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MRI of Five Patients with Mitochondrial Neurogastrointestinal Encephalomyopathy

¹ Department of Radiology, New York Presbyterian Hospital, Columbia-Presbyterian Center, 177 Fort Washington Ave., Milstein Hospital Bldg., Rm. 3-105, New York, NY 10032.
² Department of Radiology, College of Physicians and Surgeons, Columbia University in the City of New York, New York, NY 10032.
³ Department of Neurology, College of Physicians and Surgeons, Columbia University in the City of New York, 630 W 168th St., P&S 4-443, New York, NY 10032.

Received April 15, 2003; accepted after revision December 3, 2003.

 
Presented at the 2002 annual meeting of the American Roentgen Ray Society, Atlanta, GA.

Address correspondence to W. S. Millar (wsm8{at}columbia.edu).

Abstract

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OBJECTIVE. The purpose of this study was to retrospectively review MR images of the brain in five patients diagnosed with mitochondrial neurogastrointestinal encephalomyopathy.

CONCLUSION. Our research supports previously reported findings of confluent abnormal cerebral white matter in patients with mitochondrial neurogastrointestinal encephalomyopathy. In contrast to prior studies, our cohort of five patients showed that involvement of the corpus callosum as well as the capsular white matter, basal ganglia, thalami, midbrain, pons, and cerebellar white matter is not rare and does not preclude the diagnosis of mitochondrial neurogastrointestinal encephalomyopathy.

Introduction

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Defects in the mitochondrial respiratory chain produce a diverse group of disorders referred to as mitochondrial encephalomyopathies. Enzymatic defects of the respiratory chain may be the product of mutant mitochondrial DNA (mtDNA), defective nuclear DNA (nDNA), or an abnormality of the interrelationship between these two different genomes [1, 2]. Mitochondrial encephalomyopathy with lactic acidosis and strokelike episodes is a primary mitochondrial disorder commonly caused by the A3243G mtDNA point mutation. Conversely, mutations in the nDNA gene can lead to secondary mitochondrial respiratory chain deficiencies; for example, a mutation of the gene encoding the flavoprotein subunit of the succinate dehydrogenase gene causes complex II deficiency manifesting as Leigh disease [3]. Exemplifying the third situation, mutations in the nDNA gene encoding the enzyme thymidine phosphorylase located on chromosome 22q13.32-qter lead to an accumulation of cytoplasmic thymidine (Fig. 1), which is salvaged in mitochondria [2, 4]. The abnormal metabolism of thymidine and deoxyuridine [5] is thought to produce mtDNA abnormalities, which lead to mitochondrial neurogastrointestinal encephalomyopathy.

View larger version (26K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 1. —Schematic drawing of mitochondrial thymidine metabolism. Loss of thymidine phosphorylase (TP) leads to increased levels of plasma thymidine and deoxyuridine, which is hypothesized to alter mitochondrial deoxynucleotide pools leading to mitochondrial DNA (mtDNA) abnormalities. TK2 = thymidine kinase, dNT2 = deoxynucleotidase, TMP = thymidine monophosphate, TTP = thymidine triphosphate.

Mitochondrial neurogastrointestinal encephalomyopathy is a rare autosomal recessive disease associated with multiple deletions and partial depletion of mtDNA in skeletal muscle [1]. Muscle biopsy usually reveals ragged-red and cytochrome c oxidase fibers, which are typical histologic findings seen in mitochondrial disorders [4]. In one study of 35 cases [1], the average patient became symptomatic in the second decade of life (average age, 18.5 years) and the average age of death was 35 years. Gastrointestinal manifestations are debilitating and include dysmotility, diarrhea, borborygmi, abdominal cramps, early satiety, nausea, vomiting, intestinal pseudoobstruction, and gastroparesis. The neurologic manifestations are usually less debilitating and include peripheral neuropathy, ptosis, ophthalmoparesis, and hearing loss [1]. Diffuse leukoencephalopathy is reported in all patients. Despite this leukoencephalopathy, dementia is not detected clinically and mental retardation is rare.

In our study, we investigated the incidence and severity of involvement of brain anatomic structures using MR images in five patients with mitochondrial neurogastrointestinal encephalomyopathy.

Materials and Methods

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We reviewed the clinical records and brain MR images of five patients with mitochondrial neurogastrointestinal encephalomyopathy who were referred to our institution for genetic evaluation. All clinical data were collected, evaluated, and summarized by a board-certified neurologist. The diagnosis of mitochondrial neurogastrointestinal encephalomyopathy was confirmed in all five patients by the identification of thymidine phosphorylase mutations, very low or absent thymidine phosphorylase enzyme activity in buffy coat, and, in four patients tested, elevated plasma thymidine levels.

All MRI was performed on 1.5-T units (Signa, General Electric Medical Systems [in the first four patients]; Magnetom Vision, Siemens [in the fifth patient]). MRI was performed between 1995 and 2002: Three examinations were at our institution; two were elsewhere. The sequences included four axial FLAIR images (TR range/TE range, 10,002–9,000/161–110; inversion time, 2,500–2,200 msec; excitations, 2–0.5) and one axial spin-echo T2-weighted image (TR/TE, 2,200/90; excitation, 1). FLAIR images were not available for the first patient. Section thickness was uniformly 5 mm; intersection gap varied (1–2.5 mm) across institutions. Intersection gap was 1 mm for the three patients at our institution; for the two patients from outside institutions, the intersection gap was 2.0 mm for one and 2.5 mm for the other.

Two board-certified radiologists who were unaware of the clinical records retrospectively reviewed the MR images. We scored the incidence and the severity of involvement of the cerebral and cerebellar white matter, corpus callosum, basal ganglia (caudate head, putamen, and globus pallidus), thalami, white matter capsules, midbrain, and pons. An incidence score (1, present; 0, absent) and a severity score (4, severe; 3, moderate; 2, mild; 1, minimal; 0, no involvement) were used. Anatomic structures were rated as 4 (severely involved), when the entire or most (> 90%) of the structure's visualized surface area was estimated to show abnormally increased signal intensity; 3 (moderately involved), when structures showed 50–90% involvement; 2 (mildly involved), when abnormally increased signal intensity affected 10–49 % of the structure; 1 (minimally involved), when abnormal signal intensity affected less than 10% of the structure; and 0 (no involvement). Each anatomic structure was rated using its most dominant slice; adjoining slices were used as tiebreakers. Involvement of the rated anatomic structures was bilaterally symmetric; therefore, a single incidence and severity score was used for each bihemispheric structure. When rating separate bilaterally symmetric structures, we used the more extensively involved side. The subcortical U-fibers were considered to be involved when increased signal intensity directly reached the inner cortex. Images were independently reviewed and scored by each radiologist. Scoring differences were resolved by subsequent interrater consensus. A total lesion incidence score and a total lesion severity score were calculated as the sum of the scores for each patient. This retrospective review was performed under a protocol approved by the university's institutional review board.

Results

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Our cohort of five patients with mitochondrial neurogastrointestinal encephalopathy included four men and one woman who were 34–46 years old (mean age, 38.6 years) at the time of MRI. The woman was 39 years old. All five patients had ptosis, ophthalmoparesis, and peripheral neuropathy. Four of the five patients had severe gastrointestinal dysmotility with recurrent diarrhea; the remaining patient had intermittent abdominal pain. Thymidine phosphorylase mutations were present in all five patients: two had a homozygous G1419A transition, two had a homozygous T2294A mutation, and one had compound heterozygous mutations (A3371C and G3867C). Thymidine phosphorylase activity was abnormally low in all five patients and ranged from 0 to 43 nmol/hr per milligram of protein. Normal buffy coat thymidine phosphorylase activity is (mean ± standard deviation) 667 ± 212 nmol/hr per milligram of protein (n = 19). Plasma thymidine levels varied from a maximum of 10.4–13.1 to 5.5 µ mol in the four patients tested. Normal plasma thymidine is undetectable (< 0.05 µ mol). No plasma was available from the 34-year-old man who had a homozygous G1419A transition.

The incidence and severity of involvement for the evaluated anatomic structures were recorded and calculated after scoring each patient's MR images. All patients (5/5) showed severe involvement (mean severity score, 4.0) of the centrum semiovale white matter, as revealed on the FLAIR images from the 35-year-old and 39-year-old men (Figs. 2A, 2B, 2C and 3A, 3B). Although all five patients also showed some minimal occasional subcortical U-fiber involvement, usually at the convexities, the subcortical U-fibers were generally spared. The caudate heads and the thalami were involved in most patients (3/5), with mean severity scores of 1.6 and 1.2, respectively, as shown in the 39-year-old man and the 39-year-old woman (Figs. 3A, 3B and 4A, 4B). The putamina were less often involved (2/5) with mean severity scores of 1.2 and 1.0. Involvement of the splenium (mean severity score, 1.8) of the corpus callosum was noted in almost all patients (4/5), as seen in the 35-year-old and 46-year-old men (Figs. 2A, 2B, 2C and 5A, 5B, 5C), but the intensity and extent of involvement were not as severe as those of the centrum semiovale. The genu of the corpus callosum was less often involved (3/5) with a slightly lower mean severity score (1.0). The white matter tracts of the internal capsule were always involved (5/5), with mean severity scores of 2.2 for these structures. The external capsules were severely involved in the 39-year-old woman and the 46-year-old man but were otherwise uninvolved in the other three patients.

View larger version (144K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 2A. —MR images of mitochondrial neurogastrointestinal encephalomyopathy in 35-year-old man. Axial FLAIR image (TR/TE, 9,002/157; inversion time, 2,200 msec) shows confluent abnormally increased signal intensity in centrum semiovale (severity score, 4). Note sparing of subcortical U-fibers.

View larger version (148K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 2B. —MR images of mitochondrial neurogastrointestinal encephalomyopathy in 35-year-old man. Axial FLAIR image (9,002/157; inversion time, 2,200 msec) shows abnormally increased signal intensity in midline corpus callosum (splenium) and internal capsules near thalami bilaterally with severity scores of 3 and 2, respectively.

View larger version (128K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 2C. —MR images of mitochondrial neurogastrointestinal encephalomyopathy in 35-year-old man. Axial FLAIR image (9,002/157; inversion time, 2,200 msec) shows abnormally increased signal intensity in cerebellar white matter bilaterally (severity score, 2).

View larger version (159K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 3A. —MR images of mitochondrial neurogastrointestinal encephalomyopathy in 39-year-old man. Axial FLAIR image (TR/TE, 10,002/161; inversion time, 2,220 msec) shows confluent abnormally increased signal intensity in centrum semiovale (severity score, 4). Note again sparing of subcortical U-fibers.

View larger version (139K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 3B. —MR images of mitochondrial neurogastrointestinal encephalomyopathy in 39-year-old man. Axial FLAIR image (10,002/161; inversion time, 2,220 msec) shows minimal abnormally increased signal intensity in caudate heads (severity score, 1). Putamina, globi pallidi, and thalami show no abnormal signal on inferior slices (severity scores, 0, 0, and 0, respectively). Slightly increased signal intensity over both thalami is probably internal capsular white matter fanning into white matter of both corona radiata.

View larger version (148K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 4A. —MR images of mitochondrial neurogastrointestinal encephalomyopathy in 39-year-old woman. Axial FLAIR image (TR/TE, 9,000/110; inversion time, 2,500 msec) shows abnormally increased signal intensity bilaterally in caudate heads, putamina, globi pallidi, and thalami (severity scores: 4, 3, 2, and 3, respectively). Also note abnormally increased signal intensity bilaterally in internal, external, and extreme capsules (severity scores: 3, 4, and 4, respectively). Gray matter of claustrum is suggested between external and extreme capsules.

View larger version (122K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 4B. —MR images of mitochondrial neurogastrointestinal encephalomyopathy in 39-year-old woman. Axial FLAIR image (9,000/110; inversion time, 2,500 msec) shows abnormally increased signal intensity in pons (severity score, 2).

View larger version (125K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 5A. —MR images of mitochondrial neurogastrointestinal encephalomyopathy in 46-year-old man. Axial FLAIR image (TR/TE, 10,002/147; inversion time, 2,200 msec) shows extensive abnormally increased signal intensity in corpus callosum (splenium), caudate heads, putamina, globi pallidi, and thalami (severity scores: 2, 3, 3, 3, and 3, respectively). Also note abnormally increased signal intensity bilaterally in internal, external, and extreme capsules (severity scores: 3, 4, and 3, respectively).

View larger version (139K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 5B. —MR images of mitochondrial neurogastrointestinal encephalomyopathy in 46-year-old man. Axial FLAIR image (10,002/147; inversion time, 2,200 msec) shows abnormally increased signal intensity in midbrain (severity score, 4).

View larger version (136K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 5C. —MR images of mitochondrial neurogastrointestinal encephalomyopathy in 46-year-old man. Axial FLAIR image (10,002/147; inversion time, 2,200 msec) shows abnormally increased signal intensity in cerebellar white matter and pons (severity scores: 3 and 3, respectively).

The midbrain was involved in only two patients and showed one of the lowest mean severity scores (1.0). In the posterior fossa, involvement of the cerebellar white matter was common (4/5) and was associated with a mean severity score of 2.0. The pons was affected in only two patients and received a very low mean severity score (1.2).

Discussion

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Patients with mitochondrial neurogastrointestinal encephalomyopathy have been reported to have diffuse confluent cerebral and cerebellar white matter on T2-weighted images [6]. Abnormal signal intensity in the cerebral white matter is due to an abnormality of myelin rather than of the axons [6]. Despite the extensive central nervous system involvement, patients are generally unaffected cognitively. In one series of 35 patients with mitochondrial neurogastrointestinal encephalomyopathy, none had dementia [1].

In our series, all five patients with mitochondrial neurogastrointestinal encephalomyopathy had confluent abnormal centrum semiovale white matter, and most (4/5) had abnormal cerebellar white matter. Our study indicates that involvement of the corpus callosum (splenium [4/5], genu [3/5]) may be more common than previously thought [1, 6]. Although some patients had moderate-to-severe involvement (Figs. 2B and 5A), others had mild or no involvement (Fig. 3B). Abnormally increased signal intensity was clearly shown in the white matter capsules in most patients (Figs. 4A and 5A). The basal ganglia and thalami (Figs. 4A and 5A) can also show abnormally increased signal intensity. Involvement of these structures has not been previously reported in patients with mitochondrial neurogastrointestinal encephalomyopathy. We also report variable involvement (Figs. 4B, 5B, and 5C) of the midbrain and pons [1, 6].

The 46-year-old man and the 39-year-old woman had the highest total lesion incidence scores (14 and 12, respectively; mean, 9.2) and the highest total lesion severity scores (40 and 34, respectively; mean, 22.8). These two patients had no detectable thymidine phosphorylase activity, along with the 35-year-old man, whose lesion scores were intermediate. The 46-year-old man with the highest scores was the only patient with a compound heterozygous mutation (A3371C and G3867C). Two of the three remaining patients (the 34-year-old man and the 39-year-old man) with the lowest total lesion incidence and total lesion severity scores had detectable thymidine phosphorylase activity and the identical homozygous mutation (G1419A). These results suggest that brain MRI findings might vary with thymidine phosphorylase mutations and residual thymidine phosphorylase activity; however, our sample size is too small to reach any firm conclusions.

Diffusely symmetric abnormally increased MRI signal intensity in the centrum semiovale white matter on FLAIR or spin-echo T2-weighted images is not specific for mitochondrial neurogastrointestinal encephalomyopathy. For example, a diffuse symmetric cerebral white matter abnormality can be the delayed result of radiation therapy [7]. Severe cases of radiation injury generally show sparing of the cortex and the subcortical white matter and present more commonly as patient age increases. Relative sparing of the basal ganglia, internal capsule, and posterior fossa have been reported. Most patients have significant intellectual or neurologic deficits; some patients may have normal cognitive function.

Toxic encephalopathies may present as diffuse symmetric white matter abnormalities. Toxic encephalopathies that result from the interaction of exogenous toxic chemical compounds and the brain parenchyma can occur in any age group from exposure to any of a large number of exogenous chemical agents such as organic solvents, mercury, hexachlorophene, and heroin vapor [8, 9].

Inborn errors of metabolism may produce endogenous toxins such as those seen in lysosomal storage disorders [8]. In Krabbe disease, elevated levels of psychosine and cerebroside both lead to myelin breakdown; in metachromatic leukodystrophy, elevated levels of sulfatide produce diffuse myelin damage. MRI findings reported in both Krabbe disease and metachromatic leukodystrophy include abnormally increased T2-weighted signal intensity in the periventricular white matter, the corpus callosum, the posterior limbs of the internal capsules, the cerebellar white matter, and the brainstem.

Canavan's disease is a primary white matter disorder of infancy and early childhood that has diffuse symmetric abnormal cerebral white matter signal intensity [10]. The peripheral subcortical white matter, a region that is spared in Krabbe disease and metachromatic leukodystrophy, is affected early in the disease. The globi pallidi can be involved with relative sparing of the putamina [10]. Kearns-Sayre syndrome, a mitochondrial disorder characterized by ophthalmoplegia and pigmentary retinopathy, can also affect peripheral white matter early and preferentially involve the globi pallidi and thalami. Patients must display neurologic symptoms before 20 years old [10].

Congenital muscular dystrophies have diffuse symmetric cerebral white matter hypomyelination, as noted in a series of 12 patients whose ages ranged from 8 months to 10 years [11]. With the exception of the pure congenital muscular dystrophy classification, all other classifications of congenital muscular dystrophy (Fukuyama's syndrome, Walker-Warburg syndrome, and Santavuori-Haltia-Santavuori muscle-eye-brain disease) are associated with cerebral and cerebellar cortical abnormalities.

Both cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and sporadic subcortical arteriosclerotic encephalopathy have been reported to show diffuse symmetric leukoencephalopathy [12]. An inherited microangiopathy with Notch3 mutations in chromosome 19, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, has greater abnormal T2-weighted signal intensity in the anterior temporal lobe and external capsular white matter compared with sporadic subcortical arteriosclerotic encephalopathy. In one study [12], patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy were younger (mean age, 49.9 years) than patients with sporadic subcortical arteriosclerotic encephalopathy (mean age, 65 years).

Patients with pseudomitochondrial neurogastrointestinal encephalomyopathy have gastrointestinal dysmotility, cachexia, and peripheral neuropathy but lack evidence of leukoencephalopathy or thymidine phosphorylase dysfunction [4]. These pseudocases highlight the importance of MRI in the clinical workup of these symptoms.

Limitations to our study include the small sample size (n = 5), probable statistical variations in our assessment methods, and institutional case-selection bias. Gender bias is acknowledged; only one of our five patients was female. Most of the reported patients have been women [4]. Some of our patients (mean age, 38.6 years) were evaluated almost two decades after the mean age of presentation (18.5 years) in a larger series [4]. FLAIR sagittal and coronal planes were not available in this retrospective study, planes that potentially could have improved our assessment of the corpus callosum and other structures. Future prospective studies should consider using these additional planes. Similarly, variation in intersection gap (1–2.5 mm) could not be controlled retrospectively and does admittedly add some uncertainty to the rating scheme. Most patients (3/5) were imaged with 1-mm intersection gaps; the use of intersection gaps of 2.0 and 2.5 mm in two patients might lead to an underestimation of the incidence and severity scores in some structures such as the corpus callosum. However, one of the primary purposes in evaluating this small series of patients was to acknowledge that lesions are indeed present in many anatomic structures of the brain not previously reported in the literature. Future clinical, MRI, and autopsy examinations of patients with mitochondrial neurogastrointestinal encephalomyopathy should be tailored accordingly. Finally, it is not known whether the brain MRI findings progress with patient age or clinical disease and at what rate they progress, if they do. Serial MRI would address these issues.

We chose not to score the T1-weighted images in these five patients for two reasons. The subtle decreased T1-weighted signal, although noticeable in many of the severely affected structures, was not always distinguishable, in our opinion, from the adjoining normal tissues. The anatomic extent of decreased T1-weighted signal, when detected, also appeared less when compared with the corresponding FLAIR images. Enhanced T1-weighted images were also available in three patients; although not formally reviewed, the contrast-enhanced images did not show abnormal enhancement. Diffusion-weighted images were not available or obtained during the retrospective time frame (1995–2002) when the MR images were obtained.

In summary, mitochondrial neurogastrointestinal encephalomyopathy is a rare autosomal recessive mitochondrial disorder that has been reported to have diffuse confluent abnormal white matter on MRI. Our MRI evaluation of a small series of patients with this uncommon disorder of thymidine metabolism supports these reports. In addition, we show that involvement of the corpus callosum, the white matter capsules, the basal ganglia, the thalami, the midbrain, the pons, and the cerebellar white matter may be more common than previously recognized. These observations may help broaden the radiologic and pathologic understanding of patients with mitochondrial neurogastrointestinal encephalomyopathy and assist in the differential diagnosis of leukoencephalopathy.

References

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1. Nishino I, Spinazzola A, Papadimitriou A, et al. Mitochondrial neurogastrointestinal encephalomyopathy: an autosomal recessive disorder due to thymidine phosphorylase mutations. Ann Neurol2000; 47:792 –800[Medline]
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This Article Abstract Figures Only Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Millar, W. S. Articles by Hirano, M. Search for Related Content PubMed PubMed Citation Articles by Millar, W. S. Articles by Hirano, M. Social Bookmarking                      What's this? Hotlight (NEW!) What's Hotlight?