Novel, likely pathogenic variant in ATP7A associated with Menkes disease diagnosed with ultrarapid genome sequencing.

Menkes disease is a multisystem disorder caused by disturbances in copper absorption and metabolism. This lethal neurodegenerative disease presents with fine, 'kinky' hair, connective tissue dysfunction and developmental regression after 2-3 months of age. The primary variant associated with Menkes is in the ATP7A gene with X-linked recessive inheritance. Historically, the diagnosis of Menkes has relied on clinical signs and symptoms, but as the disease has varying levels of severity and presentation, it can take months to diagnose and treat. Emerging technology for ultrarapid genome sequencing offers a DNA-based route of diagnosis with preliminary results in hours, allowing for earlier discovery and treatment of Menkes with the potential for better long-term outcomes. Ultrarapid whole genome sequencing identified a novel, likely pathogenic, frameshift variant in the ATP7A gene consistent with a diagnosis of Menkes disease. The clinical manifestations and pathophysiology of this disorder, as well as a rapid DNA-based diagnosis, are described in this case.

Low function of natural killer cells in treated classic Menkes disease.

BACKGROUND: Menkes disease (MD) is a rare lethal X-linked, multisystem disorder of copper metabolism resulting from mutations in the ATP7A gene. Features such as Ehlers- Danlos syndrome, trichopoliodystrophy, urologic and skeletal changes have been reported. We present a case of classic MD treated with copper infusions who suffered from persistent natural killer (NK) cell dysfunction. CASE: A 2-year-old, Caucasian male child presented at 8-month-old of age with persistent hypotonia, kinky hair and developmental regression. Diagnosis of MD was based on low serum levels of copper [5 mg/dl (18-37)] and ceruloplasmin [18 ug/dl (75-153)] and gene-targeted deletion/duplication analysis performed by the reference laboratory. Brain MRI showed mild hypoplasia of the cerebellar vermis and vascular tortuosity typical of MD. Copper chloride treatment was immediately initiated. The child became more alert with excellent eye contact and purposeful movements. The child was hospitalized for recurrent respiratory infections, each time caused by enterovirus as confirmed by multiplex polymerase chain reaction (PCR). Extensive immunologic studies were negative, except for a severe NK cell dysfunction on multiple occasions (0.6 NK lytic Units; N > 2.6). CONCLUSION: We postulate that NK cell dysfunction in a classic MD can be explained by the deficient incorporation of copper in the endoplasmic reticulum resulting in an abnormal Fenton chemistry within phagosomes.

Report of a novel ATP7A mutation causing distal motor neuropathy.

We describe a novel ATP7A gene mutation associated with distal motor neuropathy, mild connective tissue abnormalities and autonomic disturbances. Next-generation sequencing analysis of a lower-motor neuron diseases gene panel was performed in two sibs presenting with distal motor neuropathy plus an autonomic dysfunction, which main manifestations were retrograde ejaculation, diarrhea and hyperhydrosis. Probands underwent dysmorphological, neurological, electrophysiological as well as biochemical evaluations and somatic and autonomic innervation studies on skin biopsies. A novel missense mutation (p.A991D) was identified in the X-linked ATP7A gene, segregating in both brothers and inherited from their healthy mother. Biochemical studies on patients' blood samples showed reduced serum copper and ceruloplasmin levels. Clinical and neurophysiological evaluation documented dysautonomic signs. Quantitative evaluation of skin innervation disclosed a small fiber neuropathy with prevalent autonomic involvement. Mutations in the ATP7A gene, encoding for a copper-transporting ATPase, have been associated with the severe infantile neurodegenerative Menkes disease and in its milder variant, the Occipital Horn Syndrome. Only two ATP7A mutations were previously reported as causing, a pure axonal distal motor neuropathy (dHMN-SMAX3). The phenotype we report represents a further example of this rare genotype-phenotype correlation and highlights the possible occurrence in SMAX3 of autonomic disturbances, as described for Menkes disease and Occipital Horn Syndrome.

Menkes disease complicated by concurrent Koolen-de Vries syndrome (17q21.31 deletion).

BACKGROUND: Koolen-de Vries (KdV) syndrome is caused by a 17q21.31 deletion leading to clinical symptoms of hypotonia and developmental delay and can present with abnormal hair texture. Menkes disease is an X-linked recessive inherited disease caused by pathogenic variants in ATP7A, which leads to profound copper deficiency. METHOD: We identified an infant male who presented with prematurity, hypotonia, and dysmorphic features for whom a family history of clinical Menkes disease was revealed after discussion with the clinical genetics team. RESULTS: Although initial first-tier genetic testing identified Kdv syndrome (17q21.31 syndrome), the family history led the team to consider a second diagnostic possibility, and testing of ATP7A revealed a pathogenic variant (c.601C>T, p.R201X). CONCLUSION: Menkes disease and KdV syndrome may both present with hypotonia and abnormal hair, in addition to seizures and failure to thrive. While these genetic conditions have overlapping clinical features, they have different natural histories and different therapeutic options. Here, we report on a patient affected with both disorders and review the diagnostic and therapeutic difficulties this presented.

Identification of novel ATP7A mutations and prenatal diagnosis in Chinese patients with Menkes disease.

Menkes disease (MD) is a fatal X-linked multisystem disease caused by mutations in ATP7A. In this study, clinical and genetic analysis was performed in 24 male MD patients. Development delay, seizures, kinky coarse hair, and dystonia were found in 24, 22, 24, and 24 patients, respectively. Serum ceruloplasmin/copper tested in 19 patients was low. Abnormal classic features of MD presented in the MRI/MRA of 19 patients. Seventeen mutations of ATP7A were identified in 22 patients. Twelve were novel mutations including three small deletion/insertion, one missense mutation, two nonsense mutations, three splicing-site mutations, and three gross deletions. Twenty-two patients were genetically diagnosed; neither point mutation nor deletion/duplication was found in two of them. c.2179G > A found in five patients might be a hot-spot mutation. Prenatal molecular diagnosis was performed for five unrelated fetuses (1 female and 4 male), which found four fetuses to be wild type and one male carried the same mutation as the proband. This study of the largest sample of Chinese MD patients examined to date discovered the unique phenotype and genotype spectrum in Chinese patients with 12 novel mutations of ATP7A, and that c.2179G > A might be a hot-spot mutation in MD patients. Five successful prenatal diagnosis contributed important information for MD families.

Characterization of ATP7A missense mutants suggests a correlation between intracellular trafficking and severity of Menkes disease.

Menkes disease (MD) is caused by mutations in ATP7A, encoding a copper-transporting P-type ATPase which exhibits copper-dependent trafficking. ATP7A is found in the Trans-Golgi Network (TGN) at low copper concentrations, and in the post-Golgi compartments and the plasma membrane at higher concentrations. Here we have analyzed the effect of 36 ATP7A missense mutations identified in phenotypically different MD patients. Nine mutations identified in patients with severe MD, virtually eliminated ATP7A synthesis, in most cases due to aberrant RNA splicing. A group of 21 predominantly severe mutations led to trapping of the protein in TGN and displayed essentially no activity in a yeast-based functional assay. These were predicted to inhibit the catalytic phosphorylation of the protein. Four mutants showed diffuse post-TGN localization, while two displayed copper dependent trafficking. These six variants were identified in patients with mild MD and typically displayed activity in the yeast assay. The four post-TGN located mutants were presumably affected in the catalytic dephosphorylation of the protein. Together these results indicate that the severity of MD correlate with cellular localization of ATP7A and support previous studies indicating that phosphorylation is crucial for the exit of ATP7A from TGN, while dephosphorylation is crucial for recycling back to TGN.

A Truncating De Novo Point Mutation in a Young Infant with Severe Menkes Disease.

Menkes disease is a rare neurodegenerative disorder caused by mutations in ATP7A gene. Deficiency in copper-dependent enzymes results in the unique kinky hair appearance, neurodegeneration, developmental delay, seizures, failure to thrive and other connective tissue or organ abnormalities. Other than biochemical tests, DNA-based diagnosis is now playing an important role. More than two hundred mutations in ATP7A gene were identified. Early copper supplementation can help improve neurological symptoms, but not non-neurological problems. Further molecular studies are needed to identify additional mutation types and to understand the mechanism of pathogenesis. This may help in discovering the possible treatment measures to cure the disease. We present a case with the clinical features and biochemical findings, abnormal brain magnetic resonance imaging as well as the effects of treatment with copper-histidine. Direct sequencing of ATP7A gene revealed a de novo point mutation which resulted in an early stop codon with truncated protein.

Ataxia telangiectasia, Menkes kinky hair disease and neurocutaneous melanosis.

This article explores three neurocutaneous syndromes (NCSs), i.e. genetic disorders producing developmental abnormalities of the skin and an increased risk of neurological complications. In this review, different aspects of ataxia telangiectasia, Menkes kinky hair disease and neurocutaneous melanosis are examined: clinical features, genetic defect, mutation spectrum, pathogenesis, and neurobiological basis; indications for clinical practice are also provided to the readers. The aim of this review is to stress the importance of cooperation among dermatologists, neurologists and psychiatrists, in order to provide patients suffering from these diseases with timely diagnosis and targeted treatments.

Menkes disease: importance of diagnosis with molecular analysis in the neonatal period.

Menkes disease is a congenital disorder caused by changes in copper metabolism derived from mutations in the ATP7A gene. It is characterized by physical and neurological alterations. In the neonatal period, these alterations can be nonspecific, which makes early diagnosis a challenge. Diagnosis can be suspected when there are low levels of ceruloplasmin and serum copper. Molecular analysis confirms the diagnosis. Treatment is parenteral administration of copper histidine. We report a familial case with molecular confirmation. The proband had clinical and biochemical suspicious. Treatment with copper histidine was indicated, but initiated at the age of 2 months and 27 days only. He did not present improvements and died at 6 months. The mother became pregnant again, a male fetus was identified and copper histidine was manufactured during pregnancy. He was born healthy, biochemical markers were reduced and treatment was indicated. Molecular analysis was performed confirming mutation in both the mother and the proband, while the other son did not have mutation, so treatment was discontinued. We support the clinical relevance of molecular confirmation for the correct diagnosis and genetic counseling, once clinical findings in the neonatal period are nonspecific and early treatment with parenteral copper histidine must be indicated.

Menkes disease: importance of diagnosis with molecular analysis in the neonatal period / Doença de Menkes: importância do diagnóstico com análise molecular no período neonatal

Summary Menkes disease is a congenital disorder caused by changes in copper metabolism derived from mutations in the ATP7A gene. It is characterized by physical and neurological alterations. In the neonatal period, these alterations can be nonspecific, which makes early diagnosis a challenge. Diagnosis can be suspected when there are low levels of ceruloplasmin and serum copper. Molecular analysis confirms the diagnosis. Treatment is parenteral administration of copper histidine. We report a familial case with molecular confirmation. The proband had clinical and biochemical suspicious. Treatment with copper histidine was indicated, but initiated at the age of 2 months and 27 days only. He did not present improvements and died at 6 months. The mother became pregnant again, a male fetus was identified and copper histidine was manufactured during pregnancy. He was born healthy, biochemical markers were reduced and treatment was indicated. Molecular analysis was performed confirming mutation in both the mother and the proband, while the other son did not have mutation, so treatment was discontinued. We support the clinical relevance of molecular confirmation for the correct diagnosis and genetic counseling, once clinical findings in the neonatal period are nonspecific and early treatment with parenteral copper histidine must be indicated.

Resumo A doença de Menkes é causada por uma alteração genética no metabolismo do cobre, por mutações no gene ATP7A. Caracteriza-se por alterações neurológicas e no exame físico. No período neonatal, essas alterações podem ser inespecíficas, o que torna o diagnóstico precoce um desafio. O diagnóstico pode ser suspeitado quando há baixos níveis séricos de cobre e ceruloplasmina. A análise molecular confirma o diagnóstico, e o tratamento deve ser feito com histidina de cobre. Nós relatamos um caso familial de doença de Menkes. O probando apresentava quadro clínico e alterações bioquímicas compatíveis com a doença de Menkes, em consulta com 1 mês de vida. O tratamento foi indicado, mas apenas iniciado com 2 meses e 27 dias. Ele não apresentou melhora clínica e veio a óbito com 6 meses. A mãe teve uma nova gestação, foi identificado um feto do sexo masculino e foi solicitada a manipulação da histidina de cobre ainda durante a gestação. O bebê nasceu saudável, os marcadores bioquímicos estavam diminuídos e o tratamento com histidina de cobre foi indicado. Realizamos a análise molecular, que confirmou mutação no gene ATP7A na mãe e no probando; porém, o outro filho não apresentava mutação e o tratamento foi interrompido. Nós defendemos a importância clínica da confirmação molecular para o correto diagnóstico e o aconselhamento genético da doença de Menkes, uma vez que os achados clínicos e as alterações bioquímicas no período neonatal são inespecíficos, e o tratamento com histidina de cobre parenteral deve ser rapidamente instituído.

Menkes disease in affected females: the clinical disease spectrum.

Menkes disease (MD; OMIM 309400) is an X-linked, neurodegenerative disorder resulting from deficient activity of copper-dependent enzymes and caused by alterations in the APT7A gene. In its classic form, it manifests in boys with hypotonia, seizures, skin and joint laxity, hair twisting (pili torti), cerebrovascular tortuosity, and bladder diverticulae. Menkes disease phenotypes have been reported in females with X; autosome translocations-disrupting ATP7A gene function- or ATP7A gene alterations. Those females manifest variable clinical findings, some of which, such as pili torti, seizure presence and/or age of onset, cerebrovascular tortuosity, degree of intellectual disability, and bladder divericulae are largely under-reported and under-studied. Here, we report on three females with Menkes disease and variant phenotypes, sharing characteristic features, one with classic Menkes disease and two with Menkes disease variants. We conclude that Menkes disease in females manifests with a variable spectrum of clinical findings but a few are uniformly present such as neurodevelopmental disability, hypotonia, and connective tissue findings. Others, such as seizures, cerebral atrophy, and cerebrovascular tortuosity may be present but are under-reported and under- studied. We propose that the diagnosis of Menkes disease or variants in females with suspicious clinical findings is an important one to consider as early treatment with parenteral copper may be considered. The effect of this treatment on the disease course in females with MD is unknown and remains to be seen.

Visual diagnosis: 8-day-old hypotonic newborn with sparse hair.

A hypotonic newborn or infant with pale skin and sparse, friable, hypopigmented, or depigmented hair should have his copper and ceruloplasmin plasma levels evaluated because this is the usual clinical presentation of Menkes disease. Menkes disease is an X-linked recessive disease caused by a defect in the ATP7A gene, identified in 95% to 98% of the cases. Identifying the mutation confirms the diagnosis and allows for prenatal counseling and diagnosis in a future pregnancy. When administered within the first few months of life, copper histidinate, given subcutaneously in a dose of 50 to 150 mg/kg per day, appears to be effective not only by increasing life expectancy from 3 to 13 years but also by improving neurologic symptoms and neurodevelopmental outcomes in approximately 30% of the patients.

Epilepsy in children with Menkes disease: a systematic review of literature.

Menkes disease is a lethal multisystemic disorder of copper metabolism characterized by connective tissue abnormalities, progressive neurodegeneration and peculiar "kinky hair." Epilepsy is one of the main clinical features of this disease but it has been described in detail by only a few authors. Most patients develop seizures from 2 to 3 months of age, accompanied by a neurodevelopmental regression. The history of epilepsy is usually characterized by 3 stages: an early stage with focal clonic seizures and status epilepticus, an intermediate stage with infantile spasms, and a late stage with multifocal, myoclonic, and tonic seizures. At the onset, epilepsy can be controlled with anticonvulsant therapy, whereas with the progression of disease, it becomes extremely resistant to all antiepileptic drugs. In this article, we analyze clinical and electroencephalographic (EEG) characteristics of epilepsy in patients with this syndrome.

[Clinical and ATP7A gene analysis of three infants with Menkes disease and prenatal diagnosis for a fetus at risk].

Menkes disease is a rare X-linked recessive disorder characterized by multi-systemic disorder of copper deficiency caused by ATP7A gene mutation. In this study, the clinical and laboratory features of three patients with Menkes disease were analyzed. Prenatal diagnosis had been performed for a fetus of a family. Three patients were admitted at the age of 8-9 months due to severe epilepsies and marked delayed psychomotor development. Significantly light complexion, pudgy cheeks and sparse fuzzy wooly hair were observed. On their cranial MR imaging, cortical atrophy, leukoencephalopathy, basal ganglia damage and tormesity of the intracranial vessels were found. Their plasma ceruloplasmin decreased to 70.2, 73.5 and 81 mg/L, significantly lower than normal range (210-530 mg/L). c.3914A>G (p. D1305G) was detected on ATP7A gene of case 1 and 2. A novel mutation, c.3265G>T (p.G1089X) was found in case 3. Both of them were firstly found in Chinese patients of Menkes disease. The mother of case 1 was tested at 20 weeks of pregnancy. Karyotype and ATP7A gene studies of the amniocytes were performed for the prenatal diagnosis of her fetus. Normal male karyotypes without c.3914A>G mutation on ATP7A gene was showed. Postnatal genetic analysis and normal development confirmed the prenatal diagnosis.