Infantile Neurodegeneration and Hair Changes: A Rare Case of Menkes Disease

A 4-month-old, previously healthy boy presented with acute onset of prolonged, recurrent seizure activity followed by neurodevelopmental deterioration and concurrent hair shaft hypopigmentation with fragility. Initial evaluation revealed significant low serum copper and ceruloplasmin, electrical status epilepticus on electroencephalography, and generalized subcortical white matter changes with diffuse tortuosity of intracranial vessels on MRI brain. In addition, a genetic study with whole-genome sequencing demonstrated a hemizygous pathogenic variant at c.2179G>A p(Gly727Arg) on ATP7A, thereby confirming the diagnosis of Menkes disease. Symptomatic treatment with antiepileptic medications was provided along with an urgent referral to an advanced center for multidisciplinary care and copper histidine replacement therapy.

Hair microscopy: an easy adjunct to diagnosis of systemic diseases in children

Hair, having distinct stages of growth, is a dynamic component of the integumentary system. Nonetheless, derangement in its structure and growth pattern often provides vital clues for the diagnosis of systemic diseases. Assessment of the hair structure by various microscopy techniques is, hence, a valuable tool for the diagnosis of several systemic and cutaneous disorders. Systemic illnesses like Comel-Netherton syndrome, Griscelli syndrome, Chediak Higashi syndrome, and Menkes disease display pathognomonic findings on hair microscopy which, consequently, provide crucial evidence for disease diagnosis. With minimal training, light microscopy of the hair can easily be performed even by clinicians and other health care providers which can, thus, serve as a useful tool for disease diagnosis at the patient’s bedside. This is especially true for resource-constrained settings where access and availability of advanced investigations (like molecular diagnostics) is a major constraint. Despite its immense clinical utility and non-invasive nature, hair microscopy seems to be an underutilized diagnostic modality. Lack of awareness regarding the important findings on hair microscopy may be one of the crucial reasons for its underutilization. Herein, we, therefore, present a comprehensive overview of the available methods for hair microscopy and the pertinent findings that can be observed in various diseases.

Usefulness of Trichoscopy over Hair Light Microscopy in Menkes Disease

Menkes disease (MD) is a rare X-linked recessive neurodegenerative disorder caused by mutations in the <i>ATP7A</i> gene, with a high mortality rate within the first 3 years of life. It typically affects males and is characterized by impaired copper distribution and malfunction of several copper-dependent enzymes. Patients develop progressive muscle hypotonia associated with neurological damage and hair shaft dysplasia – particularly pili torti. Pili torti is usually very subtle in the first 3 months of life and gradually increases during the first year. Light microscopy examination in search for pili torti requires the observation of more than 50 hair shafts. In contrast, trichoscopy with a hand-held dermatoscope allows to easily identify the hair shaft defect. We report a case of a Hispanic male infant with MD in whom we show that trichoscopy is superior to hair light microscopy in revealing pili torti.

Tubular Dysfunction and Ruptured Ureter in a Child with Menkes Syndrome

Children with Menkes disease may develop various urological and renal problems that evolve as the disease progresses. A 4-year-old boy with Menkes disease had multiple bladder diverticula and a history of recurrent urinary tract infection caused by urea-splitting organisms. The child developed urosepsis and right pyelonephritis. Subsequent investigations revealed multiple right renal stones and a ruptured right ureter. The child also developed hypokalemia, hypophosphatemia, and normal anion gap metabolic acidosis that required electrolyte and potassium citrate supplement. Further assessment revealed renal tubular dysfunction. Our case suggests that regular imaging surveillance, monitoring of renal function and electrolyte profile, and tubular function assessment should be considered in children with Menkes disease.

CONGENITAL CUTIS LAXA: A RARE GENODERMATOSIS

Cutis Laxa (CL) / generalized elastolysis / dermatomegaly is a heterogeneous group of disorders which are related to elastic tissue abnormalities. Depending on extent of abnormal elastic tissue, it may be mild or severe. Severe form presents with loose, inelastic, wrinkled skin resembling ill tted suit. Infant has characteristic facial features like old man appearance, a hooked nose, a short columella, a long upper lip with long philtrum, and everted lower eyelids. CL is categorised as congenital or acquired and the inheritance can be autosomal dominant or recessive, or X linked. Occasionally a few metabolic disorders like Menkes disease, disorders of glycosylation are associated with Congenital CL. Acquired cutis laxa has developed after a febrile illness and various inammatory skin diseases. Here we present a case of a full-term SGA (small for gestational age) female child born with features of CL.

Whole-Exome Sequencing, Proteome Landscape, and Immune Cell Migration Patterns in a Clinical Context of Menkes Disease

Menkes disease (MD) is a rare and often lethal X-linked recessive syndrome, characterized by generalized alterations in copper transport and metabolism, linked to mutations in the ATPase copper transporting α (ATP7A) gene. Our objective was to identify genomic alterations and circulating proteomic profiles related to MD assessing their potential roles in the clinical features of the disease. We describe the case of a male patient of 8 months of age with silvery hair, tan skin color, hypotonia, alterations in neurodevelopment, presence of seizures, and low values of plasma ceruloplasmin. Trio-whole-exome sequencing (Trio-WES) analysis, plasma proteome screening, and blood cell migration assays were carried out. Trio-WES revealed a hemizygous change c.4190C > T (p.S1397F) in exon 22 of the ATP7A gene. Compared with his parents and with child controls, 11 plasma proteins were upregulated and 59 downregulated in the patient. According to their biological processes, 42 (71.2%) of downregulated proteins had a participation in cellular transport. The immune system process was represented by 35 (59.3%) downregulated proteins (p = 9.44 × 10–11). Additional studies are necessary to validate these findings as hallmarks of MD.

ATP7A-Regulated Enzyme Metalation and Trafficking in the Menkes Disease Puzzle

Copper is vital for numerous cellular functions affecting all tissues and organ systems in the body. The copper pump, ATP7A is critical for whole-body, cellular, and subcellular copper homeostasis, and dysfunction due to genetic defects results in Menkes disease. ATP7A dysfunction leads to copper deficiency in nervous tissue, liver, and blood but accumulation in other tissues. Site-specific cellular deficiencies of copper lead to loss of function of copper-dependent enzymes in all tissues, and the range of Menkes disease pathologies observed can now be explained in full by lack of specific copper enzymes. New pathways involving copper activated lysosomal and steroid sulfatases link patient symptoms usually related to other inborn errors of metabolism to Menkes disease. Additionally, new roles for lysyl oxidase in activation of molecules necessary for the innate immune system, and novel adapter molecules that play roles in ERGIC trafficking of brain receptors and other proteins, are emerging. We here summarize the current knowledge of the roles of copper enzyme function in Menkes disease, with a focus on ATP7A-mediated enzyme metalation in the secretory pathway. By establishing mechanistic relationships between copper-dependent cellular processes and Menkes disease symptoms in patients will not only increase understanding of copper biology but will also allow for the identification of an expanding range of copper-dependent enzymes and pathways. This will raise awareness of rare patient symptoms, and thus aid in early diagnosis of Menkes disease patients.