Atp7a-Related Copper Transport Disorders

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2021-01-18
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Summary

Clinical characteristics.

Menkes disease, occipital horn syndrome (OHS), and ATP7A-related distal motor neuropathy (DMN) are disorders of copper transport caused by pathogenic variants in ATP7A (encoding a copper-transporting ATPase).

  • Infants with classic Menkes disease appear healthy until age two to three months, when loss of developmental milestones, hypotonia, seizures, and failure to thrive occur. The diagnosis is usually suspected when infants exhibit typical neurologic changes and concomitant characteristic changes of the hair (short, sparse, coarse, twisted, and often lightly pigmented). Temperature instability and hypoglycemia may be present in the neonatal period. Death usually occurs by age three years.
  • OHS is characterized by "occipital horns," distinctive wedge-shaped calcifications at the sites of attachment of the trapezius muscle and the sternocleidomastoid muscle to the occipital bone. Occipital horns may be clinically palpable or observed on skull radiographs. Individuals with OHS also have lax skin and joints, bladder diverticula, inguinal hernias, and vascular tortuosity. Intellect is normal or slightly reduced.
  • ATP7A-related DMN, an adult-onset disorder resembling Charcot-Marie-Tooth disease, shares none of the clinical or biochemical abnormalities characteristic of Menkes disease or OHS.

Diagnosis/testing.

Menkes disease and OHS are characterized by low concentrations of copper in some tissues as a result of impaired intestinal copper absorption, accumulation of copper in other tissues, and reduced activity of copper-dependent enzymes such as dopamine beta hydroxylase (DBH) and lysyl oxidase. While serum copper concentration and serum ceruloplasmin concentration are low in Menkes disease and OHS, they are normal in ATP7A-related DMN. The diagnosis of ATP7A-related copper transport disorders is most commonly established in a proband by detection of either a hemizygous ATP7A pathogenic variant in a male or a heterozygous ATP7A pathogenic variant in a female.

Management.

Treatment of manifestations: Classic Menkes disease: gastrostomy tube placement to manage caloric intake; surgery for bladder diverticula.

Prevention of primary manifestations: Subcutaneous injections of copper histidine or copper chloride before age ten days normalizes developmental outcome in some children and improves the neurologic outcome in others.

Prevention of secondary complications: Antibiotic prophylaxis may prevent bladder infection.

Genetic counseling.

The ATP7A-related copper transport disorders are inherited in an X-linked manner. Approximately one third of affected males have no family history of Menkes disease/OHS/DMN. If the mother is a heterozygote, the risk of transmitting the ATP7A pathogenic variant is 50% in each pregnancy: a male who inherits the pathogenic variant will be affected with the disorder present in his brother; females who inherit the pathogenic variant will be heterozygotes and will not be affected. Males with OHS or ATP7A-related DMN will pass the pathogenic variant to all of their daughters and none of their sons. Individuals with classic Menkes disease do not reproduce. When the pathogenic variant has been identified in an affected family member, heterozygote testing for at-risk female relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible. Prenatal testing for Menkes disease is technically possible by copper transport studies in cultured chorionic villus cells or amniocytes, although its availability is limited.

Diagnosis

Suggestive Findings

An ATP7A-related copper transport disorder (Menkes disease, occipital horn syndrome, or ATP7A-related distal motor neuropathy) should be suspected in individuals with the following clinical and laboratory findings.

Clinical Findings

Menkes disease is suspected in males who develop hypotonia, failure to thrive, and seizures between age six and ten weeks.

Shortly thereafter, hair changes become manifest: the scalp and (usually) eyebrow hair is short, sparse, coarse, twisted, and often lightly pigmented (white, silver, or gray). The hair is shorter and thinner on the sides and back of the head. The hair can be reminiscent of steel wool cleaning pads. Light microscopic hair analysis reveals pili torti (hair shafts twisting 180°), trichoclasis (transverse fracture of the hair shaft), and trichoptilosis (longitudinal splitting of the hair shaft). Because of the flattening of the normal cylindric structure, the periodicity of the twisting in pili torti is different from that found in naturally curly hair.

Specific clinical features include:

  • Distinctive facial features: jowly appearance with sagging cheeks
  • Pectus excavatum (midline depression in the bony thorax)
  • Skin laxity, particularly on the nape of the neck and trunk
  • Umbilical or inguinal hernias
  • Hypotonia, neurodevelopmental delays, and failure to thrive, typically manifest by age three to six months

Occipital horn syndrome (OHS) is suspected in males with:

  • Occipital horns (distinctive wedge-shaped calcifications at the site of attachment of the trapezius muscle and the sternocleidomastoid muscle to the occipital bone). These calcifications may be clinically palpable or observed on skull radiographs.
  • Lax skin and joints
  • Bladder diverticula
  • Inguinal hernias
  • Vascular tortuosity
  • Dysautonomia (chronic diarrhea, orthostatic hypotension)
  • Mild cognitive deficits

ATP7A-related distal motor neuropathy (DMN), an adult-onset distal motor neuropathy resembling Charcot-Marie-Tooth disease, shares none of the clinical or biochemical abnormalities characteristic of Menkes disease or occipital horn syndrome, and is characterized by:

  • Progressive distal motor neuropathy with minimal or no sensory symptoms
  • Distal muscle weakness and atrophy in feet and hands with occasional pes cavus foot deformities
  • Deep tendon reflexes varying from normal to diminished, with frequently absent ankle reflexes
  • Reduced compound motor amplitudes on nerve conduction tests with generally normal conduction velocities with positive waves and fibrillations on EMG

Laboratory Findings

Serum concentration of copper and ceruloplasmin. Males with classic Menkes disease or OHS have low serum copper concentration and low serum ceruloplasmin concentration (see Table 1).

Table 1.

Serum Copper and Serum Ceruloplasmin Concentration in Males with Menkes Disease, Occipital Horn Syndrome, and ATP7A-Related Distal Motor Neuropathy

Serum ConcentrationMenkes Disease 1OHSATP7A-Related DMNNormal
Copper0-55 µg/dL40-80 µg/dL80-100 µg/dL70-150 µg/dL;
(birth - 6 mos: 20-70 µg/dL)
Ceruloplasmin10-160 mg/L110-240 mg/L240-310 mg/L200-450 mg/L;
(birth - 6 mos: 50-220 mg/L)

DMN = distal motor neuropathy; OHS = occipital horn syndrome

1.

Diagnosis of Menkes disease using these studies alone in males under age six months is problematic given the normally low serum concentration in all children at this age.

Establishing the Diagnosis

The diagnosis of ATP7A-related copper transport disorders is most commonly established in a proband by detection of either a hemizygous ATP7A pathogenic variant in a male or a heterozygous ATP7A pathogenic variant in a female on molecular genetic testing (Table 2) or by additional biochemical studies (see Additional Biochemical Studies) if molecular genetic test results are ambiguous.

Note: The clinical/laboratory findings necessary to establish this diagnosis in a female proband are the same as for males (see Table 1). In some instances, a symptomatic female has an X-autosome translocation involving Xq21.1.

Molecular Genetic Testing

Molecular genetic testing approaches can include single-gene testing and use of a multigene panel:

  • Single-gene testing. Sequence analysis of ATP7A is performed first and followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found.
  • A multigene panel that includes ATP7A and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Table 2.

Molecular Genetic Testing Used in ATP7A-Related Copper Transport Disorders

Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method 3
ATP7ASequence analysis 4, 580%
Gene-targeted deletion/duplication analysis 620% 7
1.

See Table A. Genes and Databases for chromosome locus and protein.

2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Tümer et al [2003]

4.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5.

Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation requires additional testing by gene-targeted deletion/duplication analysis.

6.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

7.

Culotta & Gitlin [2001]

Additional Biochemical Studies

In individuals with a compelling presentation for whom molecular genetic testing fails to identify a pathogenic variant in ATP7A, the following biochemical studies may be considered:

  • Plasma and CSF catecholamine analysis. Plasma catechol concentrations are distinctively abnormal at all ages in males with Menkes disease and OHS (but normal in ATP7A-related DMN). Abnormal levels reflect partial deficiency of dopamine beta hydroxylase (DBH), a copper-dependent enzyme critical for catecholamine biosynthesis
  • Copper transport studies in cultured fibroblasts. Impaired cellular copper exodus is demonstrated by increased cellular copper retention in pulse-chase experiments with radiolabeled copper in cultured fibroblasts for Menkes disease.
    Note: This method is reserved for urgent prenatal testing when a family's ATP7A pathogenic variant is unknown; however, this situation should become exceedingly rare with increased availability and efficiency of molecular genetic testing.

Clinical Characteristics

Clinical Description

The clinical spectrum of ATP7A-related copper transport disorders ranges from classic Menkes disease at the severe end to occipital horn syndrome (OHS) to distal motor neuropathy (DMN). Classic Menkes disease is characterized by neurodegeneration and failure to thrive commencing at age two to three months. The age at diagnosis is usually about eight months. In contrast, OHS presents in early to middle childhood and is characterized predominantly by connective tissue abnormalities. ATP7A-related distal motor neuropathy is adult in onset, resembles Charcot-Marie-Tooth disease, and shares none of the clinical abnormalities characteristic of Menkes disease or OHS.

Classic Menkes disease. Infants appear healthy until age two to three months, when loss of developmental milestones, hypotonia, seizures, and failure to thrive occur. Classic Menkes disease is usually first suspected when infants exhibit typical neurologic changes and concomitant characteristic changes of the hair (short, sparse, coarse, twisted, often lightly pigmented) and jowly appearance of the face.

Autonomic dysfunction including temperature instability and hypoglycemia may be present in the neonatal period; some infants have syncope and diarrhea.

Vascular tortuosity, bladder diverticula that can result in bladder outlet obstruction, and gastric polyps are common.

Without early treatment with parenteral copper, and sometimes even with such treatment, classic Menkes disease progresses to severe neurodegeneration and death between ages seven months and 3.5 years. Subdural hematomas and cerebrovascular accidents are common. Respiratory failure, often precipitated by pneumonia, is a common cause of death.

Imaging

  • MRI shows defective myelination, atrophy with ventriculomegaly, and vascular tortuosity.
  • MR angiography reveals a "corkscrew" appearance of cerebral vessels.
  • Radiographs show Wormian bones and metaphyseal spurring and may show rib fractures.

Mild Menkes disease. A few affected individuals in whom motor and cognitive development are better than in classic Menkes disease have been described. Individuals with mild Menkes disease may walk independently and talk. Weakness, ataxia, tremor, and head bobbing are characteristic neurologic findings. Seizures, if present, commence in mid to late childhood; intellectual disability is mild. Connective tissue problems may be more prominent than in classic Menkes disease. Pili torti are present.

Occipital horn syndrome (OHS; X-linked cutis laxa). Intelligence is normal or slightly reduced. The only apparent neurologic abnormalities of OHS are dysautonomia and subtle cognitive deficits. Affected individuals typically live to at least mid-adulthood. Fertility is unknown.

ATP7A-related distal motor neuropathy (DMN). The age of onset ranges from five to 60 years, and is typically during the second or third decade of life [Kennerson et al 2010]. Findings include atrophy and weakness of distal muscles in hands and feet, foot drop with steppage gait, sometimes mild proximal weakness in the legs, with normal deep tendon reflexes or absent ankle reflexes. Sensory examination may be normal or show mild loss in the fingers and toes. The index case of the largest family reported had slow progression over 25 years, requiring ankle foot orthotics at age 38 years [Kennerson et al 2009].

Heterozygous females. Females who are heterozygous for an ATP7A pathogenic variant are typically asymptomatic, in some instances because of favorably skewed X-chromosome inactivation [Desai et al 2011]. In theory, unfavorably skewed X-chromosome inactivation in some heterozygous females could be associated with neurologic or other clinical findings related to the disorders.

About 50% of females who are obligate heterozygotes for an ATP7A pathogenic variant demonstrate regions of pili torti [Moore & Howell 1985].

Evaluation of females who are obligate heterozygotes for an ATP7A pathogenic variant causing ATP7A-related DMN has been limited to date; however, in one family the clinical neurologic examinations and motor nerve conduction studies of the females proven to be heterozygous were normal [Kennerson et al 2009].

Genotype-Phenotype Correlations

The amount of residual ATPase enzyme activity correlates with phenotype in Menkes disease, OHS, and ATP7A-related distal motor neuropathy (DMN) and with response to early copper treatment in Menkes disease [Kaler et al 2008].

Tümer et al [2003] observed that with rare exceptions gene deletions result in classic Menkes disease with death in early childhood.

Milder variants of Menkes disease and OHS are often associated with splice junction pathogenic variants that alter, but do not eliminate, proper RNA splicing (i.e., "leaky" splice junction defects).

The pathogenic variants associated with ATP7A-related DMN involve unique missense variants within or near the luminal surface of the protein, which may be relevant to the abnormal intracellular trafficking shown for these defects and to the mechanism of this form of motor neuron disease [Kennerson et al 2010].

Intrafamilial phenotypic variability is occasionally observed in Menkes disease [Kaler et al 1994, Borm et al 2004, Donsante et al 2007]. Differences noted among affected individuals from two families with ATP7A-related DMN included degree of weakness, atrophy, and sensory loss [Kennerson et al 2010].

Nomenclature

Menkes disease is also known as Menkes kinky hair syndrome or trichopoliodystrophy.

Occipital horn syndrome was formerly known as X-linked cutis laxa.

ATP7A-related distal motor neuropathy is also known as X-linked distal spinal muscular atrophy 3.

Prevalence

The incidence of Menkes disease and its variants is estimated at one in 100,000 births.

No estimates are available on the incidence of OHS and ATP7A-related DMN.

Differential Diagnosis

Menkes disease. The differential diagnosis includes other infantile-onset neurodevelopmental syndromes:

  • Biotinidase deficiency
  • Organic acidurias
  • Aminoacidurias
  • Mitochondrial myopathies (See Mitochondrial Disorders Overview.)

Occipital horn syndrome. The differential diagnosis includes:

  • FBLN5-related cutis laxa, inherited in an autosomal recessive or autosomal dominant manner (autosomal recessive inheritance is more common) and caused by mutation of FBLN5 (encoding fibulin-5);
  • ELN-related cutis laxa (OMIM 123700), inherited in an autosomal dominant manner and caused by mutation of ELN (encoding elastin).

ATP7A-related distal motor neuropathy. The differential diagnosis includes other forms of Charcot-Marie-Tooth disease.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in a male diagnosed with Menkes disease, the following evaluations are recommended:

  • Developmental assessment
  • Evaluation of feeding and nutrition
  • Assessment of bladder function
  • Consultation with a clinical geneticist and/or genetic counselor

To establish the extent of disease and needs in a male diagnosed with occipital horn syndrome (OHS), evaluations for the following are recommended:

  • Bladder diverticula
  • Inguinal hernias
  • Vascular tortuosity
  • Dysautonomia (chronic diarrhea, orthostatic hypotension). Note: Some medical centers have clinical autonomic testing laboratories.
  • Mild cognitive deficits
  • Consultation with a clinical geneticist and/or genetic counselor

To establish the extent of disease and needs in a male diagnosed with ATP7A-related distal motor neuropathy (DMN), the following evaluations are recommended:

  • Neurologic examination
  • EMG with nerve conduction studies
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Menkes disease

  • Gastrostomy tube placement to manage caloric intake and general nutrition in some males with classic Menkes disease
  • Surgery for bladder diverticula that occur in classic Menkes disease
  • Developmental intervention

ATP7A-related DMN

  • Physical therapy (strength and stretching exercises)
  • Occupational therapy
  • Ankle foot orthotics

Prevention of Primary Manifestations

Menkes disease. In classic Menkes disease, treatment with subcutaneous injections of copper histidine or copper chloride before age ten days normalizes developmental outcome in some individuals and improves the neurologic outcome in others [Kaler et al 2008, Kaler et al 2010].

Note: Despite very early copper histidine treatment, some infants show no significant improvement relative to the natural history of untreated Menkes disease [Kaler et al 1995, Kaler et al 2008]. The type and severity of the ATP7A pathogenic variant determine the response to early copper treatment.

To maintain serum copper concentration in the normal range (70-150 µg/dL), the suggested dose of copper chloride is:

  • For children age <1 year: 250 µg administered subcutaneously 2x/day
  • For children age >1 year: 250 µg administered subcutaneously 1x/day

Occipital horn syndrome. Although there is no evidence that copper replacement therapy for OHS is clinically beneficial, it would be reasonable to expect even better overall neurodevelopmental and neurocognitive outcomes if individuals with OHS were identified early and treated with copper during their first three years.

Prevention of Secondary Complications

Antibiotic prophylaxis may be necessary to prevent bladder infection.

Surveillance

For infants being treated with copper histidine or copper chloride, monitor serum copper and ceruloplasmin levels to avoid supranormal levels.

Evaluation of Relatives at Risk

It is appropriate to test male relatives at risk for Menkes disease for the ATP7A pathogenic variant identified in the family before age ten days in order to promptly begin copper replacement treatment (see Prevention of Primary Manifestations).

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Adeno-associated viral gene therapy in a mouse model is under active investigation with promising early results [Donsante et al 2011].

Newborn screening is not currently available for Menkes disease because biochemical strategies are not practical with current newborn screening platforms. A pilot study to evaluate the potential of sequence analysis of ATP7A from dried blood spots is currently in progress. If successful, such testing would allow early diagnosis and treatment.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Other

Therapies proven to be ineffective include vitamin C.