Overview
Definition:
Wilson disease (WD) is an autosomal recessive genetic disorder characterized by excessive accumulation of copper in organs, primarily the liver, brain, and eyes
In teens, neurologic manifestations are often prominent and can precede overt liver disease
It results from mutations in the ATP7B gene, leading to impaired copper transport and excretion.
Epidemiology:
WD is relatively rare, with an estimated prevalence of 1 in 30,000 to 1 in 40,000 live births worldwide
It affects individuals of all ethnic backgrounds
While symptoms can manifest at any age, presentation in adolescence is common, often between ages 5 and 35, with a peak incidence in the second decade for neurologic symptoms.
Clinical Significance:
Neurologic presentations in Wilson disease can be diverse and debilitating, mimicking other movement disorders
Early recognition and diagnosis are crucial for initiating timely treatment to prevent irreversible neurologic damage and improve patient outcomes
Understanding these presentations is vital for pediatricians and neurologists managing adolescents.
Clinical Presentation
Symptoms:
Motor symptoms: Tremors (postural, resting, intention)
Dystonia: neck, trunk, limb posturing
Dysarthria and dysphagia: slurred speech, difficulty swallowing
Gait disturbances: ataxia, unsteadiness
Drooling
Mask-like facies
Cognitive impairment: declining school performance, memory issues
Behavioral changes: aggression, depression, anxiety
Seizures are less common but can occur
Psychiatric symptoms can precede motor deficits.
Signs:
Neurologic examination may reveal: Cerebellar signs (dysmetria, nystagmus)
Extrapyramidal signs (parkinsonism, choreoathetosis)
Hyperreflexia or hyporeflexia
Muscle rigidity
Kayser-Fleischer rings (copper deposition in Descemet's membrane of the cornea, seen as golden-brown rings, may be absent in some teens)
Sunflower cataracts (less common in teens)
Hepatic signs may include hepatomegaly or signs of chronic liver disease.
Diagnostic Criteria:
No single pathognomonic test exists
diagnosis relies on a combination of clinical findings, laboratory tests, and genetic analysis
Established diagnostic criteria, such as the modified Amsterdam criteria, incorporate age, hepatic, neurologic, psychiatric, and ophthalmologic findings, along with biochemical and genetic evidence
A ceruloplasmin level below 10 mg/dL is highly suggestive but not definitive
A 24-hour urinary copper excretion exceeding 100 mcg/day is also indicative.
Diagnostic Approach
History Taking:
Detailed history of onset and progression of motor, speech, swallowing, cognitive, and behavioral changes
Inquire about family history of liver disease, neurologic disorders, or similar symptoms
Screen for psychiatric disturbances and cognitive decline
Ask about previous diagnoses of anemia or unexplained liver enzyme abnormalities.
Physical Examination:
Thorough neurologic examination to assess for extrapyramidal signs (tremor, rigidity, dystonia), cerebellar dysfunction (ataxia, dysmetria), gait abnormalities, cranial nerve deficits (dysarthria, dysphagia), and cognitive/behavioral assessment
Ophthalmic examination for Kayser-Fleischer rings using a slit lamp is essential
Assess for signs of liver disease (hepatomegaly, jaundice, ascites).
Investigations:
Biochemical tests: Serum ceruloplasmin (typically <20 mg/dL, often <10 mg/dL in symptomatic WD)
Serum copper (often low or normal)
24-hour urinary copper excretion (elevated >100 mcg/day)
Liver function tests (may be normal early on)
Genetic testing for ATP7B gene mutations (confirmatory)
Imaging: MRI brain may show T2-hyperintensities in basal ganglia (lentiform nucleus, thalamus), pons, and cerebellum
Ultrasound abdomen for liver morphology
Liver biopsy for copper content (gold standard if diagnosis remains uncertain).
Differential Diagnosis:
Other movement disorders: Idiopathic dystonia, essential tremor, Parkinson's disease (atypical presentations), Tourette syndrome
Psychiatric disorders: Depression, anxiety, obsessive-compulsive disorder
Neurodegenerative diseases: Spinocerebellar ataxias, Wilsonian-like syndromes
Hepatic encephalopathy from other causes of liver disease
Drug-induced movement disorders.
Management
Initial Management:
Prompt initiation of lifelong chelation therapy or zinc therapy upon diagnosis is paramount
Dietary modifications to reduce copper intake are supportive but not curative
Multidisciplinary team approach involving neurologists, hepatologists, psychiatrists, dietitians, and genetic counselors is recommended.
Medical Management:
Chelating agents: Penicillamine (initially 250-500 mg/day, increased gradually to 1-1.5 g/day in divided doses
monitor for side effects like bone marrow suppression, rash, renal dysfunction)
Trientine (1-1.5 g/day in divided doses
generally better tolerated than penicillamine)
Zinc salts (e.g., zinc sulfate 220 mg thrice daily, 110 mg thrice daily for children)
Zinc acts by inducing metallothionein, which binds copper in the intestine, reducing absorption
It is often used as maintenance therapy or in patients with milder symptoms or intolerance to chelators.
Surgical Management:
Liver transplantation may be indicated for patients with severe, decompensated liver failure due to Wilson disease that is refractory to medical management.
Supportive Care:
Nutritional counseling to limit high-copper foods (e.g., shellfish, liver, mushrooms, chocolate)
Speech and swallowing therapy for dysphagia and dysarthria
Physical and occupational therapy to manage motor deficits and improve function
Psychological support for behavioral and psychiatric symptoms
Regular monitoring of neurologic status, liver function, and copper levels.
Complications
Early Complications:
Neurologic worsening (especially with penicillamine initiation) known as the "initial worsening phenomenon." This can be managed by dose adjustment or switching to trientine or zinc
Gastrointestinal upset with penicillamine
Hematologic abnormalities (bone marrow suppression).
Late Complications:
Irreversible neurologic damage if treatment is delayed or inadequate
Hepatic cirrhosis and portal hypertension
Osteoporosis
Renal stones
Recurrence of disease if treatment is non-adherent
Psychiatric deterioration.
Prevention Strategies:
Early diagnosis and consistent lifelong adherence to prescribed therapy are crucial
Regular monitoring for drug toxicity and disease progression
Genetic counseling for at-risk families to identify affected individuals before symptom onset
Public health awareness campaigns to improve recognition of the disease.
Prognosis
Factors Affecting Prognosis:
Age at diagnosis and initiation of treatment
Severity of initial symptoms (neurologic vs
hepatic)
Presence of cirrhosis at diagnosis
Adherence to lifelong therapy
Response to treatment and development of complications
Early diagnosis in asymptomatic or mildly symptomatic individuals generally leads to a good prognosis.
Outcomes:
With early and consistent treatment, neurologic symptoms can stabilize or improve, and liver disease can be prevented or managed
Many patients can lead relatively normal lives
However, severe or long-standing neurologic deficits may not fully reverse
Untreated Wilson disease is fatal.
Follow Up:
Lifelong follow-up is essential
This includes regular clinical evaluations for neurologic and hepatic status, routine monitoring of liver function tests, renal function tests, and complete blood counts
Biochemical monitoring of copper status (serum ceruloplasmin, urinary copper) is important to assess treatment efficacy and adherence
Annual ophthalmologic assessment for Kayser-Fleischer rings
Genetic testing of family members for early detection.
Key Points
Exam Focus:
Key biochemical markers: low ceruloplasmin, elevated urinary copper
Classic triad: hepatic, neurologic, ophthalmic (Kayser-Fleischer rings)
ATP7B gene mutation
Differentiate WD neuro symptoms from other movement disorders
Importance of lifelong therapy adherence
Initial worsening phenomenon with penicillamine.
Clinical Pearls:
Always consider Wilson disease in adolescents with new-onset movement disorders, dystonia, or unexplained behavioral changes, even without overt liver disease
Slit lamp examination is vital for Kayser-Fleischer rings, but their absence does not rule out WD
A negative ceruloplasmin is highly suspicious
a normal or elevated value does not exclude WD
Always investigate family members of diagnosed patients.
Common Mistakes:
Diagnosing WD solely on low ceruloplasmin without considering other tests and clinical context
Delaying treatment due to mild symptoms or normal liver enzymes
Inadequate follow-up and monitoring of treatment adherence and toxicity
Misinterpreting neurologic symptoms as functional or psychiatric without a thorough workup.