Genetic Disorders: Niemann-Pick C & Cerebrotendinous Xanthomatosis

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Questions and Answers

What is the main genetic mutation associated with Wilson's disease?

ATP7B gene mutation.

Describe the characteristic neurological symptoms of Wilson’s disease.

Symptoms include asymmetric tremor, dysarthria, ataxia, dystonia, and spasticity.

What imaging finding is referred to as the 'midbrain panda sign' in Wilson’s disease?

Hyperintense signals surrounding the red nucleus and substantia nigra with low signal intensity in the superior colliculus.

Which vitamin cofactors are required for the remethylation of homocysteine in classic homocysteinemia?

Vitamin B6, B12, and folate. Signup and view all the answers

What is the primary disorder associated with Niemann-Pick C, and what are some key neurological symptoms of childhood onset?

The primary disorder is impaired cholesterol esterification. Key neurological symptoms include cerebellar ataxia, vertical supranuclear gaze palsy, dystonia, seizures, and spasticity. Signup and view all the answers

What is a common psychiatric symptom linked to classic homocysteinemia?

Vascular dementia or depression. Signup and view all the answers

List two laboratory investigations that should be included in the workup for psychiatric presentations.

CBC (Complete Blood Count) and liver enzymes. Signup and view all the answers

Discuss the treatment for Niemann-Pick C and its mechanism of action.

The treatment for Niemann-Pick C is miglustat, which reversibly inhibits glycosphingolipid synthesis. Signup and view all the answers

Identify one of the high urinary markers used for diagnosing acute porphyrias.

High urinary porphobilinogen. Signup and view all the answers

What are two significant clinical features of Cerebrotendinous Xanthomatosis, and how is it diagnosed?

Significant clinical features include xanthomas of the Achilles tendon and early cataracts. It is diagnosed with high plasma and tissue cholestanol levels. Signup and view all the answers

What gene mutation is linked to Acute Intermittent Porphyria and what are common triggers for its symptoms?

Acute Intermittent Porphyria is linked to the HMBS gene mutation. Common triggers include valproic acid (VPA), tricyclic antidepressants (TCAs), alcohol, estrogens, and acetaminophen. Signup and view all the answers

What treatment options are available for Wilson’s disease?

Chelation therapy and penicillamine. Signup and view all the answers

Describe the psychiatric symptoms observed in individuals with adolescent and adult onset of Niemann-Pick C.

Adolescent onset may present with progressive learning difficulties and behavioral dysfunction, while adult onset can lead to psychosis and affective disorders. Signup and view all the answers

Study Notes

Niemann-Pick C

Disorder of impaired cholesterol esterification
NPC1, NPC2, AR
Causes severe liver/lung disease, upgaze palsy, ataxia, apraxia, seizures, dystonia, and dementia
Childhood onset: cerebellar ataxia, vertical supranuclear gaze palsy followed by dystonia, seizures, and spasticity
Adolescent onset: progressive learning difficulties and/or behavioural dysfunction
Adult onset: psychosis and affective disorders
Treatment: miglustat; reversibly inhibits glycosphingolipid synthesis

Cerebrotendinous Xanthomatosis

CYP27A1, AR
Cholesterol accumulation in tissues (lipid storage disease)
Presents with vomiting and diarrhea in childhood
Early cataracts
Xanthomas of Achilles tendon, elbow, patella, and neck
Osteoporosis
Intellectual disability in early 20s with behavioural and personality changes including hallucinations, agitation, depression, even suicidality
Pyramidal and/or cerebellar signs in 20s-30s
Investigated with high plasma and tissue cholestanol
Treatment: chenodeoxycholic acid

Acute Intermittent Porphyria

AD, HMBS gene
Overproduction of specific heme precursors
Presents with features of autism in the first decade, typically after puberty
Triggers: VPA, TCAs, alcohol, estrogens, acetaminophen
Acute, severe, colicky abdominal pain + predominant motor neuropathy, dysautonomia
Decreased reflexes, seizures
Confusion/hallucinations/delirium
Associated with PRES
Investigated with high urinary porphobilinogen
Treatment: hematin, glucose, chloroquine

Wilson's Disease

ATP7B gene, AR
Liver disease in adolescence followed by neuropsychiatric symptoms in 20s
Behavioral, affective, schizophrenia-like, cognitive changes
Neuro: asymmetric tremor, dysarthria, ataxia followed by dystonia, spasticity, and seizures
Eyes: Kayser-Fleischer rings (copper deposits)
Investigated with low serum ceruloplasmin, high 24h urine copper
Liver biopsy shows copper accumulation; genetic testing
MRI: hyperintense basal ganglia and thalamus
Midbrain panda sign: red nucleus and substantia nigra surrounded by high T2 signal
Treatment: chelation, penicillamine

Classic Homocysteinemia

Homocysteine buildup caused by CBS deficiency, AR
Clinical features: ectopia lentis, skeletal abnormalities, thromboembolism and intellectual disability
Marfanoid appearance
Vascular dementia, depression
Uses vitamin B6, B12 and folate as cofactors to remethylate back to methionine, and requires MTHFR enzyme for its metabolism
High homocysteine is directly toxic to neurons and blood vessels
Part of “young stroke work up”

Non-IEM Psychiatric Presentations

Infections: HIV, Syphilis
Genetic: 22q11

Approach: Investigating Psychiatric Presentations

CBC, electrolytes, liver enzymes, TSH, toxicology screen
Infectious: syphilis, HIV
Autoimmune: ANA, ANCA, ds-DNA
IEM screening: ammonia, amino acids, urine organic acids, copper, ceruloplasmin
MRI brain
Encephalopathy workup if refractory, additional neuro symptoms
- EEG
- CSF

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Description

Explore the genetic disorders Niemann-Pick C and Cerebrotendinous Xanthomatosis in this quiz. Understand their genetic causes, clinical presentations, and treatment options. Dive into the complexities of these lipid storage diseases and their impact across different life stages.