Canavan disease: Difference between revisions
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{{CMG}}; {{AE}} {{ZMalik}} | {{CMG}}; {{AE}} {{ZMalik}} | ||
{{SK}} [[Aspartoacylase Deficiency]], [[Canavan–van Bogaert–Bertrand disease]], [[ASPA Deficiency]], [[Canavan's leukodystrophy]] | {{SK}} [[Aspartoacylase Deficiency]], [[Canavan–van Bogaert–Bertrand disease]], [[ASPA Deficiency]], [[Canavan's leukodystrophy]] | ||
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*There is insufficient evidence to recommend routine [[screening]] for Canavan disease in the general population. | *There is insufficient evidence to recommend routine [[screening]] for Canavan disease in the general population. | ||
*Carrier testing is suggested for people of Northern and Central Europe. | *Carrier testing is suggested for people of Northern and Central Europe. | ||
*[[Prenatal]] screening is done in high-risk cases. | *[[Prenatal]] screening is done in high-risk cases.<ref name="MatalonMatalon2002">{{cite journal|last1=Matalon|first1=Reuben|last2=Matalon|first2=Kimberlee Michals|title=Canavan disease|journal=Obstetrics and Gynecology Clinics of North America|volume=29|issue=2|year=2002|pages=297–304|issn=08898545|doi=10.1016/S0889-8545(01)00003-1}}</ref> | ||
==Natural History, Complications, and Prognosis== | ==Natural History, Complications, and Prognosis== | ||
Latest revision as of 21:21, 14 August 2020
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Zehra Malik, M.B.B.S[2]
Synonyms and keywords: Aspartoacylase Deficiency, Canavan–van Bogaert–Bertrand disease, ASPA Deficiency, Canavan's leukodystrophy
For patient information, click here
| Canavan disease | |
| ICD-9 | 330.0 |
|---|---|
| OMIM | 271900 |
| DiseasesDB | 29780 |
| MedlinePlus | 001586 |
Overview
Canavan disease is a rare autosomal recessive degenerative disease with fatal neurological deficits that begins in infancy and has rapid progression. It is a leukodystrophy with deficiency of enzyme aspartoacylase causing accumulation of N-acetylaspartic acid. It is characterized by abnormal myelination and white matter atrophy.
Historical Perspective
- Canavan disease was first described in 1931 by an American neuropathologist, Myrtelle Canavan.[1]
- She wrote a case-study in 1931 of a child who died at sixteen-month of age and was found to have cerebral spongy degenerative changes of the central nervous system.[1]
- The disease was later named after Myrtelle Canavan.
Classification
- There is no established system for the classification of Canavan disease.
- Canavan disease is categorized as a leukodystrophy.[2]
Pathophysiology
- Canavan disease is a rare inherited disorder following an autosomal recessive pattern of inheritance. [3]
- It is caused by a deficiency of enzyme aspartoacylase.
- Aspartoacylase is responsible for breakdown of N-acetyl aspartate (NAA) into aspartic acid and acetate.
- Decreased level of aspartoacylase results in accumulation of N-acetyl aspartate (NAA) in the brain causing abnormal myelination and progressive cerebral spongy degeneration.[3]
Causes
- This autosomal recessive disease is caused by mutation in ASPA gene on short arm of chromosome 17 responsible for aspartoacylase enzyme production.[4]
- Canavan disease must be differentiated from other dysmylinating diseases that affect the white matter such as:
Epidemiology and Demographics
- The prevalence of Canavan Disease is approximately 1 per 100,000 individuals in general population.[5]
- Canavan disease usually affects individuals of the Eastern European (Ashkenazi) Jewish ancestry.
- In Ashkenazi Jews the prevalence of this disease is 1 in 6000-14000 individuals and 1 in 37-57 individuals are carriers among this population.[6]
Risk Factors
- There are no established risk factors for Canavan disease.[4]
- It is an autosomal recessive disease.
- It is more common in the Ashkenazi Jew population.[6]
Screening
- There is insufficient evidence to recommend routine screening for Canavan disease in the general population.
- Carrier testing is suggested for people of Northern and Central Europe.
- Prenatal screening is done in high-risk cases.[7]
Natural History, Complications, and Prognosis
- Patients with Canavan disease may progress to develop life-threatening complications, some patients may develop earlier in the infant stage and some develop later.
- Common complications of Canavan disease include:
- Delayed/lack of motor skills
- Hypotonia that may progress to spasticity and seizures
- Swallowing difficulty
- Paralysis
- Optic atrophy leading to blindness
- Death
- Prognosis is generally poor in the most common form of the disease, and patients usually don't survive beyond age ten. Some patients may survive into teens and twenties. Patients with a mild form of the disease have a normal lifespan.
Diagnosis
Diagnostic Study of Choice
- There are no established criteria for the diagnosis of Canavan disease. However, the diagnosis is confirmed by the presence of increased urinary N-acetylaspartic acid and an MRI suggestive of white matter disease in patients presenting with the aforementioned signs and symptoms.[5]
History and Symptoms
- Most commonly patients present at three to six months of age with lethargy, weak cry, irritability, poor head control, macrocephaly, hypotonia, poor feeding due to dysfunctional swallowing, seizures. The disease have relentless progression and soon is complicated by blindness, spasticity, decerebrate posturing and eventual death.[8]
- The late-onset variant of the disease has mild and non-specific signs and symptoms including speech delay and motor skill delay. It usually presents after 5 years of age and have normal life expectancy.
Physical Examination
- Common physical examination findings of Canavan disease include hypotonia, poor head control, macrocephaly, poor visual tracking, delayed motor skills, and/or irritability. As the disease advances, hypotonia progresses to spasticity and hyperreflexia.
Laboratory Findings
- An elevated concentration of urinary N-acetyl aspartate (NAA) aids in the diagnosis of Canavan disease.[5]
- An elevated concentration of amniotic fluid N-acetyl aspartate (NAA) and/or enzyme assay of aspartoacylase in amniotic cells and chorionic villi is used for prenatal diagnosis of Canavan disease.[3]
Electrocardiogram
- There are no ECG findings associated with Canavan disease.
X-ray
- There are no x-ray findings associated with Canavan disease.
Echocardiography or Ultrasound
- There are no echocardiography/ultrasound findings associated with Canavan disease.
CT scan
- Early-stage CT shows macrencephaly with decreased subcortical white matter attenuation without post-contrast enhancement.
- CT scan obtained at late-stage shows cortical atrophy suggested by ventricular dilation and prominent sulci and basal cisterns. [9]
MRI
- MRI confirms an enlarged brain. T1 weighted images show areas of low signal intensity and T2 weighted images show high signal intensity areas within the white matter. Globus pallidus and thalamus is also involved while MRI shows sparing of internal capsule, caudate nucleus. putamen and corpus callosum.
- MRI done in late-stage shows periventricular white matter atrophy.
Imaging Findings
MR spectroscopy is helpful in the diagnosis of Canavan disease. Findings on MR spectroscopy diagnostic of Canavan disease include elevated NAA and NAA:creatine ratio.[10]
Other Diagnostic Studies
- There are no other diagnostic studies associated with Canavan disease.
Treatment
Medical Therapy
- There is no treatment for Canavan disease; the mainstay of therapy is supportive care:
- Adequate nutrition and hydration support with gastrostomy
- Physical therapy for delayed/lacking motor skills
- Antiepileptic drugs for seizure control
- Gastrostomy tube also decreases the risk of aspiration
- Botulinum toxin can help spasticity
- Special programs to help with communication skills.[11] [12]
- Experimental Treatment under research:
- Lithium citrate: Aimed at decreasing level of N-acetyl aspartate.[13]
- Gene Therapy: Aimed at replacing defective gene with a healthy one.[14] The results showed improvement in life of the patient without adverse effects during 5-year follow-up.[15]
Surgery
- Surgical intervention is not recommended for the management of Canavan disease.
Primary Prevention
- Effective measures for the primary prevention of Canavan disease include carrier testing and genetic counseling in high-risk individuals/populations.
Secondary Prevention
- There are no established measures for the secondary prevention of Canavan Disease.
References
- ↑ Froukh, Tawfiq (2019). "First Record Mutations in the Genes ASPA and ARSA Causing Leukodystrophy in Jordan". BioMed Research International. 2019: 1–7. doi:10.1155/2019/7235914. ISSN 2314-6133.
- ↑ 3.0 3.1 3.2 Matalon, R.; Michals, K.; Sebesta, D.; Deanching, M.; Gashkoff, P.; Casanova, J.; Optiz, John M.; Reynolds, James F. (1988). "Aspartoacylase deficiency and N-acetylaspartic aciduria in patients with canavan disease". American Journal of Medical Genetics. 29 (2): 463–471. doi:10.1002/ajmg.1320290234. ISSN 0148-7299.
- ↑ 4.0 4.1 von Jonquieres, Georg; Spencer, Ziggy H. T.; Rowlands, Benjamin D.; Klugmann, Claudia B.; Bongers, Andre; Harasta, Anne E.; Parley, Kristina E.; Cederholm, Jennie; Teahan, Orla; Pickford, Russell; Delerue, Fabien; Ittner, Lars M.; Fröhlich, Dominik; McLean, Catriona A.; Don, Anthony S.; Schneider, Miriam; Housley, Gary D.; Rae, Caroline D.; Klugmann, Matthias (2017). "Uncoupling N-acetylaspartate from brain pathology: implications for Canavan disease gene therapy". Acta Neuropathologica. 135 (1): 95–113. doi:10.1007/s00401-017-1784-9. ISSN 0001-6322.
- ↑ 5.0 5.1 5.2 Reddy, Nihaal; Calloni, Sonia F.; Vernon, Hilary J.; Boltshauser, Eugen; Huisman, Thierry A. G. M.; Soares, Bruno P. (2018). "Neuroimaging Findings of Organic Acidemias and Aminoacidopathies". RadioGraphics. 38 (3): 912–931. doi:10.1148/rg.2018170042. ISSN 0271-5333.
- ↑ 6.0 6.1 Zayed, Hatem (2015). "Canavan disease: An Arab scenario". Gene. 560 (1): 9–14. doi:10.1016/j.gene.2015.02.009. ISSN 0378-1119.
- ↑ Matalon, Reuben; Matalon, Kimberlee Michals (2002). "Canavan disease". Obstetrics and Gynecology Clinics of North America. 29 (2): 297–304. doi:10.1016/S0889-8545(01)00003-1. ISSN 0889-8545.
- ↑ Traeger, Eveline C.; Rapin, Isabelle (1998). "The Clinical Course of Canavan Disease". Pediatric Neurology. 18 (3): 207–212. doi:10.1016/S0887-8994(97)00185-9. ISSN 0887-8994.
- ↑ Gordon N (2001). "Canavan disease: a review of recent developments". Eur J Paediatr Neurol. 5 (2): 65–9. doi:10.1053/ejpn.2001.0467. PMID 11589315.
- ↑ Reddy N, Calloni SF, Vernon HJ, Boltshauser E, Huisman TAGM, Soares BP (2018). "Neuroimaging Findings of Organic Acidemias and Aminoacidopathies". Radiographics. 38 (3): 912–931. doi:10.1148/rg.2018170042. PMID 29757724.
- ↑ Hoshino, Hideki; Kubota, Masaya (2014). "Canavan disease: Clinical features and recent advances in research". Pediatrics International. 56 (4): 477–483. doi:10.1111/ped.12422. ISSN 1328-8067.
- ↑ Nagabhushan Kalburgi S, Khan NN, Gray SJ (2013). "Recent gene therapy advancements for neurological diseases". Discov Med. 15 (81): 111–9. PMC 5554939. PMID 23449113.
- ↑ Assadi, Mitra; Janson, Christopher; Wang, Dah-Jyuu; Goldfarb, Olga; Suri, Neeti; Bilaniuk, Larissa; Leone, Paola (2010). "Lithium citrate reduces excessive intra-cerebral N-acetyl aspartate in Canavan disease". European Journal of Paediatric Neurology. 14 (4): 354–359. doi:10.1016/j.ejpn.2009.11.006. ISSN 1090-3798.
- ↑ Janson, Christopher; McPhee, Scott; Bilaniuk, Larissa; Haselgrove, John; Testaiuti, Mark; Freese, Andrew; Wang, Dah-Jyuu; Shera, David; Hurh, Peter; Rupin, Joan; Saslow, Elizabeth; Goldfarb, Olga; Goldberg, Michael; Larijani, Ghassem; Sharrar, William; Liouterman, Larisa; Camp, Angelique; Kolodny, Edwin; Samulski, Jude; Leone, Paola (2002). "Gene Therapy of Canavan Disease: AAV-2 Vector for Neurosurgical Delivery of Aspartoacylase Gene (ASPA) to the Human Brain". Human Gene Therapy. 13 (11): 1391–1412. doi:10.1089/104303402760128612. ISSN 1043-0342.
- ↑ Leone, P.; Shera, D.; McPhee, S. W. J.; Francis, J. S.; Kolodny, E. H.; Bilaniuk, L. T.; Wang, D.-J.; Assadi, M.; Goldfarb, O.; Goldman, H. W.; Freese, A.; Young, D.; During, M. J.; Samulski, R. J.; Janson, C. G. (2012). "Long-Term Follow-Up After Gene Therapy for Canavan Disease". Science Translational Medicine. 4 (165): 165ra163–165ra163. doi:10.1126/scitranslmed.3003454. ISSN 1946-6234.