Laboratory Studies
See the list below:
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In addition to the subtle clinical manifestations in neonates with Menkes kinky hair disease (MKHD), early diagnosis is complicated by the unreliability of the usual biochemical markers (ie, low serum copper and ceruloplasmin) during the first several weeks of life.
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Laboratory findings in Menkes kinky hair disease include low copper and ceruloplasmin, although values for these are also low in healthy infants during the first 6 weeks of life and thus are not diagnostic for Menkes kinky hair disease during this time frame. The levels in healthy newborns overlap those of patients with Menkes kinky hair disease.
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In contrast, plasma and cerebrospinal fluid (CSF) catechol levels are distinctively abnormal in patients with Menkes kinky hair disease at all ages, including the newborn period and even prenatally. As noted in Pathophysiology, high levels of the catechols dihydroxyphenylalanine (DOPA), dihydrophenylacetic acid, and dopamine and low level of dihydroxyphenylglycol (DHPG), the deaminated metabolite of norepinephrine (NE), are hallmarks of the partial dopamine beta-hydroxylase (DBH) deficiency invariably associated with Menkes kinky hair disease and occipital horn syndrome (OHS). This rapid and reliable plasma or CSF catechol assay is available on a research basis at NIH.
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Copper egress in cultured fibroblasts is a time-honored method for diagnosis of Menkes kinky hair disease and OHS. Considered a definitive diagnostic test, it requires propagation of cells obtained from a skin biopsy for at least several weeks before the assay can be performed. The assay is being replaced by molecular analysis but remains useful for laboratories with experience in working with radiolabeled copper (half-life of copper Cu-64 is approximately 12 h) and in the conduct of pulse/chase experiments.
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Because optimal success of any therapeutic strategy for this condition requires recognition of patients with Menkes kinky hair disease before the onset of neurologic symptoms, rapid tests that can reliably diagnose or exclude Menkes kinky hair disease during the neonatal period are useful.
One such test recently recognized is plasma catecholamine analysis (see Other Tests). Plasma catechol levels distinctively outside the reference range, indicating deficiency of DBH, have been demonstrated in a fetus as well as newborns with Menkes kinky hair disease. Sufficient data have now accrued that this assay is considered a valuable tool for rapid accurate diagnosis of Menkes kinky hair disease in the early neonatal period when interpretation of other biochemical tests is difficult.
The placental copper level, which is increased in Menkes kinky hair disease, represents another reliable biochemical marker for neonatal diagnosis. Rapid molecular diagnostic assays eventually may facilitate early diagnosis. Realistic consideration of newborn screening for Menkes kinky hair disease requires more predictably effective therapies than are currently available but seems theoretically possible.
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Expression of Menkes kinky hair disease in females: Several female patients with Menkes kinky hair disease have been reported in whom chromosome rearrangement, XO/XX mosaicism, or unfavorable lyonization was responsible for expression of the full phenotype. With respect to detection of females who are carriers, clinical and biochemical parameters have not been uniformly reliable.
Serum copper and ceruloplasmin levels are within the reference range in carriers, as are plasma catecholamine levels (unpublished observations).
Copper egress in cultured cells of some obligate carriers demonstrate values within the range of males with Menkes kinky hair disease or intermediate between normal and affected, but many have values that overlap with the reference range, presumably because of lyonization and apparent selection against the mutant cell type.
Pili torti in the hair of the mother of a patient with Menkes kinky hair disease is considered definitive proof of her status as a gene carrier (see Other Tests).
As in prenatal testing, molecular diagnostic approaches aid immensely in carrier detection once a given family's mutation has been characterized in a male with Menkes kinky hair disease.
Imaging Studies
The following imaging studies are often helpful in the evaluation and treatment of patients with Menkes kinky hair disease or OHS:
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Brain MRI to assess for gross structural lesions, degree of myelination, and vascular tortuosity
White matter abnormalities reflecting impaired myelination, diffuse atrophy, ventriculomegaly, and tortuosity of cerebral blood vessels are typical findings on brain MRI.
Subdural hematomas are common in infants with Menkes kinky hair disease, and stroke can occur in patients with the disease who survive longer.
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Magnetic resonance angiography (MRA) of the brain for closer detail of vasculopathy: The "corkscrew" appearance of cerebral vessels is well visualized by MRA, a noninvasive method for study of the vasculature.
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Echocardiography: Dysplastic coronary vessels may be detectable by echocardiography.
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Cystography or pelvic ultrasonography: These studies reveal diverticula of the urinary bladder in nearly every patient with Menkes kinky hair disease.
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Abdominal ultrasonography: This study is used to assess for antral polyps (a rare clinical problem in Menkes kinky hair disease).
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Radiography: These images often disclose abnormalities of bone formation in the skull (wormian bones), long bones (metaphyseal spurring), and ribs (anterior flaring, multiple fractures).
Other Tests
See the list below:
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Placental copper level: In pregnancies at risk for Menkes kinky hair disease, determination of the placental copper level is a reliable and fairly rapid diagnostic test in the newborn period. According to Centano of the US Armed Forces Institute of Pathology (personal communication), placental copper is 3-fold to 5-fold elevated in pregnancies affected by Menkes kinky hair disease relative to healthy controls.
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Pili torti on light microscopic examination of hair
Pili torti on light microscopic examination of hair is another reliable diagnostic test. However, as with plasma copper and ceruloplasmin, this sign is not useful for very early diagnosis (ie, prior to neurologic symptoms) because the hair in individuals with Menkes kinky hair disease is often normal from birth until several months of age.
Pili torti in the hair of the mother of a patient with Menkes kinky hair disease is considered definitive proof of her status as a gene carrier. However, this hair abnormality is detectable in only approximately one half of obligate Menkes heterozygotes. Thus, even if microscopic examination of hair from a potential female heterozygote is negative for pili torti, the carrier state cannot be ruled out.
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Molecular analysis: Molecular analysis of the Menkes/OHS gene has been approached in several ways. The author favors a multiplex polymerase chain reaction (PCR) assay to screen for deletions, followed by heteroduplex analysis (either D-HPLC or manual) with DNA sequencing used to confirm abnormalities. The author sequences the entire coding region and intron-exon junctions if screening approaches do not suggest the location of mutation within 1 of the 23 exons that comprise the coding sequence of the gene. To date, the author has found mutations in more than 94% of NIH-protocol patients.
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Electroencephalograms: EEGs are used routinely to investigate possible seizure activity. EEG findings are usually moderately to severely abnormal, although normal tracings have been recorded in some individuals with classic Menkes kinky hair disease.
Procedures
Lumbar puncture (ie, spinal tap) to examine the CSF is almost always performed in the early evaluation of infants manifesting neurodevelopmental symptoms.
Skin biopsy procedure to establish fibroblast cultures as a source of patient RNA and DNA or to perform diagnostic studies (eg, copper transport assays) may be requested for infants suspected of having Menkes kinky hair disease.
Histologic Findings
Pathology of the brain in Menkes kinky hair disease includes marked neuronal cell loss in the cerebral cortex and cerebellum, severe demyelination, dystrophic Purkinje cells, mitochondrial proliferation, and vascular dilatation within the brain and spinal cord. Abnormal brain lipid composition, presumably reflecting impaired myelination, has been documented.
Pathologic changes of the vasculature (tortuosity and ectasia) are prominent in Menkes kinky hair disease. Defective elastin fibers have been demonstrated within the internal elastic lamina, tunica media, and intimal layers of arteries and arterioles.
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Classic Menkes kinky hair disease in an 8-month-old male infant. Note the abnormal hair, eyelid ptosis, and jowly facial appearance.
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Adolescent patient with typical occipital horn syndrome. Note elbow dislocations and genu valgum. Radiographs exhibited bilateral occipital exostoses of the skull and club-shaped distal clavicles.
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Successfully treated classic Menkes kinky hair disease. Diagnosis at birth enabled copper therapy to begin when the infant was aged 8 days. The child walked independently when aged 14 months. This patient's mutation (IVS8,AS,dup5) was associated with a transcript harboring a small in-frame deletion, potentially encoding a functional copper adenosine triphosphatase (ATPase).
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Menkes kinky hair disease copper adenosine triphosphatase (see text for detailed discussion).
