Diagnostic imaging features of Menkes disease / 中华放射学杂志

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.

Research progress in Menkes disease / 国际儿科学杂志

Menkes Disease (MD) is a multisystemic disorder of impaired copper metabolism with an X-linked recessive inheritance,which is caused by defects in ATP7A gene encoding a copper-transporting AT-Pase.It is characterized by infantile onset,peculiar curls and facial changes,mental retardation with progressive neurodegeneration,as well as hypotonia and connective tissue abnormalities.Many intermediate phenotypes have been found in recent years,the mildest form of which is occipital horn syndrome (OHS).Its clinical variants show a broad spectrum from chromosome abnormalities to single-nucleotide mutation.Early copper-histidine supplementation is still the most crucial treatment at present,and L-DOPS combination therapy may benefit some patients clinically.This article reviews the pathogenesis,clinical features and the progress of diagnosis and treatment of MD.

Urological Problems in Patients with Menkes Disease

BACKGROUND: Menkes disease (MD) is a rare X-linked hereditary multisystemic disorder that is caused by dysfunction of copper metabolism. Patients with MD typically present with progressive neurodegeneration, some connective tissue abnormalities, and characteristic “kinky” hair. In addition, various types of urological complications are frequent in MD because of underlying connective tissue abnormalities. In this study, we studied the clinical features and outcomes of MD, focusing on urological complications. METHODS: A total of 14 unrelated Korean pediatric patients (13 boys and 1 girl) with MD were recruited, and their phenotypes and genotypes were analyzed by retrospective review of their medical records. RESULTS: All the patients had early-onset neurological deficit, including developmental delay, seizures, and hypotonia. The girl patient showed normal serum copper and ceruloplasmin levels as well as milder symptoms. Mutational analysis of the ATP7A gene revealed 11 different mutations in 12 patients. Bladder diverticula was the most frequent urological complication: 8 (57.1%) in the 14 patients or 8 (72.7%) in the 11 patients who underwent urological evaluation. Urological imaging studies were performed essentially for the evaluation of accompanying urinary tract infections. Four patients had stage II chronic kidney disease at the last follow-up. CONCLUSION: Urologic problems occurred frequently in MD, with bladder diverticula being the most common. Therefore, urological imaging studies and appropriate management of urological complications, which may prevent or reduce the development of urinary tract infections and renal parenchymal damage, are required in all patients with MD.

A Case of Menkes Disease First Manifested as Severe Vesicoureteral Reflux Caused by a Novel Mutation in ATP7A Gene / 대한소아신경학회지

Menkes disease is a rare, neurodegenerative, copper metabolism disorder characterized by mutations in ATP7A gene. Clinical symptoms include epilepsy, growth delay, reduced muscle strength, skin hyperextension, hair deformation and urologic abnormalities. However, since these clinical symptoms occur 2–3 months after birth, early diagnosis of Menkes disease is very difficult for clinicians. We report here the case of a patient who initially presented urinary tract infection followed by neurologic symptoms of Menkes disease; he was accurately diagnosed via ATP7A genetic analysis and found to harbor a novel mutation. Although neurological symptoms are the primary diagnostic feature of Menkes disease, clinicians should take into account urinary abnormalities as well, which may be an important clue to the early diagnosis of these patients.

Clinical and laboratory features and gene diagnosis of Menkes disease / 中华实用儿科临床杂志

Objective To explore the clinical and laboratory features,and gene diagnosis method of Menkes disease (MD).Methods The clinical and laboratory features and gene diagnosis method of 2 infants with MD were reviewed.Results (1) Clinical features:both infants mentioned in this article were male.Their clinical manifestations were both began at 3-4 months age,including peculiar kinky hair,pale skin,pudgy cheeks,inguinal hernia,vessel abnormality,epilepsy and mental retardation.(2) Laboratory features:the ceruloplasmin concentrations significantly reduced to be ＜ 20 mg/L and 47 mg/L,respectively.The magnetic resonance angiogram images of case 1 showed the abnormal tortuosity of his intracranial vessels.The magnetic resonance images of case 2 showed a rapid progress from normal to severe brain atrophy within half a year.(3) Gene diagnosis:the sequencing of ATP7A gene in case 1 showed a nonsense mutation of c.2110 C ＞ T.The pathogenicity of this mutation had not been reported previously at home and abroad.The sequencing of the gene panel without pathogenic mutation was detected in case 2.But the multiplex ligation-dependent probe amplification test showed a gross deletion of ATP7A gene containing 8-12 exons.This mutation had been documented as a pathogenic mutation of MD.Both mothers of 2 patients were heterozygous mutation carriers of normal phenotype.Conclusions MD is a multisystemic disease caused by ATP7A gene mutation resulting in copper metabolism disorder.MD is inherited as an X-linked recessive trait.MD is characterized by kinky hair,connective tissue abnormalities and progressive neurodegeneration.Clinical diagnosis can be made on the basis of clinical features,findings of blood biochemical examination,and radiological findings.Gene sequencing and multiplex ligation dependent probe amplification test are the main technique widely used for genetic diagnosis.

Reporte de caso clínico: enfermedad de Menkes / Clinical case report: Menkes disease

La enfermedad de pelo ensortijado de Menkes es una patología congénita hereditaria, de pobre pronóstico, causada por una mutación de gen ATP7A localizado en el cromosoma X que codifica para las enzimas dependientes de cobre. Esta patología clínicamente está caracterizada por temprano retardo en el crecimiento, cabello frágil y ensortijado, degeneración arterial, cerebral y cerebelosa, lo que se explica por la disminución de la actividad de las cuproenzimas. Los severos daños neurológicos comienzan dentro del primero o segundo mes de vida y progresan rápidamente hasta la descerebración y muerte. El paciente objeto de estudio presentó desde los dos meses de edad crisis convulsivas focalizadas, que no ceden al tratamiento con anticonvulsivantes y que obligó a varias hospitalizaciones por su rápido y progresivo deterioro neurológico. La presencia además de un cabello acerado,frágil, escaso y despigmentado al igual que su piel, mejillas regordetas, frente olímpica, severa hipotonía muscular y el antecedente materno de cinco abortos, un hermano y dos tíos fallecidos tempranamente con convulsiones, permitió el diagnóstico clínico, que luego se corroboró con estudios complementarios.

Menkes disease is a congenital hereditary disease of poor prognosis caused by a mutation of the ATP7A gene located on the chromosome X, which codes for copper-dependent enzymes. This condition is clinically characterized by an early growth retardation, fragile and kinky hair, arterial degeneration and cerebral and cerebellar degeneration, which can be explained by the decreasedactivity of cuproenzimas. The severe neurological damages begin within the first or second month of life and progress rapidly to decerebration and death. The patient under study presented focal convulsive crises at the age of two months, which did not improve when treated with anticonvulsants and forced several hospitalizations because of the rapid and progressive neurologicaldeterioration. The additional presence of steely, brittle, sparse and depigmented hair as well as skin, chubby cheeks, an Olympic forehead, a severe muscular hypotonia and a maternal history of five abortions, one brother and two uncles who died early with convultions, allowed the predominant clinical diagnosis, which was then confirmed with further studies

Hair Abnormality and Cutis Laxa in Menkes Disease / 대한피부과학회지

Menkes disease, so called kinky-hair syndrome, is a rare fatal X-linked recessive disorder, which is caused by a mutation in the ATP7A gene encoding the copper transporting ATPase. Dysfunction of copper-dependent enzymes results in various clinical features, including skin and hair hypopigmentation, progressive neurologic degeneration, bone and connective tissue alterations with soft doughy skin and joint laxity, and vascular abnormalities, including aneurysms and bladder diverticula. Patients have the characteristic hair, which is kinky, colorless or steel-colored, and brittle with cutis laxa. Early diagnosis and treatments are perquisites for improving the clinical outcomes. Herein, we describe a rare case of Menkes disease accompanied by hair abnormality and cutis laxa in a 35-days-old boy.

Hair Abnormality and Cutis Laxa in Menkes Disease / 대한피부과학회지

Menkes disease, so called kinky-hair syndrome, is a rare fatal X-linked recessive disorder, which is caused by a mutation in the ATP7A gene encoding the copper transporting ATPase. Dysfunction of copper-dependent enzymes results in various clinical features, including skin and hair hypopigmentation, progressive neurologic degeneration, bone and connective tissue alterations with soft doughy skin and joint laxity, and vascular abnormalities, including aneurysms and bladder diverticula. Patients have the characteristic hair, which is kinky, colorless or steel-colored, and brittle with cutis laxa. Early diagnosis and treatments are perquisites for improving the clinical outcomes. Herein, we describe a rare case of Menkes disease accompanied by hair abnormality and cutis laxa in a 35-days-old boy.

Identification of a Novel Mutation in the ATP7A Gene in a Korean Patient with Menkes Disease

Menkes disease is an infantile-onset X-linked recessive neurodegenerative disorder caused by diverse mutations in a copper-transport gene, ATP7A. Affected patients are characterized by progressive hypotonia, seizures, failure to thrive and death in early childhood. Here, we report a case of Menkes disease presented by intractable seizures and infantile spasms. A 3-month-old male infant had visited our pediatric clinic for lethargy, floppy muscle tone, poor oral intake and partial seizures. His hair was kinky, brown colored and fragile. Partial seizures became more frequent, generalized and intractable to antiseizure medications. An EEG showed frequent posteriorly dominant generalized spikes that were consistent with a generalized seizure. From a genetic analysis, a c.2743C>T (p.Gln915X) mutation was detected and diagnosed as Menkes disease. The mutation is a novel one that has not been previously reported as a cause of Menkes disease.

Doença de Menkes: relato de caso / Menkes' Disease: case report

Relata-se um caso clássico de doença de Menkes, uma doença neurodegenerativa acompanhada de manifestações sistêmicas, dentre elas aspecto típico do cabelo. O diagnóstico se confirma pelos níveis baixos de ceruloplasmina e cobre no sangue. Os autores trazem uma revisão atualizada, não sistemática, da literatura.

A classical case of Menkes? disease is discussed, a neurodegenerative disease accompanied by systemic manifestations, including a typicalaspect of the hair. The diagnosis is confirmed by low serum levels of ceruloplasmin and copper. The authors bring forth an updated nonsystematic revision of the literature.

A case of Menkes disease with unusual hepatomegaly / 소아과

Menkes disease is an X-linked recessive copper transport disorder characterized by neurological deterioration, connective-tissue damage, and abnormal hair growth. It is caused by the mutation of the ATP7A gene. This report describes a four-month-old boy with neurological symptoms typical of Menkes disease plus unusual liver involvement. He developed seizures at three months of age and exhibited hypotonia, cephalhematoma, a sagging face, redundant and hypopigmented skin, and abnormal hair growth. In addition, he had unexplained hepatomegaly and high hepatic transaminase. We confirmed the diagnosis of Menkes disease by mutation analysis of the ATP7A gene. To exclude other possible causes for the hepatic abnormalities, a liver biopsy was performed, revealing intracytoplasmic cholestasis, focal spotty necrosis, and minimal lobular activity. The patient's liver involvement may be an underestimated complication of Menkes disease.

Controversial issues in the legal restriction for prenatal genetic testing in Korea

More than 6,000 rare disorders including genetic diseases have been reported. Of them, 1,500 diseases (1,211 for clinical diagnosis and 289 for research only) are technically possible for genetic testing. In Korea, since 2005, only 63 genetic diseases is permitted for prenatal genetic testing by the "Bioethics and Biosafety Law". The article 25 in the law prescribes 63 genetic diseases without clear indication for its selection and inclusion criteria. In EU, USA, and other foreign countries, however, there is no provision in the statute on prenatal genetic testing; it is not restricted by a law. Recently, a woman (Mrs. L, 38y) who is a carrier for Menkes disease made an appeal to a government for an amendment of the "Bioethics and Biosafety Law" prohibiting the prenatal diagnosis of her pregnancy at risk for Menkes disease. Menkes disease (MNK) is an X-linked recessive disorder characterized by neurodegeneration, connective tissue defects and hair abnormalities, and no effective treatment is available yet. The prevalence rate of MNK is one in about 250,000 live births. Menkes syndrome patients fail to absorb copper from the gastrointestinal tract in quantities adequate for meeting nutritional needs. These needs seem particularly acute during the initial 12 month of life, when the velocity of brain growth and motor neurodevelopment. Most of pts. die around 3yrs. of age. Mrs. L had a boy with Menkes disease who died at 2y.o. in 2001. Subsequent pregnancy in 2003, she was able to have prenatal genetic testing for mutation of the Menkes (ATP7A) gene and delivered a healthy baby boy. Now, She is pregnant again and wants to have prenatal diagnosis. however, this time, she was not allowed to have any more because Menkes disease is not included in 63 genetic diseases permitted by the law for prenatal genetic testing, in spite of the fact that she is a Menkes disease carrier and her pregnancy is at risk to have an affected baby. This case shows the practical problem of the legal restriction for prenatal genetic testing in Korea. In this study, we report a arguable case and discuss the controversial issues in the legal restriction for prenatal genetic testing in Korea.

Identification of novel mutations of the ATP7A gene and prenatal diagnosis of Menkes disease by mutation analysis

PURPOSE: Menkes disease is an X-linked recessively inherited disorder caused by the mutation of the ATP7A gene encoding copper-transporting P-type ATPase. The phenotypic features are progressive neurological degeneration, mental retardation, loose skin, and vascular complications. Early diagnosis and treatment are very important for the prognosis of Menkes disease. Here, we describe novel mutations of the ATP7A gene and prenatal diagnosis by mutation analysis. METHODS: Five unrelated Korean Menkes patients were included in this study. They presented with depigmented wool-like hair, progressive neurologic deterioration, and hypotonia in infancy. Serum copper and ceruloplasmin levels were decreased. Brain magnetic resonance imaging revealed tortuous intracranial vessels. Mutation analysis has been carried out using cDNA from cultured skin fibroblasts or genomic DNA from peripheral leukocytes. Prenatal diagnosis was performed in two cases using chorionic villi samples or amniocytes. RESULTS: Four novel mutations have been identified from four different families; c.3511+1G

An Anesthetic Experience in a Patient with Menkes Disease: A case report / 대한마취과학회지

Menkes disease, so-called kinky hair disease or steely hair disease, is a rare X-linked recessive disorder of intracellular copper transport protein ATP7A defect, due to mutation of ATP7A gene, resulting in copper deficiency. It is characterized by seizure, retarded neurological development, kinky hair, skeletal abnormality, recurrent infection and subnormal body temperature. In addition, gastroesophageal reflux with the risk of aspiration is another important feature. This article is the first report of anesthetic management in a patient with Menkes disease who underwent gastrostomy and bladder diverticulectomy in Korea.

A Case of Menkes disease with Infantile Spasm / 대한소아신경학회지

Menkes disease, so called kinky-hair syndrome, is a rare, genetic and progressive neurodegenerative disorder. It is caused by a mutation in the ATP7A gene, which codes for the copper transporting ATPase in the cell organelles. The dysfunction of many copper-dependent enzymes results in low concentration of copper in some tissues and accumulation of copper in others. We report a boy presented with kinky hairs, developmental delay, hypotonia and connective tissue abnormalities at the age of 4 months. Despite the treatment with various antiepileptic drugs, atonic seizures still persisted. At the age of 7 months, his atonic seizures was changed into extensor spasms with modified hypsarrhythmia for some years. The seizure were controlled by topiramate and vigabatrin. At the age of 22 months, serum copper and ceruloplasmin rechecked as 17 ug/dL(80-150 ug/dL) and 7.3 mg/dL(20-46 mg/ dL) respectively. The gene study showed ATP7A mutation and the patient was diagnosed as Menkes disease so that copper-histidine was daily injected. We experienced a case of a 4-month-old boy with Menkes disease and infantile spasm, confirmed by ATP7A mutation.

3-year Follow-up of a Menkes Disease Patient / 대한소아신경학회지

Menkes disease is a rare fatal X-linked recessive disorder characterized by a generalized defect in intracelluar copper transport. The clinical features which arise from copper deficiency include progressive neurologic deterioration, epilepsy, hair and connective tissue abnormalities. Menkes disease is caused by mutations in the gene encoding the Menkes protein(ATP7A, copper transporting P-type ATPase), which is located on the long arm 13 of the X-chromosome. ATP7A mutations are found in 60 to 70% of the patients. We have experienced a case of Menkes disease in a 6-month-old male who showed developmental delay, myoclonic seizures and kinky hair. The serum copper and ceruloplasmin levels were low and the missense mutation(c.3352G>A, resulting in p.G1118S) in exon 17 of ATP7A gene was found. During 3-year follow-up, he regressed developmentally and showed brain atrophy, multiple bladder deverticula, and bony deformities.

Diffusion-Weighted MR Imaging of Unusual White Matter Lesion in a Patient with Menkes Disease

We report here on the diffusion-weighted imaging of unusual white matter lesions in a case of Menkes disease. On the initial MR imaging, the white matter lesions were localized in the deep periventricular white matter in the absence of diffuse cortical atrophy. The lesion showed diffuse high signal on the diffusion-weighted images and diffuse progression and persistent hyperintensity on the follow up imaging. Our case suggests that the white matter lesion may precede diffuse cortical atrophy in a patient with Menkes disease.

Clinical and Gene Diagnosis on Menkes Disease in Two Families / 实用儿科临床杂志

Objective To detect the mutation of ATP7A gene in 2 families with Menkes disease.Met-hods Genomic DNA of 6 members from 2 families were extracted with salt fractionation.The encoding exons and 2 sides flanking intron of ATP7A gene were amplified from genomic DNA of the probands and their parents by PCR and directly sequence.Light microscope was used to test the hair of probands and normal healthy children.Results Proband 1 had a deletion mutation of c.3 045del T in exon 14 of ATP7A gene and resulted in a stop codon just several nucleotides behind the deletion site.His mother was a heterozygote of the mutation and had normal phenotype.Proband 2 had a nonsense mutation of c.2 956 in exon 14 of ATP7A gene and resulted in a stop of amino acid synthesis.His mother was not a heterozygote of the mutation.Genetype and phenotype in fathers of the 2 probands were normal.Hair of the probands in light microscope were tenuity,midheaven,the color of hair also turned to light.Conclusions The c.3 045del T mutation of ATP7A gene cause the phenotype of Menkes disease in proband 1.His mother is a heterozygote of the disease without symptoms and he is of familial inheritance.The c.2 956 nonsense mutation of ATP7A gene cause the phenotype of Menkes disease in proband 2.His mother is not a heterozygote of the disease and he is not of familial inheritance.