Lafora Disease and Congenital Generalized Lipodystrophy: a Case Report

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LAFORA DISEASE AND CONGENITAL GENERALIZED LIPODYSTROPHY: A CASE REPORT

Chih-Fan Tseng,1 Che-Sheng Ho,1,2 Nan-Chang Chiu,1,2 Shuan-Pei Lin,1,2,3 Chi-Yuan Tzen,2,4 and Yu-Hung Wu2,5 Departments of 1Pediatrics, 3Medical Research, 4Pathology and 5Dermatology, Mackay Memorial Hospital; and 2Mackay Medicine, Nursing and Management College, Taipei, Taiwan.

We report a patient with congenital generalized lipodystrophy who had suffered from seizures, myoclonus, ataxia and cognitive decline since late childhood. Lafora disease was diagnosed based on skin biopsy results, which revealed pathognomonic Lafora bodies. The results of genetic analysis for mutations in EPM2A and EPM2B genes were negative. This is the first case report describing an association between congenital generalized lipodystrophy and Lafora disease. Further studies focusing on the relationship between these two diseases and the identification of a third locus for Lafora disease are needed.

Key Words: Lafora disease, lipodystrophy, myoclonus, progressive myoclonic epilepsy (Kaohsiung J Med Sci 2009;25:663–8)

Congenital generalized lipodystrophy (Berardinelli- develop during late childhood or adolescence. We Seip syndrome) was initially reported by Berardinelli report a child with congenital generalized lipodys- [1] and Seip [2] and is an extremely rare autosomal trophy and LD, a previously undescribed association, recessive disorder with genetic heterogeneity. Its and attempt to clarify the relationship between these prevalence has been estimated to be less than one in two diseases. one million. Three different loci (AGPAT2, BSCL2 and CAV1), which map to chromosomes 9q34, 11q13 and 7q31, respectively, have been identified [3–5]. The CASE PRESENTATION disease is characterized by a generalized lack of body fat and extreme muscularity from birth, acromega- An 11-year-old boy presented at our pediatric neurol- loid features, hypertriglyceridemia, hepatomegaly and ogy division with a 2-year history of seizures, insulin resistance (manifested as acanthosis nigri- myoclonus, ataxia and cognitive decline. The patient cans). The central nervous system is seldom affected, was born uneventfully to unrelated Taiwanese parents. except for the presence of mental retardation in ap- Generalized lipodystrophy with muscular hypertro- proximately 80% of individuals with mutations in phy, acromegaloid features, hepatomegaly, hirsutism, BSCL2 [6]. Lafora disease (LD) is also an uncommon hypertrophic cardiomyopathy, hypertriglyceridemia autosomal recessive disorder that presents with (triglycerides, 6.9 mmol/L) and insulin resistance seizures, myoclonus and cognitive decline, which (insulin, 450.7 pmol/L and acanthosis nigricans) had been noted since infancy, and congenital generalized lipodystrophy was diagnosed clinically. He was pre- Received: Mar 6, 2009 Accepted: May 15, 2009 scribed diet modification (a low-fat diet) and received Address correspondence and reprint requests to: regular follow-up at our pediatric genetic division. Dr Che-Sheng Ho, Department of Pediatrics, Mackay Memorial Hospital, 92, Section 2, Chung- The patient had psychomotor retardation; he started Shan North Road, Taipei 10449, Taiwan. walking at 3 and talking at 4 years of age. The condi- E-mail: [email protected] tion improved gradually after he received special

Kaohsiung J Med Sci December 2009 • Vol 25 • No 12 663 © 2009 Elsevier. All rights reserved. C.F. Tseng, C.S. Ho, N.C. Chiu, et al education, and he was able to ambulate freely and Fp2-F4 express himself in simple sentences. From the age of F4-C4 9 years, dysarthria, decreased verbal output and ataxia C4-P4 P4-O2 were noted by his school teacher. Several months later, Fp1-F3 he experienced tonic-clonic seizures with fever. Elec- F3-C3 troencephalography (EEG) showed posteriorly dom- C3-P3 P3-O1 inant irregular spike-wave discharges (Figure 1). F8-T4 During the following 2 years, the patient developed T4-T6 erratic myoclonus, global developmental regression F7-T3 T3-T5 with loss of language and cognition, and became O1-O2 bedridden. Treatment with valproate and levetiracetam was initiated and he was hospitalized due to Figure 1. Electroencephalogram of the 9-year-old boy after his intractable seizures. first episode of seizure, showing epileptiform discharges with Neurological examination showed severe cognitive occipital predominance. impairment, frequent small-amplitude myoclonus and few spontaneous movements. Diffuse fragmentary myoclonus was present at rest and was exaggerated by action and excitement. The cranial nerves were intact and deep tendon reflexes were slightly decreased. His head size, weight and height were normal for his age. A general physical examination was unremark- able except for the lipodystrophic, acromegaloid features (including prognathism, prominent orbital ridges and enlarged hands and feet), acanthosis nigricans and hepatomegaly mentioned previously (Figure 2). Examination of ocular fundi was normal. The results of routine hematological, biochemical and metabolic investigations, including lactate/pyruvate ratio, cop- per, ceruloplasmin, and cerebrospinal fluid examination were within normal limits. Brain magnetic Figure 2. The patient, showing lipodystrophic, acromegaloid resonance imaging scans showed mild generalized face (including prognathism and prominent orbital ridges) and atrophy with ventriculomegaly. EEG showed diffuse acanthosis nigricans on the neck. slow background activity and absence of normal sleep rhythms and epileptiform activity. Visual evoked potentials showed increased bilateral P100 latency and auditory brainstem evoked potentials revealed bilateral poor wave responses at 90 dB click stimula- tion. Somatosensory evoked potentials were not investigated due to excessive myoclonus and difficulty with sedation. The results of genetic studies for spinocerebellar ataxias and dentatorubropalli- doluysian atrophy were negative. LD was suspected on the basis of the clinical findings. The diagnosis was confirmed following a skin biopsy obtained from the axilla, which revealed periodic acid-Schiff (PAS)-positive intracellular polyglucosan inclusion bodies in the eccrine sweat gland Figure 3. Skin biopsy from the axilla stained with periodic acid- duct cells (Figure 3), the pathognomonic Lafora bodies. Schiff revealing Lafora bodies, the intracellular polyglucosan The results of further genetic studies using sequence inclusions (arrows), in eccrine sweat gland duct cells (400×).

664 Kaohsiung J Med Sci December 2009 • Vol 25 • No 12 Lafora disease and congenital lipodystrophy analysis for mutations in EPM2A and EPM2B genes of glycogen termed polyglucosan that accumulates in were negative. Clonazepam, nitrazepam and lor- neurons and other tissues, such as the heart, liver, azepam were prescribed in addition to valproate and muscle, and skin sweat glands, though only the cen- levetiracetam; chloral hydrate was also administered tral nervous system is clinically affected. In the skin, as required, since the continuous myoclonus only Lafora bodies are found in eccrine gland duct cells and resolved during sleep. The patient’s myoclonus im- in apocrine myoepithelial cells, and a skin biopsy is proved and the frequency of seizures was reduced the least invasive pathologic diagnostic method, with under this drug regimen. The patient remained at very high, though not perfect, sensitivity [10–13]. home in a near-vegetative state, with tracheostomy Interpretation of skin biopsy findings carries a risk of and tube feeding. false-negative results, especially in newly sympto- matic individuals, and a risk of false-positive results because of the difficulty in distinguishing Lafora DISCUSSION bodies from normal PAS-positive polysaccharides in apocrine glands in axillary or genital biopsies [12,14]. The term progressive myoclonic epilepsy covers a The biopsy in our patient came from the axilla and large and varied group of diseases characterized by revealed PAS-positive inclusions in the eccrine gland myoclonus, generalized tonic-clonic seizures, and duct cells, which could be identified as unmistakable progressive neurological deterioration, which is typi- Lafora bodies. To confirm our diagnosis, we reviewed cally accompanied by cerebellar signs and dementia. the related literature to identify any other conditions LD, an autosomal recessive disorder, is referred to as associated with similar inclusion bodies; similar PAS- progressive myoclonic epilepsy type 2, and its clinical positive inclusions occurred in the human brain, and histopathological features were first described called corpora amylacea, and in hepatocytes due to by Gonzalo Lafora, a Spanish neurologist, in 1911. LD medication effects in one case [15], but no such bodies occurs worldwide, though exact prevalence figures were reported in the skin. Lafora bodies also resem- are not available. Although rare in the out-bred pop- ble the polyglucosan bodies found in glycogen storage ulations of the United States, Canada, China, and disease type IV and adult polyglucosan body dis- Japan, LD is relatively common in the Mediterranean ease, but the clinical presentations are different. basin including in Spain, France, and Italy, as well as Therefore, the specific skin pathology provides a in restricted regions of central Asia, India, Pakistan, reliable diagnosis of LD: PAS-positive inclusion bod- northern Africa, the Middle East and other parts of ies in a previously normal child between 6 and 18 the world with a high rate of consanguinity [7]. To years of age with myoclonic epilepsy are pathogno- the best of our knowledge, there have been no docu- monic of LD [9]. mented cases in Taiwan. The characteristic clinical LD is genetically heterogeneous with at least three presentation of LD includes the onset of myoclonus, loci, of which two are known, EPM2A and EPM2B visual hallucinations or transient blindness (occipital (NHLRC1). EPM2A is a four-exon gene located on seizures) and multiple seizure types in a previously chromosome 6q24 encoding laforin, a dual-specificity normal child. The mean age of onset is 14 years, but phosphatase with a carbohydrate-binding domain. It ranges from 10 to 17 years [8]. Myoclonus and occipi- could be involved in detecting the appearance of tal seizures are cardinal components of LD [9]. In the polyglucosans and initiating mechanisms to eliminate years following onset, the symptoms of LD progress these compounds, or preventing their further forma- towards intractable action-sensitive and stimulus- tion [16]. EPM2B has a single large exon at 6p22, sensitive myoclonus, refractory seizures, psychosis, which encodes the malin E3 ubiquitin ligase working ataxia, dysarthria, and dementia. Most patients die in the ubiquitin-proteasome system, the major non- within 10 years of onset, usually from complications lysosomal pathway for intracellular protein degrada- related to degeneration of the nervous system and tion [17]. The mechanism by which mutations in status epilepticus [8]. either EPM2A or EPM2B result in LD and the exact The diagnosis of LD depends on the presence of role of the Lafora bodies in the pathogenesis of LD pathognomonic Lafora bodies. These are PAS-positive requires further study. Accumulated evidence points to intracellular inclusions consisting of an abnormal form LD as primarily a disorder of cell death with impaired

Kaohsiung J Med Sci December 2009 • Vol 25 • No 12 665 C.F. Tseng, C.S. Ho, N.C. Chiu, et al clearance of misfolded proteins, though the mecha- lamotrigine, should be avoided to prevent worsening nism of polyglucosan inclusion body accumulation of myoclonus [26]. The promising ketogenic diet used remains unknown. Laforin and malin interact and for LD was not suitable for our lipodystrophic patient. their primary roles appear to be in protecting tissues Experiments to replace EPM2A using immunoliposo- from accumulating polyglucosans by regulating the mal vectors are currently in progress [22]. Better proteins involved in glycogen metabolism [18–21]. understanding of the pathogenetics of LD may allow Several studies are investigating the biochemical path- the development of gene-replacement therapies, which ways that connect laforin and malin to polyglucosan could improve the prognosis for patients with LD. synthesis or degradation [22]. More than 90% of LD patients can be shown to har- bor mutations in EPM2A or EPM2B [23]. The remain- ACKNOWLEDGMENTS ing patients, such as our patient, may have mutations in noncoding regions or in a third, as yet unidentified, The authors thank Dr Yi-Ning Su and his staff from gene [24]. Laboratories offering genetic testing for LD the Department of Medical Genetics, National Taiwan currently use only sequencing, and a mutation that University Hospital, for genetic studies. cannot be amplified by polymerase chain reaction would therefore remain undetected. Subsequent link- age and haplotype analyses should therefore be per- REFERENCES formed in some patients and efforts should be made to map the third LD locus. These results suggest that, 1. Berardinelli W. An undiagnosed endocrinometabolic despite advances in our understanding of the genetics syndrome: report of 2 cases. J Clin Endocrinol Metab 1954;14:193–204. of LD, skin biopsy remains a primary diagnostic 2. Seip M. Lipodystrophy and gigantism with associated modality and the current gold standard, since the endocrine manifestations: a new diencephalic syn- number of different mutations is large and mutation drome? Acta Paediatr 1959;48:555–74. detection requires genetic technology not routinely 3. Garg A, Wilson R, Barnes R, et al. A gene for congenital available outside research laboratories. generalized lipodystrophy maps to human chromo- To the best of our knowledge, no direct associa- some 9q34. J Clin Endocrinol Metab 1999;84:3390–4. 4. Magre J, Delepine M, Khallouf E, et al. Identification of tion between these two rare diseases, congenital gen- the gene altered in Berardinelli-Seip congenital lipodys- eralized lipodystrophy and LD, has been described. trophy on chromosome 11q13. Nat Genet 2001;28:365–70. LD is a genetic disorder of carbohydrate metabolism, 5. Kim CA, Delépine M, Boutet E, et al. Association of while lipodystrophy is associated with insulin resist- a homozygous nonsense caveolin-1 mutation with ance and its complications, though any interaction Berardinelli-Seip congenital lipodystrophy. J Clin between their pathogeneses remains unclear. Some Endocrinol Metab 2008;93:1129–34. 6. Van Maldergem L, Magre J, Khallouf TE, et al. studies have shown that some functions of the endo- Genotype-phenotype relationships in Berardinelli-Seip plasmic reticulum, such as protein synthesis and the congenital lipodystrophy. J Med Genet 2002;39:722–33. secretion and degradation of any misfolded proteins, 7. Delgado-Escueta AV, Ganesh S, Yamakawa K. may be deranged in hyperglycemic patients with Advances in the genetics of progressive myoclonus lipodystrophies [25]. Interestingly, Lafora bodies are epilepsy. Am J Med Genet 2001;106:129–38. endoplasmic reticulum-associated polyglucosan dep- 8. Van Heycop MW. Lafora disease, a form of progressive myoclonus epilepsy. In: Vinken PJ, Bruyn GW, eds. ositions. Nevertheless, further studies are needed to Handbook of Clinical Neurology, Chapter 15: The clarify the relationship between these two diseases. Epilepsies. Amsterdam: Elsevier, 1975:382–422. The prognosis of LD is presently poor, and treat- 9. Minassian B. Lafora’s disease: towards a clinical, patho- ment remains palliative. Antiepileptic drugs, including logic, and molecular synthesis. Pediatr Neurol 2001; valproate, benzodiazepines (especially clonazepam), 25:21–9. levetiracetam, piracetam and zonisamide are com- 10. Carpenter S, Karpati G. Sweat gland duct cells in Lafora disease: diagnosis by skin biopsy. Neurology monly used for the management of seizures and 1981;31:1564–8. myoclonus. There is a risk of overmedication when 11. Busard HLSM, Gobreels-Festen AAWM, Renih WU, treating drug-resistant myoclonus. Phenytoin, viga- et al. Axilla skin biopsy: a reliable test for the diagnosis batrin, carbamazepine, gabapentin, and probably of Lafora’s disease. Ann Neurol 1987;21:599–601.

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Kaohsiung J Med Sci December 2009 • Vol 25 • No 12 667 Lafora 氏症合併先天性全身脂質營養不良症－病例報告

1 1,2 1,2 1,2,3 2,4 2,5 曾至凡何啟生邱南昌林炫沛曾岐元吳育弘

1 3 4 5 台北馬偕紀念醫院小兒部醫學研究部病理科皮膚科

2 馬偕醫護管理專科學校

本文報告一 11 歲患先天性全身脂質營養不良症的男性病童於後兒童期出現抽搐痙攣、肌陣攣、運動失調及認知功能衰退等症狀，皮膚切片發現汗腺有 Lafora 小體而診斷為 Lafora 氏症，做基因序列分析並未發現 EPM2A 及 EPM2B 之基因突變。之前的文獻並未報告過此類合併先天性全身脂質營養不良症與 Lafora 氏症的案例，而本病例為首例；至於兩者間是否有關聯性以及如何確認 Lafora 氏症的第三個基因位點仍待進一步的研究。

關鍵詞：Lafora 氏症，脂質營養不良症，肌陣攣，進行性肌陣攣癲癇症 ( 高雄醫誌 2009;25:663–8)

收文日期：98 年 3 月 6 日接受刊載：98 年 5 月 15 日通訊作者：何啟生醫師馬偕紀念醫院小兒部台北市中山區 10449 中山北路二段 92 號

668 Kaohsiung J Med Sci December 2009 • Vol 25 • No 12