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  Table of Contents    
CASE REPORT  
Year : 2011  |  Volume : 54  |  Issue : 2  |  Page : 374-375
Lafora disease: A case report, pathologic and genetic study


1 Iranian Center of Neurological Research, Tehran University of Medical Sciences, Tehran, Iran
2 Program in Genetics and Genome Biology, Hospital for Sick Children, Toronto, Canada
3 Program in Genetics and Genome Biology: Department of Neurology, Hospital for Sick Children, Toronto, Canada
4 Department of Pathology, Tehran university of medical science, Tehran, Iran

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Date of Web Publication27-May-2011
 

   Abstract 

A 19-year-old male patient presented with progressive myoclonic seizures and speech disorder. The patient had photosensitivity, a few episodes of sudden transient blindness, and infrequent complex visual auras, dysarthria and mild ataxia, frequent myoclonic jerks prominently in the legs and severe dementia. Microscopic examination of the axillary skin biopsy revealed periodic acid-Schiff positive inclusion bodies in abluminal side of the apocrine sweat gland acini. Molecular screening showed a homozygous R241X mutation in EPM2A. Genotyping helps in the correct diagnosis of the Lafora disease (LD), which may be difficult to diagnose based on the available histopathological testing only. Our study is an effort to determine the distribution of mutations in LD patients in our region.

Keywords: EPM2A, EPM2B , Lafora disease, laforin, skin biopsy

How to cite this article:
Harirchian M H, Shandiz E E, Turnbull J, Minassian B A, Shahsiah R. Lafora disease: A case report, pathologic and genetic study. Indian J Pathol Microbiol 2011;54:374-5

How to cite this URL:
Harirchian M H, Shandiz E E, Turnbull J, Minassian B A, Shahsiah R. Lafora disease: A case report, pathologic and genetic study. Indian J Pathol Microbiol [serial online] 2011 [cited 2019 Dec 10];54:374-5. Available from: http://www.ijpmonline.org/text.asp?2011/54/2/374/81645



   Introduction Top


Autosomal recessively inherited, progressive myoclonic epilepsies (PMEs) include Lafora disease (LD), Unverricht-Lundborg disease, the neuronal ceroid lipofuscinoses, type I sialidosis (cherry-red spot myoclonus), action myoclonus-renal failure syndrome, and type III Gaucher disease. Almost all the autosomal recessively inherited PMEs are lysosomal diseases, with the exception of LD in which neither the accumulating material nor the gene products are in lysosomes. [1] LD is the most severe form of progressive myoclonus epilepsy, characterized by intractable tonic-clonic seizures, myoclonus, ataxia, visual hallucinations, and progressive dementia. [2] The disease is caused by mutations in either the EPM2A or EPM2B/NHLRC1 gene in 58% and 35% of cases, respectively. [3] The EPM2A gene encodes a protein phosphatase "laforin", a dual-specificity tyrosine phosphatase protein localized at plasma membrane and endoplasmic reticulum. EPM2B gene encodes malin which is an ubiquitin ligase that ubiquitinates and promotes proteosomal degradation of laforin. [4] Nearly 100 distinct mutations have been discovered in the two genes in over 200 independent LD families. Approximately half of them are missense mutations, and the deletion mutations account for one-quarter. [5] Mutations in at least one other as yet unknown gene also cause LD. [6],[7] The disease is caused by accumulation of pathognomonic periodic acid-Schiff positive diastase resistant (PAS-D+) intracellular polyglucosan inclusion bodies, (Lafora bodies) in central nervous system, retina, heart, liver, muscle and skin. [8] LD is almost universally fatal within 10 years, by the second or third decade of life. [5],[9]

In this article, the clinical, pathological and genetic details of a typical case of LD in Iran are reported. To our knowledge, the common types of genetic defects in Iran are not yet known. This case report will serve to help further correct diagnoses of LD and signifies a start in determining the common Iranian mutations in LD.


   Case Report Top


In November 2008, a 19-year-old male patient was referred to our clinic with myoclonic seizures and speech disorder. He had been healthy until 18 months before admission. He had normal development during childhood and early adolescence. The patient was born by normal vaginal delivery at full term, with no history of complicated pregnancy. His parents were consanguineous. Their first daughter was affected by a similar undiagnosed illness and she died 2 years later when she was 19 years old. The patient reported photosensitivity, a few episodes of sudden transient blindness, and infrequent complex visual auras. Neurologic examination revealed dysarthria, mild ataxia, severe dementia, as well as frequent myoclonic jerks prominently in the legs. Cranial nerves were intact. He had no sensory or motor disturbances.

Routine lab tests including complete blood cell count, liver enzyme tests, and urinalysis as well as cerebrospinal fluid (CSF) analysis were within normal limits. Electroencephalography (EEG) showed generalized slowing with polyspike-wave complexes. Magnetic resonance imaging (MRI) showed mild cerebral atrophy and hydrocephalus.

Skin biopsy was performed from the axillary region. Microscopic examination of the specimen revealed PAS positive inclusion bodies in the abluminal side of the apocrine sweat gland acini [Figure 1], which indicated, along with the clinical symptoms, the diagnosis of LD. We considered that interpretation of the axillary skin biopsy in LD can be difficult since apical granules in secretory apocrine acini can be mistaken for the Lafora bodies and mutation screening of the two known LD genes would be beneficial. [10]
Figure 1: Apocrine acini of axillary region showing Lafora bodies. Arrow shows a Lafora body, arrow-head shows apocrine apical inclusion (PAS; ×1000)

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Mutation screening for both EPM2A and EPM2B was performed as previously described. [5] Briefly, venous blood was collected and genomic DNA was extracted from 200 L whole blood employing High Pure Template Preparation Kit (Roche Diagnostics, Indianapolis, IN, USA). The extracted DNA was sent to the Hospital for Sick Children after lyophilization. The coding sequences from both EPM2A and EPM2B were amplified by polymerase chain reaction (PCR). PCR products were purified using QuiQuick Gel Extraction Kit (Qiagen), Hiden, Germany. Purified products were then sequenced and screened for mutations. This screening showed a homozygous R241X mutation in EPM2A, the most common causative mutation in this gene. [11]


   Discussion Top


Genotyping has started to help the neurologic practitioners to treat patients with some types of epilepsy. It also helps in the correct diagnosis of diseases such as LD, which may be difficult to diagnose based on the available histopathologic testing. Genotyping is also important because it identifies nonsense mutations in Lafora PME. It has been reported that nonsense mutations in mice with LD can be corrected by premature stop codon readthrough drugs such as gentamicin. [12] Further studies, both in mice and in humans, need to be performed to test this theory. Our study is an effort to determine the distribution of mutations in LD patients in our region.


   Acknowledgment Top


We thank Mr. Sina Rafiee and Mr. Omid Mardani, MD, for excellent comments on the article.

 
   References Top

1.Ramachandran N, Girard JM, Turnbull J, Minassian BA. The autosomal recessively inherited progressive myoclonus epilepsies and their genes. Epilepsia 2009;50:29-36.  Back to cited text no. 1
    
2.Minassian BA. Lafora's Disease: towards a clinical, pathologic, and molecular synthesis. Pediatr Neurol 2001;25:21-9.  Back to cited text no. 2
[PUBMED]  [FULLTEXT]  
3.Delgado-Escueta AV. Advances in lafora progressive myoclonus epilepsy. Curr Neurol Neurosci Rep 2007;7:428-33.  Back to cited text no. 3
    
4.Ganesh S, Puri R, Singh S, Mittal S, Dubey D. Recent advances in the molecular basis of Lafora's progressive myoclonus epilepsy. J Hum Genet 2006;51:1-8.   Back to cited text no. 4
[PUBMED]  [FULLTEXT]  
5.Lohi H, Turnbull J, Zhao XC, Pullenayegum S, Ianzano L, Yahyaoui M, et al. Genetic diagnosis in Lafora disease: genotype-phenotype correlations and diagnostic pitfalls. Neurology 2007;68:996-1001.  Back to cited text no. 5
[PUBMED]  [FULLTEXT]  
6.Chan EM, Omer S, Ahmed M, Bridges LR, Bennett C, Scherer SW, et al. Progressive myoclonus epilepsy with polyglucosans: evidence for a third locus. Neurology 2004;63:565-7.  Back to cited text no. 6
[PUBMED]  [FULLTEXT]  
7.Singh S, Ganesh S. Lafora progressive myoclonus epilepsy: a meta-analysis of reported mutations in the first decade following the discovery of the EPM2A and NHLRC1 genes. Hum Mutat 2009;30:715-23.  Back to cited text no. 7
[PUBMED]  [FULLTEXT]  
8.Striano P, Zara F, Turnbull J, Girard JM, Ackerley CA, Cervasio M, et al. Typical progression of myoclonic epilepsy of the Lafora type: a case report. Nat Clin Pract Neurol 2008;4:106-11.  Back to cited text no. 8
[PUBMED]  [FULLTEXT]  
9.Berkovic SF, So NK, Andermann F. Progressive myoclonus epilepsies: clinical and neurophysiological diagnosis. J Clin Neurophysiol 1991;8:261-74.  Back to cited text no. 9
[PUBMED]    
10.Andrade DM, Ackerley CA, Minett TS, Teive HA, Bohlega S, Scherer SW, et al. Skin biopsy in Lafora disease Genotype-phenotype correlations and diagnostic pitfalls. Neurology 2003;61:1611-4.  Back to cited text no. 10
[PUBMED]  [FULLTEXT]  
11.Ianzano L, Zhang J, Chan EM, Zhao XC, Lohi H, Scherer SW, et al. Lafora progressive myoclonus epilepsy mutation database-EPM2A and NHLRC1 (EPM2B) genes. Hum Mutat 2005;26:397.  Back to cited text no. 11
[PUBMED]  [FULLTEXT]  
12.Delgado-Escueta AV, Bourgeois BF. Debate: Does genetic information in humans help us treat patients? PRO--genetic information in humans helps us treat patients. CON--genetic information does not help at all. Epilepsia 2008;49:3-24.  Back to cited text no. 12
    

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Correspondence Address:
R Shahsiah
Department of Pathology, Tehran University of Medical Sciences, Keshavarz blvd, Tehran
Iran
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0377-4929.81645

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    Abstract
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