Table 180.1.

Neurological, biochemical, and molecular features in copper transport disorders

Condition	Age of onset (years)	Neurological signs	Other clinical manifestations	Biochemical findings	Molecular defects	Treatment options	Prognosis	Future directions
Wilson disease	10–40	Dysarthria, dystonia, rigidity, abnormal gait, poor handwriting, tremor	Kayser–Fleischer ring (corneal deposition of copper)	Low serum copper and ceruloplasmin; increased urinary copper excretion; high liver copper	Diverse mutations in ATP7B	Copper chelation with penicillamine, trien,*** tetrathiomolybdate, zinc acetate	Favorable, if patient compliant with medical treatment	Liver-directed gene therapy; hepatocyte transfer
Menkes disease	0–1	Hypotonia, seizures, developmental delay, brain atrophy	Coarse hair, jowly facies, lax skin and joints, decreased bone density, bladder diverticula, gastric polyps, vascular tortuousity	Low serum copper and ceruloplasmin; abnormal plasma and CSF neurochemicals; increased urine β2-microglobulin	Diverse mutations in ATP7A (Fig. 180.2A)	Early copper replacement	Difficult, unless very early diagnosis/ treatment (within 2 weeks of birth)	Newborn screening for early detection; brain-directed combination therapy: copper + ATP7A viral gene therapy
Occipital horn syndrome (OHS)	3–10	Dysautonomia,* muscle weakness	Coarse hair, occipital exostoses, hammer-shaped clavicular heads, lax skin and joints, bladder diverticula, vascular tortuousity	Low-normal serum copper and ceruloplasmin; abnormal plasma and CSF neurochemicals	“Leaky” splice junction and hypofunctional missense mutations in ATP7A (Fig. 180.2B)	L-dihydroxyphenylserine (L-DOPS) for dysautonomia	Fair (long-term natural history not known)	Newborn screening for early detection and early copper replacement
X-linked distal hereditary motor neuropathy (dHMN)	5–50	Atrophy and weakness of distal muscles, foot drop, abnormal nerve conduction studies**	No other specific clinical abnormalities	No specific laboratory abnormalities	Missense mutations in carboxyl half of ATP7A (Fig. 180.2C)	Copper replacement in selected patients	Unknown (long-term natural history uncertain)	Motor neuron-directed viral gene therapy
Huppke–Brendel syndrome	0–1	Global developmental delay, hypotonia, sensorineural deafness, brain atrophy	Cataracts, nystagmus	Low serum copper and ceruloplasmin	SLC33A1 (acetyl-CoA transporter)	None available at present	Poor	Possibly viral gene therapy to replete SLC33A1
CCS deficiency	0–1	Neonatal hypotonia, global developmental delay, abnormal brain MRI, epilepsy	Pericardial effusion	Low SOD1 activity (superoxide dismutase)	CCS (copper chaperone to SOD)	None available at present	Poor	Possibly viral gene therapy to replete CCS
MEDNIK	0–1	Mental retardation, deafness, neuropathy	Enteropathy, ichthyosis, keratodermia	Low copper and ceruloplasmin, high liver copper, high plasma very long-chain fatty acids	AP1S1 (sigma1A subunit of adaptor protein complex 1)	Zinc acetate	Poor neurological prognosis, liver disease treatable	Possibly viral gene therapy to replete AP1S1

^*Syncope, dizziness, orthostatic hypotension, abnormal sinoatrial conduction, nocturnal bradycardia, and bowel or bladder dysfunction.

^**Decreased peroneal and median muscle amplitudes with normal conduction velocities.

^***Triethylene tetramine dihydrochloride.