Neuroacanthocytosis (Levine-Critchley Syndrome, Choreoacanthocytosi)

What is Neuroacanthocytosis?

Also known as Levine-Critchley syndrome, neuroacanthocytosis relates to a group of rare progressive conditions that affect movement. This group is characterised by the combination of abnormal spiny red blood cells and abnormalities that affect the neurological system.

There are 4 main types of the disorder, including:

chorea-acanthocytosis
McLeod syndrome
Huntington’s disease-like 2
PKAN (panthothenate kinase-associated degeneration)

The most common sign of neuroacanthocytosis is rapid involuntary muscle movements that affect the hands, feet and face.

What causes neuroacanthocytosis?

The core disorders of neuroacanthocytosis are genetic disorders, meaning that they arise as a result of defects in specific genes. The severity and stage of onset varies according to the individual disorder.

Both chorea-acanthocytosis and PKAN are recessive disorders, meaning that one defective copy of the gene must be inherited from each parent in order for a child to develop the condition. If the child only inherits one defective copy of the gene, this will mean that they a carrier and they won’t develop symptoms. If both parents are carriers, there is a 25% chance of the child developing the disorder, a 50% chance of the child being a barer and a 25% chance that the child will be unaffected. Males and females are affected in the same way.

Chorea-acanthocytosis is linked to mutations on VPS13A gene, which contains coding instructions for the protein chorein. PKAN is caused by defects in the PANK2 gene, which contains instructions for PANK2 protein.

Huntington’s disease-like 2 follows a dominant inheritance pattern and this means that only one copy of the mutated gene is required for the child to develop the disorder. With each pregnancy, there is a 50% chance that the child will develop the disorder. This disorder is caused by mutations that affect the JPH3 gene, which codes for the protein JPH3. This is involved in calcium regulation.

McLeod syndrome follows an X-linked inheritance pattern and this relates to a mutation on the X chromosome. Females have two X chromosomes and males have one X and one Y chromosome. If a female inherits a defective gene on the X chromosome, they are likely to be a carrier. If a male inherits a defective gene on the X chromosome, they will inherit the disorder. For each pregnancy, a carrier female has a 25% chance of having a carrier daughter, a 25% chance of having an unaffected daughter, a 25% chance of having an affected son and a 25% chance of having an unaffected son. McLeod syndrome is linked to mutations on the XK gene, which codes XK protein found in the brain, heart and muscle cells and in red blood cells.

What are the symptoms?

Symptoms vary according to the type of disorder and even two people with the same sub-division of neuroacanthocytosis may have different symptoms.

All types of neuroacanthocytosis are characterised by involuntary muscle movements, impaired cognitive function and abnormal spiny blood cells (acanthocytosis). However, additional symptoms may vary.

Symptoms of chorea-acanthocytosis

Chorea-acanthocytosis tends to progress slowly and symptoms include:

chorea (rapid involuntary muscle movements in the arms, legs and face)
abnormal movements in the pelvis, shoulders and feet
involuntary bending of the knees
abnormal walking style
dystonia (involuntary contractions that affect movement and posture)
grimacing
abnormal jaw movements
drooling
feeding problems
dysphagia (difficulty swallowing)
speech problems
nerve damage that affects reflexes and sensation
muscle weakness
behavioural and personality changes
Parkinsonism (symptoms similar to those associated with Parkinson’s disease)

Symptoms of McLeod syndrome

McLeod syndrome is more common in males than females. Symptoms include:

impaired cognitive function and memory problems
chorea
muscle weakness and deterioration
mental health problems
heart problems (most notably arrhythmia and cardiomyopathy, which causes the ventricles to become enlarged)
enlarged liver
enlarged spleen
increased risk of aversion to blood transfusions (this is linked to the genetic mutation, which affects the expression of Kx red blood cell antigen)

Symptoms of Huntington’s disease-like 2

Symptoms include:

dystonia
chorea
exaggerated reflexes (known as hyperreflexia)
very slow muscle movements (known as bradykinesia)
speech problems
impaired cognitive function
dementia
behavioural changes
increased risk of mental health disorders, including anxiety and depression
hallucinations

Symptoms of PKAN

The most common characteristic of PKAN is iron accumulation with the brain cells. It tends to progress relatively slowly but there may be episodes when symptoms become more severe rapidly. Examples of symptoms include:

rigidity in the muscles
muscle spasms
involuntary movements
clumsiness and unsteadiness
dystonia
lack of muscle tone
retinopathy (gradual deterioration of the retina)
speech problems
stiffness
impaired cognition

Who is affected?

Chorea-acanthocytosis: this is most common in people aged between 20 and 40 years old.

McLeod syndrome: this is most common in males aged between 40 and 60 years old.
PKAN: this is most common in children under the age of 10.
Huntington’s disease-like 2: the age of onset varies and this disorder has been most commonly found in families of African descent.

How is neuroacanthocytosis diagnosed?

Doctors will take family and medical history, physical evaluation and symptoms into account when making a diagnosis. A variety of tests can also be used to confirm a suspected diagnosis, including:

blood tests: blood tests can be used to detect acanthocytosis
imaging scans (such as MRI and CT scans)
EEG (electroencephalogram): this test measures electrical activity in the brain
EMG (electromyography): this test measures electrical activity in the muscles
ECG (electrocardiogram): this test measures electrical activity in the heart
genetic testing

Treating neuroacanthocytosis

There is currently no cure for neuroacanthocytosis and treatments are targeted at specific types of symptoms. Often, treatment is provided by a multi-disciplinary team of health professionals.
Types of treatment used include:

Medication: a variety of medications, including anti-psychotic, anti-depressant, anti-convulsant and sedative medications, may be recommended. The functions and possible side-effects of medications will be discussed with the patient prior to the start of the course.
Botox (botulinum toxin type A): Botox can be beneficial for treating dystonia
Diet and nutritional support: swallowing can be affected and in this case, dietary support and advice will be provided
Physiotherapy
Occupational therapy
Speech and language therapy
Surgical treatment: surgery may be used to stimulate specific parts of the brain
Genetic counselling