Pediatric Neurology 51 (2014) 713e716
Contents lists available at ScienceDirect
Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu
Clinical Observations
Lafora Disease With Novel Autopsy Findings: A Case Report With Endocrine Involvement and Literature Review Liat Corcia MD a, *, Samantha Hohensee MD b, Anthony Olivero MD c, Jackson Wong MD c a
Department of Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts Department of Pathology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts c Department of Medicine, Critical Care, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts b
abstract BACKGROUND: Lafora disease is a rare, autosomal recessive, progressive myoclonic epilepsy with onset typically in the second decade of life and uniformly fatal outcome. Most of the current literature focuses on diagnosis, genetic basis, neurological signs, and possible treatment of this currently incurable disease. On literature review of over 50 articles including over 300 patients, there were no comments on or pathologic description of endocrinologic issues in relation to Lafora disease. PATIENT DESCRIPTION: We describe a patient with Lafora disease with severe neurological deterioration. During hospitalization for urosepsis, he exhibited thyrotoxicosis with a free thyroxine (T4) level greater than 7.77 ng/dL. On autopsy, he had lymphocytic thyroiditis and Lafora bodies throughout his organs including the anterior pituitary, hypothalamus, and pancreas. CONCLUSIONS: This is the first report of the pathologic findings of Lafora bodies in endocrine organs. Although this patient’s thyrotoxic state was likely not a direct result of his Lafora disease, given the diffuse deposition of Lafora bodies, endocrinologic abnormalities should be considered in patients with Lafora disease. Furthermore, acute decompensation in these individuals may arise not from a declining neurological status but from a coincidental disease process. Keywords: epilepsy, Lafora disease, thyrotoxicosis, progressive myoclonic epilepsy, endocrinologic abnormalities
Pediatr Neurol 2014; 51: 713-716 Ó 2014 Elsevier Inc. All rights reserved.
Introduction
Lafora disease is a rare, autosomal recessive, progressive myoclonic epilepsy. More than 90% of cases of Lafora disease are due to mutations in EPM2A (coding for laforin protein) and EPM2B (coding for Malin protein).1 Dysfunction usually begins in the second decade of life, and they are ultimately fatal. The major characteristic sign is progressive myoclonic epilepsy leading to severe neurological deterioration and loss of motor control including the ability to speak. Diagnosis is based on skin,2 liver, or muscle biopsy that reveals Lafora body deposition within various organ
Article History: Received April 30, 2014; Accepted in final form July 31, 2014 * Communications should be addressed to: Dr. Corcia; Department of Pediatric Endocrinology; University of Miami; 1601 NW 12th Avenue; 3044A; Miami, Florida 33136. E-mail address: [email protected] 0887-8994/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pediatrneurol.2014.07.034
systems.3 Previously, diagnosis was also made via cerebral cortex biopsy.4 On autopsy, Lafora bodies are most prominently present in the brain, with current theory relating this deposition to the neurological consequences observed in these patients. Lafora bodies are poorly branched, insoluble, glycogen-like carbohydrates called polyglucosan, and are the hallmark of Lafora disease.1 These depositions are Periodic Acid Schiff positive5,6 and are most abundantly found in organs with the highest glucose metabolism.7 There have been hypotheses that relate Lafora disease with its abnormal aggregates of polyglucosan to glycogen storage disease type IV.8 Patient Description Our patient was a 22-year-old man who was previously healthy and developmentally appropriate until he was 14 years old when he experienced a seizure, with subsequent development of jerking upper and lower extremity movements. He had progressive neurological
714
L. Corcia et al. / Pediatric Neurology 51 (2014) 713e716
deterioration including a decrease in purposeful movements and the in ability to perform activities of daily living. Of note, during the diagnostic evaluation, skin biopsy revealed unremarkable ultrastructure with no evidence of storage or mitochondrial disease or Lafora bodies. Lafora disease mutation testing revealed a known pathologic mutation in EPM2B at nucleotide 205 and a novel mutation at 1031, and a diagnosis of Lafora disease was made. With disease progression he became nonverbal and required a gastrostomy tube for feeding intolerance and nighttime noninvasive positive pressure ventilation for chronic respiratory failure. In spite of therapy with various antiepileptic drugs, experienced progressive decline in mental status, hypertonia, movement disorder manifested as jerking movements, and autonomic instability. He was admitted for respiratory distress and worsening myoclonic activity. At that time, his medications included levetiracetam, valproic acid, rufinimide, zonisamide, topiramate, quetiapine, citalopram, clobazam, lorazepam, ranitidine, esomeprazole, chlorothiazide, albuterol, and ipratropium. He had Klebsiella urosepsis and was treated with 1 week of piperacillin and/or tazobactam. Although his respiratory abnormalities improved on antibiotic therapy and an increased pulmonary clearance regimen, he developed increased autonomic instability (tachycardia, hypertension, sweating, and temperature instability), increased seizure frequency and myoclonic jerks, and worsening of his mental status, as well as feeding intolerance with profuse diarrhea (Table 1). Thyroid function tests (Table 2) revealed a suppressed thyroid stimulating hormone level, an extremely elevated free thyroxine (T4) level, a high total T4 level, a high triiodothyroxine (T3) level, and a high thyroid hormone binding ratio. Thus, he was diagnosed with thyrotoxicosis, and his increased stool output and a portion of his autonomic instability were attributed to his thyroid dysfunction. TABLE 1. Clinical Manifestations: Baseline and During Hospitalization
Clinical Manifestations Associated With Hyperthyroidism
Baseline
During Hospitalization Before Diagnosis
Anxiety Restlessness
Yes With respiratory distress Yes With illness Autonomic instability Autonomic instability
Yes Yes
Irritability Weight loss Tachycardia Hypertension Wide pulse pressure Ophthalmopathy Eye stare Goiter Heat intolerance Warm smooth skin Excessive sweating
Yes Yes Autonomic instability
Hyperpigmentation Pruritus/hives Yes Thinning and loss of hair Pretibial myxedema Hyperdefecation No Hyperphagia Nutrition by G-tube feeds Hyperglycemia Dyspnea Chronic respiratory failure Emesis No Increased serum calcium Increased myoclonic With disease activity progression
Yes Yes Yes No No No Unable to assess No Yes Yes Yes No Yes No Yes Yes Not applicable No Yes
Yes Yes Yes
TABLE 2. Summary of Laboratory Values
Laboratory Test Thyroid stimulating hormone level (mU/L) Free thyroxine (T4) (ng/dL) Total T4 level (mg/dL) Triiodothyroxine (T3) (ng/dL) Thyroid hormone binding ratio Thyroperoxidase autoantibody (IU/mL) TSH receptor antibody (TBII) Thyroid stimulating immunoglobulin Thyroglobulin Thyroglobulin antibody High-density lipoprotein (mg/dL) baseline level Cholesterol (mg/dL) baseline level Alkaline phosphatase (U/L) Total/direct bilirubin (mg/dL) Calcium (mg/dL) Phosphate (mg/dL) Glucose (mg/dL) Urine ketones Parathyroid hormone (pg/mL) baseline level Cortisol (mg/dL) baseline level 25 hydroxy vitamin D (ng/mL)
Patient’s Values
Normal Range
0.211
0.4-4.2
>7.77 19.7 401 >2
Contents lists available at ScienceDirect
Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu
Clinical Observations
Lafora Disease With Novel Autopsy Findings: A Case Report With Endocrine Involvement and Literature Review Liat Corcia MD a, *, Samantha Hohensee MD b, Anthony Olivero MD c, Jackson Wong MD c a
Department of Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts Department of Pathology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts c Department of Medicine, Critical Care, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts b
abstract BACKGROUND: Lafora disease is a rare, autosomal recessive, progressive myoclonic epilepsy with onset typically in the second decade of life and uniformly fatal outcome. Most of the current literature focuses on diagnosis, genetic basis, neurological signs, and possible treatment of this currently incurable disease. On literature review of over 50 articles including over 300 patients, there were no comments on or pathologic description of endocrinologic issues in relation to Lafora disease. PATIENT DESCRIPTION: We describe a patient with Lafora disease with severe neurological deterioration. During hospitalization for urosepsis, he exhibited thyrotoxicosis with a free thyroxine (T4) level greater than 7.77 ng/dL. On autopsy, he had lymphocytic thyroiditis and Lafora bodies throughout his organs including the anterior pituitary, hypothalamus, and pancreas. CONCLUSIONS: This is the first report of the pathologic findings of Lafora bodies in endocrine organs. Although this patient’s thyrotoxic state was likely not a direct result of his Lafora disease, given the diffuse deposition of Lafora bodies, endocrinologic abnormalities should be considered in patients with Lafora disease. Furthermore, acute decompensation in these individuals may arise not from a declining neurological status but from a coincidental disease process. Keywords: epilepsy, Lafora disease, thyrotoxicosis, progressive myoclonic epilepsy, endocrinologic abnormalities
Pediatr Neurol 2014; 51: 713-716 Ó 2014 Elsevier Inc. All rights reserved.
Introduction
Lafora disease is a rare, autosomal recessive, progressive myoclonic epilepsy. More than 90% of cases of Lafora disease are due to mutations in EPM2A (coding for laforin protein) and EPM2B (coding for Malin protein).1 Dysfunction usually begins in the second decade of life, and they are ultimately fatal. The major characteristic sign is progressive myoclonic epilepsy leading to severe neurological deterioration and loss of motor control including the ability to speak. Diagnosis is based on skin,2 liver, or muscle biopsy that reveals Lafora body deposition within various organ
Article History: Received April 30, 2014; Accepted in final form July 31, 2014 * Communications should be addressed to: Dr. Corcia; Department of Pediatric Endocrinology; University of Miami; 1601 NW 12th Avenue; 3044A; Miami, Florida 33136. E-mail address: [email protected] 0887-8994/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pediatrneurol.2014.07.034
systems.3 Previously, diagnosis was also made via cerebral cortex biopsy.4 On autopsy, Lafora bodies are most prominently present in the brain, with current theory relating this deposition to the neurological consequences observed in these patients. Lafora bodies are poorly branched, insoluble, glycogen-like carbohydrates called polyglucosan, and are the hallmark of Lafora disease.1 These depositions are Periodic Acid Schiff positive5,6 and are most abundantly found in organs with the highest glucose metabolism.7 There have been hypotheses that relate Lafora disease with its abnormal aggregates of polyglucosan to glycogen storage disease type IV.8 Patient Description Our patient was a 22-year-old man who was previously healthy and developmentally appropriate until he was 14 years old when he experienced a seizure, with subsequent development of jerking upper and lower extremity movements. He had progressive neurological
714
L. Corcia et al. / Pediatric Neurology 51 (2014) 713e716
deterioration including a decrease in purposeful movements and the in ability to perform activities of daily living. Of note, during the diagnostic evaluation, skin biopsy revealed unremarkable ultrastructure with no evidence of storage or mitochondrial disease or Lafora bodies. Lafora disease mutation testing revealed a known pathologic mutation in EPM2B at nucleotide 205 and a novel mutation at 1031, and a diagnosis of Lafora disease was made. With disease progression he became nonverbal and required a gastrostomy tube for feeding intolerance and nighttime noninvasive positive pressure ventilation for chronic respiratory failure. In spite of therapy with various antiepileptic drugs, experienced progressive decline in mental status, hypertonia, movement disorder manifested as jerking movements, and autonomic instability. He was admitted for respiratory distress and worsening myoclonic activity. At that time, his medications included levetiracetam, valproic acid, rufinimide, zonisamide, topiramate, quetiapine, citalopram, clobazam, lorazepam, ranitidine, esomeprazole, chlorothiazide, albuterol, and ipratropium. He had Klebsiella urosepsis and was treated with 1 week of piperacillin and/or tazobactam. Although his respiratory abnormalities improved on antibiotic therapy and an increased pulmonary clearance regimen, he developed increased autonomic instability (tachycardia, hypertension, sweating, and temperature instability), increased seizure frequency and myoclonic jerks, and worsening of his mental status, as well as feeding intolerance with profuse diarrhea (Table 1). Thyroid function tests (Table 2) revealed a suppressed thyroid stimulating hormone level, an extremely elevated free thyroxine (T4) level, a high total T4 level, a high triiodothyroxine (T3) level, and a high thyroid hormone binding ratio. Thus, he was diagnosed with thyrotoxicosis, and his increased stool output and a portion of his autonomic instability were attributed to his thyroid dysfunction. TABLE 1. Clinical Manifestations: Baseline and During Hospitalization
Clinical Manifestations Associated With Hyperthyroidism
Baseline
During Hospitalization Before Diagnosis
Anxiety Restlessness
Yes With respiratory distress Yes With illness Autonomic instability Autonomic instability
Yes Yes
Irritability Weight loss Tachycardia Hypertension Wide pulse pressure Ophthalmopathy Eye stare Goiter Heat intolerance Warm smooth skin Excessive sweating
Yes Yes Autonomic instability
Hyperpigmentation Pruritus/hives Yes Thinning and loss of hair Pretibial myxedema Hyperdefecation No Hyperphagia Nutrition by G-tube feeds Hyperglycemia Dyspnea Chronic respiratory failure Emesis No Increased serum calcium Increased myoclonic With disease activity progression
Yes Yes Yes No No No Unable to assess No Yes Yes Yes No Yes No Yes Yes Not applicable No Yes
Yes Yes Yes
TABLE 2. Summary of Laboratory Values
Laboratory Test Thyroid stimulating hormone level (mU/L) Free thyroxine (T4) (ng/dL) Total T4 level (mg/dL) Triiodothyroxine (T3) (ng/dL) Thyroid hormone binding ratio Thyroperoxidase autoantibody (IU/mL) TSH receptor antibody (TBII) Thyroid stimulating immunoglobulin Thyroglobulin Thyroglobulin antibody High-density lipoprotein (mg/dL) baseline level Cholesterol (mg/dL) baseline level Alkaline phosphatase (U/L) Total/direct bilirubin (mg/dL) Calcium (mg/dL) Phosphate (mg/dL) Glucose (mg/dL) Urine ketones Parathyroid hormone (pg/mL) baseline level Cortisol (mg/dL) baseline level 25 hydroxy vitamin D (ng/mL)
Patient’s Values
Normal Range
0.211
0.4-4.2
>7.77 19.7 401 >2
