What Is Neuroacanthocytosis (NA)?
They are diverse syndromes with similar characteristic neurological features and red blood cell anomalies. They are extremely rare and are caused due to genetic mutations (alterations) or inherited.
The syndromes under NA can be divided into three groups-
1) Core NA Syndromes - These are syndromes with specific clinical features of NA. They are degeneration of the basal ganglia (a group of structures near the brain's center that form important connections), cognitive impairment, movement disorders, and psychiatric features.
The syndromes which satisfy these criteria are-
Chorea-Acanthocytosis (ChAc) - It is a late-onset (usually in the twenties) progressive autosomal neurodegenerative condition. Mutations in the VPS13A gene are known to cause this condition. It is said to have an autosomal recessive inheritance because the affected individual will have both copies of mutated genes (one from the mother and one from the father). Chorea refers to involuntary jerking movements made by individuals with this disorder, and acanthocytosis is the obvious abnormally star-shaped red blood cells. In addition to chorea and acanthocytosis, patients with ChAc will also have the following features:
- Involuntary tensing of various muscles (dystonia) in the face, mouth, tongue, throat, limbs, etc.
- Vocal tics such as grunting.
- Involuntary belching.
- Impaired eating as twitching the tongue and throat interferes with chewing and swallowing.
- Uncontrollable biting of the lips, tongue, and insides of the mouth.
- Seizures.
- Difficulty in processing, learning, and remembering information, all of which are the classical features of cognitive impairment.
- Reduced sensation and weakness in the arms and the limbs (peripheral neuropathy).
- Myopathy (muscle weakness).
- Speech difficulties and inability to speak.
- Behavioral changes like obsessive-compulsive disorder, lack of self-restraint, inability to take care of oneself, and personality changes.
Mcleod Syndrome (MLS) - Also a genetically inherited neurological condition that exclusively affects boys and men. It is caused due to mutations in the XK gene, which provides instructions to produce a protein called XK. The XK protein carries the blood antigen called Kx, which is important in determining the blood type. MLS has an X-linked recessive inheritance pattern, which means one copy of the mutated gene (always present on the X chromosome) is sufficient to cause the condition. The neurological manifestations and the acanthocytosis part of the condition are similar to those of the ChAc; additional symptoms include neurogenic atrophy (atrophy of the nerves that connect to the muscles), life-threatening heart problems like arrhythmias (irregular heartbeats), dilated cardiomyopathy (weakened and enlarged heart), and psychiatric disorder like depression, and bipolar disorder.
Huntington’s Disease-Like 2 (HDL2) - It is an autosomally inherited neurological condition caused due to mutations in the JPH3 gene. The condition has a dominant inheritance pattern, which means one copy of the layered gene (either from the mother or the father) is enough to cause the condition. As the name suggests, HDL2 is a condition that resembles Huntington's disease (which is caused due to mutations in the HTT gene) and usually appears in early to mid-adulthood. The neurological and acanthocytosis manifestations seen in HDL2 are similar to those of ChAc and MLS.
Pantothenate Kinase Associated Neurodegeneration (PKAN) - It is an autosomally inherited genetic condition caused due to mutations in the PANK2 gene responsible for making an enzyme called pantothenate kinase 2. This enzyme plays a critical role in forming a molecule called coenzyme A, which, in turn, is essential to make energy from carbohydrates and fats. The inheritance has an autosomal recessive pattern. The clinical features of the condition are similar to those seen in other NA syndromes; additional features include vision loss, dementia, and the development of an eye-of-the-tiger sign due to the accumulation of iron in certain parts of the brain.
2) NA with Lipoprotein Disorders - These disorders have NA's characteristic neurological and acanthocytosis features and alteration in lipoprotein metabolism. The syndromes with these features are-
Bassen-Kornzweig Syndrome - It is a rare disease that makes the affected individual unable to absorb dietary fats from the intestines. It is caused due to mutations in the MTTP gene. Apart from the typical neurological and acanthocytosis features, this condition also causes spine curvature, abdominal protrusion, and stool abnormalities (like pale, frothy, and foul-smelling stools).
Familial Hypobetalipoproteinemia - Also a genetic disorder that causes an abnormal buildup of large amounts of cholesterol and triglycerides in the blood. It is caused due to mutations in the APOE gene, which produces the apolipoprotein (ApoE). The ApoE protein mediates the catabolism of very low-density lipoproteins (VLDL) and intermediate-density lipoproteins (IDL). Symptoms include neurological degeneration, acanthocytosis, chest pain, and other signs of coronary artery disease at a young age, cramping of both calves, and sudden stroke-like symptoms.
Anderson Disease - It is a rare, hereditary hypocholesterolemic syndrome characterized by chronic diarrhea and steatorrhea (increase in fat excretion in the stools), along with the neurological and acanthocytosis features of NA.
Atypical Wolman Disease - A rare genetic disorder characterized by a complete absence of an enzyme known as lysosomal acid lipase (LIPA or LAL). The condition is caused due to mutations in the LIPA gene and is inherited in an autosomal recessive pattern. Without the LIPA enzyme, certain fats will accumulate in the tissues and organs of the body, causing symptoms like boating, vomiting, hepatosplenomegaly (enlargement of the liver and spleen), and other life-threatening conditions. The typical features of NA are also seen in atypical Wolman disease.
3) Sporadic Conditions Associated with Acanthocytosis - This category includes systemic conditions with characteristic features of their own. Still, the neurological symptoms and acanthocytosis seen in NA are only present to a certain extent. This category includes severe malnutrition, cancers, thyroid disorders, liver cirrhosis, psoriasis, and Eale’s disease (an idiopathic inflammatory venous occlusive disease).
How Are the Syndromes Of Neuroacanthocytosis Diagnosed?
Most of the syndromes seen in NA are caused due to genetic mutations, which can be definitely diagnosed only with the help of genomic testing, which is often unavailable and expensive. This is where the following investigations will be helpful-
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Electroneurography - Helps to demonstrate the sensorimotor axonal neuropathy seen in ChAc and MLS.
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Cerebral MRI (Magnetic Resonance Imaging) - It helps diagnose PKAN.
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Electromyography - Helps to show the myopathic and neurogenic alterations of ChAc and MLS.
How Are the Syndromes Of Neuroacanthocytosis Treated?
There is no definite cure for various syndromes grouped under NA. Treatment primarily involves managing the current symptoms and slowing down the disease process. This is done with the help of an inter-professional team consisting of medical specialists like neurologists, ophthalmologists, neuropsychiatrists, geneticists, etc. Genetic counseling also plays an important role in providing information to the affected individual and their family members, which helps to understand the condition and possibly prevent it.
Conclusion:
NA comprises a group of syndromes and conditions with similar clinical features but different origins. Most syndromes under this condition are caused due to genetic mutations, which can happen de novo (spontaneously) or be passed on from one generation to the next. Treatment is primarily supportive, and early detection improves the prognosis.
