Wilson Disease & NBIA

What Do You Need to Know?

Wilson disease: AR, ATP7B gene (chromosome 13), copper transport defect → accumulation in liver and brain
Diagnosis: low ceruloplasmin, elevated 24-hour urine copper (>100 µg), Kayser-Fleischer rings on slit-lamp, MRI “face of the giant panda” in midbrain
PKAN: PANK2 gene (AR), “eye-of-the-tiger” sign on MRI (globus pallidus), childhood-onset dystonia + pigmentary retinopathy
Manganese toxicity: T1 hyperintensity in globus pallidus (not T2), parkinsonism with “cock-walk” gait, no levodopa response
Screen for Wilson disease in ALL young patients (<50 yr) with unexplained movement disorders — treatable and fatal if missed

Wilson Disease

Genetics & Pathophysiology

Gene: ATP7B (chromosome 13q14) — copper-transporting P-type ATPase
Inheritance: autosomal recessive; carrier frequency ~1:90; prevalence ~1:30,000
>500 mutations described; most patients are compound heterozygotes; H1069Q most common in Europeans
Normal: ATP7B incorporates copper into ceruloplasmin and excretes excess into bile
Wilson: impaired biliary copper excretion → hepatocyte accumulation → liver injury → copper released into blood → deposits in basal ganglia (putamen), cornea (KF rings), kidneys
Free (non-ceruloplasmin-bound) copper causes oxidative damage via Fenton reaction
Age: typically 5–40 years; hepatic presentation younger (~11 yr), neurologic later (~20 yr)

Neurologic Features

Dystonia: most common movement disorder; often orofacial → “risus sardonicus” (sardonic grin)
Tremor: classic “wing-beating” tremor (proximal, high-amplitude postural tremor of outstretched arms)
Parkinsonism: rigidity, bradykinesia, hypomimia — may mimic juvenile-onset PD
Dysarthria: often the first neurologic symptom; mixed cerebellar-extrapyramidal pattern
Drooling: from orofacial dystonia + impaired swallowing
Cerebellar signs: ataxia, intention tremor in some patients
Chorea: less common but may occur, especially early in disease
Neurologic Wilson nearly always has underlying hepatic copper accumulation, even if liver is clinically silent

Psychiatric & Hepatic Features

Psychiatric (30–40%): personality changes, depression, impulsivity, academic decline — may precede neurologic signs by years
Chronic hepatitis/cirrhosis: may be asymptomatic; mimics autoimmune hepatitis
Fulminant liver failure: Coombs-negative hemolytic anemia + acute liver failure + very low ceruloplasmin = Wilson until proven otherwise
Alkaline phosphatase characteristically low relative to bilirubin in fulminant Wilson

Ophthalmologic Findings

Kayser-Fleischer rings: copper in Descemet’s membrane; golden-brown ring at limbus
Present in ~95% with neurologic Wilson, ~50% with hepatic-only presentation
Requires slit-lamp — not always visible to the naked eye
Sunflower cataracts: copper deposits in lens; less common

Clinical Pearl

Coombs-negative hemolytic anemia + acute liver failure in a young patient = Wilson disease until proven otherwise. This is a medical emergency requiring urgent transplant evaluation. Hemolysis results from massive copper release from necrotic hepatocytes.

Wilson Disease — Diagnosis & Treatment

Laboratory Studies

Test	Result	Key Notes
Serum ceruloplasmin	<20 mg/dL	Low in ~85–90%; can be falsely normal in inflammation/pregnancy/estrogen (acute-phase reactant)
24-hr urine copper	>100 µg/day	Most reliable single screening test; >40 µg/day suspicious
Free serum copper	>25 µg/dL	Calculated: total Cu − (3 × ceruloplasmin); toxic fraction
Total serum copper	Low/low-normal	Paradoxically low because ceruloplasmin-bound Cu (90% of total) is reduced
Hepatic copper	>250 µg/g dry wt	Gold standard; requires liver biopsy; normal <50 µg/g
ATP7B sequencing	Biallelic variants	Confirmatory; useful for family screening

Leipzig Score

Combines KF rings, neurologic symptoms, ceruloplasmin, hemolytic anemia, liver copper, urinary copper, mutation analysis
≥4: diagnosis highly likely | 3: possible | ≤2: unlikely

MRI Brain

T2/FLAIR hyperintensity: putamen (most common), globus pallidus, caudate, thalamus, midbrain, pons
“Face of the giant panda”: T2 axial midbrain — tegmentum hyperintensity with preserved red nuclei and lateral pars reticulata forming the “eyes”
“Face of the miniature panda”: seen in pontine tegmentum (less commonly tested)
T1 hyperintensity in GP may also be seen (copper paramagnetic effect)
Cortical and white matter changes in advanced disease

Treatment

D-Penicillamine: chelator; mobilizes copper for urinary excretion; side effects: nephrotoxicity, marrow suppression, lupus-like syndrome, neurologic worsening in ~10–50% at initiation
Trientine: alternative chelator; better tolerated; preferred by many as first-line for neurologic Wilson
Zinc: induces intestinal metallothionein → blocks copper absorption; used for maintenance or presymptomatic patients; separate from chelators by ≥5 hours
Liver transplant: for fulminant hepatic failure or decompensated cirrhosis; curative (new liver has functional ATP7B)
Diet: avoid liver, shellfish, chocolate, mushrooms, nuts (high copper)
Screen all first-degree relatives; treatment is lifelong — non-compliance causes rapid deterioration

💎 Board Pearl

Low ceruloplasmin + elevated 24-hr urine copper + KF rings = classic triad. Ceruloplasmin alone is insufficient — normal in 10–15% of Wilson patients and low in carriers/nephrotic syndrome.
“Face of the giant panda” on midbrain MRI is highly specific but not always present. Putaminal T2 hyperintensity is the most common finding.
Penicillamine can paradoxically worsen neurologic symptoms early in treatment due to copper mobilization. Many experts prefer trientine first-line for neurologic Wilson.

NBIA Overview

Neurodegeneration with brain iron accumulation (NBIA): group of inherited disorders with progressive iron deposition in basal ganglia
Common features: progressive dystonia, spasticity, parkinsonism, cognitive decline
MRI hallmark: T2/T2* hypointensity (dark signal) in globus pallidus and/or substantia nigra
Most are autosomal recessive; exceptions: neuroferritinopathy (AD) and BPAN (X-linked)
PKAN is the most common subtype (~50% of NBIA cases)

PKAN (Pantothenate Kinase-Associated Neurodegeneration)

Genetics

Gene: PANK2 (chromosome 20p13) — pantothenate kinase 2, rate-limiting enzyme in coenzyme A synthesis
Inheritance: autosomal recessive
Formerly Hallervorden-Spatz disease (name abandoned; still appears in older references)
PANK2 deficiency → cysteine accumulation + cysteine-iron chelates → oxidative damage and iron deposition in GP

Classic Form (<6 years)

Progressive dystonia (often oromandibular), spasticity, gait difficulty
Pigmentary retinopathy: important diagnostic clue in classic form
Cognitive decline, dysarthria, dysphagia
Acanthocytosis on peripheral blood smear in some patients
Rapid progression; most wheelchair-bound within 10–15 years of onset

Atypical Form (2nd–3rd Decade)

Prominent speech difficulty (palilalia, dysarthria) and psychiatric symptoms
Slower progression than classic form
Pigmentary retinopathy less common

MRI: Eye-of-the-Tiger Sign

T2 MRI: bilateral GP hypointensity (dark/iron) with central hyperintensity (bright/gliosis) → resembles a tiger’s eye
Virtually pathognomonic for PKAN; ~100% sensitivity in PANK2-confirmed cases
May be present before symptom onset

💎 Board Pearl

“Eye-of-the-tiger” sign on T2 MRI = PKAN (PANK2 mutation) — classic boards image. Bilateral GP hypointensity with central hyperintensity is virtually pathognomonic.
PKAN + pigmentary retinopathy + acanthocytosis in a child with progressive dystonia = classic board vignette.

Other NBIA Subtypes

Disorder	Gene	Inheritance	Key Features	Distinguishing Clue
Neuroferritinopathy	FTL	AD	Adult-onset chorea/dystonia; cavitating basal ganglia lesions	Low serum ferritin; only AD NBIA; cystic BG on MRI
Aceruloplasminemia	CP	AR	Diabetes + retinal degeneration + movement disorder; onset 40–60 yr	Absent ceruloplasmin; iron overload (not copper); anemia
PLAN/INAD	PLA2G6	AR	Infantile neuroaxonal dystrophy; 6 mo–3 yr; psychomotor regression	Cerebellar atrophy; axonal spheroids; also adult dystonia-parkinsonism
MPAN	C19orf12	AR	Childhood/young adult; dystonia, spasticity, optic atrophy	GP + SN iron; motor neuron features may coexist
BPAN	WDR45	X-linked	Static childhood encephalopathy → rapid adult decline (dystonia-parkinsonism, dementia)	Biphasic course; T1 hyperintense halo in SN
Kufor-Rakeb	ATP13A2	AR	Juvenile parkinsonism, spasticity, supranuclear gaze palsy	Initial levodopa response with early motor complications; mini-myoclonus

💎 Board Pearl

Neuroferritinopathy is the only AD NBIA — low serum ferritin is the clue.
Aceruloplasminemia vs. Wilson: both have low/absent ceruloplasmin, but aceruloplasminemia has iron overload (not copper) with diabetes and retinal degeneration.
BPAN: biphasic course (static childhood encephalopathy → rapid adult-onset decline) is the key distinguishing feature.

Manganese Toxicity

Exposure Sources

Occupational: welders, miners, smelter workers, dry battery manufacturers
Other: total parenteral nutrition (TPN), chronic liver disease, methcathinone (ephedrone) abuse, contaminated well water

Clinical Features

Manganism: parkinsonism with prominent gait disorder
“Cock-walk” gait: walking on toes with strutting pattern — highly suggestive
Dystonia, bradykinesia, rigidity; rest tremor less prominent than PD
Early psychiatric symptoms: irritability, emotional lability, hallucinations (“manganese madness”)
No levodopa response — pathology is post-synaptic (GP), not presynaptic (SN as in PD)

Imaging & Management

T1 hyperintensity in bilateral globus pallidus — hallmark finding; manganese is paramagnetic (shortens T1)
T1 signal normalizes after exposure cessation (unlike permanent iron deposition in NBIA)
DaTSCAN: normal (presynaptic dopaminergic neurons intact) — distinguishes from PD
Elevated blood and urine manganese levels (may not correlate with clinical severity)
Treatment: remove from exposure (most important step); chelation (CaNa2-EDTA, para-aminosalicylic acid) has variable results
Neurologic deficits may be partially irreversible despite exposure cessation

💎 Board Pearl

T1 hyperintensity in GP = manganese. Manganese = T1 bright; iron (NBIA) = T2 dark. Do not confuse them.
Manganese vs. PD: manganese → “cock-walk” gait, targets GP (not SN), no levodopa response, normal DaTSCAN. PD → SN degeneration, levodopa-responsive, abnormal DaTSCAN.

References

European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Wilson’s disease. J Hepatol. 2012;56(3):671-685.
Ferenci P, Caca K, Loudianos G, et al. Diagnosis and phenotypic classification of Wilson disease. Liver Int. 2003;23(3):139-142.
Hayflick SJ, Westaway SK, Levinson B, et al. Genetic, clinical, and radiographic delineation of Hallervorden-Spatz syndrome. N Engl J Med. 2003;348(1):33-40.
Gregory A, Hayflick SJ. Neurodegeneration with brain iron accumulation. Folia Neuropathol. 2005;43(4):286-296.
Hogarth P. Neurodegeneration with brain iron accumulation: diagnosis and management. J Mov Disord. 2015;8(1):1-13.
Ala A, Walker AP, Ashkan K, et al. Wilson’s disease. Lancet. 2007;369(9559):397-408.
Racette BA, Aschner M, Guilarte TR, et al. Pathophysiology of manganese-associated neurotoxicity. Neurotoxicology. 2012;33(4):881-886.
Lorincz MT. Neurologic Wilson’s disease. Ann N Y Acad Sci. 2010;1184:173-187.