Clinical characteristics.

Lafora disease (LD) is characterized by fragmentary, symmetric, or generalized myoclonus and/or generalized tonic-clonic seizures, visual hallucinations (occipital seizures), and progressive neurologic degeneration including cognitive and/or behavioral deterioration, dysarthria, and ataxia beginning in previously healthy adolescents between ages 12 and 17 years. The frequency and intractability of seizures increase over time. Status epilepticus is common. Emotional disturbance and confusion are common at or soon after onset of seizures and are followed by dementia. Dysarthria and ataxia appear early, spasticity late. Most 受累的 individuals die within ten years of onset, usually from status epilepticus or from complications related to nervous system degeneration.

Diagnosis/testing.

Diagnosis is usually based on clinical and EEG findings and detection of two pathogenic variants in one of the two genes known to be associated with LD: EPM2A or NHLRC1 (EPM2B). On rare occasion skin biopsy to detect Lafora bodies is necessary to confirm the diagnosis.

Management.

Treatment of manifestations: Antiepileptic drugs (AEDs) are effective against generalized seizures.

Prevention of secondary complications: Overmedication in treating drug-resistant myoclonus is a risk. Gastrostomy feedings can decrease the risk of aspiration pneumonia when disease is advanced.

Surveillance: Clinical and psychosocial evaluation at three- to six-month intervals throughout the teenage years.

Agents/circumstances to avoid: Phenytoin, and possibly carbamazepine, oxcarbazepine, and lamotrigine.

Genetic counseling.

Lafora disease is inherited in an 常染色体隐性遗传 manner. Heterozygotes (carriers) are asymptomatic. At conception, each sib of an 受累的 individual has a 25% chance of being affected, a 50% chance of being an asymptomatic 携带者, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and 产前诊断 for at-risk pregnancies are possible if the pathogenic variants in the family are known.

总结

临床特征 Lafora病（LD）可以分为片断性、对称或全面性肌阵挛和/或全面性强直阵挛性发作、视觉幻觉（枕叶癫痫）和进行性神经变性，包括认知和/或行为恶化，构音障碍和共济失调。青少年期（12-17岁）发病，之前可完全正常。癫痫发作的频率和难医治程度随时间增加。癫痫持续状态常见，情绪紊乱和意识模糊在癫痫发作时或之后常见，之后发生失忆。构音障碍和共济失调早期出现，痉挛相对较晚。大多数受累者在发病后十年内死亡，通常源于癫痫持续状态或与神经系统退化有关的并发症。

诊断/检测

诊断通常基于临床、EEG结果和对已知与LD相关的任一基因（EPM2A或NHLRC1（EPM2B））中的两个致病性变异位点的检测。在少数情况下，利用皮肤活检发现Lafora小体对于疾病的确诊是必要的。

管理

症状的治疗：抗癫痫药（AEDs）对抗全面性癫痫发作有效。

继发并发症的预防：对耐药性肌阵挛过度治疗存在风险。胃造口术管道进食可以降低疾病严重时吸入性肺炎的风险。

监测：青少年期间每隔三至六个月进行临床和社会心理评估。

需避免试剂/环境：苯妥英、卡马西平、奥卡西平和拉莫三嗪。

遗传咨询

 Lofora病以常染色体隐性遗传方式遗传。杂合子（携带者）无症状。受累者的兄弟姐妹有25%的概率患病，50％是无症状携带者，25％既不患病也不是携带者。如果家族携带已知的致病性变异，可以对高危亲属进行携带者筛查和对高风险妊娠予以产前诊断。

Clinical Diagnosis

The diagnosis of Lafora disease (LD) is suspected in a previously healthy older child or adolescent (usually in the early teens) who has the following:

• Fragmentary, symmetric, or generalized myoclonus and/or generalized tonic-clonic seizures
• Visual hallucinations (occipital seizures)
• Progressive neurologic degeneration including cognitive and/or behavioral deterioration, dysarthria, ataxia, and, at later stages, spasticity and dementia
• Slowing of background activity, loss of α-rhythm and sleep features, and photosensitivity on early EEGs
• Periodic acid Schiff-positive intracellular inclusion bodies (Lafora bodies) on skin biopsy
• Normal MRI of the brain at onset

See Table 1.

Testing

Skin biopsy reveals Lafora bodies [Carpenter et al 1974, Carpenter & Karpati 1981] composed of starch-like polyglucosans, which are insufficiently branched and hence insoluble glycogen molecules. Lafora bodies are present in either eccrine duct cells or in apocrine myoepithelial cells.

Note: (1) Normal PAS-positive apical granules in secretory apocrine cells found in the axilla can be mistaken for Lafora bodies; thus, biopsy of skin outside the axilla and genital regions is favored, as eccrine duct cell Lafora bodies are unmistakable [Andrade et al 2003]. (2) Interpretation of findings on skin biopsy involves a risk of false negative results [Lesca et al 2010], especially in newly symptomatic individuals, and a risk of false positive results because of the difficulty in distinguishing Lafora bodies from normal PAS-positive polysaccharides in apocrine glands [Drury et al 1993, Andrade et al 2003]. (3) Although sequencing and deletion/duplication analysis of EPM2A and NHLRC1 represent the gold standard for confirming the diagnosis, skin biopsy remains a useful diagnostic tool in individuals with a clinical diagnosis of Lafora disease in whom no 致病性变异 can be identified.

Testing Strategy

诊断

临床诊断

曾经健康的大龄儿童或青少年（通常为十几岁），但具有以下症状的可怀疑为Lafora病（LD）：

•片断性，对称性或全面肌阵挛性和/或全面强直阵挛性发作

•视幻觉（枕叶癫痫）

•进行性神经变性包括认知和/或行为恶化，构音障碍，共济失调，以及后期阶段的痉挛和痴呆

•背景活动减慢，α节律丧失和睡眠特征以及早期脑电图的光敏性

•皮肤活检，细胞内包涵体（Lafora小体）高碘酸希夫氏染色（PAS）呈阳性反应

•发作时脑部MRI正常

见表1

表1  Lafora 病临床评估

Minassian [2001], Minassian [2002], Villanueva et al [2006], Pichiecchio et al [2008], Altindag et al [2009], Canafoglia et al [2010]

1与疾病进展没有显著相关性

2症状发作后至少2年

检测

皮肤活检显示Lafora小体由淀粉状多聚葡萄糖组成[Carpenter et al 1974, Carpenter & Karpati 1981]，因其分支不足形成不可溶解的糖原分子。 Lafora小体存在于外分泌腺导管细胞或顶浆肌分泌上皮细胞中。

注意：（1）腋下发现的分泌性顶浆细胞中正常的PAS阳性顶端颗粒可能被误认为是Lafora小体；因此，腋下和生殖器区域外的皮肤活检更为推荐，因为分泌腺导管细胞的Lafora小体非常明显[Andrade et al 2003]。（2）皮肤活检存在假阴性结果的风险[Lesca et al 2010]，尤其是具有一些新症状的个体；在顶分泌腺中，由于难以区分Lafora小体与正常PAS阳性多糖，会存在假阳性结果的风险[Drury et al 1993, Andrade et al 2003]。（3）虽然EPM2A和NHLRC1的测序和缺失/重复分析是确认诊断的黄金标准，但对于没有可鉴定出致病性变异的个体，皮肤活检仍然是临床诊断为Lafora病有用的诊断工具。

分子遗传学检测

基因：EPM2A[Minassian et al 1998]和NHLRC1（也叫EPM2B）[Chan et al 2003b]的致病性变异可以导致LD。。见表2。

表2.进行性肌阵挛性癫痫，Lafora型的分子遗传测试

1. 参见表A. 染色体位点和蛋白质信息相关基因和数据库。在该基因中检测到的等位基因变异的信息，请参阅分子遗传学。

2. Gómez-Abad et al [2005] 发现97％（75/77）LD家系可检测到致病性变异：EPM2A（70％）和NHLRC1（27％）。

3. Franceschetti et al [2006]发现21/22（95％）LD家系可检测到致病性变异：EPM2A（22％）和NHLRC1（73％）。

4. Lohi et al [2006]发现88％（75/85）LD家系可检测到致病性变异：EPM2A（45％）和NHLRC1（43％）。

5．Singh et al [2006]发现84％（23/28）LD家系可检测到致病性变异：EPM2A（54％）和NHLRC1（34％）。

6. 检出率的显着差异可以反映出种族差异、偶然性和小的样本量。

7．测序分析可检出良性、可能良性、意义未明、可能致病性或致病性变异。致病性变异可包括基因内小的缺失/插入、错义、无义和剪接位点变异；一般情况下，很难检测到外显子或全基因水平的缺失/重复。对于在解释序列分析结果时要考虑的问题，请点击这里这里。

8. 通过对EPM2A和NHLRC1的序列分析，整合致病性变异检出频率的研究表明，仅使用序列分析可在这两个基因中检出88％至97％的致病性变异[Gómez-Abad et al 2005, Franceschetti et al 2006, Lohi et al 2006]。

9。基因组DNA的编码区域及其侧翼的内含子区域的序列分析不能检测到的外显子或全基因水平的缺失/重复。可以使用多种其他方法进行检测，包括：定量PCR，长片段PCR，多重连接探针扩增技术（MLPA）和包含该基因/染色体组的染色体微阵列（CMA）。

10．序列分析未检测到EPM2A和NHLRC1致病性变异中，因缺失而导致的致病性变异所占的比例未知。Lohi et al [2007] 在一项研究中，对三个个体中可检出的杂合致病性变异的可疑缺失进行筛选，在三个家系中发现了3个缺失，一个在EPM2A中，另两个在NHLRC1中。参见Molecular Genetics.。 Kecmanović等报道了一个患者发生了整个NHLRC1基因发生纯合缺失，其临床进程比大多数具有NHLRC1突变的个体发展更为迅速[Kecmanović et al 2013]。

11. 其他不止一个基因的致病性变异也会引起LD。Chan et al [2004]描述了在一个家系中，有三个个体已经经生物活检确诊患LD，却在EPM2A或NHLRC1中没有检出任何致病性的变异。连锁和单倍型分析排除了这2个基因与该家系中表型的关联性，同时也为LD存在第三个致病基因提供了间接证据。研究结果得到独立研究的支持[Singh et al 2005, Singh et al 2006]。

对检测结果的解释：以下情况应该怀疑是否存在缺失的情况：

•在受累者中检测到其中一个基因存在单个杂合致病性变异;

•在受累者中检测到其中一个基因存在一个明显的纯合致病性变异，但是只有一个亲本携带该位点。

检测策略

在先证者中确认/建立诊断

分子遗传检测：可以包括一系列单基因检测，使用表型靶向检测和更全面的基因组检测：

•一系列单基因检测。疑似患有LD的先证者的一种分子诊断策略是NHLRC1或EPM2A的靶向分析。需要在EPM2A或NHLRC1中鉴定双等位致病性变异：

o可以首先考虑NHLRC1的序列分析。

o如果在NHLRC1中未发现致病性变异，则应进行EPM2A的序列分析。

o如果在NHLRC1或EPM2A中只鉴定出一个致病变异，请考虑对该基因进行缺失/重复分析（分子遗传学检测，检测结果的解   释）。

•基因包。对疑似患有LD的先证者的分子诊断的另一种策略是使用包括EPM2A，NHLRC1和其他感兴趣基因（详见鉴别诊断）的基因包。注意：基因包中包含的基因和使用的方法因实验室和使用时期的不同而不同。

有关基因包的更多信息，请点击这里。
•更全面的基因组检测。 如果一系列单基因检测（和/或使用基因包检测）不能对具有LD特征的个体确诊，则可考虑包括外显子组测序，基因组测序和线粒体测序在内的更全面的基因组检测。有关综合基因组测序的更多信息，请点击这里。

注意：尽管有证据表明NHLRC1相关LD患者的生存期比EPM2A相关LD患者更长[Gómez-Abad et al 2005, Franceschetti et al 2006]，但LD相关基因的致病性变异所引起的临床表现非常相似，以至于在某个体中不可能预测哪个基因将会发生突变。

皮肤活检。皮肤活检可以检测到Lafora小体。注意：Lafora小体也可能在早发性Lafora小体疾病的个体中发现；请参见鉴别诊断。

Clinical Description

Lafora disease (LD) typically starts between ages 12 and 17 years, after a period of apparently normal development. Many 受累的 individuals experience isolated febrile or nonfebrile convulsions in infancy or early in childhood. Intractable seizures rarely begin as early as age six years. In families with more than one affected child, clinical signs such as subtle myoclonus, visual hallucinations, or headaches are noted earlier in subsequent affected children than in the 先证者 [Minassian et al 2000b, Minassian 2002]. Intra- and 家系间差异 in age at onset is considerable [Gómez-Abad et al 2007, Lohi et al 2007].

The main seizure types in LD include myoclonic seizures and occipital seizures, although generalized tonic-clonic seizures, atypical absence seizures, and atonic and complex partial seizures may occur.

Myoclonus can be fragmentary, symmetric, or massive (generalized). It occurs at rest and is exaggerated by action, photic stimulation, or excitement. Both negative (loss of tone) and positive (jerking) myoclonus can occur. Myoclonus usually disappears with sleep. Trains of massive myoclonus with relative preservation of consciousness have been reported. Myoclonus is the primary reason for early wheelchair dependency. In the advanced stages of the disease, 受累的 individuals often have continuous generalized myoclonus.

Occipital seizures present as transient blindness, simple or complex visual hallucinations, photomyoclonic or photoconvulsive seizures, or migraine with scintillating scotomata [Berkovic et al 1993, Minassian et al 2000b].

The course of the disease is characterized by increasing frequency and intractability of seizures. Status epilepticus with any of the previously mentioned seizure types is common. Cognitive decline becomes apparent at or soon after the onset of seizures. Dysarthria and ataxia appear early, spasticity late. Emotional disturbance and confusion are common in the early stages of the disease and are followed by dementia.

By their mid-twenties, most 受累的 individuals are in a vegetative state with continuous myoclonus and require tube feeding. Some maintain minimal interactions with the family such as a reflex-like smiling upon cajoling. Affected individuals who are not tube-fed aspirate frequently as a result of seizures; death from aspiration pneumonia is common.

Most 受累的 individuals die within ten years of onset, usually from status epilepticus or from complications related to nervous system degeneration [Minassian 2002].

Genotype-Phenotype Correlations

Genotype-表型 correlations are difficult to establish in LD because compound heterozygotes in different combinations are common [Chan et al 2005, Gómez-Abad et al 2005]. Variation by country in the care available for individuals with LD may in part influence longevity and disease complications.

Within an ethnic group of individuals sharing the same 致病性变异 the 表型 can be highly variable [Gómez-Abad et al 2007] or very similar [Turnbull et al 2008].

Intra- and 家系间差异 in age at onset is considerable, suggesting that genetic factors other than the EPM2A or NHLRC1 pathogenic variants may influence the pathogenesis of LD [Gómez-Abad et al 2007, Lohi et al 2007]. The LD 基因 products laforin and malin are known to interact with a diverse set of proteins and variations in gene(s) that code for these interacting protein(s) could contribute to variations in 表型 [Singh & Ganesh 2012]. It has indeed been demonstrated that a sequence variant in PPP1R3C, which codes for the protein PTG (protein targeting to glycogen), contributes to a milder course of LD [Guerrero et al 2011].

To date, no correlations between 表型 and variant type (错义 or truncating) or location of the 致病性变异 in the 基因 have been demonstrated

• Although a sub-表型 consisting of childhood-onset learning disorder followed by epilepsy and neurologic deterioration has been associated with either pathogenic variants in 外显子 1 of EPM2A [Ganesh et al 2002a, Annesi et al 2004] or the p.Ile198Asn致病性变异 located in an NHL protein-protein interaction 结构域 of NHLRC1 [Gómez-Abad et al 2005], these findings need to be replicated, expanded, and studied further in order to understand their relationship to the underlying pathophysiologic processes.
• Individuals with pathogenic variants in NHLRC1 appear to live longer than those with pathogenic variants in EPM2A [Gómez-Abad et al 2005, Franceschetti et al 2006, Singh et al 2006]. This finding has been demonstrated repeatedly for persons with the NHLRC1致病性变异p.Asp146Asn [Baykan et al 2005, Gómez-Abad et al 2005, Franceschetti et al 2006]. However, this does not apply to all persons with pathogenic variants in NHLRC1, as some may have extremely severe phenotypes [Traoré et al 2009, Brackmann et al 2011].

Nomenclature

Lafora disease (LD) is also referred to as myoclonic epilepsy of Lafora or progressive myoclonic epilepsy type 2.

The term progressive myoclonus epilepsy (PME) covers a large and varied group of diseases characterized by myoclonus, generalized tonic-clonic seizures, and progressive neurologic deterioration [Berkovic et al 1986].

Prevalence

Exact prevalence figures for LD are not available.

LD occurs worldwide. Although relatively rare in the non-近亲婚配的 populations of the United States, Canada, China, and Japan, LD is relatively common in the Mediterranean basin of Spain, France, and Italy, in restricted regions of central Asia, India, Pakistan, northern Africa, and the Middle East, in ethnic isolates from the southern United States and Quebec, and in other parts of the world with a high rate of 近亲婚配 [Delgado-Escueta et al 2001].

Within the Italian and Japanese populations, pathogenic variants in NHLRC1 are more common than pathogenic variants in EPM2A. Conversely, EPM2A pathogenic variants are more common in the Spanish and French populations. Within the Indian and Arab populations the distribution of pathogenic variants in the two genes is more or less even [Singh & Ganesh 2009, Lesca et al 2010].

Note: LD has not been reported in Finland, where founder effects for a number of genetic disorders are common, and where EPM1 (Unverricht-Lundborg disease) has the highest prevalence [A Lehesjoki & R Kälviäinen, personal communication].

临床特征

临床描述

Lafora病（LD）通常始发于12至17岁之间，在此之前会经过一段看似正常的发育期。许多患病个体在婴儿期或童年早期经历孤立的发热或非发热惊厥。难治性癫痫发作很少从六岁开始。在有一个以上患儿的家庭中，与先证者相比，后续受累患儿中有一些早期临床症状会被注意到，如轻微的肌阵挛，视幻觉或头痛[Minassian et al 2000b, Minassian 2002]。发病年龄在家族内和家族间变化是相当大的[Gómez-Abad et al 2007, Lohi et al 2007]。

LD的主要癫痫发作类型包括肌阵挛发作和枕叶癫痫发作，其它如全面强直-阵挛性发作、非典型失神发作和失张力发作和复杂部分性发作也可能发生。

肌阵挛可以是片段性的、对称性的或全面性的。它在静止时发生，在运动、光刺激或兴奋时被激化。可能会出现负性（肌张力丧失）和正性（抽动性）肌阵挛。肌阵挛通常随着睡眠消失。有过意识保留的一连串的全面性肌阵挛发生的报道。肌阵挛是很早开始使用轮椅的主要原因。在疾病的晚期阶段，患病的个体经常发生持续的全身性肌阵挛。

枕叶癫痫发作表现为暂时性失明、简单或复杂的幻视、光敏感肌阵挛性或光敏感惊厥性癫痫发作、或伴有闪烁发亮盲点的偏头痛[Berkovic et al 1993, Minassian et al 2000b]。

该病的病程以癫痫发作的频率增加和发作的难治性为特征。伴随有前面提到的各种发作形式的癫痫持续状态非常普遍。在癫痫发作期间或发作不久之后，认知明显下降。构音障碍和共济失调较早出现，痉挛随后发生。情绪紊乱和意识模糊常见于疾病的早期阶段，其后出现痴呆。

到二十几岁的时候，大多数患者处于植物状态伴随持续性肌阵挛，需要管饲。有些人与家人保持着最小的互动，例如逗笑后会报以反射般的微笑。由于癫痫发作，患者若不进行管饲，常常会发生吸入（窒息）。吸入性肺炎通常是导致死亡的原因。

大多数患者在发病十年内死亡，通常死于癫痫持续状态或与神经系统变性有关的并发症[Minassian 2002]。

基因型-表型相关性

在LD中很难建立基因型-表型相关性，因为其常常以不同组合形式的复合杂合出现 [Chan et al 2005, Gómez-Abad et al 2005]。 LD患者在不同国家获得的护理差异可能部分影响寿命和疾病并发症。

同一个人群中，具有相同致病性变异的个体表型可以是高度变化的[Gómez-Abad et al 2007]或非常相似的[Turnbull et al 2008]。发病年龄在家族内和家系间差异相当大，表明除EPM2A或NHLRC1致病性变异外，存在其它的遗传因素可能影响LD的发病机制[Gómez-Abad et al 2007, Lohi et al 2007]。LD基因产物laforin和malin已知与不同的蛋白质互作，编码这些互作蛋白的基因的变异可能导致表型的变化[Singh & Ganesh 2012]。事实证明，编码PTG蛋白（靶向糖原的蛋白）的PPP1R3C中的序列变异使得LD进程变得更缓和[Guerrero et al 2011]。

迄今为止，还没有证据显示该基因的致病性变异所导致的表型和变异类型（错义或截短）或变异在基因中所处的位置之间的相关性。

•尽管由儿童期发作的癫痫继发性学习障碍和神经系统恶化所组成的亚表型与EPM2A外显子1中的致病性变异 [Ganesh et al 2002a, Annesi et al 2004]或位于NHLRC1基因的NHL蛋白互作结构域中的p.Ile198Asn致病性变异有一定的关联性[Gómez-Abad et al 2005]，但这些发现需要重复、扩展和进一步研究以理解它们与潜在的病理生理过程的关系。

•具有NHLRC1致病性变异的个体似乎比具有EPM2A致病性变异的个体寿命更长[Gómez-Abad et al 2005, Franceschetti et al 2006, Singh et al 2006]。该结果已经在具有NHLRC1致病性变异p.Asp146Asn的患者中得到重复验证[Baykan et al 2005, Gómez-Abad et al 2005, Franceschetti et al 2006]。然而，这并不适用于所有具有NHLRC1致病性变异的人群，因为有些人可能有极其严重的表型[Traoré et al 2009, Brackmann et al 2011]。

命名法

Lafora病（LD）也被称为Lafora型肌阵挛性癫痫或2型进行性肌阵挛性癫痫。

术语进行性肌阵挛癫痫（PME）包括大量不同类型的以肌阵挛、全面性强直-阵挛发作和进行性神经病变恶化为特征的疾病[Berkovic et al 1986]。

发病率

关于LD发病率还没有确切的数字描述。LD在全世界范围内发生。虽然在美国、加拿大、中国和日本的非近亲婚配的人群中发病率相对较低，但是在西班牙、法国和意大利的地中海盆地、中亚、印度、巴基斯坦、北非、中东、美国南部和魁北克以及世界其他高近亲婚配的人群所在地区的LD相对常见[Delgado-Escueta et al 2001]。

在意大利和日本人群中，NHLRC1的致病性变异比EPM2A中的致病性变异更常见。相反，EPM2A致病变异在西班牙和法国人群中则更为常见。在印度和阿拉伯人群中，这两个基因的致病性变异的分布比较均匀[Singh & Ganesh 2009, Lesca et al 2010]。

注意：在一些遗传性疾病的祖先效应常见的芬兰人群中，没有过LD的报道，但EPM1（Unverricht-Lundborg疾病）有非常高的发病率[A Lehesjoki＆RKälviäinen，personal communication]。

遗传相关（等位基因）疾病

除本次GeneReview中讨论的那些与EPM2A或NHLRC1中的致病变异相关的表型外，还未发现其它的表型。

鉴别诊断

早发型Lofora小体疾病是一种新发现的以进行性肌阵挛癫痫和Lofora小体为特征的疾病[Turnbull et al 2012]。与Lofora病（LD）不同的是，典型的早发性LD在五岁左右出现。症状包括构音障碍、肌阵挛和共济失调，这可能与晚期婴儿期异型神经元蜡样质脂褐质沉积症混淆。然而，病理学显示为Lafora小体而非蜡样脂褐质沉着。早发性LD的病程比婴儿神经元蜡样质脂褐质沉着症或Lafora病更长。PRDM8的致​​病性变异可导致早发性LD。

青少年肌阵挛性癫痫（OMIM 254770）。虽然青春期发生肌阵挛和全身强直阵挛性发作可能增加青少年肌阵挛性癫痫发作的可能性，但脑电图背景慢化和认知功能障碍的持续状态会引起对疾病是否为更为严重的癫痫综合征的怀疑，如PME等。

发病年龄较早，疾病进展速度较慢，皮肤活检中不存在Lafora小体，根据这些特征可将Unverricht-Lundborg 疾病 （EPM1）与Lafora病（LD）区分开来。

仔细的眼科检查，包括视网膜电图检查，可用于区分神经元蜡样质脂褐质沉着症和唾液酸沉积症。

脑脊液的乳酸浓度和麻疹抗体的效价可助于排除 肌阵挛性癫痫伴蓬毛样红纤维（MERRF）和亚急性硬化性全脑炎（SSPE）[Minassian 2001, Minassian 2002]诊断。

视幻觉、戒断和认知能力下降可能引起精神分裂症，精神分裂症与惊厥发作和癫痫样脑电图不太可能同时出现。

磁共振成像(MRI)可以排除结构异常，脑电图后方显著不规则棘波放电可怀疑为LD。

参见癫痫、进行性肌阵挛、OMIM表型系列以查看OMIM中与此表型相关的基因。

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Lafora disease (LD), the following are recommended:

• Clinical evaluation
• Evaluation of speech, walking, coordination, handwriting, school performance, and emotional status
• Clinical genetics consultation

Treatment of Manifestations

Antiepileptic drugs (AEDs) have a major effect against generalized seizures, sometimes controlling seizures for many months. Generalized seizures are rare in individuals who are treated, even years after disease onset.

Valproic acid is the traditional antiepileptic treatment for LD; because it is a broad-spectrum AED, it controls both the generalized tonic-clonic seizures and myoclonic jerks.

Clonazepam can be used as an adjunctive medication for control of myoclonus, as in other forms of PME, although the literature does not provide clear evidence for its effect on myoclonus in LD.

Zonisamide has had a significant effect on both seizures and myoclonus in a small number of individuals with Unverricht-Lundborg disease and Lafora disease.

Both piracetam and levetiracetam have been effective, sustained, and well tolerated as add-on treatment for myoclonus in progressive myoclonus epilepsy (PME) [Koskiniemi et al 1998, Genton et al 1999, Fedi et al 2001, Crest et al 2004]. Levetiracetam had a significant effect on myoclonus in two sisters with LD [Boccella et al 2003]. Lohi et al [2006] reported that levetiracetam exacerbated seizures while improving myoclonus in two persons with LD.

Prevention of Secondary Complications

Because the myoclonus associated with LD may be drug resistant, overmedication may be a risk in individuals with LD .

Placement by percutaneous endoscopy of a gastrostomy tube for feeding can be helpful in decreasing the risk of aspiration pneumonia in individuals with advanced disease.

Surveillance

Clinical and psychosocial evaluation should be performed at three- to six-month intervals throughout the teen years.

Agents/Circumstances to Avoid

As in other forms of progressive myoclonus epilepsies, the use of phenytoin should be avoided.

Anecdotal reports describe possible exacerbation of myoclonus with the following:

• Carbamazepine [Nanba & Maegaki 1999]
• Oxcarbazepine [Kaddurah & Holmes 2006]
• Lamotrigine [Cerminara et al 2004, Crespel et al 2005]

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to evaluation of at-risk relatives for 遗传咨询 purposes.

Therapies Under Investigation

Work in animal models has shown that glycogen synthesis is requisite for glycogen accumulation and Lafora body formation; such glycogen accumulation is pathogenic [Turnbull et al 2011, Pederson et al 2013, Duran et al 2014, Turnbull et al 2014]. This suggests a therapeutic window for potential treatments using known and future small-molecule inhibitors of glycogen synthesis in individuals with LD.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

管理

初步诊断后的评估

为了确定被诊断患有Lafora病（LD）的患病程度和个体需求程度，建议如下：

•临床评估

•评估语言、行走、协调、书写、学校表现和情绪状态

•临床遗传咨询

症状的治疗

抗癫痫药物（AEDs）对于全面性癫痫发作有重要作用，有时可以控制癫痫发作数月。在接受治疗的个体中全面性癫痫发作是罕见的，甚至在发病后数年内。

丙戊酸（Valproic acid）是LD的传统抗癫痫药物；因为它是广谱抗癫痫药，它可同时控制全面性强直 - 阵挛性发作和肌阵挛。

与其他形式的进行性肌阵挛性癫痫（PME）一样，氯硝西泮（Clonazepam）可作为控制肌阵挛的辅助药物，尽管文献没有提供明确的证据证明其对肌阵挛的影响。

唑尼沙胺（Zonisamide）对少数Unverricht-Lundborg病和Lafora病患者的癫痫发作和肌阵挛具有显著的效果。

吡拉西坦（piracetam）和左乙拉西坦（levetiracetam）作为进行性肌阵挛性癫痫（PME）中的肌阵挛的附加治疗，是有效、持续且良好耐受的[Koskiniemi et al 1998, Genton et al 1999, Fedi et al 2001, Crest et al 2004]。左乙拉西坦对患有LD病的两个姐妹的肌阵挛症状具有显著效果[Boccella et al 2003]。  Lohi 等 [2006]报道，左乙拉西坦可加重癫痫发作，但可改善LD患者的肌阵挛。

继发性并发症的预防

因为与LD相关的肌阵挛可能是耐药的，所以在LD患者中过量用药可能具有一定的风险。

通过经皮内镜胃管造瘘管进食可有助于降低晚期疾病患者吸入性肺炎的风险。

监督

临床和社会心理评估应在青少年时期以三到六个月的间隔进行。

药剂/环境避免

与其他形式的进行性肌阵挛癫痫一样，应该避免使用苯妥英钠。

散在的报告描述了使用如下药物可能导致肌阵挛的恶化：

• 卡马西平[Nanba & Maegaki 1999]
• 奥卡西平[Kaddurah & Holmes 2006]
• 拉莫三嗪[Cerminara et al 2004, Crespel et al 2005]

对风险亲属的评估

有关遗传咨询目的与风险亲属评估有关的问题见遗传咨询。

潜在治疗方案

动物模型研究表明，糖原合成是糖原积累和Lafora小体形成的必要条件；这样的糖原累积是致病的[Turnbull et al 2011, Pederson et al 2013, Duran et al 2014, Turnbull et al 2014]。这提示了对LD患者使用已知的和候选的小分子糖原合成抑制剂进行潜在治疗可能会产生一定的效果

搜索ClinicalTrials.gov获取有关各种疾病和病症临床研究的信息。

Clinical characteristics.

Lafora disease (LD) is characterized by fragmentary, symmetric, or generalized myoclonus and/or generalized tonic-clonic seizures, visual hallucinations (occipital seizures), and progressive neurologic degeneration including cognitive and/or behavioral deterioration, dysarthria, and ataxia beginning in previously healthy adolescents between ages 12 and 17 years. The frequency and intractability of seizures increase over time. Status epilepticus is common. Emotional disturbance and confusion are common at or soon after onset of seizures and are followed by dementia. Dysarthria and ataxia appear early, spasticity late. Most 受累的 individuals die within ten years of onset, usually from status epilepticus or from complications related to nervous system degeneration.

Diagnosis/testing.

Diagnosis is usually based on clinical and EEG findings and detection of two pathogenic variants in one of the two genes known to be associated with LD: EPM2A or NHLRC1 (EPM2B). On rare occasion skin biopsy to detect Lafora bodies is necessary to confirm the diagnosis.

Management.

Treatment of manifestations: Antiepileptic drugs (AEDs) are effective against generalized seizures.

Prevention of secondary complications: Overmedication in treating drug-resistant myoclonus is a risk. Gastrostomy feedings can decrease the risk of aspiration pneumonia when disease is advanced.

Surveillance: Clinical and psychosocial evaluation at three- to six-month intervals throughout the teenage years.

Agents/circumstances to avoid: Phenytoin, and possibly carbamazepine, oxcarbazepine, and lamotrigine.

Genetic counseling.

Lafora disease is inherited in an 常染色体隐性遗传 manner. Heterozygotes (carriers) are asymptomatic. At conception, each sib of an 受累的 individual has a 25% chance of being affected, a 50% chance of being an asymptomatic 携带者, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and 产前诊断 for at-risk pregnancies are possible if the pathogenic variants in the family are known.

总结

临床特征 Lafora病（LD）可以分为片断性、对称或全面性肌阵挛和/或全面性强直阵挛性发作、视觉幻觉（枕叶癫痫）和进行性神经变性，包括认知和/或行为恶化，构音障碍和共济失调。青少年期（12-17岁）发病，之前可完全正常。癫痫发作的频率和难医治程度随时间增加。癫痫持续状态常见，情绪紊乱和意识模糊在癫痫发作时或之后常见，之后发生失忆。构音障碍和共济失调早期出现，痉挛相对较晚。大多数受累者在发病后十年内死亡，通常源于癫痫持续状态或与神经系统退化有关的并发症。

诊断/检测

诊断通常基于临床、EEG结果和对已知与LD相关的任一基因（EPM2A或NHLRC1（EPM2B））中的两个致病性变异位点的检测。在少数情况下，利用皮肤活检发现Lafora小体对于疾病的确诊是必要的。

管理

症状的治疗：抗癫痫药（AEDs）对抗全面性癫痫发作有效。

继发并发症的预防：对耐药性肌阵挛过度治疗存在风险。胃造口术管道进食可以降低疾病严重时吸入性肺炎的风险。

监测：青少年期间每隔三至六个月进行临床和社会心理评估。

需避免试剂/环境：苯妥英、卡马西平、奥卡西平和拉莫三嗪。

遗传咨询

 Lofora病以常染色体隐性遗传方式遗传。杂合子（携带者）无症状。受累者的兄弟姐妹有25%的概率患病，50％是无症状携带者，25％既不患病也不是携带者。如果家族携带已知的致病性变异，可以对高危亲属进行携带者筛查和对高风险妊娠予以产前诊断。

资源

GeneReviews的工作人员已经选择了以下特异性疾病和/或伞状支持组织和/或登记系统，以帮助患有此病的个人及其家属。 GeneReviews不负责其他组织提供的信息。有关选择标准的信息，请点击这里。

• American Epilepsy Society (AES)www.aesnet.org
• Epilepsy Foundation

8301 Professional Place East

Suite 200

Landover MD 20785-7223

Phone: 800-332-1000 (toll-free)

Email: ContactUs@efa.org

www.epilepsyfoundation.org

Molecular Genetic Pathogenesis

The mechanism by which pathogenic variants in either EPM2A or NHLRC1 result in Lafora disease (LD) and the exact role of the Lafora bodies in the pathogenesis of LD have been the subject of intensive research efforts over the past few years.

Pathology in LD consists of the progressive formation of polyglucosans (insoluble glucose polysaccharides that precipitate and aggregate into concretized masses called Lafora bodies) resulting in neurodegeneration. Lafora bodies form in neuronal perikarya and in neuronal short processes (mostly dendrites). Lafora bodies in the neuronal processes are much smaller but they massively outnumber Lafora bodies in the perikarya. Extraneurally, Lafora bodies also form in heart, liver, and skeletal muscle, but cause no symptoms in these organs [Turnbull et al 2011].

A normal glycogen molecule contains up to 55,000 glucose units, yet remains soluble because its glucose chains are short (13 units), each chain is a branch of another, and the whole molecule is a sphere, the surface of which is composed of the hydrophilic ends of chains [Graham et al 2010]. This unique organization allows mammalian cells to store large amounts of carbohydrate energy in a soluble, rapidly accessible form. Without branching, glucose polymers 13 units or longer are poorly soluble and tend to precipitate and crystallize [Hejazi et al 2008]. Polyglucosans are malformed glycogen molecules. They have very long chains, insufficient branches, and a resultant lack of spherical organization. They are more similar to plant amylopectin or starch than to glycogen, and like these plant carbohydrates they are insoluble, precipitate, and accumulate [Minassian 2001]. It has been demonstrated that in plants, variants in the starch excess 4 基因 (SEX4) result in the accumulation of amylopectin, similar to the way loss of laforin leads to the accumulation of polyglucosans with formation of Lafora bodies in humans [Niittylä et al 2006, Gentry et al 2007, Gentry et al 2009]. In plants, human laforin can rescue the SEX4-mutated 表型 [Gentry et al 2007].

Glycogen is synthesized through coordinated actions of glycogen synthase (GS) and glycogen branching enzyme, the former responsible for chain elongation, the latter for chain branching. Glycogen is digested by glycogen phosphorylase (GP) and glycogen debranching enzyme. PTG (protein targeting to glycogen) is an indirect activator of GS and an indirect inhibitor of both GP and glycogen phosphorylase kinase (GPK), the enzyme that activates GP. PTG performs this reciprocal activation of synthesis and inhibition of breakdown by binding the pleiotropic phosphatase PP1 through its C-terminus, binding glycogen, and through a common region in its N-terminus binding GS, GP, or GPK, thus targeting PP1 to each of the three enzymes. PP1 dephosphorylates each of the three enzymes, activating GS and inhibiting GP and GPK [Turnbull et al 2011].

Absence of laforin results in glycogen hyperphosphorylation, which disturbs the construction of glycogen, preventing its elaborate spherical architecture essential to solubility [Worby et al 2006, Tagliabracci et al 2008, Nitschke et al 2013]. The malformed glycogen (polyglucosan) precipitates, aggregates, and accumulates into Lafora bodies (LB). Glycogen synthase (GS) is essential to glycogen synthesis, whether the final structure is normal or polyglucosan [Tagliabracci et al 2008]. Glycogen accumulation has been shown to account for the neurodegeneration and functional consequences in LD mice, identifying the regulation of glycogen synthesis as a key target for the treatment of LD [Duran et al 2014]. Treating LD through downregulation of GS has been shown effective in different mouse models. Genetically removing brain GS from laforin-lacking LD mice resulted in correction of the LD 表型, including elimination of LB, neurodegeneration, and seizure predisposition [Pederson et al 2013]. The same result was obtained through partial reduction of glycogen synthesis by genetically removing PTG, a protein that activates GS. This was shown effective in laforin-deficient LD mice [Turnbull et al 2011] as well as in malin-deficient LD mice [Worby et al 2008, Turnbull et al 2014].

Malin has been suggested to regulate autophagy [Criado et al 2012], the misfolded protein response [Mittal et al 2007], microRNA silencing [Singh et al 2012], Wnt signal transduction [Sharma et al 2012], and neuronatin-mediated endoplasmic reticulum stress [Sharma et al 2013], implying a possible complex causality in the EPM2B form of LD. Nevertheless, LD caused by mutation of EPM2B is as responsive to glycogen synthesis downregulation as is LD caused by mutation of EPM2A [Turnbull et al 2014].

分子遗传学

分子遗传学和OMIM表中的信息可能与GeneReview中的某些信息不同：表中可能包含更新的信息。

表A. 进行性肌阵挛性癫痫，Lafora型：基因和数据库

数据来源于以下标准参考：基因来自于HGNC；染色体座位，基因座名称，临界区域，互补群来源于OMIM；蛋白质来源于UniProt。关于数据库（Locus Specific，HGMD）的说明，相关链接已提供，请单击此处。

表B. OMIM进行性肌阵挛性癫痫，Lafora型（查看全部OMIM）

分子遗传学发病机理

EPM2A或NHLRC1致病变异导致Lafora病（Lafora disease，LD）的机制以及Lafora小体在LD发病机制中的确切作用一直是过去几年深入研究的课题。

LD病理学指由多聚葡萄糖（不溶性葡萄糖多糖，沉淀并聚集成为Lafora小体）的逐渐形成所导致的神经退行性疾病。Lafora小体形成于神经元核周体（perikarya）和神经元短轴突（主要是树突）。神经轴突中的Lofora小体（Lafora bodies）较小，但比核周体中的Lofora小体的数量要多。除神经系统外，Lafora小体也可形成于心脏、肝脏和骨骼肌中，但是在这些器官中没有任何症状[Turnbull et al 2011]。

一个正常的糖原分子含有高达55,000个葡萄糖单元，并且是可溶性的。因为它的葡萄糖链很短（13个单元），每条链都是另一条链的支链，而且整个分子是一个球体，其表面由链的亲水性末端组成[Graham et al 2010]。这种独特的组织结构使得哺乳动物细胞以可溶的、快速获得的形式储存大量的碳水化合物能量。因为没有支链，葡萄糖聚合物的13个单元（或更长）的溶解性差，倾向于沉淀和结晶[Hejazi et al 2008]。多聚葡萄糖是畸形的糖原分子，他们具有很长的链，而且分支不足，因此缺乏球形组成。它们与植物支链淀粉或淀粉更类似，并且像这些植物碳水化合物一样，它们是不溶的，易发生沉淀并积累[Minassian 2001]。在植物中已经被证明，starch excess 4 gene（SEX4）中的变异会导致支链淀粉的积累，类似于在人体中laforin的缺失导致多聚葡聚糖积聚并形成​​Lofora小体[Niittylä et al 2006, Gentry et al 2007, Gentry et al 2009]。在植物中，人类laforin可以恢复SEX4的突变表型 [Gentry et al 2007]。

糖原是通过糖原合成酶（GS）和糖原分支酶的协同作用合成的，前者负责链的延伸，后者负责链的分支。糖原被糖原磷酸化酶（GP）和糖原脱支酶消化。 PTG（靶向糖原的蛋白质）是GS的间接激活剂，也是GP和糖原磷酸化酶激酶（GPK​​）的间接抑制剂，GPK是激活GP的酶。 PTG进行这种反复的合成激活和阻断抑制作用主要是通过其C-末端结合多效性磷酸酶PP1、结合糖原、并通过其N-末端的共同区域结合GS、GP或GPK，从而将PP1靶向这三种酶。 PP1通过对这三种酶的去磷酸化作用，激活GS和抑制GP和GPK[Turnbull et al 2011]。

缺乏laforin会导致糖原过度磷酸化，从而干扰糖原的结构，阻碍对溶解度至关重要的复杂的球形结构的形成[Worby et al 2006, Tagliabracci et al 2008, Nitschke et al 2013]。畸形糖原（多聚葡萄糖）沉淀、聚集、并积聚到Lofora小体（LB）中。无论最终结构是正常还是形成多聚葡萄糖，糖原合成酶（GS）对于糖原合成都是必不可少的。[Tagliabracci et al 2008]。糖原累积可以解释LD小鼠中神经变性和功能变化，可将对糖原合成的调控确定为治疗LD的关键靶标[Duran et al 2014]。通过下调GS来治疗LD已经在不同的小鼠模型中显示出有效。从laforin缺乏的LD小鼠中去除大脑GS可恢复LD表型，包括Lafora小体清除、神经变性和癫痫倾向[Pederson et al 2013]。遗传学方式去除PTG（一种激活GS的蛋白质）导致糖原合成的部分减少也可获得相同的结果。这在laforin缺陷的LD小鼠[Turnbull et al 2011]以及malin缺陷的LD小鼠[Worby et al 2008, Turnbull et al 2014]也同样有效。

Malin已经被证明可以调节自噬[Criado et al 2012]、错误折叠的蛋白质应答[Mittal et al 2007]、microRNA沉默[Singh et al 2012]、Wnt信号转导[Sharma et al 2012]和neuronatin介导的内质网应激[Sharma et al 2013]，这意味着在EPM2B导致的LD中可能存在复杂的因果关系。然而，由EPM2B突变引起的LD对糖原合成下调的响应与EPM2A突变引起的LD的响应一样 [Turnbull et al 2014]。

EPM2A

基因结构：EPM2A有四个外显子，长130 kb；它们选择性剪切成两个主要的EPM2A转录本[Minassian et al 1998, Serratosa et al 1999, Ganesh et al 2000, Gómez-Garre et al 2000]。NM_005670.3代表了较长的转录本并且编码由331个氨基酸组成的较长的laforin异构型（a）。有关基因、转录本和蛋白质同种型信息的详细总结，请参阅表A，基因和正常基因产物。

良性变异：EPM2A中有一些良性变异已经被报道[Gómez-Garre et al 2000, Minassian et al 2000b, Singh et al 2005]。其中，136G> C（p.Ala46Pro）在日本和中国人群中是特异的[Ganesh et al 2001]。

意义不确定变异：在存在NHLRC1基因大片段杂合缺失的两个患者中也发现了EPM2A基因p.Gln55Lys替换，以及在500个无LD，但具有成年期发病的疾病的个体中，有七个也发现了该位点的杂合。迄今为止，尚不清楚这种改变是否是一种罕见的良性单核苷酸多态性（SNP），在纯合子时是否会引起LD，或者在某些情况下是否容易导致NHLRC1缺失[Lohi et al 2007]。

致病变异：迄今为止，在100多个家族中报道了EPM2A中超过60种不同的致病变异[Minassian et al 1998, Serratosa et al 1999, Gómez-Garre et al 2000, Minassian et al 2000a, Minassian et al 2000b, Ganesh et al 2002a, Ki et al 2003, Annesi et al 2004, Ianzano et al 2004, Singh et al 2005, Lohi et al 2006, Singh & Ganesh 2009, Lesca et al 2010, Harirchian et al 2011, Khiari et al 2011]。无义和错义的单核苷酸变异占61％，移码变异占29％，大片段缺失占10％。也报道过EPM2A的一种剪接位点变异[Lesca et al 2010]。在Lafora进行性肌阵挛性癫痫突变和多态性数据库中可以找到不同致病变异的概述[Ianzano et al 2005]。

迄今为止所描述的EPM2A中所有类型的致病变异中，45％为错义变异；所有已知的错义变异常靶向laforin的碳水化合物结合结构域（CBD）或双重特异性磷酸酶结构域（DSPD）[Ganesh et al 2006, Singh & Ganesh 2009, Khiari et al 2011]。

除了大片段缺失外，所有致病变异都均匀地分布在EPM2A上。唯一的例外是无义变异c.721C> T具有较高的检出率，即所谓的“西班牙”致病性变异，在超过20个家系中被检出。其高检出率是建立者（founder）效应和复发事件的结果[Minassian et al 1998, Serratosa et al 1999, Gómez-Garre et al 2000, Ganesh et al 2002b]。

表3

Geneview中关于EPM2A变异的讨论

关于变异分类的说明：表中列出的变异由作者提供。GeneReviews员工没有对变异的分类进行独立的验证。命名注释：GeneReviews遵循人类基因组变异协会（varnomen​.hgvs.org）的标准命名规则。有关命名的解释，请参阅快速参考。

正常的基因产物：EPM2A通过选择性剪接编码两种不同的蛋白质；磷酸酶活性胞质异构型（a）(laforin, NP_005661.1)和磷酸酶非活性核亚型（b）(NP_001018051.1)。两种laforin蛋白的异构型都具有独特的C末端[Ganesh et al 2002c, Ianzano et al 2004]。异构型（b）的羧基末端将laforin靶向细胞核，更长的laforin异构型（a）却不具备该特征。Ianzano等人[2004] 证明，laforin异构型（a）的生理功能紊乱是LD发病机制的基础，而异构型（b）不能在功能上取代laforin异构型（a）。laforin异构型的共同部分由碳水化合物结合结构域和双特异性蛋白磷酸酶结构域组成[Ganesh et al 2000]。

Dubey等人鉴定了三个额外的EPM2A剪接变异，其可能在不同的读码框中编码五种不同的蛋白质。当在细胞系中异位表达时，新的异构型显示出不同的亚细胞定位，与malin（NHLRC1的蛋白质产物）相互作用并作为其底物。选择性剪接可能是EPM2A调节其编码的蛋白质的细胞功能的机制之一[Dubey et al 2012]。

Laforin由外显子1编码的N末端碳水化合物结合结构域（CBD）和跨越外显子3和4的双特异性磷酸酶结构域（DSPD）组成[Minassian et al 2000b, Ganesh et al 2002b]。

Laforin在所有的脊椎动物中都是保守的。而在绝大多数低等生物体中缺失，这是一种古老的蛋白质，它在部分原生生物和无脊椎动物中保守，分子进化速度较慢，并且/或者代谢类似于Lafora小体的碳水化合物。 laforin蛋白在进化生物学中占有独特的地位，并且已经对葡聚糖代谢和Lafora病的分子病因学产生了深刻的见解[Gentry & Pace 2009。

异常的基因产物：EPM2A基因的无义变异、插入和缺失在功能上预测是“无效的”并丧失磷酸酶活性。在体外试验中，EPM2A基因的错义突变也可导致磷酸酶活性的缺乏，产生“无效”效应[Fernández-Sánchez et al 2003, Ganesh et al 2006]。磷酸酶活性的丧失并不只限于位于双特异性磷酸酶结构域（DSPD）中的致病性变异；同时还观察到影响EPM2A的碳水化合物结合结构域（CBD）的致病性变异 [Wang et al 2002, Fernández-Sánchez et al 2003]。错义变异可能影响laforin蛋白的正确折叠，如通过过表达错义突变的突变体的转染实验所证明的，其导致泛素阳性的细胞质聚集体，表明它们是用于降解的折叠突变体[Ganesh et al 2000, Ganesh et al 2002a]。错义变异也影响laforin的亚细胞定位[Ganesh et al 2002a, Mittal et al 2007]，破坏laforin与R5和malin（蛋白质产物NHLRC1）蛋白的相互作用[Fernández-Sánchez et al 2003, Gentry et al 2005]。很明显，并不是所有错义突变的蛋白质功能都会被检测到，并且用于检查致病变异对蛋白质功能的影响的灵敏测定还有待开发[Singh & Ganesh 2009]。

NHLRC1（EPM2B）

基因结构：NHLRC1是单外显子基因，全长1199个碱基，其5'端具有真核翻译起始位点的共有序列的所有的特征，在其3'端具有两个假定的多聚腺苷酸化信号。 Northern印迹分析表明在所有检测的组织中存在1.5kb和2.4kb的NHLRC1基因两个转录本，包括脑的特异亚区[Chan et al 2003b]。基因和蛋白质信息的详细总结见表 A，基因。

良性变异：已经报道了六种良性变异[Chan et al 2003b, Singh et al 2005]。

致病性变异：迄今为止，在超过125个家系中报告了60多种致病性变异。大部分都是错义变异，但也有插入、缺失和无义变异的报道[Chan et al 2003b, Gómez-Abad et al 2005, Singh et al 2005, Franceschetti et al 2006, Singh et al 2006, Lohi et al 2007, Singh & Ganesh 2009, Traoré et al 2009, Lesca et al 2010, Couarch et al 2011]。在意大利和塞尔维亚家系中报道了整个NHLRC1基因的杂合性缺失[Lohi et al 2007]。在Lafora进行性肌阵挛性癫痫突变和多态性数据库中可以找到不同致病变异的概述。

•错义变异c.205C>G，影响环指结构域，是NHLRC1中最常见的错义突变（> 30个家族）。它存在于葡萄牙裔的所有受累个体中，并且已经在意大利、法国和西班牙的患者中被反复报告[Chan et al 2003a, Gómez-Abad et al 2005, Franceschetti et al 2006, Lesca et al 2010]。这种致病性变异的高检出率也由创始人（founder）效应和复发性突变事件解释[Chan et al 2003a, Gómez-Abad et al 2005, Franceschetti et al 2006]。

•c.468_469delAG致病变异，在编码区缺失了2个碱基，是NHLRC1中第二个最常见的致病变异，并且是迄今为止最常见的缺失（25个家系）。有14个个体已经被鉴定是属于同一个阿曼部族遗传隔离部落。所有人都有一个相同的单体型，表明建立者效应（founder-effect）[Turnbull et al 2008]。

•注意：尽管c.205C> G致病变异在意大利和西班牙的患者中很常见，在不同的种族群体中都发现了c.205C> G和c.468_469delAG致病变异，表明其为复发性突变事件；这两个位点代表了NHLRC1致病变异的热点[Ganesh et al 2006]。

•错义致病变异c.76T> A在属于加拿大法语区的种族隔离的患者中常见[Chan et al 2003a, Singh et al 2006]，并且这些家系的共有染色体6p22单倍型提示了创始人的效应 [Chan et al 2003a]。迄今为止，除了一名加拿大法语区的人以外，所有人都是c.76T> A纯合致病变异。而这个人含有另外两个NHLRC1杂合致病变异，据知他有德国和其他欧洲血统[Chan et al 2003a]。迄今为止，这种致病性变异尚未在非加拿大法语区家系中发现。

表4：GeneReview中关于NHLRC1致病变异的讨论

关于变异分类的说明：表中列出的变异由作者提供。GeneReviews员工没有对变异的分类进行独立的验证。命名注释：GeneReviews遵循人类基因组变异协会（varnomen​.hgvs.org）的标准命名规则。有关命名的解释，请参阅快速参考。

1细节请参考致病变异

正常基因产物：NHLRC1编码E3泛素蛋白连接酶NHLRC1（也称为malin），该蛋白由395个氨基酸的组成。 Malin含有RING类型的锌指和六个NHL-重复的蛋白质-蛋白质相互结构域[Chan et al 2003b]。锌指的存在预示了E3泛素连接酶功能[Freemont 2000]。 Malin在内质网中与laforin共定位[Mittal et al 2007]。 Laforin和malin与错误折叠的蛋白相互作用，并通过泛素-蛋白酶体系统促进它们的降解[Garyali et al 2009]。malin是单亚基E3泛素连接酶，参与泛素介导的蛋白质水解级联反应[Gentry et al 2005, Lohi et al 2005]。malin还与laforin相互作用和laforin的泛素化，导致其降解[Gentry et al 2005]。因此，malin的关键功能之一是通过泛素介导的降解来调节laforin的细胞浓度[Gentry et al 2005]。

异常基因产物：参见Ganesh et al [2006]。NHLRC1基因中几乎所有的致病性变异预测都会导致malin功能的丧失Chan et al 2003b, Gómez-Abad et al 2005, Singh et al 2005]。与LD相关的NHLRC1致病性错义突变破坏了malin通过泛素介导的降解调节laforin细胞浓度的关键功能[Gentry et al 2005]。

点击这里查看Lofora病动物模型的更多信息。

Literature Cited

• Altindag E, Kara B, Baykan B, Terzibasioglu E, Sencer S, Onat L, Sirvanci M. MR spectroscopy findings in Lafora disease. J Neuroimaging. 2009;19:359鈥�65. [PubMed: 19040628]
• Andrade DM, Ackerley CA, Minett TS, Teive HA, Bohlega S, Scherer SW, Minassian BA. Skin biopsy in Lafora disease: genotype-phenotype correlations and diagnostic pitfalls. Neurology. 2003;61:1611鈥�4. [PubMed: 14663053]
• Annesi G, Sofia V, Gambardella A, Candiano IC, Spadafora P, Annesi F, Cutuli N, De Marco EV, Civitelli D, Carrideo S, Tarantino P, Barone R, Zappia M, Quattrone A. A novel exon 1 mutation in a patient with atypical lafora progressive myoclonus epilepsy seen as childhood-onset cognitive deficit. Epilepsia. 2004;45:294鈥�5. [PubMed: 15009235]
• Baykan B, Striano P, Gianotti S, Bebek N, Gennaro E, Gurses C, Zara F. Late-onset and slow-progressing Lafora disease in four siblings with EPM2B mutation. Epilepsia. 2005;46:1695鈥�7. [PubMed: 16190947]
• Berkovic SF, Andermann F, Carpenter S, Wolfe LS. Progressive myoclonus epilepsies: specific causes and diagnosis. N Engl J Med. 1986;315:296鈥�305. [PubMed: 3088452]
• Berkovic SF, Cochius J, Andermann E, Andermann F. Progressive myoclonus epilepsies: clinical and genetic aspects. Epilepsia. 1993;34 Suppl 3:S19鈥�30. [PubMed: 8500430]
• Boccella P, Striano P, Zara F, Barbieri F, Sarappa C, Vacca G, de Falco FA, Striano S. Bioptically demonstrated Lafora disease without EPM2A mutation: a clinical and neurophysiological study of two sisters. Clin Neurol Neurosurg. 2003;106:55鈥�9. [PubMed: 14643920]
• Brackmann FA, Kiefer A, Agaimy A, Gencik M, Trollmann R. Rapidly progressive phenotype of Lafora disease associated with a novel NHLRC1 mutation. Pediatr Neurol. 2011;44:475鈥�7. [PubMed: 21555062]
• Canafoglia L, Ciano C, Visani E, Anversa P, Panzica F, Viri M, Gennaro E, Zara F, Madia F, Franceschetti S. Short and long interval cortical inhibition in patients with Unverricht-Lundborg and Lafora body disease. Epilepsy Res. 2010;89:232鈥�7. [PubMed: 20117916]
• Carpenter S, Karpati G. Sweat gland duct cells in Lafora disease: diagnosis by skin biopsy. Neurology. 1981;31:1564鈥�8. [PubMed: 6796905]
• Carpenter S, Karpati G, Andermann F, Jacob JC, Andermann E. Lafora's disease: peroxisomal storage in skeletal muscle. Neurology. 1974;24:531鈥�8. [PubMed: 4220225]
• Cerminara C, Montanaro ML, Curatolo P, Seri S. Lamotrigine-induced seizure aggravation and negative myoclonus in idiopathic rolandic epilepsy. Neurology. 2004;63:373鈥�5. [PubMed: 15277643]
• Chan EM, Andrade DM, Franceschetti S, Minassian B. Progressive myoclonus epilepsies: EPM1, EPM2A, EPM2B. Adv Neurol. 2005;95:47鈥�57. [PubMed: 15508913]
• Chan EM, Bulman DE, Paterson AD, Turnbull J, Andermann E, Andermann F, Rouleau GA, Delgado-Escueta AV, Scherer SW, Minassian BA. Genetic mapping of a new Lafora progressive myoclonus epilepsy locus (EPM2B) on 6p22. J Med Genet. 2003a;40:671鈥�5. [PMC free article: PMC1735578] [PubMed: 12960212]
• Chan EM, Omer S, Ahmed M, Bridges LR, Bennett C, Scherer SW, Minassian BA. Progressive myoclonus epilepsy with polyglucosans (Lafora disease): evidence for a third locus. Neurology. 2004;63:565鈥�7. [PubMed: 15304597]
• Chan EM, Young EJ, Ianzano L, Munteanu I, Zhao X, Christopoulos CC, Avanzini G, Elia M, Ackerley CA, Jovic NJ, Bohlega S, Andermann E, Rouleau GA, Delgado-Escueta AV, Minassian BA, Scherer SW. Mutations in NHLRC1 cause progressive myoclonus epilepsy. Nat Genet. 2003b;35:125鈥�7. [PubMed: 12958597]
• Couarch P, Vernia S, Gourfinkel-An I, Lesca G, Gataullina S, Fedirko E, Trouillard O, Depienne C, Dulac O, Steschenko D, Leguern E, Sanz P, Baulac S. Lafora progressive myoclonus epilepsy: NHLRC1 mutations affect glycogen metabolism. J Mol Med (Berl) 2011;89:915鈥�25. [PMC free article: PMC3154284] [PubMed: 21505799]
• Crespel A, Genton P, Berramdane M, Coubes P, Monicard C, Baldy-Moulinier M, Gelisse P. Lamotrigine associated with exacerbation or de novo myoclonus in idiopathic generalized epilepsies. Neurology. 2005;65:762鈥�4. [PubMed: 16157917]
• Crest C, Dupont S, Leguern E, Adam C, Baulac M. Levetiracetam in progressive myoclonic epilepsy: an exploratory study in 9 patients. Neurology. 2004;62:640鈥�3. [PubMed: 14981187]
• Criado O, Aguado C, Gayarre J, Duran-Trio L, Garcia-Cabrero AM, Vernia S, San Millán B, Heredia M, Romá-Mateo C, Mouron S, Juana-López L, Domínguez M, Navarro C, Serratosa JM, Sanchez M, Sanz P, Bovolenta P, Knecht E, Rodriguez de Cordoba S. Lafora bodies and neurological defects in malin-deficient mice correlate with impaired autophagy. Hum Mol Genet. 2012;21:1521鈥�33. [PubMed: 22186026]
• Delgado-Escueta AV, Ganesh S, Yamakawa K. Advances in the genetics of progressive myoclonus epilepsy. Am J Med Genet. 2001;106:129鈥�38. [PubMed: 11579433]
• Drury I, Blaivas M, Abou-Khalil BW, Beydoun A. Biopsy results in a kindred with Lafora disease. Arch Neurol. 1993;50:102鈥�5. [PubMed: 8418793]
• Dubey D, Parihar R, Ganesh S. Identification and characterization of novel splice variants of the human EPM2A gene mutated in Lafora progressive myoclonus epilepsy. Genomics. 2012;99:36鈥�43. [PubMed: 22036712]
• Duran J, Gruart A, García-Rocha M, Delgado-García JM, Guinovart JJ. Glycogen accumulation underlies neurodegeneration and autophagy impairment in Lafora disease. Hum Mol Genet. 2014;23:3147鈥�56. [PubMed: 24452334]
• Fedi M, Reutens D, Dubeau F, Andermann E, D'Agostino D, Andermann F. Long-term efficacy and safety of piracetam in the treatment of progressive myoclonus epilepsy. Arch Neurol. 2001;58:781鈥�6. [PubMed: 11346373]
• Fernández-Sánchez ME, Criado-Garcia O, Heath KE, Garcia-Fojeda B, Medrano-Fernandez I, Gomez-Garre P, Sanz P, Serratosa JM, Rodriguez de Cordoba S. Laforin, the dual-phosphatase responsible for Lafora disease, interacts with R5 (PTG), a regulatory subunit of protein phosphatase-1 that enhances glycogen accumulation. Hum Mol Genet. 2003;12:3161鈥�71. [PubMed: 14532330]
• Franceschetti S, Gambardella A, Canafoglia L, Striano P, Lohi H, Gennaro E, Ianzano L, Veggiotti P, Sofia V, Biondi R, Striano S, Gellera C, Annesi G, Madia F, Civitelli D, Rocca FE, Quattrone A, Avanzini G, Minassian B, Zara F. Clinical and genetic findings in 26 Italian patients with Lafora disease. Epilepsia. 2006;47:640鈥�3. [PubMed: 16529633]
• Freemont PS. RING for destruction? Curr Biol. 2000;10:R84鈥�7. [PubMed: 10662664]
• Ganesh S, Agarwala KL, Ueda K, Akagi T, Shoda K, Usui T, Hashikawa T, Osada H, Delgado-Escueta AV, Yamakawa K. Laforin, defective in the progressive myoclonus epilepsy of Lafora type, is a dual-specificity phosphatase associated with polyribosomes. Hum Mol Genet. 2000;9:2251鈥�61. [PubMed: 11001928]
• Ganesh S, Delgado-Escueta AV, Sakamoto T, Avila MR, Machado-Salas J, Hoshii Y, Akagi T, Gomi H, Suzuki T, Amano K, Agarwala KL, Hasegawa Y, Bai DS, Ishihara T, Hashikawa T, Itohara S, Cornford EM, Niki H, Yamakawa K. Targeted disruption of the Epm2a gene causes formation of Lafora inclusion bodies, neurodegeneration, ataxia, myoclonus epilepsy and impaired behavioral response in mice. Hum Mol Genet. 2002a;11:1251鈥�62. [PubMed: 12019206]
• Ganesh S, Delgado-Escueta AV, Suzuki T, Francheschetti S, Riggio C, Avanzini G, Rabinowicz A, Bohlega S, Bailey J, Alonso ME, Rasmussen A, Thomson AE, Ochoa A, Prado AJ, Medina MT, Yamakawa K. Genotype-phenotype correlations for EPM2A mutations in Lafora's progressive myoclonus epilepsy: exon 1 mutations associate with an early-onset cognitive deficit subphenotype. Hum Mol Genet. 2002b;11:1263鈥�71. [PubMed: 12019207]
• 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鈥�8. [PubMed: 16311711]
• Ganesh S, Shoda K, Amano K, Uchiyama A, Kumada S, Moriyama N, Hirose S, Yamakawa K. Mutation screening for Japanese Lafora's disease patients: identification of novel sequence variants in the coding and upstream regulatory regions of EPM2A gene. Mol Cell Probes. 2001;15:281鈥�9. [PubMed: 11735300]
• Ganesh S, Suzuki T, Yamakawa K. Alternative splicing modulates subcellular localization of laforin. Biochem Biophys Res Commun. 2002c;291:1134鈥�7. [PubMed: 11883934]
• Garyali P, Siwach P, Singh PK, Puri R, Mittal S, Sengupta S, Parihar R, Ganesh S. The malin-laforin complex suppresses the cellular toxicity of misfolded proteins by promoting their degradation through the ubiquitin-proteasome system. Hum Mol Genet. 2009;18:688鈥�700. [PubMed: 19036738]
• Genton P, Guerrini R, Remy C. Piracetam in the treatment of cortical myoclonus. Pharmacopsychiatry. 1999;32 Suppl 1:49鈥�53. [PubMed: 10338109]
• Gentry MS, Dixon JE, Worby CA. Lafora disease: insights into neurodegeneration from plant metabolism. Trends Biochem Sci. 2009;34:628鈥�39. [PMC free article: PMC2805077] [PubMed: 19818631]
• Gentry MS, Dowen RH 3rd, Worby CA, Mattoo S, Ecker JR, Dixon JE. The phosphatase laforin crosses evolutionary boundaries and links carbohydrate metabolism to neuronal disease. J Cell Biol. 2007;178:477鈥�88. [PMC free article: PMC2064834] [PubMed: 17646401]
• Gentry MS, Pace RM. Conservation of the glucan phosphatase laforin is linked to rates of molecular evolution and the glucan metabolism of the organism. BMC Evol Biol. 2009;9:138. [PMC free article: PMC2714694] [PubMed: 19545434]
• Gentry MS, Worby CA, Dixon JE. Insights into Lafora disease: malin is an E3 ubiquitin ligase that ubiquitinates and promotes the degradation of laforin. Proc Natl Acad Sci U S A. 2005;102:8501鈥�6. [PMC free article: PMC1150849] [PubMed: 15930137]
• Gómez-Abad C, Afawi Z, Korczyn AD, Misk A, Shalev SA, Spiegel R, Lerman-Sagie T, Lev D, Kron KL, Gomez-Garre P, Serratosa JM, Berkovic SF. Founder effect with variable age at onset in Arab families with Lafora disease and EPM2A mutation. Epilepsia. 2007;48:1011鈥�4. [PubMed: 17509003]
• Gómez-Abad C, Gomez-Garre P, Gutierrez-Delicado E, Saygi S, Michelucci R, Tassinari CA, Rodriguez de Cordoba S, Serratosa JM. Lafora disease due to EPM2B mutations: a clinical and genetic study. Neurology. 2005;64:982鈥�6. [PubMed: 15781812]
• Gómez-Garre P, Sanz Y, Rodriguez De Cordoba SR, Serratosa JM. Mutational spectrum of the EPM2A gene in progressive myoclonus epilepsy of Lafora: high degree of allelic heterogeneity and prevalence of deletions. Eur J Hum Genet. 2000;8:946鈥�54. [PubMed: 11175283]
• Graham TE, Yuan Z, Hill AK, Wilson RJ. The regulation of muscle glycogen: the granule and its proteins. Acta Physiol (Oxf) 2010;199:489鈥�98. [PubMed: 20353490]
• Guerrero R, Vernia S, Sanz R, Abreu-Rodríguez I, Almaraz C, García-Hoyos M, Michelucci R, Tassinari CA, Riguzzi P, Nobile C, Sanz P, Serratosa JM, Gómez-Garre P. A PTG variant contributes to a milder phenotype in Lafora disease. PLoS One. 2011;6:e21294. [PMC free article: PMC3127956] [PubMed: 21738631]
• Harirchian MH, Shandiz EE, Turnbull J, Minassian BA, Shahsiah R. Lafora disease: A case report, pathologic and genetic study. Indian J Pathol Microbiol. 2011;54:374鈥�5. [PubMed: 21623095]
• Hejazi M, Fettke J, Haebel S, Edner C, Paris O, Frohberg C, Steup M, Ritte G. Glucan, water dikinase phosphorylates crystalline maltodextrins and thereby initiates solubilization. Plant J. 2008;55:323鈥�334. [PubMed: 18419779]
• Ianzano L, Young EJ, Zhao XC, Chan EM, Rodriguez MT, Torrado MV, Scherer SW, Minassian BA. Loss of function of the cytoplasmic isoform of the protein laforin (EPM2A) causes Lafora progressive myoclonus epilepsy. Hum Mutat. 2004;23:170鈥�6. [PubMed: 14722920]
• Ianzano L, Zhang J, Chan EM, Zhao XC, Lohi H, Scherer SW, Minassian BA. Lafora progressive Myoclonus Epilepsy mutation database-EPM2A and NHLRC1 (EPM2B) genes. Hum Mutat. 2005;26:397. [PubMed: 16134145]
• Kaddurah AK, Holmes GL. Possible precipitation of myoclonic seizures with oxcarbazepine. Epilepsy Behav. 2006;8:289鈥�93. [PubMed: 16356781]
• Kecmanović M, Jović N, Cukić M, Keckarević-Marković M, Keckarević D, Stevanović G, Romac S. Lafora disease: severe phenotype associated with homozygous deletion of the NHLRC1 gene. J Neurol Sci. 2013;325:170鈥�3. [PubMed: 23317923]
• Khiari HM, Lesca G, Malafosse A, Mrabet A. A novel exon 3 mutation in a Tunisian patient with Lafora's disease. J Neurol Sci. 2011;304:136鈥�7. [PubMed: 21371719]
• Ki CS, Kong SY, Seo DW, Hong SB, Kim HJ, Kim JW. Two novel mutations in the EPM2A gene in a Korean patient with Lafora's progressive myoclonus epilepsy. J Hum Genet. 2003;48:51鈥�4. [PubMed: 12560877]
• Koskiniemi M, Van Vleymen B, Hakamies L, Lamusuo S, Taalas J. Piracetam relieves symptoms in progressive myoclonus epilepsy: a multicentre, randomised, double blind, crossover study comparing the efficacy and safety of three dosages of oral piracetam with placebo. J Neurol Neurosurg Psychiatry. 1998;64:344鈥�8. [PMC free article: PMC2169975] [PubMed: 9527146]
• Lesca G, Boutry-Kryza N, de Toffol B, Milh M, Steschenko D, Lemesle-Martin M, Maillard L, Foletti G, Rudolf G, Nielsen JE, Rogvi-Hansen B, Erdal J, Mancini J, Thauvin-Robinet C, M'Rabet A, Ville D, Szepetowski P, Raffo E, Hirsch E, Ryvlin P, Calender A, Genton P. Novel mutations in EPM2A and NHLRC1 widen the spectrum of Lafora disease. Epilepsia. 2010;51:1691鈥�8. [PubMed: 20738377]
• Lohi H, Chan EM, Scherer SW, Minassian BA. On the road to tractability: the current biochemical understanding of progressive myoclonus epilepsies. Adv Neurol. 2006;97:399鈥�415. [PubMed: 16383151]
• Lohi H, Ianzano L, Zhao XC, Chan EM, Turnbull J, Scherer SW, Ackerley CA, Minassian BA. Novel glycogen synthase kinase 3 and ubiquitination pathways in progressive myoclonus epilepsy. Hum Mol Genet. 2005;14:2727鈥�36. [PubMed: 16115820]
• Lohi H, Turnbull J, Zhao XC, Pullenayegum S, Ianzano L, Yahyaoui M, Mikati MA, Quinn NP, Franceschetti S, Zara F, Minassian BA. Genetic diagnosis in Lafora disease: genotype-phenotype correlations and diagnostic pitfalls. Neurology. 2007;68:996鈥�1001. [PubMed: 17389303]
• Minassian BA. Lafora's disease: towards a clinical, pathologic, and molecular synthesis. Pediatr Neurol. 2001;25:21鈥�9. [PubMed: 11483392]
• Minassian BA. Progressive myoclonus epilepsy with polyglucosan bodies: Lafora disease. Adv Neurol. 2002;89:199鈥�210. [PubMed: 11968446]
• Minassian BA, Ianzano L, Delgado-Escueta AV, Scherer SW. Identification of new and common mutations in the EPM2A gene in Lafora disease. Neurology. 2000a;54:488鈥�90. [PubMed: 10668720]
• Minassian BA, Ianzano L, Meloche M, Andermann E, Rouleau GA, Delgado-Escueta AV, Scherer SW. Mutation spectrum and predicted function of laforin in Lafora's progressive myoclonus epilepsy. Neurology. 2000b;55:341鈥�6. [PubMed: 10932264]
• Minassian BA, Lee JR, Herbrick JA, Huizenga J, Soder S, Mungall AJ, Dunham I, Gardner R, Fong CY, Carpenter S, Jardim L, Satishchandra P, Andermann E, Snead OC 3rd, Lopes-Cendes I, Tsui LC, Delgado-Escueta AV, Rouleau GA, Scherer SW. Mutations in a gene encoding a novel protein tyrosine phosphatase cause progressive myoclonus epilepsy. Nat Genet. 1998;20:171鈥�4. [PubMed: 9771710]
• Mittal S, Dubey D, Yamakawa K, Ganesh S. Lafora disease proteins malin and laforin are recruited to aggresomes in response to proteasomal impairment. Hum Mol Genet. 2007;16:753鈥�62. [PubMed: 17337485]
• Nanba Y, Maegaki Y. Epileptic negative myoclonus induced by carbamazepine in a child with BECTS. Benign childhood epilepsy with centrotemporal spikes. Pediatr Neurol. 1999;21:664鈥�7. [PubMed: 10513696]
• Niittylä T, Comparot-Moss S, Lue WL, Messerli G, Trevisan M, Seymour MD, Gatehouse JA, Villadsen D, Smith SM, Chen J, Zeeman SC, Smith AM. Similar protein phosphatases control starch metabolism in plants and glycogen metabolism in mammals. J Biol Chem. 2006;281:11815鈥�8. [PubMed: 16513634]
• Nitschke F, Wang P, Schmieder P, Girard JM, Awrey DE, Wang T, Israelian J, Zhao X, Turnbull J, Heydenreich M, Kleinpeter E, Steup M, Minassian BA. Hyperphosphorylation of glucosyl C6 carbons and altered structure of glycogen in the neurodegenerative epilepsy Lafora disease. Cell Metab. 2013;17:756鈥�67. [PubMed: 23663739]
• Pederson BA, Turnbull J, Epp JR, Weaver SA, Zhao X, Pencea N, Roach PJ, Frankland PW, Ackerley CA, Minassian BA. Inhibiting glycogen synthesis prevents lafora disease in a mouse model. Ann Neurol. 2013;74:297鈥�300. [PMC free article: PMC3823666] [PubMed: 23913475]
• Pichiecchio A, Veggiotti P, Cardinali S, Longaretti F, Poloni GU, Uggetti C. Lafora disease: spectroscopy study correlated with neuropsychological findings. Eur J Paediatr Neurol. 2008;12:342鈥�7. [PubMed: 18063398]
• Serratosa JM, Gomez-Garre P, Gallardo ME, Anta B, de Bernabe DB, Lindhout D, Augustijn PB, Tassinari CA, Malafosse RM, Topcu M, Grid D, Dravet C, Berkovic SF, de Cordoba SR. A novel protein tyrosine phosphatase gene is mutated in progressive myoclonus epilepsy of the Lafora type (EPM2). Hum Mol Genet. 1999;8:345鈥�52. [PubMed: 9931343]
• Sharma J, Mukherjee D, Rao SN, Iyengar S, Shankar SK, Satishchandra P, Jana NR. Neuronatin-mediated aberrant calcium signaling and endoplasmic reticulum stress underlie neuropathology in Lafora disease. J Biol Chem. 2013;288:9482鈥�90. [PMC free article: PMC3611017] [PubMed: 23408434]
• Sharma J, Mulherkar S, Mukherjee D, Jana NR. Malin regulates Wnt signaling pathway through degradation of dishevelled2. J Biol Chem. 2012;287:6830鈥�9. [PMC free article: PMC3307269] [PubMed: 22223637]
• 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鈥�23. [PubMed: 19267391]
• Singh S, Ganesh S. Phenotype variations in Lafora progressive myoclonus epilepsy: possible involvement of genetic modifiers? J Hum Genet. 2012;57:283鈥�5. [PubMed: 22456482]
• Singh S, Sethi I, Francheschetti S, Riggio C, Avanzini G, Yamakawa K, Delgado-Escueta AV, Ganesh S. Novel NHLRC1 mutations and genotype-phenotype correlations in patients with Lafora's progressive myoclonic epilepsy. J Med Genet. 2006;43:e48. [PMC free article: PMC2564581] [PubMed: 16950819]
• Singh S, Singh PK, Bhadauriya P, Ganesh S. Lafora disease E3 ubiquitin ligase malin is recruited to the processing bodies and regulates the microRNA-mediated gene silencing process via the decapping enzyme Dcp1a. RNA Biol. 2012;9:1440鈥�9. [PubMed: 23131811]
• Singh S, Suzuki T, Uchiyama A, Kumada S, Moriyama N, Hirose S, Takahashi Y, Sugie H, Mizoguchi K, Inoue Y, Kimura K, Sawaishi Y, Yamakawa K, Ganesh S. Mutations in the NHLRC1 gene are the common cause for Lafora disease in the Japanese population. J Hum Genet. 2005;50:347鈥�52. [PubMed: 16021330]
• Tagliabracci VS, Girard JM, Segvich D, Meyer C, Turnbull J, Zhao X, Minassian BA, Depaoli-Roach AA, Roach PJ. Abnormal metabolism of glycogen phosphate as a cause for Lafora disease. J Biol Chem. 2008;283:33816鈥�25. [PMC free article: PMC2590708] [PubMed: 18852261]
• Traoré M, Landouré G, Motley W, Sangaré M, Meilleur K, Coulibaly S, Traoré S, Niaré B, Mochel F, La Pean A, Vortmeyer A, Mani H, Fischbeck KH. Novel mutation in the NHLRC1 gene in a Malian family with a severe phenotype of Lafora disease. Neurogenetics. 2009;10:319鈥�23. [PMC free article: PMC2758214] [PubMed: 19322595]
• Turnbull J, DePaoli-Roach AA, Zhao X, Cortez MA, Pencea N, Tiberia E, Piliguian M, Roach PJ, Wang P, Ackerley CA, Minassian BA. PTG depletion removes Lafora bodies and rescues the fatal epilepsy of Lafora disease. PLoS Genet. 2011;7:e1002037. [PMC free article: PMC3084203] [PubMed: 21552327]
• Turnbull J, Epp JR, Goldsmith D, Zhao X, Pencea N, Wang P, Frankland PW, Ackerley CA, Minassian BA. PTG protein depletion rescues malin-deficient Lafora disease in mouse. Ann Neurol. 2014;75:442鈥�6. [PubMed: 24419970]
• Turnbull J, Girard JM, Lohi H, Chan EM, Wang P, Tiberia E, Omer S, Ahmed M, Bennett C, Chakrabarty A, Tyagi A, Liu Y, Pencea N, Zhao X, Scherer SW, Ackerley CA, Minassian BA. Early-onset Lafora body disease. Brain. 2012;135:2684鈥�98. [PMC free article: PMC3437029] [PubMed: 22961547]
• Turnbull J, Kumar S, Ren ZP, Muralitharan S, Naranian T, Ackerley CA, Minassian BA. Lafora progressive myoclonus epilepsy: disease course homogeneity in a genetic isolate. J Child Neurol. 2008;23:240鈥�2. [PubMed: 18263761]
• Villanueva V, Alvarez-Linera J, Gomez-Garre P, Gutierrez J, Serratosa JM. MRI volumetry and proton MR spectroscopy of the brain in Lafora disease. Epilepsia. 2006;47:788鈥�92. [PubMed: 16650146]
• Wang J, Stuckey JA, Wishart MJ, Dixon JE. A unique carbohydrate binding domain targets the lafora disease phosphatase to glycogen. J Biol Chem. 2002;277:2377鈥�80. [PubMed: 11739371]
• Worby CA, Gentry MS, Dixon JE. Laforin, a dual specificity phosphatase that dephosphorylates complex carbohydrates. J Biol Chem. 2006;281:30412鈥�8. [PMC free article: PMC2774450] [PubMed: 16901901]
• Worby CA, Gentry MS, Dixon JE. Malin decreases glycogen accumulation by promoting the degradation of protein targeting to glycogen (PTG). J Biol Chem. 2008;283:4069鈥�76. [PMC free article: PMC2251628] [PubMed: 18070875]

Suggested Reading

• Noebels JL. The inherited epilepsies. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill. Chap 230.

Author Notes

Montreal Neurological Institute and Hospital

Revision History

• 22 January 2015 (me) Comprehensive update posted live
• 3 November 2011 (me) Comprehensive update posted live
• 28 December 2007 (me) Review posted to live Web site
• 2 January 2007 (ea) Original submission