Case report

Merosin-negative congenital muscular dystrophy: magnetic

resonance spectroscopy findings

Mehmet Aslana,*, Alpay Alkanb, Cengiz Yakincia, Ergun Sonmezgoza,Ugur Bicaka, Suzan Zorludemirc

aDepartment of Pediatrics, Inonu University, Turgut Ozal Medical Center, School of Medicine, Malatya 44069, TurkeybDepartment of Radiology, Inonu University, Turgut Ozal Medical Center, Malatya, Turkey

cDepartment of Pathology, Cukurova University School of Medicine, Adana, Turkey

Received 28 July 2003; received in revised form 9 July 2004; accepted 3 August 2004

Abstract

Congenital muscular dystrophies (CMD) are heterogenous group of muscle disorders with autosomal recessive inheritance. Merosin

deficiency has been identified in some patients with CMD all of whom also had white matter abnormalities on MRI. In postmortem studies,

the brain showed extensive myelin pallor with a spongy appearance of white matter and moderate astrocytosis or demyelination. Direct

assessment of neuropathologic aspects of MN-CMD such as demyelination is possible with MR spectroscopy (MRS). Although previous

reports have described several neuro-imaging findings of this disease, MRS findings have not been reported in literature. In this case, we

report MRS features of a 4-year old girl with MN-CMD. MRS of brain demonstrated that N-acetylaspartate (NAA)/Creatine (Cr) ratio was

normal. Increased Choline (Cho)/Cr and Myo-inositol (MI)/Cr ratios were obtained. These findings were interpreted as demyelination and

gliosis of white matter.

q 2004 Elsevier B.V. All rights reserved.

Keywords: Magnetic resonance spectroscopy; Congenital muscular dystrophy

1. Introduction

A primary deficiency of merosin caused by mutations of

the laminin a2 chain gene produces MN-CMD.

Conventional MRI findings of the white matter changes

have been interpreted as leukodystrophy-like demyelina-

tion, arrest in myelination, or dysfunction of blood brain

barrier [1,2]. Therefore, MRS study seems to be important

to clarify the nature of this abnormality. Demyelination and

astrocytosis are the most important features of neurological

involvement of this disease [3–5]. MRS provides valuable

information regarding in vivo brain metabolism and

neuronal functions. It is a promising method that may

illustrate the pathophysiologic events for MN-CMD.

0387-7604/$ - see front matter q 2004 Elsevier B.V. All rights reserved.

doi:10.1016/j.braindev.2004.08.004

* Corresponding author. Tel.: C90 422 341 06 60x5304; fax: C90 422

3410 728 29.

E-mail address: mirzaaslan@hotmail.com (M. Aslan).

Although it is not specific or diagnostic for MN-CMD,

MRS could show substantial metabolic impairments in the

white matter, especially in the early stages. We performed

single voxel proton MRS in a 4-year old girl with proven

diagnosis of MN-CMD and white matter involvement. To

our knowledge, this is the first report of proton MRS

features of MN-CMD.

2. Case report

A 4-year old girl was admitted to our clinic due to muscle

weakness. Her first admission to the hospital was at

23 months at which time hypotonia and delay in develop-

ment were present. On physical examination, her

weight was 10 kg (!3 percentile) and length was 88 cm

(!3 percentile). Motor activity was decreased and sym-

metric muscular weakness was detected. Deep tendon

Brain & Development 27 (2005) 308–310

www.elsevier.com/locate/braindev

Fig. 1. T2 weighted image (TR: 4530, TE: 100 ms) shows symmetric

hyperintensities in white matter.

Table 1

Metabolite ratios of white matter in the case with MN-CMD and control

group

Metabolite ratios Case PWM Control group PWM

(n:3)

NAA/Cr 1.78 1.74G0.10

Cho/Cr 1.19 0.69G0.11

MI/Cr 0.98 0.61G0.13

PWM: parietal white matter.

M. Aslan et al. / Brain & Development 27 (2005) 308–310 309

reflexes were hypoactive also Babinski’s sign was negative.

Marked joint contractures were noted and no lateralizing

features were present. The optical discs and fundi

were normal. The rest of the physical examination was

unremarkable. Denver-II test showing gross motor and fine

motor-adaptive development abnormalities. In laboratory

evaluation, creatine kinase was 1063 U/L. Muscle biopsy

Fig. 2. MR spectrum (TR: 1500, TE: 31 ms) obtained from the posterior

parietal white matter showed that NAA/Cr ratio was normal but increased

Cho/Cr, MI/Cr ratios and lipid peaks were detected.

revealed dystrophic changes and merosin staining was

deficient. EMG had myopathic features.

Magnetic resonance imaging (MRI) and spectroscopy of

the brain were performed on a 1.5-T system. She was

sedated with chloral hydrate. T2-weighted images showed

diffuse and symmetric hyperintensity in white matter

(Fig. 1). Single voxel spectroscopy (SVS) performed using

a point-resolved spectroscopy sequence (PRESS) (TR:

1500, TE: 31 ms) with 256 averages; voxel sizes of 20!20!20 mm was used (Fig. 2). Localized shimming and

optimizations of the Gaussian pulse amplitude for maxi-

mum water suppression were adjusted prior to acquisition of

the spectra. A spectral sweep width of 1000 Hz was used

with data size of 1024 points. Analysis of the spectra was

performed with spectroscopy software package of the MR

system supplied by the manufacturer. Voxels were placed in

the posterior parietal white matter. Total study time

averaged 30 min. The spectra were referenced to creatine

(2.98 ppm). The signals from N-acetylaspartate (NAA),

choline (Cho), creatine (Cr), and myo-inositol (MI) were

integrated.

Peak area metabolite ratios (NAA/Cr, Cho/Cr and MI/Cr)

were calculated. A group of three age-matched healthy

children constituted the control group for MRS. In our

study, MRS of brain demonstrated that NAA/Cr ratio was

normal. Increased Cho/Cr and MI/Cr ratios were obtained

(Table 1).

3. Discussion

One kind of MN-CMD caused by a primary defect in

the expression of the laminin a2 chain of merosin. Laminin

a2 is also found in the basement membrane of Schwann

cells and in blood vessels within the brain as well as in

other tissues. Merosin deficiency, resulting in an abnormal

basal lamina constriction and in a deficient extracellular

matrix composition, may lead the myelin arrest in both

central and peripheral nervous system. It has recently been

suggested that merosin deficiency in the basement

membrane of the blood vessels has a role in the

pathophysiology of brain abnormalities in patients with

MN-CMD [6].

MRI has provided a significant improvement in our

knowledge regarding the involvement of the central nervous

M. Aslan et al. / Brain & Development 27 (2005) 308–310310

system in children with MN-CMD. Diffuse cerebral white

matter changes can be recognized on MRI. It is of interest

that only the cerebral areas are the last to be myelinated in

the developing brain (subcortical and periventricular

regions) are affected, whereas the areas that are myelinated

earlier in life (corpus callosum and internal capsule) are not

affected. Although this is the case, the determination of

neuroimaging features of MN-CMD is important from the

point of diagnosis and follow up [7]. In our case, we

obtained significant hyperintensities in cerebral white

matter on T2-weighted images.

MRS provides some advantages as a noninvasive

method in investigating brain metabolism in infants and

children. It offers the potential for investigating changes in

metabolites produced by disease and following the changes

occurring with progression. Information on neuronal/ax-

onal viability, cellular energetics, and cellular membrane

status could be obtained by MRS [8–10]. The prominent

resonances detected on MRS in normal brains include

NAA, Cho, and Cr. Since NAA is a neuroaxonal marker,

abnormalities of neuronal structures, like reduced neuronal

density or viability, lead to the reductions in NAA/Cr

ratios. Major components of the Cho resonance are

choline-containing compounds with small molecular

weight, such as phosphocholine and glycerophosphocho-

line, forming a pool involved in membrane synthesis and

degradation. The increase in the Cho/Cr ratio might point

to an inability in properly incorporating Cho-containing

molecules into myelin. Also, loss or disruption of normal

myelin increases the availability Cho-containing com-

pounds [10–12]. Increased MI levels may be related to

intracellular sodium content and glial activation and have

been associated with increased osmolality in the brain. In

our case, MRS of white matter showed that NAA/Cr ratio

was normal but increased Cho/Cr and MI/Cr ratios were

detected. The increased Cho/Cr, and MI/Cr ratios, which

could indicate increased membrane turnover, and myelin

breakdown and astrocytosis respectively, might correspond

to glial cell proliferation in the white matter of infants with

MN-CMD [10–12].

As a result, MRS, in particular, can be readily

incorporated into integrated MRI examination and it is

apparent that spectroscopy can provide new insights into the

biochemical and pathophysiologic basis of neurological

disorders [10–12]. We suggest that patients with newly

diagnosed MN-CMD should have brain MRS as a part of

their assessment. We believe that MRS could play an

important role in the determination of metabolic changes in

the brains of infants with MN-CMD.

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