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Original Contribution |

Novel Infantile-Onset Leukoencephalopathy With High Lactate Level and Slow Improvement FREE

Marjan E. Steenweg, MD; Adeline Vanderver, MD, PhD; Berten Ceulemans, MD, PhD; Prab Prabhakar, FRCPCH; Luc Régal, MD, PhD; Aviva Fattal-Valevski, MD; Lawrence Richer, MD, MSc; Barbara Goeggel Simonetti, MD; Frederik Barkhof, MD, PhD; Richard J. T. Rodenburg, MD, PhD; Petra J. W. Pouwels, PhD; Marjo S. van der Knaap, MD, PhD
[+] Author Affiliations

Author Affiliations: Departments of Child Neurology (Drs Steenweg and van der Knaap), Radiology (Dr Barkhof), and Physics and Medical Technology (Dr Pouwels), VU University Medical Center, Amsterdam, and Department of Pediatrics, Radboud University Nijmegen Medical Center, Nijmegen (Dr Rodenburg), the Netherlands; Department of Neurology, Children's National Medical Center, Washington, DC (Dr Vanderver); Department of Child Neurology, University Medical Center Antwerp, Antwerp (Dr Ceulemans), and Department of Pediatrics, University Hospitals Leuven, Leuven (Dr Régal), Belgium; Department of Neurology, Great Ormond Street Hospital for Children, London, England (Dr Prabhakar); Department of Paediatric Neurology, “Dana” Children's Hospital, Tel Aviv-Sourasky Medical Center, Tel Aviv, Israel (Dr Fattal-Valevski); Department of Pediatrics, Division of Neurology, University of Alberta, Edmonton, Alberta, Canada (Dr Richer); and Department of Paediatric Neurology, Children's University Hospital Inselspital, Berne, Switzerland (Dr Goeggel Simonetti).


Arch Neurol. 2012;69(6):718-722. doi:10.1001/archneurol.2011.1048.
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Objective To describe a novel pattern of magnetic resonance imaging (MRI) abnormalities as well as the associated clinical and laboratory findings.

Design The MRIs of more than 3000 patients with an unclassified leukoencephalopathy were systematically reviewed. Clinical and laboratory data were retrospectively collected.

Setting University hospital.

Patients Seven patients (3 male) shared similar MRI abnormalities and clinical features.

Main Outcome Measures Pattern of MRI abnormalities and clinical and laboratory findings.

Results The MRIs showed signal abnormalities of the deep cerebral white matter, corpus callosum, thalamus, basal ganglia, brainstem, and cerebellar white matter between the ages of 9 months and 2 years. On follow-up, abnormalities gradually improved. Clinical regression occurred in the second half-year of life with spasticity and loss of milestones. From the second year on, clinical improvement occurred. So far, no second episode of regression has happened. Lactate levels were elevated during clinical regression.

Conclusion These patients represent a single novel leukoencephalopathy, probably caused by a mitochondrial defect.

Figures in this Article

Childhood white matter disorders constitute a vexing problem, because causes are numerous and clinical signs are generally not discriminative. During the last 2 decades, multiple novel leukoencephalopathies have been identified.1 A considerable proportion of the patients, however, still remain without a specific diagnosis.2

Individual leukoencephalopathies usually present with distinct and homogeneous patterns of magnetic resonance imaging (MRI) abnormalities, facilitating the diagnosis.3 In our search for novel disorders among the unclassified leukoencephalopathies, we use MRI pattern recognition as a primary tool. Patients sharing a distinct MRI pattern and clinical features are thought to have the same disease. Identification of associated genes has confirmed the validity of this approach.49 Herein, we present 7 children with a novel pattern of MRI abnormalities and their clinical and laboratory findings.

The MRIs of more than 3000 patients are part of our ongoing study on unclassified leukoencephalopathies. All MRIs were obtained for regular patient care. The study received institutional review board approval with waiver of informed consent. The MRIs included at least T1- and T2-weighted images; fluid-attenuated inversion recovery and diffusion-weighted images were available for some cases (eTable 1). The MRIs were assessed according to standard protocol.10 Evaluated items included presence, location, and appearance of white and gray matter lesions and stage of myelination. To minimize the effects of subjective rating, all items were only scored as present or absent.

Seven unrelated patients shared a distinct MRI pattern, dissimilar from known patterns.3 They had 18 MRIs (ages in eTable 1). Patient 1 underwent proton magnetic resonance spectroscopy 3 times (ages in eTable 2). Metabolite concentrations were calculated using LCModel11 and compared with age-matched control values.12 Clinical and laboratory data were obtained.

EARLY MRI ABNORMALITIES

One MRI obtained in a patient at 2 months of age revealed no abnormalities. The MRIs made between the ages of 8 and 18 months showed confluent, symmetrical cerebral white matter abnormalities, predominantly affecting the deep white matter and corpus callosum. These structures had prominently increased signal on T2-weighted images and prominently decreased signal on T1-weighted images, indicating a lesion. Strikingly, a rim of periventricular white matter was preserved. The subcortical white matter had mildly elevated T2 as well as T1 signal, indicating lack of myelin deposition rather than a lesion (Figure 1A). Rarefaction of the affected cerebral white matter was seen in 1 patient. The posterior limb of the internal capsule was affected in 1 patient. The thalamus was affected in all patients (Figure 1B). The anterior part of the putamen, globus pallidus, and head of the caudate nucleus were mildly T2 hyperintense in all patients (Figure 1B) and in 3, this was in combination with focal lesions with a more prominent T2 hyperintensity. Infratentorially, the midbrain (n = 6), dorsal part of the pons (n = 5), medulla oblongata (n = 6), and peridentate cerebellar white matter (n = 5) (Figure 1C and D) had high T2 and low T1 signal. No cerebral or cerebellar atrophy was seen. Restricted diffusion was observed, especially in the borders of the white matter lesions, corpus callosum, and brainstem (Figure 1E and F).

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Figure 1. Magnetic resonance imaging of patient 6. At age 11 months, T2 signal abnormalities are present in the deep cerebral white matter, thalamus, basal ganglia, brainstem, and cerebellar white matter (A-D). Restricted diffusion is indicated by high signal on diffusion-weighted images (E) and low signal on apparent diffusion coefficient maps (F). At age 3 years (G-I), the abnormalities have improved substantially.

EVOLUTION OF MRI ABNORMALITIES

Around age 2 years, patients still had abnormalities of the deep cerebral white matter, thalamus, and brainstem (Figure 2A-C). The cerebellar signal alterations had improved. The degree of white matter involvement was variable. Three patients had some rarefaction.

Place holder to copy figure label and caption
Graphic Jump Location

Figure 2. Axial T2-weighted images of patient 1. At age 2 years (A-C), abnormalities are seen in the deep cerebral white matter, thalamus, and brainstem. At age 10 years (D-F), the abnormalities have improved. Mild T2 hyperintensity of the putamen and caudate nucleus persists.

After the age of 2 years, improvement of the cerebral white matter, brainstem, and thalamic lesions occurred (Figure 1G-I and Figure 2D-F). No new abnormalities developed. The basal ganglia lesions disappeared, but the mild T2 hyperintensity of the anterior part of the putamen, globus pallidus, and head of the caudate nucleus persisted (Figure 1H and Figure 2E). The mild T2 hyperintensity of the subcortical white matter faded, indicating further myelin deposition, but complete T2 hypointensity was not reached. There was mild white matter volume loss (Figure 1G-I and Figure 2D-F. Restricted diffusion disappeared.

Proton magnetic resonance spectroscopy at age 2 years showed elevated lactate levels in the affected white matter, which normalized on follow-up (Figure 3) (quantitative details for white matter and the basal ganglia in eTable 2).

Place holder to copy figure label and caption
Graphic Jump Location

Figure 3. Short echo time proton spectroscopy of the deep parietal white matter in patient 1. At age 2 years (A), an elevated lactate (Lac) level is seen; the N-acetylaspartate (NAA) level is decreased. At age 10 years (B), lactate is not detectable. The NAA and choline-containing (Cho) compounds are marginally decreased. The myoinositol (Ins) level is increased. Cre indicates creatine.

CLINICAL FINDINGS

Clinical characteristics and ages at last examination are summarized in eTable 1. Two patients presented soon after birth with feeding difficulties and failure to thrive. Five patients had delayed early development; development was initially normal in 2. All patients regressed in the second half-year of life, with loss of developmental milestones (n = 3), irritability (n = 2), axial hypotonia (n = 6), limb spasticity (n = 7), and feeding difficulties (n = 3). In 2 patients, provoking factors were noticed: gastrointestinal illness and vaccination. At age 1 year, spasticity, especially of the legs, was the central feature. Muscle tone started to improve in the second year of life. All patients still displayed variable signs of spasticity at their latest examination (ages 1.3-10 years) (eTable 1) but much less than before. Four patients could walk without support and run (ages 3.3, 3.5, 5, and 9 years); 2 required support (ages 2.5 and 10 years). The youngest patient started to stand with support at the latest examination at 1.3 years of age. Initial language development was delayed in all patients except for 1 patient, who had normal language and lost it at disease onset. At the latest examination, 3 patients (ages 5, 9, and 10 years) could speak in simple sentences, 2 patients (ages 2.5 and 3.5 years) used single words, and 2 patients (ages 1.3 and 3.3 years) were nonverbal. Receptive language skills were better than expressive skills. None of the patients experienced further episodes of regression.

Less consistent neurological signs were mild cerebellar ataxia (n = 3), dystonia (n = 1), and seizures (n = 2). The patients had no signs of dysfunction of other organs than the central nervous system. They had no signs of dysmorphism.

LABORATORY FINDINGS

Lactate levels in blood (n = 6) and cerebrospinal fluid (n = 5) were elevated during regression (3.1-8.6 mmol/L and 2.4-3.7 mmol/L, respectively). Follow-up measurements in blood (n = 4) showed a decrease to normal values in 2 patients at ages 1.3 and 2.2 years and a steady elevation in the other 2 at ages 2.9 and 1.7 years. Cerebrospinal fluid lactate levels were not assessed again.

Respiratory chain enzyme activities in muscle (n = 5), fibroblasts (b = 2), and the liver (n = 1) were normal. Lysosomal enzyme activities in leukocytes, especially arylsulfatase A (n = 3) and galactocerebrosidase (n = 3), were normal. Acylcarnitine profile results (n = 5) and amino acid (plasma, n = 6; urine, n = 1), urinary organic acid (n = 7), and very-long-chain fatty acid (n = 4) levels were normal. Transferrin isoelectric focusing for congenital defects in glycosylation was normal (n = 2). Chromosome analysis revealed no abnormalities (conventional technique, n = 2; high-resolution technique, n = 1). Sequencing of mitochondrial DNA (screening for deletions and duplications as well as analysis of the known genes, n = 7; analysis of the entire mitochondrial genome [human mitochondrial resequencing array; Affymetrix], n = 2) and nuclear genes encoding mitochondrial proteins (ie, PDSS1, SCO1, SCO2, COX10, SURF1, PDHA1, TYMP, POLG1, and SUCLA2 [n = 2]) did not reveal mutations.

We present 7 patients with a similar pattern of MRI abnormalities. The most striking abnormalities were seen between the ages of 9 months and 2 years and consisted of selective involvement of the deep cerebral white matter, thalamus, and brainstem, especially the midbrain. An MRI at 2 months of age was normal in 1 patient, suggesting that the abnormalities arose in the first year of life. After 2 years of age, MRI abnormalities improved and no new lesions were seen.

The clinical features are in line with the MRI abnormalities. Characteristically, there is a regression in the second half-year of life with loss of developmental milestones and progressive spasticity, often preceded by delayed early development. Gradual clinical improvement starts in the second year of life. So far, no second episode of regression has occurred.

The MRI abnormalities are reminiscent of those seen in Kearns-Sayre syndrome. Kearns-Sayre syndrome, a mitochondrial disorder caused by deletions in the mitochondrial DNA,3,13 also shows abnormalities of the cerebral white matter with sparing of a periventricular rim and abnormalities of the basal ganglia, thalamus, and brainstem. Kearns-Sayre syndrome, however, preferentially affects subcortical instead of deep cerebral white matter and MRI abnormalities increase over time. Kearns-Sayre syndrome was excluded in our patients by mitochondrial DNA analysis.

Rapid neurological regression around age 1 year, the MRI pattern, and the elevated lactate level are suggestive of a mitochondrial defect. The fact that analysis of respiratory chain function did not reveal abnormalities does not exclude a mitochondrial disorder. In leukoencephalopathy with brainstem and spinal cord involvement and elevated lactate level and in a subset of patients with neuropathy, ataxia, and retinitis pigmentosa syndrome, no abnormalities of respiratory chain activities in muscle are seen, although both are known mitochondrial disorders.8,14,15

Although the patients described herein are sporadic cases from unrelated families and there is no known consanguinity between the parents, the disorder is probably genetic. We have initiated studies to identify the related gene.

Correspondence: Marjo S. van der Knaap, MD, PhD, Department of Child Neurology, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, the Netherlands (ms.vanderknaap@vumc.nl).

Accepted for Publication: July 21, 2011.

Published Online: February 6, 2012. doi:10.1001/archneurol.2011.1048

Author Contributions: Dr Steenweg had access to all the data. Dr van der Knaap was the principal investigator and had full access to all the data and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study and concept design: van der Knaap. Acquisition of data: Steenweg, Vanderver, Ceulemans, Prabhakar, Régal, Fattal-Valaveski, Richer, Goeggel Simonetti, Barkhof, Rodenburg, Pouwels, and van der Knaap. Analysis and interpretation of data: Steenweg, Vanderver, Régal, Fattal-Valevski, Barkhof, Rodenburg, Pouwels, and van der Knaap. Drafting of the manuscript: Steenweg, Prabhakar, Régal, Richer, and van der Knaap. Critical revision of the manuscript for important intellectual content: Vanderver, Ceulemans, Prabhakar, Régal, Fattal-Valaveski, Goeggel Simonetti, Barkhof, Rodenburg, Pouwels, and van der Knaap. Administrative, technical, and material support: Vanderver, Prabhakar, Régal, Goeggel Simonetti, Barkhof, and Rodenburg. Study supervision: Régal and van der Knaap.

Financial Disclosure: None reported.

Funding/Support: The study received financial support from the Dutch Organization for Scientific Research (ZonMw TOP grant 9120.6002) and the Optimix Foundation for Scientific Research.

Additional Contributions: We thank the patients, families, and colleagues for their cooperation.

Schiffmann R, van der Knaap MS. The latest on leukodystrophies.  Curr Opin Neurol. 2004;17(2):187-192
PubMed   |  Link to Article
Schiffmann R, van der Knaap MS. Invited article: an MRI-based approach to the diagnosis of white matter disorders.  Neurology. 2009;72(8):750-759
PubMed
van der Knaap MS, Valk J. Magnetic Resonance of Myelination and Myelin Disorders. 3rd ed. Heidelberg, Germany: Springer; 2005
Zara F, Biancheri R, Bruno C,  et al.  Deficiency of hyccin, a newly identified membrane protein, causes hypomyelination and congenital cataract.  Nat Genet. 2006;38(10):1111-1113
PubMed
Inoue K, Tanabe Y, Lupski JR. Myelin deficiencies in both the central and the peripheral nervous systems associated with a SOX10 mutation.  Ann Neurol. 1999;46(3):313-318
PubMed
Leegwater PA, Vermeulen G, Könst AA,  et al.  Subunits of the translation initiation factor eIF2B are mutant in leukoencephalopathy with vanishing white matter.  Nat Genet. 2001;29(4):383-388
PubMed
Leegwater PA, Yuan BQ, van der Steen J,  et al.  Mutations of MLC1 (KIAA0027), encoding a putative membrane protein, cause megalencephalic leukoencephalopathy with subcortical cysts.  Am J Hum Genet. 2001;68(4):831-838
PubMed
Scheper GC, van der Klok T, van Andel RJ,  et al.  Mitochondrial aspartyl-tRNA synthetase deficiency causes leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation.  Nat Genet. 2007;39(4):534-539
PubMed
Henneke M, Diekmann S, Ohlenbusch A,  et al.  RNASET2-deficient cystic leukoencephalopathy resembles congenital cytomegalovirus brain infection.  Nat Genet. 2009;41(7):773-775
PubMed
van der Knaap MS, Breiter SN, Naidu S, Hart AA, Valk J. Defining and categorizing leukoencephalopathies of unknown origin: MR imaging approach.  Radiology. 1999;213(1):121-133
PubMed
Provencher SW. Estimation of metabolite concentrations from localized in vivo proton NMR spectra.  Magn Reson Med. 1993;30(6):672-679
PubMed
Pouwels PJW, Brockmann K, Kruse B,  et al.  Regional age dependence of human brain metabolites from infancy to adulthood as detected by quantitative localized proton MRS.  Pediatr Res. 1999;46(4):474-485
PubMed
Chu BC, Terae S, Takahashi C,  et al.  MRI of the brain in the Kearns-Sayre syndrome: report of four cases and a review.  Neuroradiology. 1999;41(10):759-764
PubMed
van der Knaap MS, van der Voorn P, Barkhof F,  et al.  A new leukoencephalopathy with brainstem and spinal cord involvement and high lactate.  Ann Neurol. 2003;53(2):252-258
PubMed
Cortés-Hernández P, Vázquez-Memije ME, García JJ. ATP6 homoplasmic mutations inhibit and destabilize the human F1F0-ATP synthase without preventing enzyme assembly and oligomerization.  J Biol Chem. 2007;282(2):1051-1058
PubMed

Figures

Place holder to copy figure label and caption
Graphic Jump Location

Figure 1. Magnetic resonance imaging of patient 6. At age 11 months, T2 signal abnormalities are present in the deep cerebral white matter, thalamus, basal ganglia, brainstem, and cerebellar white matter (A-D). Restricted diffusion is indicated by high signal on diffusion-weighted images (E) and low signal on apparent diffusion coefficient maps (F). At age 3 years (G-I), the abnormalities have improved substantially.

Place holder to copy figure label and caption
Graphic Jump Location

Figure 2. Axial T2-weighted images of patient 1. At age 2 years (A-C), abnormalities are seen in the deep cerebral white matter, thalamus, and brainstem. At age 10 years (D-F), the abnormalities have improved. Mild T2 hyperintensity of the putamen and caudate nucleus persists.

Place holder to copy figure label and caption
Graphic Jump Location

Figure 3. Short echo time proton spectroscopy of the deep parietal white matter in patient 1. At age 2 years (A), an elevated lactate (Lac) level is seen; the N-acetylaspartate (NAA) level is decreased. At age 10 years (B), lactate is not detectable. The NAA and choline-containing (Cho) compounds are marginally decreased. The myoinositol (Ins) level is increased. Cre indicates creatine.

Tables

References

Schiffmann R, van der Knaap MS. The latest on leukodystrophies.  Curr Opin Neurol. 2004;17(2):187-192
PubMed   |  Link to Article
Schiffmann R, van der Knaap MS. Invited article: an MRI-based approach to the diagnosis of white matter disorders.  Neurology. 2009;72(8):750-759
PubMed
van der Knaap MS, Valk J. Magnetic Resonance of Myelination and Myelin Disorders. 3rd ed. Heidelberg, Germany: Springer; 2005
Zara F, Biancheri R, Bruno C,  et al.  Deficiency of hyccin, a newly identified membrane protein, causes hypomyelination and congenital cataract.  Nat Genet. 2006;38(10):1111-1113
PubMed
Inoue K, Tanabe Y, Lupski JR. Myelin deficiencies in both the central and the peripheral nervous systems associated with a SOX10 mutation.  Ann Neurol. 1999;46(3):313-318
PubMed
Leegwater PA, Vermeulen G, Könst AA,  et al.  Subunits of the translation initiation factor eIF2B are mutant in leukoencephalopathy with vanishing white matter.  Nat Genet. 2001;29(4):383-388
PubMed
Leegwater PA, Yuan BQ, van der Steen J,  et al.  Mutations of MLC1 (KIAA0027), encoding a putative membrane protein, cause megalencephalic leukoencephalopathy with subcortical cysts.  Am J Hum Genet. 2001;68(4):831-838
PubMed
Scheper GC, van der Klok T, van Andel RJ,  et al.  Mitochondrial aspartyl-tRNA synthetase deficiency causes leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation.  Nat Genet. 2007;39(4):534-539
PubMed
Henneke M, Diekmann S, Ohlenbusch A,  et al.  RNASET2-deficient cystic leukoencephalopathy resembles congenital cytomegalovirus brain infection.  Nat Genet. 2009;41(7):773-775
PubMed
van der Knaap MS, Breiter SN, Naidu S, Hart AA, Valk J. Defining and categorizing leukoencephalopathies of unknown origin: MR imaging approach.  Radiology. 1999;213(1):121-133
PubMed
Provencher SW. Estimation of metabolite concentrations from localized in vivo proton NMR spectra.  Magn Reson Med. 1993;30(6):672-679
PubMed
Pouwels PJW, Brockmann K, Kruse B,  et al.  Regional age dependence of human brain metabolites from infancy to adulthood as detected by quantitative localized proton MRS.  Pediatr Res. 1999;46(4):474-485
PubMed
Chu BC, Terae S, Takahashi C,  et al.  MRI of the brain in the Kearns-Sayre syndrome: report of four cases and a review.  Neuroradiology. 1999;41(10):759-764
PubMed
van der Knaap MS, van der Voorn P, Barkhof F,  et al.  A new leukoencephalopathy with brainstem and spinal cord involvement and high lactate.  Ann Neurol. 2003;53(2):252-258
PubMed
Cortés-Hernández P, Vázquez-Memije ME, García JJ. ATP6 homoplasmic mutations inhibit and destabilize the human F1F0-ATP synthase without preventing enzyme assembly and oligomerization.  J Biol Chem. 2007;282(2):1051-1058
PubMed

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