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Neuroacanthocytosis syndromes (NAS), previously known collectively as Levine-Critchley syndrome, are characterized by basal ganglia degeneration, acanthocytosis, and normal serum lipoprotein.
There are four core NAS:
- chorea-acanthocytosis (ChAc)
- McLeod syndrome (MLS)
- Huntington disease-like 2 (HDL2)
- pantothenate kinase-associated neurodegeneration (PKAN)
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NAS are incredibly rare, with an estimated prevalence of 1-5:1000000 3,4.
The presentation within and between each NAS is heterogeneous. Generally, patients present with movement disorder (commonly chorea and dystonia), cognitive decline and psychiatric disturbance 4,12.
Acanthocytosis, red blood cells defined by the presence of multiple thorny projections, is most often seen in ChAc and MLS, and less frequently in HDL2 and PKAN. The presence of acanthocytes is not necessary for diagnosis 12.
Elevated creatinine kinase is often found in ChAc and MLS.
Unique features of chorea-acanthocytosis
Of note, the finding of 'feeding dystonia' is pathognomonic of ChAc. Upon food touching the tongue, the tongue protrudes and forces the bolus out 5. In addition, the presence of 'rubber-man appearance', truncal instability and loss of axial tone with sudden spasms of flexion and extension, is highly suggestive of ChAc 12.
ChAc is caused by mutations in the gene encoding chorein, vacuolar protein sorting 13 homolog A (VPS13A) 5. The function of chorein is unclear, but has been shown to be of importance in exocytosis and cytoskeleton structure 6,7.
The McLeod blood group disorder arises from X-linked mutations in the XK gene at the Xp21.1 locus. The XK locus controls the expression of the ubiquitously expressed XK protein, which is predominantly found in nervous tissue, the myocardium and the erythrocytes cell surface 8. XK forms a disulphide bond with erythrocyte surface Kell antigens, forming a complex. XK and Kell expression is thereby correlated, and so reduced XK causes a reciprocal reduction in Kell. Most carriers of the McLeod blood group will develop the central nervous system features of MLS in later life. Of note, due to myocardial XK protein expression, cardiomyopathy often occurs in MLS. Upon laboratory testing, diminished Kell antigen expression should be seen on the red cell surface of MLS patients 9.
Huntington disease-like 2
Trinucleotide repeat expansions of junctophilin 3 (JPH3) are found in HDL2, which are thought to cause the formation of intracellular aggregates and subsequent cell death 4,10.
Pantothenate kinase-associated neurodegeneration
PKAN results from mutations in the pantothenate kinase 2 gene (PANK2) at the 20p13 locus. PANK2 encodes an enzyme, pantothenate kinase 2, which indirectly regulates mitochondria energy production via coenzyme A synthesis 4,11.
The genes identified in each subgroup and not clearly linked to a common pathway. However, there is a theme of membrane processing failure 12. It is worth noting that acanthocytes are present in a proportion of individuals affected by neurological dysfunction in other contexts. Specifically, inherited disorders of lipoprotein metabolism and systemic diseases, such as severe malnutrition, cancer and liver cirrhosis 4. These are distinct from the core NAS.
- atrophy and gliosis of the basal ganglia are typical, and so these deep brain structures may appear reduced in size
- regions of the basal ganglia may be hyperintense, indicating gliosis
- the head of the caudate is most often affected in ChAc, with the putamen, globus pallidus and substantia nigra affected to a lesser extent 12
- bilateral atrophy of the caudate and putamen is again observed in MLS and HDL2 12
- PKAN is characterized by an eye of the tiger iron deposition pattern - a round hyperintensity in the anteromedial globus pallidus 13
Treatment and prognosis
There are no curative therapies for NAS, with clinical management focusing on symptom control and quality of life 12.
History and etymology
Acanthos is the Greek word for "thorn", from which the name of the red blood cell abnormality in NAS, acanthocytosis, is derived. The first case reports of adult acanthocytosis associated with neurological dysfunction, by MacDonald Critchley and Irvine Levine, date to the late 1960s 1-3. Interestingly, NAS was originally known as Levine-Critchley syndrome, however, modern techniques could not confirm the originally identified families had NAS, as they were lost to follow-up, thus the eponymous term has been abandoned 4.
- 1. Critchley EM, Nicholson JT, Betts JJ, Weatherall DJ. Acanthocytosis, normolipoproteinaemia and multiple tics. (1970) Postgraduate medical journal. 46 (542): 698-701. Pubmed
- 2. Critchley EM, Clark DB, Wikler A. Acanthocytosis and neurological disorder without betalipoproteinemia. (1968) Archives of neurology. 18 (2): 134-40. Pubmed
- 3. Levine IM, Estes JW, Looney JM. Hereditary neurological disease with acanthocytosis. A new syndrome. (1968) Archives of neurology. 19 (4): 403-9. Pubmed
- 4. Jung HH, Danek A, Walker RH. Neuroacanthocytosis syndromes. (2011) Orphanet journal of rare diseases. 6: 68. doi:10.1186/1750-1172-6-68 - Pubmed
- 5. Velayos Baeza A, Dobson-Stone C, Rampoldi L, et al. Chorea-Acanthocytosis. 2002 Jun 14 [Updated 2014 Jan 30]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019. Pubmed
- 6. Shiokawa N, Nakamura M, Sameshima M, Deguchi A, Hayashi T, Sasaki N, Sano A. Chorein, the protein responsible for chorea-acanthocytosis, interacts with β-adducin and β-actin. (2013) Biochemical and biophysical research communications. 441 (1): 96-101. doi:10.1016/j.bbrc.2013.10.011 - Pubmed
- 7. Föller M, Hermann A, Gu S, Alesutan I, Qadri SM, Borst O, Schmidt EM, Schiele F, vom Hagen JM, Saft C, Schöls L, Lerche H, Stournaras C, Storch A, Lang F. Chorein-sensitive polymerization of cortical actin and suicidal cell death in chorea-acanthocytosis. (2012) FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 26 (4): 1526-34. doi:10.1096/fj.11-198317 - Pubmed
- 8. Lee S, Russo D, Redman CM. The Kell blood group system: Kell and XK membrane proteins. (2000) Seminars in hematology. 37 (2): 113-21. Pubmed
- 9. Redman CM, Russo D, Lee S. Kell, Kx and the McLeod syndrome. (1999) Bailliere's best practice & research. Clinical haematology. 12 (4): 621-35. Pubmed
- 10. Margolis RL. Huntington Disease-Like 2. 2004 Jan 30 [Updated 2012 Apr 26]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019. Pubmed
- 11. Gregory A, Hayflick SJ. Pantothenate Kinase-Associated Neurodegeneration. 2002 Aug 13 [Updated 2017 Aug 3]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019. Pubmed
- 12. Walker RH, Jung HH, Danek A. Neuroacanthocytosis. (2011) Handbook of clinical neurology. 100: 141-51. doi:10.1016/B978-0-444-52014-2.00007-0 - Pubmed
- 13. Zeng J, Xing W, Liao W, Wang X. Magnetic resonance imaging, susceptibility weighted imaging and quantitative susceptibility mapping findings of pantothenate kinase-associated neurodegeneration. (2019) Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia. 59: 20-28. doi:10.1016/j.jocn.2018.10.090 - Pubmed