- Email: [email protected]
Lafora disease: Diagnosis by skin biopsy
790 Briefreports
J AM
ACAD DERMATOL NOVEMBER
1999
--------------.~--------------
Lafora disease: Diagnosis by skin biopsy Darius Karimipour, MD,a Lori Lowe, MD,a,d Mila Blaivas, MD,d Dana Sachs, MD,a and Timothy M. Johnson, MDa,b,c AnnArbor, Michigan Lafora disease is a fatal neurometabolic disorder characterized by progressive myoclonic epilepsy. Diagnosis relies upon the discovery of specific inclusion bodies in any of several organs. Dermatologists and dermatopathologists should be familiar with this condition because axillary skin biopsy is useful to diagnose this disorder. We present a case of Lafora disease diagnosed by axillary skin biopsy and review the condition's clinical, histologic, and ultrastructural features. Am Acad DermatoI1999;41:790-2.)
a
L
afora disease is a neurometabolic disorder characterized by progressive myoclonic epilepsy: This fatal disorder initially presents as a generalized form of epilepsy usually between 10 and 17 years of age. 1-16 Within a decade the disorder progresses to dementia, total disability, and death subsequent to a vegetative period. Cutaneous findings are rare. 4 However, the usefulness and diagnostic value of a skin biopsy in Lafora disease has been confirmed. 4-16 We describe a rare case of Lafora disease diagnosed by axillary skin biopsy.
CASE REPORT A 16-year-old white male adolescent presented with a history of seizures and mental deterioration. Neurologic complaints were first noted at age 14 with occasional uncontrollable movements of all extremities. Progression to generalized tonic-clonic seizures occurred and an extensive neurologic work-up resulted in the diagnosis of presumed juvenile myoclonic epilepsy. Treatment with divalproex sodium initially controlled the seizure disorder. Over the next year, several breakthrough seizures occurred despite increasing the dosage of divalproex sodium and the addition of c1onazepam. His neurologic condition deteriorated. He experienced difficulty doing school work, somnolence, and deficits in attention, memory, and fund of knowledge. Upon re-evaluation, a family history was obtained describing a similar condition in 3 paternal cousins, all of whom subsequently died of a deteriorating neurologic condition. It was also discovered that the parents of this reference case were distant cousins. The
From the Departments of Dermatology,· Otorhinolaryngology,b Surgery (Division of Plastic Surgery),' and Pathology,d University of Michigan Medical Center and University of Michigan Comprehensive Cancer Center. Reprint requests: Timothy M. Johnson, MD, University of Michigan/Dermatology, 1910 Taubman Center, Box 0314, Ann Arbor, MI 48109-0314. Copyright © 1999 by the American Academy of Dermatology, Inc. 0190-9622/99/$8.00 + 0 16/54/100899
Fig 1. Photomicrograph of axillary skin biopsy specimen demonstrates numerous PAS-pOSitive, diastase resistant round to oval inclusion bodies within secretory portion of apocrine glands. (PAS stain; original magnification x200.)
patient was then referred to dermatology for an axillary skin biopsy to confirm the diagnosis of Lafora disease. Two axillary 4-mm punch skin biopsies were performed and sent for routine histopathologic and electron microscopic evaluation. Paraffin-embedded sections stained with hematoxylin and eosin demonstrated no discernible histopathologic abnormality. However, staining with the periodic acid-Schiff (PAS) stain with diastase revealed PASpOSitive, diastase-resistant inclusion bodies within the secretory portion of the apocrine glands consistent with a diagnosis of Lafora disease (Fig 1). The electron microscopic specimen was fixed in paraformaldehyde-glutaraldehyde by Karnovsky, postfixed in 1% osmic acid, washed, dehydrated, embedded in epoxy resin, sectioned, contrasted with 1% ureayl magnesium acetate-based citrate, and examined with an electron microscope. Electron microscopy revealed round to oval electron-lucent areas within the cytoplasm of eccrine duct cells (Fig 2). These inclusions lacked a limiting membrane. These findings were diagnostic of Lafora disease.
J AM ACAD DERMATOL VOLUME 41, NUMBER 5, PART
Brief reports 791 1
Within 2 years of his initial presentation, our patient has continued to deteriorate mentally and has suffered multiple episodes of pneumonia resulting from his inability to protect his airway.
DISCUSSION Lafora disease, also known as Unverricht's disease, is a rare, progressive, fatal myoclonic epilepsy that is transmitted in an autosomal recessive pattern,1-16 It is characterized clinically by the triad of seizures, myoclonus, and dementia, Light and electron microscopy are useful tools to confirm the clinical diagnosis, PAS-positive intracytoplasmic inclusions termed Lafora bodies or polyglucosan bodies are found in multiple organs such as the brain, heart, liver, striated muscle, and skin,+16 In 1911, Lafora I7 first described "intracellular amyloid bodies" in the brain and spinal cord of a patient with adolescent, fatal, progressive myoclonic epilepsy. In 1981, Carpenter and Karpati 6 proposed that diagnosis of this condition could be made on the basis of a combination of clinical findings and identification of the characteristic Lafora t50dies demonstrated in tissue obtained by skin biopsy. Light microscopy reveals round to oval, 8- to 1511m, PAS-positive intracytoplasmic inclusion bodies in the peripheral cells of eccrine ducts and in the myoepithelial cells of apocrine acini. These Lafora bodies may be identified in clinically normal skin. Eccrine acini and apocrine duct cells are usually spared. 4-16 Ultrastructurally, these inclusions are typically juxtanuclear in position and composed of fine filamentous material that is not separated from the cell cytoplasm by a delimiting membrane. 4 ,15 Amyloid stains are negative. Biochemical studies reveal that Lafora bodies consist of branched glucose polymers (polyglucosans) with small amounts of phosphate and sulfate groups and less than 5% associated protein. 18 The gene for Lafora disease has been mapped to a 17 cM region in chromosome 6q23-25 flanked by D6S292 and D6S420. 19 The precise enzymatic biochemical defect responsible for Lafora disease and its products remains unknown. The disease, however, is viewed as an inborn error in carbohydrate metabolism. The inclusion bodies found in Lafora disease are not present in unaffected parents and siblings (carriers).4 However, similar polyglucosan inclusion bodies rarely can be found in normal aging, double athetosis, amyotrophic lateral sclerosis, and type N glycogen storage disease.7· 8 ,18 Hence the diagnosis of Lafora disease should only be made in the correct clinical context. A skin biopsy is preferable to biopsy of the central nervous system or other organ. 4-I6 The skin biopsy is
Fig 2. Oval intracytoplasmic inclusion is sharply delineated but not membrane bound. It contains fine filamentous/granular material. (Original magnification reduced from x42,500.)
easier, more cost-effective, and safer. The axilla is the best site for biopsy because this area contains a relatively high concentration of eccrine and apocrine glands. Electron microscopy is recommended and may be required to confirm the diagnosis if light microscopic findings are equivocal. Dermatologists and dermatopathologists should be aware that a skin biopsy, preferably from the axilla, is an appropriate diagnostic test for Lafora disease. REFERENCES 1. Janeway R, Ravens JR, Pearce LA, Odor DL, Suzuki K. Progressive myoclonus epilepsy with Lafera inclusion bodies. Arch Neurol 1967;16:565-82. 2. Iannaccone S, Zucconi M, Quattrini A, Nemni R, Comola M, Taccagni L, et al. Early detection of skin and muscular involvement in Lafora disease. J Neurol 1991 ;238:217-20. 3. Gambetti P, Di Mauro S, Hirt L, Blume RP. Myoclonic epilepsy with Lafora bodies. Arch NeuroI1971;2S:483-93. 4. Busard HLSM, Gabreels-Festen AA, Renier WO, Gabreels FJM, Stadhouders AM. Axilla skin biopsy: a reliable test for the diagnosis of Lafora's disease. Ann Neuro11987;21 :599-601. 5. Drury I, Blaivas M, Abou-Khalil BW, Beydoun A. Biopsy results in a kindred with Lafora disease. Arch NeuroI1993;50:102-5. 6. Carpenter S, Karpati G. Sweat gland duct cells in Lafora disease: diagnosis by skin biopsy. Neurology 1981 ;31 :1564-8. 7. Samlaska CP, McBurney J, Sau P, James WD. Lafora's disease: What is the best site for skin biopsy? J Am Acad Dermatol 1989;21:791-2. 8. White JW, Gomez MR. Diagnosis of Lafora disease by skin biopsy. J Cutan PathoI1988;1S:171-S. 9. Tinuper P, Aguglia U, Pellissier JF, Gastaut H. Visual ictal phenomena in a case of Lafora disease proven by skin biopsy. Epilepsia 1983;24:214-8. 10. Newton GA, Sanchez RL, Swedo J, Smith EB. Lafora's disease: the role of skin biopsy. Arch DermatoI1987;123:1667-9. 11. Idoate MA, Vazquez JJ, Soto J, de Castro P. Diagnosis of Lafora's
792 Brief reports
J AM ACAD DERMATOL NOVEMBER
12.
13.
14.
15.
16.
disease in apocrine sweat glands of the axilla. Am J Dermatopathol 1991 ;13:410-3. Yalciner B, Ozer F, Hanoglu L, Ozkara C, Ozbay G, Arpaci B. A case of Lafora's disease: diagnosis by skin biopsy. Acta Neurol Belg 1993;93:97-8. Thom M, Revesz T. Typical polyglucosan bodies are present in the sweat gland lumina in Lafora's disease. Acta Neuropathol 1996;92:102-3. Rubio G, Guijo CG, Mallada JJ, Cabello A, Merino AG. Diagnosis by axilla skin biopsy in an early case of Lafora's disease.J Neurol 1992;55:1084-5. Busard BLsM, Renier WO, Gabreels FJM, Jaspar HHJ, van Haelst UJG, siooff JL. Lafora's disease: comparison of inclusion bodies in skin and in brain. Arch Neurol 1986;43:296-9. Acharya IN, satishchandra P, Asha T, Shankar sK. Lafora's disease
1999
in South India: a clinical, electrophysiologic, and pathologic study. Epilepsia 1993;34:476-87. 17. LaFora GR. The presence of amyloid bodies in the protoplasm of the ganglion cells; a contribution to the study of the amyloid substance in the nervous system. Bull Gov Hosp Insane 1911; 3:83-92. 18. Robitaille Y, Carpenter 5, Karpati G, DiMauro sD. A distinct form of adult polyglucosan body disease with massive involvement of the central and peripheral neuronal processes and astrocytes. Brain 1980;103:315-36. 19. serratosa M, Delgado-Escueta AV, Posada I, Shih 5, Drury I, Berciano J, et al. The gene for progressive myoclonus epilepsy of the Lafora type maps to chromosome 6q. Hum Mol Genet 1995;4:1657-63.
J AM
ACAD DERMATOL NOVEMBER
1999
--------------.~--------------
Lafora disease: Diagnosis by skin biopsy Darius Karimipour, MD,a Lori Lowe, MD,a,d Mila Blaivas, MD,d Dana Sachs, MD,a and Timothy M. Johnson, MDa,b,c AnnArbor, Michigan Lafora disease is a fatal neurometabolic disorder characterized by progressive myoclonic epilepsy. Diagnosis relies upon the discovery of specific inclusion bodies in any of several organs. Dermatologists and dermatopathologists should be familiar with this condition because axillary skin biopsy is useful to diagnose this disorder. We present a case of Lafora disease diagnosed by axillary skin biopsy and review the condition's clinical, histologic, and ultrastructural features. Am Acad DermatoI1999;41:790-2.)
a
L
afora disease is a neurometabolic disorder characterized by progressive myoclonic epilepsy: This fatal disorder initially presents as a generalized form of epilepsy usually between 10 and 17 years of age. 1-16 Within a decade the disorder progresses to dementia, total disability, and death subsequent to a vegetative period. Cutaneous findings are rare. 4 However, the usefulness and diagnostic value of a skin biopsy in Lafora disease has been confirmed. 4-16 We describe a rare case of Lafora disease diagnosed by axillary skin biopsy.
CASE REPORT A 16-year-old white male adolescent presented with a history of seizures and mental deterioration. Neurologic complaints were first noted at age 14 with occasional uncontrollable movements of all extremities. Progression to generalized tonic-clonic seizures occurred and an extensive neurologic work-up resulted in the diagnosis of presumed juvenile myoclonic epilepsy. Treatment with divalproex sodium initially controlled the seizure disorder. Over the next year, several breakthrough seizures occurred despite increasing the dosage of divalproex sodium and the addition of c1onazepam. His neurologic condition deteriorated. He experienced difficulty doing school work, somnolence, and deficits in attention, memory, and fund of knowledge. Upon re-evaluation, a family history was obtained describing a similar condition in 3 paternal cousins, all of whom subsequently died of a deteriorating neurologic condition. It was also discovered that the parents of this reference case were distant cousins. The
From the Departments of Dermatology,· Otorhinolaryngology,b Surgery (Division of Plastic Surgery),' and Pathology,d University of Michigan Medical Center and University of Michigan Comprehensive Cancer Center. Reprint requests: Timothy M. Johnson, MD, University of Michigan/Dermatology, 1910 Taubman Center, Box 0314, Ann Arbor, MI 48109-0314. Copyright © 1999 by the American Academy of Dermatology, Inc. 0190-9622/99/$8.00 + 0 16/54/100899
Fig 1. Photomicrograph of axillary skin biopsy specimen demonstrates numerous PAS-pOSitive, diastase resistant round to oval inclusion bodies within secretory portion of apocrine glands. (PAS stain; original magnification x200.)
patient was then referred to dermatology for an axillary skin biopsy to confirm the diagnosis of Lafora disease. Two axillary 4-mm punch skin biopsies were performed and sent for routine histopathologic and electron microscopic evaluation. Paraffin-embedded sections stained with hematoxylin and eosin demonstrated no discernible histopathologic abnormality. However, staining with the periodic acid-Schiff (PAS) stain with diastase revealed PASpOSitive, diastase-resistant inclusion bodies within the secretory portion of the apocrine glands consistent with a diagnosis of Lafora disease (Fig 1). The electron microscopic specimen was fixed in paraformaldehyde-glutaraldehyde by Karnovsky, postfixed in 1% osmic acid, washed, dehydrated, embedded in epoxy resin, sectioned, contrasted with 1% ureayl magnesium acetate-based citrate, and examined with an electron microscope. Electron microscopy revealed round to oval electron-lucent areas within the cytoplasm of eccrine duct cells (Fig 2). These inclusions lacked a limiting membrane. These findings were diagnostic of Lafora disease.
J AM ACAD DERMATOL VOLUME 41, NUMBER 5, PART
Brief reports 791 1
Within 2 years of his initial presentation, our patient has continued to deteriorate mentally and has suffered multiple episodes of pneumonia resulting from his inability to protect his airway.
DISCUSSION Lafora disease, also known as Unverricht's disease, is a rare, progressive, fatal myoclonic epilepsy that is transmitted in an autosomal recessive pattern,1-16 It is characterized clinically by the triad of seizures, myoclonus, and dementia, Light and electron microscopy are useful tools to confirm the clinical diagnosis, PAS-positive intracytoplasmic inclusions termed Lafora bodies or polyglucosan bodies are found in multiple organs such as the brain, heart, liver, striated muscle, and skin,+16 In 1911, Lafora I7 first described "intracellular amyloid bodies" in the brain and spinal cord of a patient with adolescent, fatal, progressive myoclonic epilepsy. In 1981, Carpenter and Karpati 6 proposed that diagnosis of this condition could be made on the basis of a combination of clinical findings and identification of the characteristic Lafora t50dies demonstrated in tissue obtained by skin biopsy. Light microscopy reveals round to oval, 8- to 1511m, PAS-positive intracytoplasmic inclusion bodies in the peripheral cells of eccrine ducts and in the myoepithelial cells of apocrine acini. These Lafora bodies may be identified in clinically normal skin. Eccrine acini and apocrine duct cells are usually spared. 4-16 Ultrastructurally, these inclusions are typically juxtanuclear in position and composed of fine filamentous material that is not separated from the cell cytoplasm by a delimiting membrane. 4 ,15 Amyloid stains are negative. Biochemical studies reveal that Lafora bodies consist of branched glucose polymers (polyglucosans) with small amounts of phosphate and sulfate groups and less than 5% associated protein. 18 The gene for Lafora disease has been mapped to a 17 cM region in chromosome 6q23-25 flanked by D6S292 and D6S420. 19 The precise enzymatic biochemical defect responsible for Lafora disease and its products remains unknown. The disease, however, is viewed as an inborn error in carbohydrate metabolism. The inclusion bodies found in Lafora disease are not present in unaffected parents and siblings (carriers).4 However, similar polyglucosan inclusion bodies rarely can be found in normal aging, double athetosis, amyotrophic lateral sclerosis, and type N glycogen storage disease.7· 8 ,18 Hence the diagnosis of Lafora disease should only be made in the correct clinical context. A skin biopsy is preferable to biopsy of the central nervous system or other organ. 4-I6 The skin biopsy is
Fig 2. Oval intracytoplasmic inclusion is sharply delineated but not membrane bound. It contains fine filamentous/granular material. (Original magnification reduced from x42,500.)
easier, more cost-effective, and safer. The axilla is the best site for biopsy because this area contains a relatively high concentration of eccrine and apocrine glands. Electron microscopy is recommended and may be required to confirm the diagnosis if light microscopic findings are equivocal. Dermatologists and dermatopathologists should be aware that a skin biopsy, preferably from the axilla, is an appropriate diagnostic test for Lafora disease. REFERENCES 1. Janeway R, Ravens JR, Pearce LA, Odor DL, Suzuki K. Progressive myoclonus epilepsy with Lafera inclusion bodies. Arch Neurol 1967;16:565-82. 2. Iannaccone S, Zucconi M, Quattrini A, Nemni R, Comola M, Taccagni L, et al. Early detection of skin and muscular involvement in Lafora disease. J Neurol 1991 ;238:217-20. 3. Gambetti P, Di Mauro S, Hirt L, Blume RP. Myoclonic epilepsy with Lafora bodies. Arch NeuroI1971;2S:483-93. 4. Busard HLSM, Gabreels-Festen AA, Renier WO, Gabreels FJM, Stadhouders AM. Axilla skin biopsy: a reliable test for the diagnosis of Lafora's disease. Ann Neuro11987;21 :599-601. 5. Drury I, Blaivas M, Abou-Khalil BW, Beydoun A. Biopsy results in a kindred with Lafora disease. Arch NeuroI1993;50:102-5. 6. Carpenter S, Karpati G. Sweat gland duct cells in Lafora disease: diagnosis by skin biopsy. Neurology 1981 ;31 :1564-8. 7. Samlaska CP, McBurney J, Sau P, James WD. Lafora's disease: What is the best site for skin biopsy? J Am Acad Dermatol 1989;21:791-2. 8. White JW, Gomez MR. Diagnosis of Lafora disease by skin biopsy. J Cutan PathoI1988;1S:171-S. 9. Tinuper P, Aguglia U, Pellissier JF, Gastaut H. Visual ictal phenomena in a case of Lafora disease proven by skin biopsy. Epilepsia 1983;24:214-8. 10. Newton GA, Sanchez RL, Swedo J, Smith EB. Lafora's disease: the role of skin biopsy. Arch DermatoI1987;123:1667-9. 11. Idoate MA, Vazquez JJ, Soto J, de Castro P. Diagnosis of Lafora's
792 Brief reports
J AM ACAD DERMATOL NOVEMBER
12.
13.
14.
15.
16.
disease in apocrine sweat glands of the axilla. Am J Dermatopathol 1991 ;13:410-3. Yalciner B, Ozer F, Hanoglu L, Ozkara C, Ozbay G, Arpaci B. A case of Lafora's disease: diagnosis by skin biopsy. Acta Neurol Belg 1993;93:97-8. Thom M, Revesz T. Typical polyglucosan bodies are present in the sweat gland lumina in Lafora's disease. Acta Neuropathol 1996;92:102-3. Rubio G, Guijo CG, Mallada JJ, Cabello A, Merino AG. Diagnosis by axilla skin biopsy in an early case of Lafora's disease.J Neurol 1992;55:1084-5. Busard BLsM, Renier WO, Gabreels FJM, Jaspar HHJ, van Haelst UJG, siooff JL. Lafora's disease: comparison of inclusion bodies in skin and in brain. Arch Neurol 1986;43:296-9. Acharya IN, satishchandra P, Asha T, Shankar sK. Lafora's disease
1999
in South India: a clinical, electrophysiologic, and pathologic study. Epilepsia 1993;34:476-87. 17. LaFora GR. The presence of amyloid bodies in the protoplasm of the ganglion cells; a contribution to the study of the amyloid substance in the nervous system. Bull Gov Hosp Insane 1911; 3:83-92. 18. Robitaille Y, Carpenter 5, Karpati G, DiMauro sD. A distinct form of adult polyglucosan body disease with massive involvement of the central and peripheral neuronal processes and astrocytes. Brain 1980;103:315-36. 19. serratosa M, Delgado-Escueta AV, Posada I, Shih 5, Drury I, Berciano J, et al. The gene for progressive myoclonus epilepsy of the Lafora type maps to chromosome 6q. Hum Mol Genet 1995;4:1657-63.