4 ± 5mg/dl (p<0.05). Conclusionp.His1069Gln is the most frequent variant (14,2%) and exons 14, 8, and 2 of the ATP7B gene account for 41.7% of total variants. However, there is significant heterogeneity in the French population concerning the other ATP7B variants. Nonsense / Frameshift variants were associated with lower ceruloplasmin levels.

Review on Parkinson’s Disease, a Neurodegenerative Disorder and The Role of Ceruloplasmin Protein in It

Parkinson’s disease (PD), a neurodegenerative disease is becoming major health concern mainly for elder people of age over 60 years. The main cause of PD is permanent loss/death of dopaminergic nerve cells present in brain part called substantia nigra, which is responsible for dopamine synthesis. MAO-B, monoamine oxidase B, regulates dopamine metabolism and increased activity of MAO-B causes dopamine degradation which in turn promotes the accumulation of glutamate and oxidative stress with free radical liberation. Several factors like oxidative stress, free radical formation, increased cholesterol, mitochondrial dysfunction, nitric oxide toxicity, signal-mediated apoptosis, head trauma, and environmental toxins and gene mutations like VPS35, SNCA, EIF4G1, GBA, CHCHD, LRRK2, PINK1, DNAJC13 and SOD2 are associated with PD. Symptoms of PD include bradykinesia, muscle rigidity, resting tremors, postural instability and shuffling gait, constipation, sleep problems, fatigue, apathy, loss of smell and taste, excessive sweating, frequent nightmares, dream enacting behaviour, anxiety, depression, daytime drowsiness. In PD, low levels of ceruloplasmin were observed in people with early onset of PD. Ceruloplasmin, a ferroxidase enzyme which is synthesized in liver parenchymal cell, regulates iron metabolism and lower level of which causes iron accumulation in brain which is responsible for the early onset of PD. Levodopa-based preparations, Dopamine agonists, Catechol-o-methyltransferase (COMT) inhibitors, MOA-B inhibitors, Adjunctive therapy, Antiglutamatergics drugs are currently used for the treatment of PD.

Severe Protein-Calorie Malnutrition-Associated Hepatic Steatosis in a Woman Who Had Roux-en-Y Gastric Bypass for Morbid Obesity Thirteen Years Ago

Hepatic steatosis is common in everyday liver pathology practice. There are many etiologies leading to hepatic steatosis. These etiologies include metabolic syndrome, alcohol, medications, monogenetic disease, infectious diseases, and malnutrition. Correct diagnosis of underlying etiology through clinicopathological correlation is key to adequate treatment and optimal outcome for the patient. In this case report, we describe severe protein-calorie malnutrition as an etiology for hepatic steatosis in a middle-aged woman who presented with lethargy, low body mass index (15.8 kg/m2), abdominal distention and bilateral lower extremity edema, hyperammonemia, and hypoalbuminemia, 13 years after Roux-en-Y gastric bypass for morbid obesity. Laboratory tests revealed hyperammonemia, hypoalbuminemia, and low ceruloplasmin levels. Hemodynamic measurement demonstrated high hepatic venous pressure gradient of 12 mm Hg. Transjugular liver biopsy showed moderate macrovesicular steatosis, mild siderosis, and abundant lipofuscin but no evidence of fibrosis, cirrhosis, or steatohepatitis. This patient was treated with lactulose and enteral feeding, however, the patient died of progressive liver failure 3 weeks after admission. We also review relevant literature to help diagnose protein-calorie malnutrition (kwashiorkor) and hepatic steatosis as a possible late complication of Roux-en-Y gastric bypass. In patients with hepatic steatosis, encephalopathy, hyperammonemia and portal hypertension, malnutrition should be considered as an etiology and diagnosed with a synthesis of clinical, pathological, and laboratory information. Kwashiorkor is a severe disease and should be treated promptly as it may be fatal as in our case.

Value of Kayser-Fleischer ring as a diagnostic tool for Wilson’s disease in children

The Kayser-Fleischer(K-F) ring is the hallmark of Wilson’s disease (WD). In most adults or older children, the diagnosis of Wilson’s disease may be made easily when K-Frings and low ceruloplasmin levels are present. In this study presence of K-F ring has been evaluated among children with liver disease in Bangladesh to improve the management of Chronic liver disease due to WD and reduce complications. This cross-sectional study was carried out at the Department of Paediatric Gastroenterology and Nutrition, BSMMU, Dhaka on 60 children presented with liver disease. Thirty children over three years of age considered as cases (Group-I) and thirty children with non- Wilsonian liver disease as control (Group-II). Slit lamp examination for K-F ring and twenty-four hour urinary copper excretion after giving one gram d-penicillamine 12-hour apart were done in each patient. The efficacy of K-F ring was studied. Mean age of WD patients was 8.9± 2.78 years, with a male female ratio of 1.3: 1. There was significant low level of serum ceruloplasmin in 93.33% of cases (p&lt;.001). After penicillamine challenge, 24-hour urinary copper excretion was found significantly higher in patients with WD (median 3626.5±1698 μg/24h, range 1262- 195000) than non-Wilsonian liver disease (median 450±278.09 μg/24-h, range 47- 2062 μg/24h), (p&lt;.001). K-F ring was found in 15 (50%) patients, absent in all patients of non-Wilsonian liver disease group and the difference was statistically significant (p&lt;.001). Evaluation of Kayser-Fleischer ring is still a very essential diagnostic tool and is a non-invasive, affordable way to assist in the diagnosis of a potentially fatal disease.

S2670 Wilson Disease Presenting With Autoimmune Hepatitis Features: A Clinical Enigma

INTRODUCTION: Wilson disease (WD) is a genetic disorder that commonly presents with neuropsychiatric and hepatic symptoms due to an inherited defect in the metabolism of copper. In some cases, the presence of autoimmune hepatitis (AIH) markers despite features of WD can result in diagnostic delays. We present the case of a 25 year old woman presenting with decompensated liver cirrhosis attributed to WD with confounding factors of AIH. CASE DESCRIPTION/METHODS: A 25 year old woman presented to the emergency department with abdominal distension and bilateral lower extremity edema. Her physical exam was remarkable for abdominal ascites and bilateral pitting leg edema. Laboratory analysis demonstrated an elevated alkaline phosphatase at 211 U/L, as well as aspartate aminotransferase and alanine aminotransferase at 97 IU/L and 62 IU/L respectively. CT abdomen demonstrated small sclerotic liver with evidence for portal hypertension. Further studies were significant for a low ceruloplasmin level, positive antinuclear antibody (ANA) and low titer positive anti-smooth muscle antibodies (ASMA). She underwent upper endoscopy that revealed Grade 2 esophageal varices (Figure 1). Patient underwent liver biopsy and pathology revealed extensive bands of bridging fibrosis consistent with cirrhosis (Figure 2). Glycogenated nuclei, iron stain and alpha-1 antitrypsin test were negative with copper stain positive for occasional deposits in hepatocytes (Figure 3). After discharge, a 24 hour urinary copper level was elevated at 595μg/and dry weight copper level was 910.3 mcg/mg confirming WD. DISCUSSION: WD is a rare genetic condition that involves hepatic and neurological dysfunctions occurring in 1 to 30,000 of the worldwide population. Intriguingly, our patient did not have any neurological or psychiatric symptoms at the moment of presentation. Of note, the patient did not undergo slit lamp examination so the presence or absence of Kayser-Fleischer rings that are present in almost every patient with neurologic disease could not be determined. We report a case of a diagnosis of WD presenting with a positive ANA and ASMA initially misdiagnosed as AIH. The confounding factor of this case was the early detection of a positive ANA and ASMA suggesting AIH as the culprit for the decompensated cirrhosis. The correct identification of the etiology for this patient’s cirrhosis is critical as treatment and prognosis differ greatly between these two entities and can prevent delays in effective interventions.Figure 1.: EGD demonstrating grade II esophageal varices.Figure 2.: Liver biopsy slide with extensive thick bands of bridging fibrosis consistent with cirrhosis.Figure 3.: Liver biopsy slide showing copper deposits in hepatocytes.

Genotype-phenotype variable correlation in Wilson disease: clinical history of two sisters with the similar genotype

BackgroundWilson disease (WD) is an Autosomal-Recessive disorder due to mutations of ATP7B gene on chromosome 13q14.3. Inadequate protein function leads to low ceruloplasmin blood levels and copper accumulation in liver, basal ganglia and chornea. Main clinical manifestations are hypertransaminasemia, tremors, dysarthria, dystonia and psychiatric symptoms. The phenotypic variability in WD is considerable and its onset can be heterogeneous: the most common type in childhood is the hepatic involvement, followed by the neurological one or others. The presence of a genotype-phenotype correlation has not yet been fully demonstrated. The phenotypic variability may be explained by the intervention of other modifier genes regulating copper metabolism in the presence of mutations ATP7B.Case presentationA streaking phenotypic variability was observed in two Sicilian sisters carrying the same genotype for ATB7B gene [c.3207C > A / c.3904-2A > G]. Although both started to present signs at age 10 years, onset was characterized by neurological signs in the first (tremors, motor incoordination, language and cognitive impairment), while liver involvement has been the only sign in the other. They started the same chelation therapy. After a 20-year follow-up the former is severely affected (MRI evidence of basal ganglia copper deposits and hyperchogenic liver, thrombocytopenia), while the latter presents only a moderate liver enlargement. In literature, the splice mutation c.3904-2A > G is also reported in Egypt population, associated with acute liver failure or chronic hepatic disease, and it could be typical of Mediterranean area, not being reported in other geographical zones.ConclusionBased on our clinical experience in Eastern Sicily, there is a considerable phenotypic variability in WD, even in the presence of an identical genotype. The mutation c.3904-2A > G could be associated with this phenotypic variability in Mediterranean population, but further studies should be conducted. This condition could be explained by the intervention of modifier genes regulating copper metabolism in the presence of defective ATP7B protein function. Further investigations on their role by Next Generation Sequencing or Whole Exome Analysis might have a profound impact on patients’ management and in particular on therapy.

Clinical, biochemical and allergological indices characterizing occupational diseases of the bronchial and pulmonary system in employees at aluminium production

There are many harmful factors that possess a damaging impact on the body of employees at aluminum production. It leads to the development of bronchial asthma (BA), chronic nonobstructive bronchitis (CNB) and chronic obstructive pulmonary disease (COPD). The pathogenesis of these disorders, as well as sensitizing effect offluorine in the aluminum production is not fully understood. The purpose of this work was to study the characteristics of laboratory indices in patients with occupational diseases of the respiratory system. In workers of aluminum production with the diagnosis of occupational diseases of respiratory system (15 patients with a diagnosis of asthma, 30 CNB cases, 20 COPD patients) we evaluated the content of total protein, total cholesterol, high density lipoprotein cholesterol (HDLC), total calcium, phosphorus, ceruloplasmin, hematological indices and performed emigration of leukocytes braking test (TTEEL). Clinical and biochemical profile ofpersons with occupational asthma was characterized by a low level of total calcium and ceruloplasmin, a high concentration of phosphorus in the blood serum and inhibition of leukocyte emigration in the test with sodium fluoride. For aluminum production CNB workers characteristic active proatherogenic process was pronounced by a decrease in the HDLC level and an increase in atherogenic index; higher hematocrit value and concentration of erythrocytes, and more than 50% of cases of sensitization to the presence of sodium fluoride. COPD cases had occupational lower average concentration of hemoglobin in the erythrocyte, total protein in serum, as well as polymorphic variant response to sodium fluoride in the form of a depression and activation of leucocytes emigration.

Diagnostic imaging features of Menkes disease

Objective To analyze the imaging features of Menkes disease in children, and in order to identify the diagnostic value and improve the knowledge of it. Methods The imaging findings of 9 Menkes disease patients confirmed by the clinical and laboratory examinations were retrospectively analyzed. All the patients were male aged from 2.0 to 7.0 months with a median age of 3.0 months. The clinical manifestations including seizures, psychomotor retardation, dystonia accompanied with light complexion and curly hair. The laboratory examinations showed low serum copper and ceruloplasmin levels. All the patients were performed with plain MR scan and MR angiography, 7 cases were performed with chest X-ray examinations and 4 cases were performed with bone X-ray examinations and 1 were performed with hand X-ray examinations. Results The plain MR scan showed white matter lesions in 8 cases, abnormality signal intensity of basal ganglia in 4 cases, subdural effusion in 2 cases. 8 cases had cerebral and cerebellar atrophy at different degrees. The MR angiography showed abnormal tortuosity of the main intracranial arteries. The chest X-ray of 5 in 7 cases showed that the front end of bilateral ribs were spherical and enlarged. 4 cases were performed with bone X-ray presenting, 3 out of 4 cases showed the widened metaphysis of tibia, fibula, femoral, humerus ulna and radius with the shape like cup-mouth and the formation of bony spur locally. The X ray examination of 1 case with connecting palm showed symphysodactylia. Conclusion Brain MR, X-ray of chest and bone showed imaging features of Menkes disease. MR angiography finding was the most distinctive feature, which has important value in the diagnosis of Menkes disease. Key words: Menkes disease; Magnetic resonance imaging; Copper

An electrochemical ceruloplasmin aptasensor using a glassy carbon electrode modified by diazonium-functionalized multiwalled carbon nanotubes

Fast and accurate determination of biological compounds in human fluids plays a crucial role in clinical analysis. Low levels and high levels of ceruloplasmin (Cp) in serum cause several diseases such as Wilson’s disease, therefore, its accurate determination in human fluids is important. A selective and sensitive electrochemical biosensor was developed for Cp detection using a Cp-specific recognition aptamer. The proposed aptasensor was based on a glassy carbon electrode modified with diazonium-functional multiwall carbon nanotubes. The aptamer was linked to the electrode surface using electrochemical approach, followed by chemical immobilization of aminated-aptamer. All fabrication steps were accompanied by changes to the electrochemical parameters. The binding of Cp to aptamer was monitored by cyclic voltammetry, differential pulse voltammetry, and electrochemical impedance spectroscopy. The effective parameters were optimized. The calibration curve for Cp concentration was linear at 0.02–3.0 ng mL−1 and 3.0–80.0 ng mL−1 with a detection limit (signal-to-noise ratio of 3) of 3.7 pg mL−1. The fabricated aptasensor can serve as a powerful sensor for rapid diagnosis of Cp in the human serum sample and shows a great potential for practical bioapplication.

Menkes kinky hair disease: Role of dermatologist

Menkes kinky hair disease is an X-linked recessive multisystem disorder which mainly involves a central nervous system and usually presents in early infancy. The underlying defect is in copper metabolism leading to impaired function of copper-dependent enzymes. Diagnosis is confirmed by low level of serum copper and serum ceruloplasmin. Classical disease is associated with poor prognosis. Hereby, we report a classical case of Menkes kinky hair disease with characteristic clinical as well as laboratory findings and radiological features. We are reporting this case because of its early presentation.

Incidental Diagnosis of Wilsonʼs Disease: A Case Report

Wilson's disease (WD) is a genetic disorder of copper metabolism caused by complete absence or dysfunction of a copper transporting enzyme which is a transmembrane protein ATPase (ATP7B) encoded on chromosome 13. The incidence of this condition is seen in 1 in 30 000 individuals. The presentation of WD is variable and usually involves the hepatic and neuropsychiatric systems with symptoms ranging from chronic liver disease, compensated or decompensated cirrhosis, fulminant liver failure, dystonia,choreiform movements, tremor, gait disturbances, personality changes and cognitive impairments which are attributed to copper accumulation. We present a case where routine imaging for a persistent problem considered to be chronic pelvic pain led to the diagnosis of WD. A 28-year-old female with history of longstanding depression and Type 1 Diabetes Mellitus was admitted with recurrent abdominopelvic pain. She had been hospitalized multiple times for evaluation of recurrent abdominopelvic pain. Her initial episode of abdominopelvic pain was evaluated with a CT Abdomen that showed a pelvic abscess which was managed surgically with complete resolution and since then, she has had extensive evaluation including serial imaging during subsequent hospitalizations which were negative for any acute process. During this admission, a repeat CT Abdomen showed new onset cirrhosis of the liver which was absent on previous imaging studies. Patient denied alcohol use and after a negative infectious, autoimmune and hematological workup, further laboratory evaluation showed low serum levels of ceruloplasmin (5.4 mg/dl) and an elevated 24 hour urine copper excretion (302 ug/d).Slit light examination of the eyes was negative for Kayser-Fleisher rings. MRI Brain showed T2 high signal intensity in the pons. She was empirically started on zinc gluconate. Genetic testing showed heterozygous mutation in the gene ATP7B and a diagnosis of Wilson's disease was made. Patient continues to be maintained on zinc therapy and is closely being followed as an outpatient for liver transplant evaluation. The diagnosis of WD can be easily missed and if diagnosed early could potentially prevent or reverse many of its serious manifestations. Despite the involvement of the hepatic and neurological system on imaging, our patient was completely asymptomatic which makes this case unique. Our case further reiterates the importance of always keeping WD on the differential in evaluating patients with cirrhosis.