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11 notes available
1 Last Minute Review 2 Parkinson Disease 3 Atypical Parkinsonism 4 Tremor 5 Dystonia 6 Chorea & Ballism 7 Myoclonus 8 Tics & Tourette Syndrome 9 Wilson Disease & NBIA 10 Hereditary Ataxias 11 Drug-Induced Movement Disorders
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Wilson Disease & NBIA

Wilson Disease & NBIA

What You'll Learn

  • 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
HighYield Pearls
  • Wilson = ATP7B, AR, chromosome 13: impaired biliary copper excretion; presents 5–40 yr (hepatic earlier ~11, neurologic later ~20).
  • Screen EVERY patient <50 yr with unexplained movement disorder, psychiatric change, or chronic hepatitis — Wilson is treatable and fatal if missed.
  • Coombs-negative hemolytic anemia + acute liver failure + low ALP : bilirubin ratio (<4) + AST : ALT >2.2: fulminant Wilson until proven otherwise → urgent transplant evaluation.
  • Wing-beating tremor + dysarthria + risus sardonicus dystonia + juvenile parkinsonism: classic neuro-Wilson tetrad.
  • Kayser-Fleischer rings: ~95–100% of NEUROLOGIC Wilson; only ~50–60% of hepatic-only; requires SLIT-LAMP (not naked eye). Sunflower cataract = lens copper.
  • Diagnostic triad: LOW ceruloplasmin (<20; falsely normal in inflammation/estrogen) + 24-hr urinary copper >100 µg (≥40 raises suspicion) + KF rings. Free Cu >25 µg/dL. Hepatic Cu >250 µg/g dry wt = gold standard. Use Leipzig score ≥4.
  • “Face of the giant panda” = T2 midbrain (red nuclei = eyes, SNpr = ears, superior colliculus = chin); “double panda” adds pontine tegmentum sign.
  • Treatment: D-penicillamine (paradoxical neuro worsening 10–50% — many prefer TRIENTINE first-line for neuro Wilson) → ZINC for maintenance/presymptomatic; liver transplant corrects the hepatic ATP7B defect and is indicated for fulminant hepatic failure or decompensated cirrhosis (neurologic recovery is variable — transplant is not a guaranteed neurologic cure). Lifelong therapy; continue chelation in pregnancy with specialist dose adjustment (stopping anticopper therapy risks relapse). Screen all first-degree relatives.
  • “Eye-of-the-tiger” sign (T2 GP hypointensity with central hyperintensity) = PKAN (PANK2, AR); chelation NOT helpful; deferiprone trialed; DBS-GPi for dystonia.
  • Classic PKAN child: dystonia + pigmentary retinopathy + acanthocytosis + cognitive decline, onset <6 yr.
  • Neuroferritinopathy (FTL, AD) is the only AD NBIA — adult chorea-dystonia, LOW serum ferritin (paradoxical), cavitating putamen.
  • Aceruloplasminemia (CP, AR): adult diabetes + retinal degeneration + movement disorder; ceruloplasmin ~0 (vs Wilson’s low-normal); iron (not copper) overload; microcytic anemia.
  • BPAN (WDR45, X-linked dominant): female intellectual disability + Rett-like features + seizures → biphasic adult dystonia-parkinsonism; SN “halo sign” on T1.
  • MPAN (C19orf12, AR): childhood/young-adult dystonia + spasticity + optic atrophy + motor neuron features.
  • Kufor-Rakeb (ATP13A2, AR): juvenile parkinsonism + spasticity + supranuclear gaze palsy + mini-myoclonus; early levodopa-responsive then complications.
  • Manganese: T1 bright GP (not T2 dark), “cock-walk” gait, no levodopa response, normal DaTSCAN; remove from exposure.
🔍 Quick ReferenceClinical · Imaging · Genetics / pathology / treatment
Clinical phenotype
  • Wing-beating tremor (proximal high-amplitude postural tremor of outstretched arms) → Wilson disease
  • Risus sardonicus / sardonic grin orofacial dystonia + drooling + dysarthria in a young adult → Wilson disease
  • Coombs-negative hemolytic anemia + acute liver failure in a young patient → Fulminant Wilson
  • Juvenile parkinsonism + psychiatric/behavioral decline + chronic hepatitis → Wilson disease
  • Childhood dystonia + pigmentary retinopathy + acanthocytosis → PKAN (classic)
  • Palilalia + psychiatric features + later-onset dystonia → PKAN (atypical)
  • Adult-onset chorea-dystonia, AD inheritance → Neuroferritinopathy
  • Adult diabetes + retinal degeneration + movement disorder + microcytic anemia → Aceruloplasminemia
  • Girl with intellectual disability + Rett-like features + seizures → biphasic adult dystonia-parkinsonism → BPAN (WDR45)
  • Childhood dystonia + spasticity + optic atrophy + motor neuron signs → MPAN (C19orf12)
  • Juvenile parkinsonism + supranuclear gaze palsy + mini-myoclonus + spasticity → Kufor-Rakeb (ATP13A2)
  • “Cock-walk” toe-strutting gait + manganese madness, no levodopa response → Manganese toxicity
Imaging signs
  • “Face of the giant panda” sign on T2 midbrain → Wilson disease
  • “Face of the miniature/double panda” (pontine tegmentum) → Wilson disease
  • T2/FLAIR putaminal hyperintensity (most common Wilson finding) → Wilson disease
  • Kayser-Fleischer ring at corneal limbus (Descemet’s membrane) → Wilson disease
  • Sunflower cataract → Wilson disease (lens copper)
  • “Eye-of-the-tiger” sign — T2 GP hypointensity with central hyperintensity → PKAN (PANK2)
  • Cavitating/cystic basal ganglia lesions with low ferritin → Neuroferritinopathy
  • SN “halo sign” — T1 hyperintense halo with central hypointensity, plus GP/SN iron on T2*/SWI → BPAN
  • T1 hyperintensity in bilateral globus pallidus → Manganese toxicity (also chronic liver disease, TPN)
  • Cerebellar atrophy + axonal spheroids → PLAN/INAD (PLA2G6)
Genetics / pathology / treatment
  • ATP7B (chromosome 13q14), AR, P-type copper ATPase → Wilson disease (H1069Q most common European mutation)
  • Low ceruloplasmin + 24-hr urine Cu >100 µg + hepatic Cu >250 µg/g + Leipzig ≥4 → Wilson disease
  • ALP : total bilirubin <4 + AST : ALT >2.2 → Fulminant Wilson
  • D-penicillamine paradoxical neurologic worsening (10–50%) → Wilson — prefer trientine first-line for neuro disease
  • Zinc → intestinal metallothionein blocks copper absorption → Wilson maintenance
  • Liver transplant corrects the ATP7B hepatic defect (indicated for fulminant failure or decompensated cirrhosis; neurologic recovery is variable — NOT a guaranteed neurologic cure) → Wilson disease
  • PANK2 (20p13), AR — coenzyme A synthesis defect; formerly Hallervorden-Spatz → PKAN
  • FTL gene, autosomal DOMINANT (only AD NBIA), LOW serum ferritin → Neuroferritinopathy
  • CP gene, AR; absent ceruloplasmin (~0) with brain/systemic IRON overload → Aceruloplasminemia
  • WDR45, X-linked dominant; biphasic course → BPAN
  • C19orf12, AR; GP + SN iron with optic atrophy → MPAN
  • ATP13A2, AR; early levodopa response with motor complications → Kufor-Rakeb
  • PLA2G6, AR; axonal spheroids on biopsy → PLAN/INAD
  • Normal DaTSCAN with parkinsonism (post-synaptic GP injury) → Manganese toxicity
  • Chelation (deferiprone) trialed; DBS-GPi for dystonia; chelation NOT helpful in PKAN copper-style → NBIA management
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 (30–50%): 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.
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