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Observation |

Is It ADEM, POLG, or Both? FREE

Mandy O. Harris, MD; Laurence E. Walsh, MD; Eyas M. Hattab, MD; Meredith R. Golomb, MD, MSc
[+] Author Affiliations

Author Affiliations: Department of Neurology, Division of Pediatric Neurology (Drs Harris, Walsh, and Golomb), and Department of Pathology and Laboratory Medicine (Dr Hattab), Indiana University School of Medicine, Indianapolis.


Arch Neurol. 2010;67(4):493-496. doi:10.1001/archneurol.2010.36.
Text Size: A A A
Published online

Objective  To describe a child with apparent brain biopsy–confirmed acute disseminated encephalomyelitis (ADEM) but genetic confirmation of compound heterozygosity for DNA mutations of the polymerase γ (POLG) gene.

Design  Case report.

Setting  Tertiary referral center.

Patient  A 4-year-old boy presented with ataxia and encephalopathy.

Results  Magnetic resonance imaging demonstrated multiple focal areas of T2 prolongation. The patient's family refused steroid treatment. His symptoms improved then progressed. Magnetic resonance imaging findings also progressed. A cerebrospinal fluid specimen revealed myelin basic protein and oligoclonal bands. A brain biopsy specimen demonstrated demyelination, suggesting progression of ADEM. However, polymerase chain reaction amplification and sequencing revealed 2 heterozygous mutations of the POLG gene, suggesting mitochondrial disease. The patient died 9 months after his initial presentation.

Conclusions  This case raises interesting questions about whether ADEM triggered severe neurologic degeneration in a patient with mitochondrial disease, whether mitochondrial disease predisposed to a pathologic immune response, or whether mitochondrial disease can mimic an autoimmune disease. Mitochondrial disease–causing mutations may help explain the poor outcome in some cases of apparent autoimmune central nervous system disease.

Figures in this Article

Improved genetic and radiographic testing techniques have blurred the borders between autoimmune and neurogenetic disease. Several patients who clinically appeared to have multiple sclerosis or variations of autoimmune demyelination but carried variants of the proteolipid protein 1 (PLP1) gene have been described in the literature. The PLP1 gene usually causes Pelizaeus-Merzbacher disease or hereditary spastic paraparesis type 2. It was unclear whether the cases were unusual presentations of a neurogenetic disease or whether the mutation induced an abnormal autoimmune response.1,2 Mouse studies of juvenile Batten disease, another neurogenetic disease, have revealed an autoimmune attack against glutamic acid decarboxylase 65; the authors speculated that the causative gene might affect glutamic acid decarboxylase 65 in a way that induces the abnormal autoimmune response.3 In Duchenne muscular dystrophy, dystrophinopathy appears to induce a secondary autoimmune response4; prednisone has become a standard part of therapy in these cases.5 We describe a patient with apparent brain biopsy–proved progressive acute disseminated encephalomyelitis (ADEM) in whom genetic testing supported mitochondrial disease due to compound heterozygous mutations in the polymerase γ (POLG) gene.

A 4-year-old boy presented with 1 week of ataxia after an otitis media infection. His birth and developmental and medical histories were unremarkable. His family history revealed only 1 relative with cerebral palsy due to hypoxia (further details not available). Initial brain magnetic resonance imaging in this case revealed multiple focal areas of T2 prolongation with gadolinium enhancement. The affected regions included the left parietal lobe, the internal capsule and head of the caudate, and the right middle cerebellar peduncle (Figure 1A). The findings were thought to be most compatible with ADEM. The family declined treatment with steroids, and the patient improved during hospitalization. After discharge, the family failed to appear for routine follow-up appointments but brought the child to the emergency department several times for worsening ataxia. Each time, they refused admission. With the help of social services, the patient was readmitted 3 months after his initial presentation.

Place holder to copy figure label and caption
Figure 1.

The findings of magnetic resonance imaging are consistent with acute disseminated encephalomyelitis (A and B) and then suggestive of aggressive tumor (C). A, Initial fluid-attenuated inversion recovery magnetic resonance imaging demonstrates involvement of the left internal capsule and caudate. B, Subsequent fluid-attenuated inversion recovery magnetic resonance imaging 3 months later demonstrates increased involvement. C, Magnetic resonance spectroscopy on the second admission demonstrates an elevated level of choline (arrow 1), a depressed level of N-acetylaspartate (arrow 2), and an elevated lactate doublet (arrow 3) in the left basal ganglia.

Graphic Jump Location

At readmission, he was somnolent and responded only to tactile stimuli, with loss of extraocular movement on the right and right arm and leg spasticity and hyperreflexia. Magnetic resonance imaging revealed enlargement of previously identified lesions and new foci of T2 prolongation in the left frontoparietal subcortical white matter, genu of the corpus callosum, genu of the right internal capsule, anterior thalamus, and bilateral cerebellar hemispheres, with extension into the bilateral cerebellar peduncles. Subacute hemorrhage was present in the left thalamus and putamen (Figure 1B). Magnetic resonance spectroscopy showed an elevated lactate level, a markedly depressed N-acetylaspartate level, and a markedly elevated choline level in the left basal ganglia, findings most compatible with an aggressive tumor such as glioblastoma multiforme (Figure 1C). However, magnetic resonance perfusion studies showed no evidence of increased perfusion in the lesions, findings more consistent with a fulminant inflammatory process such as tumefactive demyelination than with neoplasm. Biopsy of the deep left frontal lesion revealed multiple fragments of heavily gliotic white matter diffusely infiltrated by abundant foamy histiocytes, scattered lymphocytes, and occasional plasma cells (Figure 2A). A myelin stain showed remarkable loss of myelin with macrophages containing myelin particles (Figure 2B). As expected, the reactive astrocytes were intensely highlighted by glial fibrillary acidic protein (Figure 2C), and the macrophages stained for the macrophage marker CD68 (Figure 2D). No microorganisms were identified, and there was no evidence of a neoplasm. These findings were most consistent with an active demyelinating process.

Place holder to copy figure label and caption
Figure 2.

Pathologic findings of a brain biopsy are consistent with acute disseminated encephalomyelitis. A, A stereotactic biopsy specimen from the left frontal lobe shows diffuse infiltration by reactive astrocytes (arrows) and foamy macrophages (arrowheads) (hematoxylin-eosin, original magnification ×500). B, A myelin stain shows severe pallor of white matter (loss of blue-staining myelin). Note the myelin particles engulfed by macrophages (arrows) (Luxol fast blue; original magnification ×500). C, An immunostain for polyclonal glial fibrillary acidic protein (Dako, Carpinteria, California) intensely highlights reactive astrocytes (arrows), while leaving macrophages unstained (original magnification ×500). D, Conversely, the macrophage marker CD68 (Dako) positively stains macrophages (arrows). Note the perivascular aggregates of macrophages (arrowheads). Reactive astrocytes are nonreactive (original magnification ×500).

Graphic Jump Location

The patient was treated with 30 mg/kg of methylprednisolone sodium succinate (Solu-Medrol) for 5 daily doses followed by an oral prednisolone taper, with only minimal clinical improvement. His hospitalization was complicated by steroid-induced hyperglycemia and witnessed physical abuse by his mother. He was subsequently placed in state custody. He eventually required percutaneous gastrostomy tube placement for feeding and was discharged to a long-term care facility. He died 9 months after his initial presentation.

After his discharge but before his death, several of his laboratory test results returned and were reviewed. Urinary organic acids demonstrated a mild increase in vanillate levels, presumably from diet. Levels of serum amino acids, very long-chain fatty acids, and plasma carnitine were normal, as were the results of an acyl carnitine profile. The cerebrospinal fluid specimen demonstrated normal levels of protein, but the myelin basic protein level was higher than 1000 ng/mL and oligoclonal bands were present. No atypical cells were present on cytologic examination. Epstein-Barr virus, cytomegalovirus, and human herpesvirus 6 were not detected by polymerase chain reaction. The serum lactate level was slightly high at 23.4 mg/dL (reference range, 4.5-19.8 mg/dL) (to convert to millimoles per liter, multiply by 0.111); however, the cerebrospinal fluid lactate level was normal. DNA POLG sequencing revealed compound heterozygous mutations C752T (T251I) and C1760T (P587L).

DNA POLG is the nuclear-encoded polymerase that is responsible for replication of the mitochondrial genome. It consists of 2 subunits, a catalytic subunit encoded by POLG1 (now known as POLG) and an accessory subunit encoded by POLG2. POLG is located on chromosome 15q25.6 Homozygosity for the A467T mutation and compound heterozygosity for A467T in POLG are most commonly associated with autosomal recessive progressive external ophthalmoplegia, sensory ataxic neuropathy, and Alpers syndrome, which is characterized by a clinical triad of psychomotor retardation, intractable epilepsy, and liver failure in infants and young children.7 Our patient's POLG sequencing revealed compound heterozygosity at T251I and P587L. Horvath et al8 described 8 patients with this combination of mutations; all were adults, and 7 of the 8 had progressive external ophthalmoplegia. Six patients also had myopathy; 1 had ataxia; and 1 had neuropathy. One patient had only isolated myopathy. This combination of mutations was also described in 2 sisters with mitochondrial neurogastrointestinal syndrome but no leukoencephalopathy.9,10 Also, 3 families with autosomal recessive progressive external ophthalmoplegia were compound heterozygous for the T251I and the P587L gene mutations.11 Our patient had progressive ataxia, asymmetrical right ophthalmoplegia, seizures, and brain biopsy findings that were consistent with rapidly progressive demyelination, suggesting a wider phenotypic spectrum associated with POLG mutations.

Demyelinating disease—or what appears to be demyelinating disease—has been reported previously in patients carrying other mutations associated with mitochondrial disease. There is a “Leber plus” phenotype that has a radiographic appearance suggestive of multiple sclerosis12; however, most patients with multiple sclerosis do not carry Leber mitochondrial DNA mutations.13 An adult man with a multiple sclerosis–like clinical presentation, compatible radiographic imaging results, and oligoclonal bands in a cerebrospinal fluid specimen had a heterozygous S646L mutation in the optic atrophy 1 (OPA1) gene, which codes for a mitochondrial protein and is associated with autosomal dominant optic atrophy.14 Carelli and Bellan15 suggested that mitochondrial dysfunction in Leber and OPA1 mutations may induce an autoimmune response. Conversely, mitochondrial dysfunction has been proposed as a contributor to axonal degeneration in multiple sclerosis, although the initial trigger of this dysfunction remains unclear.16 Our patient's presentation, antecedent infectious prodrome, and radiographic, laboratory, and pathologic evidence were all consistent with acute autoimmune demyelinating disease, but the subsequent degenerative course was unusual for ADEM and triggered the search for mitochondrial causes. We wonder whether the underlying POLG mutation triggered an autoimmune reaction, as suggested by Carelli and Bellan15 for other mitochondrial mutations, or whether the stress of ADEM triggered severe mitochondrial dysfunction, leading to our patient's decline and death.

Which came first? Mitochondrial dysfunction or the autoimmune response? Did both occur, or can mitochondrial disease mimic autoimmune disease? Could the POLG mutation have been an incidental finding in a child with severe ADEM? Further work is needed to clarify the time line and pathogenesis in cases like these and to clarify how mitochondrial dysfunction contributes to poor outcomes in other patients who appear to have autoimmune disease.

Correspondence: Meredith R. Golomb, MD, MSc, Department of Neurology, Indiana University School of Medicine, Bldg XE, Room 040, 575 West Dr, Indianapolis, IN 46202 (mgolomb@iupui.edu).

Accepted for Publication: September 22, 2009.

Author Contributions: Drs Harris and Golomb had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Harris, Walsh, and Golomb. Acquisition of data: Harris, Hattab, and Golomb. Analysis and interpretation of data: Harris, Walsh, Hattab, and Golomb. Drafting of the manuscript: Harris, Walsh, Hattab, and Golomb. Critical revision of the manuscript for important intellectual content: Harris, Walsh, Hattab, and Golomb. Obtained funding: Golomb. Administrative, technical, and material support: Harris, Walsh, and Golomb. Study supervision: Walsh and Golomb. Pathologic interpretation: Hattab.

Financial Disclosure: None reported.

Funding/Support: Dr Golomb is supported by the National Institutes of Health National Institute of Neurological Disorders and Stroke grant K23 NS048024 and an Indiana University Research Support Funds Grant.

Additional Contributions: Mary Edwards-Brown, MD, provided discussion of radiographic findings, and Monica Barkat-Masih, MD, MBBS, provided technical support.

Warshawsky  IRudick  RAStaugaitis  SMNatowicz  MR Primary progressive multiple sclerosis as a phenotype of a PLP1 gene mutation. Ann Neurol 2005;58 (3) 470- 473
PubMed
Gorman  MPGolomb  MRWalsh  LE  et al.  Steroid-responsive neurologic relapses in a child with a proteolipid protein-1 mutation. Neurology 2007;68 (16) 1305- 1307
PubMed
Chattopadhyay  SIto  MCooper  JD  et al.  An autoantibody inhibitory to glutamic acid decarboxylase in the neurodegenerative disorder Batten disease. Hum Mol Genet 2002;11 (12) 1421- 1431
PubMed
László  AHudák  JSzabó  EVarga  L Antinuclear factor, smooth and striated muscle antibodies in Duchenne-type muscular dystrophy. Acta Paediatr Hung 1983;24 (4) 331- 336
PubMed
Moxley  RT  IIIAshwal  SPandya  S  et al. Quality Standards Subcommittee of the American Academy of Neurology; Practice Committee of the Child Neurology Society, Practice parameter: corticosteroid treatment of Duchenne dystrophy: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology 2005;64 (1) 13- 20
PubMed
Kaguni  LS DNA polymerase gamma, the mitochondrial replicase. Annu Rev Biochem 2004;73293- 320
PubMed
Harding  BNAlsanjari  NSmith  SJ  et al.  Progressive neuronal degeneration of childhood with liver disease (Alpers' disease) presenting in young adults. J Neurol Neurosurg Psychiatry 1995;58 (3) 320- 325
PubMed
Horvath  RHudson  GFerrari  G  et al.  Phenotypic spectrum associated with mutations of the mitochondrial polymerase gamma gene. Brain 2006;129 (pt 7) 1674- 1684
PubMed
Vissing  JRavn  KDanielsen  ER  et al.  Multiple mtDNA deletions with features of MNGIE. Neurology 2002;59 (6) 926- 929
PubMed
Van Goethem  GSchwartz  MLofgren  ADermaut  BVan Broeckhoven  CVissing  J Novel POLG mutations in progressive external ophthalmoplegia mimicking mitochondrial neurogastrointestinal encephalomyopathy. Eur J Hum Genet 2003;11 (7) 547- 549
PubMed
Lamantea  EZeviani  M Sequence analysis of familial PEO shows additional mutations associated with the 752C→T and 3527C→T changes in the POLG1 gene. Ann Neurol 2004;56 (3) 454- 455
PubMed
Harding  AESweeney  MGMiller  DH  et al.  Occurrence of a multiple sclerosis–like illness in women who have a Leber's hereditary optic neuropathy mitochondrial DNA mutation. Brain 1992;115 (pt 4) 979- 989
PubMed
Kellar-Wood  HRobertson  NGovan  GGCompston  DAHarding  AE Leber's hereditary optic neuropathy mitochondrial DNA mutations in multiple sclerosis. Ann Neurol 1994;36 (1) 109- 112
PubMed
Verny  CLoiseau  DScherer  C  et al.  Multiple sclerosis–like disorder in OPA1-related autosomal dominant optic atrophy. Neurology 2008;70 (13, pt 2) 1152- 1153
PubMed
Carelli  VBellan  M Myelin, mitochondria, and autoimmunity: what's the connection? Neurology 2008;70 (13, pt 2) 1075- 1076
PubMed
Dutta  R McDonough  JYin  X  et al.  Mitochondrial dysfunction as a cause of axonal degeneration in multiple sclerosis patients. Ann Neurol 2006;59 (3) 478- 489
PubMed

Figures

Place holder to copy figure label and caption
Figure 1.

The findings of magnetic resonance imaging are consistent with acute disseminated encephalomyelitis (A and B) and then suggestive of aggressive tumor (C). A, Initial fluid-attenuated inversion recovery magnetic resonance imaging demonstrates involvement of the left internal capsule and caudate. B, Subsequent fluid-attenuated inversion recovery magnetic resonance imaging 3 months later demonstrates increased involvement. C, Magnetic resonance spectroscopy on the second admission demonstrates an elevated level of choline (arrow 1), a depressed level of N-acetylaspartate (arrow 2), and an elevated lactate doublet (arrow 3) in the left basal ganglia.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Pathologic findings of a brain biopsy are consistent with acute disseminated encephalomyelitis. A, A stereotactic biopsy specimen from the left frontal lobe shows diffuse infiltration by reactive astrocytes (arrows) and foamy macrophages (arrowheads) (hematoxylin-eosin, original magnification ×500). B, A myelin stain shows severe pallor of white matter (loss of blue-staining myelin). Note the myelin particles engulfed by macrophages (arrows) (Luxol fast blue; original magnification ×500). C, An immunostain for polyclonal glial fibrillary acidic protein (Dako, Carpinteria, California) intensely highlights reactive astrocytes (arrows), while leaving macrophages unstained (original magnification ×500). D, Conversely, the macrophage marker CD68 (Dako) positively stains macrophages (arrows). Note the perivascular aggregates of macrophages (arrowheads). Reactive astrocytes are nonreactive (original magnification ×500).

Graphic Jump Location

Tables

References

Warshawsky  IRudick  RAStaugaitis  SMNatowicz  MR Primary progressive multiple sclerosis as a phenotype of a PLP1 gene mutation. Ann Neurol 2005;58 (3) 470- 473
PubMed
Gorman  MPGolomb  MRWalsh  LE  et al.  Steroid-responsive neurologic relapses in a child with a proteolipid protein-1 mutation. Neurology 2007;68 (16) 1305- 1307
PubMed
Chattopadhyay  SIto  MCooper  JD  et al.  An autoantibody inhibitory to glutamic acid decarboxylase in the neurodegenerative disorder Batten disease. Hum Mol Genet 2002;11 (12) 1421- 1431
PubMed
László  AHudák  JSzabó  EVarga  L Antinuclear factor, smooth and striated muscle antibodies in Duchenne-type muscular dystrophy. Acta Paediatr Hung 1983;24 (4) 331- 336
PubMed
Moxley  RT  IIIAshwal  SPandya  S  et al. Quality Standards Subcommittee of the American Academy of Neurology; Practice Committee of the Child Neurology Society, Practice parameter: corticosteroid treatment of Duchenne dystrophy: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology 2005;64 (1) 13- 20
PubMed
Kaguni  LS DNA polymerase gamma, the mitochondrial replicase. Annu Rev Biochem 2004;73293- 320
PubMed
Harding  BNAlsanjari  NSmith  SJ  et al.  Progressive neuronal degeneration of childhood with liver disease (Alpers' disease) presenting in young adults. J Neurol Neurosurg Psychiatry 1995;58 (3) 320- 325
PubMed
Horvath  RHudson  GFerrari  G  et al.  Phenotypic spectrum associated with mutations of the mitochondrial polymerase gamma gene. Brain 2006;129 (pt 7) 1674- 1684
PubMed
Vissing  JRavn  KDanielsen  ER  et al.  Multiple mtDNA deletions with features of MNGIE. Neurology 2002;59 (6) 926- 929
PubMed
Van Goethem  GSchwartz  MLofgren  ADermaut  BVan Broeckhoven  CVissing  J Novel POLG mutations in progressive external ophthalmoplegia mimicking mitochondrial neurogastrointestinal encephalomyopathy. Eur J Hum Genet 2003;11 (7) 547- 549
PubMed
Lamantea  EZeviani  M Sequence analysis of familial PEO shows additional mutations associated with the 752C→T and 3527C→T changes in the POLG1 gene. Ann Neurol 2004;56 (3) 454- 455
PubMed
Harding  AESweeney  MGMiller  DH  et al.  Occurrence of a multiple sclerosis–like illness in women who have a Leber's hereditary optic neuropathy mitochondrial DNA mutation. Brain 1992;115 (pt 4) 979- 989
PubMed
Kellar-Wood  HRobertson  NGovan  GGCompston  DAHarding  AE Leber's hereditary optic neuropathy mitochondrial DNA mutations in multiple sclerosis. Ann Neurol 1994;36 (1) 109- 112
PubMed
Verny  CLoiseau  DScherer  C  et al.  Multiple sclerosis–like disorder in OPA1-related autosomal dominant optic atrophy. Neurology 2008;70 (13, pt 2) 1152- 1153
PubMed
Carelli  VBellan  M Myelin, mitochondria, and autoimmunity: what's the connection? Neurology 2008;70 (13, pt 2) 1075- 1076
PubMed
Dutta  R McDonough  JYin  X  et al.  Mitochondrial dysfunction as a cause of axonal degeneration in multiple sclerosis patients. Ann Neurol 2006;59 (3) 478- 489
PubMed

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