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Lafora Disease and Congenital Generalized Lipodystrophy: a Case Report

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Lafora Disease and Congenital Generalized Lipodystrophy: a Case Report View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector 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 dis- ease. Further studies focusing on the relationship between these two diseases and the identifica- tion 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 levetirac- etam 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 fea- tures (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 examina- tion 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 diffi- culty 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 find- ings. The diagnosis was confirmed following a skin biopsy obtained from the axilla, which revealed peri- odic acid-Schiff (PAS)-positive intracellular polyglu- cosan 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
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