#geneticdisorders

WILSON'S DISEASEHepato- Lenticular Degeneration

Demographics

Prevalence: 3/100,000

Hepatic symptoms begin in childhood/adolescence (~ 11yo) and are multivariate.

Neurologic manifestations present in adolescence/early adulthood (~ 19yo).

HEPATO- DEGENERATION

Toxic buildup of copper in the liver

Can result from any of several hundred mutations in the ATP7B gene on chromosome 13.

ATP7B gene mutation results in elevated in liver copper, secondary to a biochemical defect in copper metabolism (specifically a failure of incorporation of copper into apoceruloplasmin which results in low ceruloplasmin levels), which results in an impairment of biliary excretion of copper (and a back-up of copper in the liver).

Note that in addition to fulminant hepatitis, copper release can disseminate to numerous organs and cause many systemic manifestations, including:

The liver is the initial site of toxicity from copper accumulation (~ 25% of cases will first present with acute hepatitis).

Elevated copper levels on liver biopsy is the gold standard diagnostic test (in the appropriate clinical setting).

“Sunflower catarcts” or skin pigmentary changes

Renal, cardiac, skeletal, and endocrine disease

Acute intravascular hemolysis is an especially worrisome complication.

Kayser-Fleischer Rings

Release of nonceruloplasmin-bound copper into the bloodstream occurs once the liver is overloaded with copper and forms Kayser-Fleischer rings (K-F rings): gold/greenish/brown rings at the outer rim of the cornea.

These rings form when copper complexes with sulfur in Descemet’s membrane.

They begin superiorly, so they can hide under the eyelid and they may require a slit-lamp examination to be observed.

LENTICULAR DEGENERATION

Degeneration of the Lentiform Nucleus

Next, show that the lenticular portion of the degeneration refers to injury to the lentiform nucleus, which comprises the globus pallidus and putamen of the basal ganglia.

Wing-beating tremor

Indicate that it manifests with a characteristic coarse, proximal wing-beating tremor, which refers to when the patient holds his/her arms up in a winged position, the arms appear to flap, as if there is a pair of wings on the patient’s shoulders.

Note that this tremor can be found elsewhere, as well, such as in essential tremor.

Additional Manifestations

Also, note that a variety of movement disorders, such as other tremors; dysarthria; dystonia; gait abnormalities; chorea; and tics can be seen, as can neuropsychiatric manifestations.

"Face of the Panda” Sign on MRI

Finally, let's draw the "Face of the Panda” sign, which is a common MRI finding in Wilson's disease (and also Leigh disease).

Draw an outline of the midbrain.

Shade in the normal gray appearance on T2-weighted MRI imaging.

Next, show the pathology, which is a loss of this intensity in the center of the midbrain (hypointensity on T2-weighted imaging).

Include the dark red nuclei (the eyes) and the dark substantia nigra, (the ears). There is also hypointensity of the superior colliculus.

DIAGNOSTIC TESTING

Copper abnormalities

In symptomatic Wilson’s disease, when copper spills out of the liver into the circulation, we detect high urine copper levels on 24-hour urinary copper excretion testing.

We detect LOW serum ceruLOplasmin levels because of an associated apoceruloplasminemia, due to failure of incorporation of copper into apoceruloplasmin.

We detect a HIGH free copper level, which is tricky because the total copper can be low.

Caveats in Diagnostic Testing

Ceruloplasmin can be normal or elevated because it is an acute phase reactant and its levels can spike in an inflammatory condition.

Urine copper will only be elevated once copper has spilled out of the liver into the bloodstream.

Total copper levels can be low because they are directly tied to ceruloplasmin levels, since ~90% of copper is bound to ceruloplasmin.For these reasons, in the appropriate clinical setting, liver biopsy to look for elevated copper is the best diagnostic tool. We address the full pathophysiology in our notes, which will help us understand serum copper and ceruloplasmin levels.

WILSON'S DISEASE GENETICS

Autosomal recessive disorder, ATP7B gene on chromosome 13

Wilson’s disease is an autosomal recessive disorder that can result from any of several hundred mutations in the ATP7B gene on chromosome 13. The numerous potential combinations of heterozygous mutations that lead to Wilson’s disease has made it nearly impossible to create a coherent genotype–phenotype correlation but the pathophysiology, itself, is well understood.

The ATP7B gene produces copper-transporting ATPase 2, a key transporter of hepatic copper into the bile, thus the underlying pathophysiology results from a characteristic reduction of copper excretion into the bile.

The ATP7B gene mutation causes low ceruloplasmin levels and copper accumulation and, as expected, free copper (non-ceruloplasmin bound) levels will be elevated. But total serum copper levels combine both free copper (which is the toxic component) and ceruloplasmin-bound copper (which comprises ~ 90% of total copper), so total copper can be low because the ceruloplasmin, itself, is low.

As well, there is also reduced incorporation of copper into ceruloplasmin, which contains six copper atoms per molecule and is primarily synthesized in the liver.

The ATP7B gene is key to the incorporation of copper into apoceruloplasmin, thus in Wilson’s disease, there is typically reduced circulating levels of ceruloplasmin.

Conditions such as unexplained liver enzyme abnormalities, a family history of liver disease, early-onset liver issues, or symptoms that do not respond to standard treatments may indicate the need for genetic evaluation. These disorders can progress gradually without obvious symptoms in the initial stages, which is why they are often diagnosed late unless proactively investigated.

Genetic testing helps identify underlying mutations responsible for liver dysfunction, enabling accurate diagnosis, personalized treatment planning, and early intervention to prevent long-term liver damage. In many cases, early detection can significantly improve disease management and quality of life through targeted therapies and regular monitoring.

At Mission Gastro Hospital, advanced diagnostic tools and specialist care help in identifying complex liver conditions at an early stage, ensuring patients receive timely and effective treatment.

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Down’s Syndrome, a genetic condition affecting physical and cognitive development, is primarily caused by an extra copy of chromosome 21. This condition, also known as Trisomy 21, highlights the significant role genetics play in human development.

Key Points:

Genetic Cause: Down's Syndrome is a chromosomal disorder where individuals have three copies of chromosome 21 instead of two.

Types of Down’s Syndrome: The three genetic variations include Trisomy 21 (most common), Mosaic Down's Syndrome, and Translocation Down's Syndrome.

Genetic Testing: Prenatal screening and diagnostic tests help identify the likelihood or presence of the condition in a fetus.

Parental Age Factor: Advanced maternal age increases the risk due to changes in egg cell division, though most babies with Down’s are born to mothers under 35.

Ongoing Research: Genetics continues to play a vital role in understanding the condition, improving diagnostics, and offering better support to families.

Understanding the genetics behind Down’s Syndrome not only helps in early diagnosis but also aids in offering tailored support and therapy. With increasing awareness and medical advancements, individuals with Down’s Syndrome are leading more enriched and independent lives.