2023.09.11 | Questions 60-62
Neurogenetics (2/3) - An infant with seizures and regression
Hello,
This week’s questions highlight an infantile-onset disorder that presents with seizures and developmental delays. This is the 2nd of 3 posts in a series on neurogenetics. I also uploaded a video related to the topic of this newsletter post.
Please feel free to reach out with any feedback or ideas for future posts (daniel@studyrare.com).
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Have a great week!
-Daniel
Questions
Question 60
A 7-month-old boy is brought to the pediatrician due to developmental regression and hypotonia. Physical exam shows sparse, wooly hair and loose skin. The mother mentions that he has experienced recurrent seizure-like episodes. Lab results show low copper and ceruloplasmin levels. An inpatient EEG confirms the presence of seizures. He has a 2-year-old brother with similar symptoms. Which of the following is the most likely diagnosis?
Question 61
Subsequent genetic testing on the patient in question 60 shows a pathogenic variant in the ATP7A gene. This disorder most likely arose in which of the following manners?
Question 62
In addition to standard anti-epileptic medications and supportive care, which of the following should be initiated for the infant in Question 60?
Explanation
Question 60: Menkes disease
Question 61: Inherited from a carrier mother
Question 62: Subcutaneous copper histidinate
This infant’s clinical presentation is consistent with Menkes disease, an X-linked recessive disorder caused by pathogenic variants in ATP7A, which encodes a copper-transporting ATPase. Given the history of an affected older brother, the ATP7A variant was most likely inherited from the patient’s mother, who is a carrier (Question 61). Menkes disease is characterized by severe copper deficiency that results in developmental regression, hypotonia, sparse and coarse hair, loose skin, and seizures. Symptoms usually begin within a few weeks to months after birth. The laboratory findings of Menkes disease include low serum copper and low ceruloplasmin levels (note that these same lab findings are also seen in Wilson disease — see table in the “incorrect answers” section). Measuring serum copper and ceruloplasmin levels has limited diagnostic utility in the first few months of life, as levels of both are low in healthy infants in the first few months of life.
Copper transport and pathophysiology of Menkes disease
Normally, copper is obtained from the diet and absorbed through the small intestine. The protein encoded by ATP7A helps transport copper from the intestinal epithelial cells into the bloodstream. When ATP7A is not functioning, copper gets stuck inside the intestinal epithelial cells and is unable to enter the circulation, resulting in a copper deficiency throughout the body. There are a number of enzymes that depend on copper as a cofactor such as lysyl oxidase, which helps form mature collagen and elastin fibrils found in connective tissues (e.g. skin). In addition, the hypopigmentation seen in Menkes can be attributed to decreased activity of the copper-dependent enzyme tyrosinase, which catalyzes the first step in melanin synthesis.
Management of Menkes disease
Supplementing patients with subcutaneous copper histidinate (Question 62) bypasses the GI tract and allows for copper to be delivered more effectively to the body. Some recent evidence from an early-stage clinical trial suggests that starting treatment early with subcutaneous copper is associated with improved overall survival. Note that this treatment is the opposite of the treatment for Wilson disease, where copper chelators are used to remove excess copper from the body. Treatment for Menkes is otherwise supportive, with antiepileptics for seizure management and therapies (e.g. speech, occupational, and physical therapy) to help address developmental delays and maximize function.
Incorrect answers (Question 60)
The table below provides a comparison between Menkes and Wilson disease (WD), the two main disorders of copper transport.
💡If you flip the “M” in “Menkes” upside-down, you get a “W” (for Wilson disease). This helps me remember that the underlying pathophysiology (copper deficiency vs copper excess) and treatment (copper supplementation vs copper chelation) are the opposite for these two diseases.
Rett syndrome is an X-linked dominant disorder due to variants in MECP2 that primarily affects females and is characterized by neurological regression, hand wringing, and seizures. Development is initially normal with symptoms first appearing at 6-18 months of life. While developmental regression also can be seen in Menkes disease, Menkes primarily affects Men (boys), in contrast to Rett, which primarily affects girls.
Krabbe disease is an autosomal recessive leukodystrophy and lysosomal storage disease characterized by developmental regression, spasticity, and irritability that can present in infancy. Loss-of-function variants in galactocerebrosidase (GALC) are responsible for disease. While Menkes disease also presents in infancy with developmental regression, the distinctive hair and skin manifestations, as well as the laboratory abnormalities in copper and ceruloplasmin, are more characteristic of Menkes disease. Treatment of Krabbe disease includes hematopoetic stem cell transplantation prior to the onset of symptoms.
Incorrect answers (Question 62)
Copper chelation therapy with penicillamine or trientene is used in Wilson disease to remove excess copper from the body. This is the opposite of what we would want to do for Menkes disease, where copper levels in the body are already low. Hydroxocobalamin injections are used in disorders of cobalamin metabolism, such as cobalamin C or D deficiency, which can present with methylmalonic acidemia and/or homocystinuria. High-dose zinc supplementation is used in acrodermatitis enteropathica, a disorder caused by the loss of function of the intestinal zinc transporter and characterized clinically by a triad of alopecia, diarrhea, and a perioral rash. Zinc is also used in Wilson disease, as it helps reduce copper absorption in the intestine.
Learning objective
Menkes disease is an X-linked recessive disorder caused by loss-of-function variants in ATP7A that impair intestinal copper absorption. Menkes disease presents in infancy with developmental regression, hypotonia, coarse wooly hair, and recurrent seizures secondary to decreased copper in the brain and connective tissue. Without treatment, Menkes disease is fatal in early childhood. Recent evidence from an early-stage clinical trial suggests that copper histidinate may improve overall survival in Menkes disease. Wilson disease is the other major copper transport disorder and presents in childhood or adolescence with neuropsychiatric symptoms and liver disease.
2023 ABMGG General Exam Blueprint | V. Single Gene Inheritance → d. Single Gene Disorders → v. Neurogenetic disorders & ix. Metabolic disease
2023 ABGC Exam Content Outline | Domain 1. Clinical Information, Human Development, and Genetic Conditions → C. Genetic Conditions → 1. Clinical features & 7. Mode of inheritance
References
ATP7A-related copper transport disorders: A systematic review and definition of the clinical subtypes (2023, JIMD)
Menkes disease (YouTube video)
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