Paternally inherited case of congenital DM1: brain MRI and review of literature

The congenital form of myotonic dystrophy type 1 (CDM1) has an almost exclusively maternal transmission and is characterized by mental retardation and by moderate/severe ventriculomegaly and white matter hyperintensities on brain magnetic resonance imaging (MRI). We report a 20-year-old case of CDM1 with paternal inheritance showing mental retardation and normal brain MRI, and presenting at birth with hypotonia, facial weakness and feeding difficulties. We reviewed the literature for studies addressing the brain neuroimaging in paternally transmitted CDM1 and found four studies reporting diffuse cerebral, frontal lobe or mild parietal cortical atrophy, or mild ventricular dilatation, without white matter abnormalities. To our knowledge, this is the first report describing normal brain MRI in a mentally retarded CDM1 patient with paternal transmission.     

Three-dimensional MR imaging of brain surface anomalies in fukuyama-type congenital muscular dystrophy

Fukuyama-type congental muscular dystrophy (FCMD), the second most common childhood muscular dystrophy in Japan, is characterized by the association with severe brain anomalies such as pachygyria and focal interhemispheric fusion. Conventional imaging techniques such as X-ray CT scan and MRI are ineffective for visualization of these brain surface anomalies. Here we investigated the efficacy of three-dimensional (3-D) reconstruction of brain surface MR images for the detection of brain anomalies in FCMD patients. 3-D brain surface MR images clearly visualized anomalies of cerebral gyrus such as pachygyria, as well as focal interhemispheric fusion. In addition, reconstructed horizontal images visualized structural derangement such as abnormal protrusion of white matter into gray matter. MR image abnormalities were confirmed by autopsy in 1 patient. These abnormalities were never observed in Duchenne muscular dystrophy (DMD) patients. Our results indicate the efficacy of the present method for the differential diagnosis between FCMD and DMD with severe mental retardation, which is essential for the genetic study to identify the causative gene of FCMD. © 1995 John Wiley & Sons, Inc.     

Four Caucasian patients with mutations in the fukutin gene and variable clinical phenotype

Fukuyama congenital muscular dystrophy (FCMD) is frequent in Japan, due to a founder mutation of the fukutin gene (FKTN). Outside Japan, FKTN mutations have only been reported in a few patients with a wide spectrum of phenotypes from Walker–Warburg syndrome to limb-girdle muscular dystrophy (LGMD2M). We studied four new Caucasian patients from three unrelated families. All showed raised serum CK initially isolated in one case and muscular dystrophy. Immunohistochemical studies and haplotype analysis led us to search for mutations in FKTN. Two patients (two sisters) presented with congenital muscular dystrophy, mental retardation, and posterior fossa malformation including cysts, and brain atrophy at Brain MRI. The other two patients had normal intelligence and brain MRI. Sequencing of the FKTN gene identified three previously described mutations and two novel missense mutations. Outside Japan, fukutinopathies are associated with a large spectrum of phenotypes from isolated hyperCKaemia to severe CMD, showing a clear overlap with that of FKRP.     

Merosin-deficient congenital muscular dystrophy: the spectrum of brain involvement on magnetic resonance imaging

Children with merosin-deficient congenital muscular dystrophy (CMD) have striking white matter changes on T-2 weighted brain magnetic resonance imaging (MRI). There have been occasional cases with structural abnormalities, mainly involving the occipital cortex. We report our brain imaging findings in 14 children with merosin-deficient CMD. Ten cases had a severe reduction or absence of merosin on immunocytochemistry and four cases had partial reduction. All 14 cases had white matter changes, which appeared after the first 6 months of life and persisted with time. The changes were diffuse and the oldest child scanned (14 years) also showed involvement of the U fibres. Five children with total absence of merosin also had structural abnormalities. One child had moderate mental retardation and epilepsy, mainly characterised by complex partial seizures, with atypical absences, which had been difficult to treat. Brain MRI showed marked occipital agyria and pontocerebellar hypoplasia. The gyral pattern of the rest of the brain looked normal. The four other cases, all with normal intelligence, also had cerebellar hypoplasia with variable involvement of the pons. They did not, however, have neuronal migration defects. It is recognised that several forms of congenital muscular dystrophy, namely Fukuyama CMD, muscle-eye-brain disease and Walker-Warburg syndrome, have structural brain abnormalities and associated severe mental retardation. Our cases demonstrate that a range of structural malformations can also be found in a significant number of children with merosin-deficient CMD.     

Merosin-deficient congenital muscular dystrophy with mental retardation and cerebellar cysts,unlinked to the LAMA2, FCMD,MEB and CMD1B loci,in three Tunisian patients

We report three Tunisian patients affected by congenital muscular dystrophy with mental retardation and cerebellar cysts on cranial magnetic resonance imaging. The clinical features were characterized by hypotonia at birth, joint contractures associated with severe psychomotor retardation, absence of speech, inability to walk in three patients, but calf hypertrophy was noted only in two patients. Brain magnetic resonance imaging showed several cerebellar cysts and vermis hypoplasia in all of the patients. Abnormality of the white matter was present in two patients. The pattern of gyration was normal in all cases. Serum creatine kinase was elevated in all three cases and their muscle biopsy showed dystrophic changes compatible with congenital muscular dystrophy. The immunohistochemical analysis of the skeletal muscle revealed partial merosin deficiency, more pronounced for the N-terminal antibody. Linkage analysis excluded congenital muscular dystrophy loci on chromosomes 6q22, 9q31, 1p32 and 1q42. These patients constituted a particular form of congenital muscular dystrophy with a combination of severe motor delay, mental retardation, partial merosin deficiency and cerebellar cysts. Two patients showed white matter abnormalities on magnetic resonance imaging and hypertrophy of the calves. These cases, in addition to those reported previously, confirmed the large phenotypic variability in the group of secondary merosin deficiency congenital muscular dystrophy.     

Magnetic resonance imaging in classification of congenital muscular dystrophies with brain abnormalities

A survey was performed of magnetic resonance imaging (MRI) findings in 21 patients with congenital muscular dystrophy (CMD) with cerebral abnormalities to evaluate the contribution of MRI to the classification of CMD patients. In 5 patients with Walker-Warburg syndrome (WWS), MRI showed hydrocephalus due to aqueduct stenosis, generalized cerebral cortical agyric or pachygyric polymicrogyria, diffuse cerebral hemispheric white matter abnormalities, and malformations of posterior fossa structures. In 4 patients with muscle–eye–brain disease, MRI showed cortical dysplasia, but less severe than in WWS. The cerebral white matter either was normal or contained multiple focal abnormalities. Malformations of posterior fossa structures were present. Eight patients, classified as having classic merosin-deficient CMD (MD-CMD), had diffuse cerebral hemispheric white matter abnormalities, no other abnormalities. One patient with MD-CMD had only a few, focal white matter abnormalities. Three CMD patients had occipital agyria, otherwise normal gyration, multifocal or more diffuse cerebral white matter changes, and variable hypoplasia of pons and vermis. Two of the 3 patients had negative muscle merosin staining. The conclusion of the study is that MRI is an important adjunct in the classification of CMD patients. CMD with occipital agyria can be regarded as a newly recognized, separate CMD subtype.     

Congenital muscular dystrophy and cerebral CT scan anomalies. Results of a collaborative study of the Société de Neurologie Infantile

We present the results of a collaborative study on the association of congenital muscular dystrophy with central nervous system anomalies revealed by CT scan investigation of 10 patients. In seven children, an abnormal hypodensity of the cerebral white matter is found; in four of these patients, this radiological anomaly is either isolated, or associated with a moderate intellectual impairment; in one case, severe mental retardation and ocular changes had occurred; in the other two cases, the muscular disease was progressing slowly, in association with microcephaly, epilepsy, and moderate mental retardation. Three children were afflicted with a severe early encephalopathy and congenital muscular dystrophy, and presented signs of cortical and subcortical atrophy on CT scan. Two of these patients corresponded to different types of cerebro-ocular dysplasia-muscular dystrophy syndromes, and the third patient of Fukuyama's congenital muscular dystrophy. These observations are discussed and compared with those reported in the literature. The authors emphasize the need to investigate possible cerebral CT scan anomalies in congenital muscular dystrophies, and to look for muscular changes in some prenatal encephalopathies.     

Cognitive abilities in children with congenital muscular dystrophy: correlation with brain MRI and merosin status.

The aim of the study was to evaluate whether children with merosin-positive or merosin-deficient congenital muscular dystrophy (CMD) show any cognitive impairment and whether this is related to brain abnormalities on magnetic resonance imaging (MRI). Twenty-two patients (age range: 5.8-15.3 years) were assessed by the Wechsler Intelligence Scales. Twelve were merosin-positive and ten merosin-deficient. One child had severe mental retardation and could not be tested. The full scale IQ in the remaining 21 ranged from 51 to 134, the verbal IQ ranged from 78 to 136 and the performance from 51 to 136. Of the twelve children with normal merosin one had a mild delay (IQ < 75) and two were borderline (IQ 75-95). Of the ten children with merosin-deficiency, one showed severe mental retardation and could not be tested, one showed a mild delay and two had borderline results. While the children with merosin deficiency with the typical diffuse white matter changes on MRI had normal scores, the children who in addition had cerebellar hypoplasia had lower performance IQ. The child with cortical dysplasia had severe mental retardation. Our results suggest that the spectrum of cognitive abilities in CMD is very wide even within genetically homogeneous conditions.     

Magnetic resonance imaging of muscle and brain in myotonic dystrophy

Myotonic dystrophy (MD) is characterized by myotonia, weakness and extramuscular symptoms, including intellectual impairment. We performed magnetic resonance imaging (MRI) of brain and muscle in 25 MD patients: 81% had cerebral atrophy (severe in 36%); 68% had focal white matter lesions, which were large and multiple in 27%. Brain MRI findings correlated with mental impairment; the severity of both correlated with disease duration. Changes in brain and muscle MRI were progressive with time, but independent of each other. Muscle MRI findings were fatty degeneration and loss of bulk. In the calves, the medial gastrocnemius muscles were involved earliest and the posteriortibial muscles relatively spared. In the thighs the vastus muscles were damaged most often and the rectus femoris least. Focal muscle damage was efficiently visualized, sometimes preceding clinical detection. Muscle MRI was less sensitive than conventional methods for early diagnosis, but ideal for follow-up, owing to its non-invasiveness and examiner-independence.     

Spectrum of brain changes in patients with congenital muscular dystrophy and FKRP gene mutations

OBJECTIVES: To report the spectrum of brain magnetic resonance imaging findings in 13 patients with congenital muscular dystrophy and FKRP gene mutations and to explore possible genotype-phenotype correlations. DESIGN: We retrospectively reviewed brain magnetic resonance imaging in patients with congenital muscular dystrophy and FKRP gene mutations. PATIENTS: Thirteen patients with congenital muscular dystrophy and mutations in the FKRP gene. RESULTS: Five of the 13 patients had the typical phenotype originally described for congenital muscular dystrophy (MDC1C) with normal intelligence and normal brain magnetic resonance imaging while 3 other patients had isolated cerebellar cysts and mental retardation without any other sign of posterior fossa of supratentorial abnormalities. In the remaining 5 patients cerebellar cysts were associated with structural brain changes involving the posterior fossa and the cortex, ranging from focal unilateral periventricular nodular heterotopia to marked cerebellar dysplasia and pontine hypoplasia. In 2 of these 5 patients the severity and distribution of changes resembled muscle-eye-brain disease in 1 patient who had mild Walker-Warburg syndrome. The distribution of FKRP gene mutations identified in this group of patients did not reveal any obvious association with the severity of central nervous system involvement. CONCLUSIONS: The severity of central nervous system involvement observed in our patients in contrast broadly reflected the severity of the disruption of alpha-dystroglycan glycosylation. In particular, dystroglycan expression was almost absent in the patients with muscle-eye-brain diseaselike phenotype and less severely reduced in the patients with congenital muscular dystrophy (MDC1C) with or without cerebellar cysts. This study further highlights the central role that dystroglycan has in neuronal migration.     

Merosin-positive congenital muscular dystrophy with mental retardation, microcephaly and central nervous system abnormalities unlinked to the Fukuyama muscular dystrophy and muscular-eye-brain loci: report of three siblings

Classical merosin (2 laminin)-positive congenital muscular dystrophy is a heterogeneous subgroup of disorders; a few cases characterized by severe mental retardation, brain involvement and no ocular abnormalities were called Fukuyama-like congenital muscular dystrophy. We report a family of healthy non-consanguineous parents, with four affected siblings, of which one died at the age of 7 months due to an intercurrent illness, who presented congenital hypotonia, severe mental retardation, microcephaly, delayed psychomotor development, generalized muscular wasting and weakness with mild facial involvement, calf pseudohypertrophy, joint contractures and areflexia. Muscle biopsy disclosed severe muscular dystrophy. Immunostaining for laminin 2 80 kDa and clone Mer3/22B2 monoclonal antibodies, 1 and 1 chain was preserved. Magnetic resonance imaging findings were consistent with pontocerebellar hypoplasia, bilateral opercular abnormalities and focal cortical dysplasia as well as minute periventricular white matter changes. Clusters of small T2-weighted focal hyperintensities in both cerebellar hemispheres consistent with cysts were observed in two of the three siblings studied with magnetic resonance imaging. Ophthalmologic and cardiologic examination was normal. Haplotype analysis using microsatellite markers excluded the Fukuyama congenital muscular dystrophy, LAMA2 and muscle-eye-brain disease loci. Thus, a wider spectrum of phenotypes, gene defects and protein deficiencies might be involved in congenital muscular dystrophy with brain abnormalities.     

Magnetic resonance imaging of the brain in phenylketonuria

To investigate the correlation between the abnormalities of magnetic resonance imaging (MRI) of the brain and blood phenylalanine (Phe) levels in phenylketonuria (PKU) and hyperphenylalaninemia (HPA), we reviewed MRIs from 16 patients with early treated PKU and HPA. Their ages ranged from 4-24 years and were found by mass screening and treated from early infancy, and 5 patients with late detected PKU who were aged 24-33 years. The former patients had no remarkable neurological signs or symptoms. One patient of the latter had severe mental retardation and 3 patients had mild to border mental retardation. Axial T1-weighted and T2-weighted spin echo sequences, fluid attenuated inversion recovery MR sequences (FLAIR) through the brain were performed. The scans were graded according to the extent of increased signal intensity of white matter on T2-weighted and FLAIR sequences. To investigate the influence of plasma Phe levels, three approaches were used. Firstly an average of all yearly serial blood Phe concentration was calculated for each patient, then Phe was determined for a period of 6 months and 12 months prior to MRI, and also for their lifetime up to their age at the time this study began. These average blood Phe levels were classified into four categories: group A:Phe level below 5 mg/dl, group B:5-8 mg/dl, group C:9-12 mg/dl, group D:above 12 mg/dl. MRI findings were not significant in group A. Remarkable high signals of white matter were obtained in group C and D, except for one patient in group D whose MRI finding was normal. MRI findings correlated to long-term dietary control stronger than those of 6 months prior to MRI. The clinical significance of MRI abnormalities is still unclear, and further study is required to clarify the relationship of the MRI findings and clinical conditions.     

Neuroanatomy of Down's syndrome: a high-resolution MRI study

OBJECTIVE: Down's syndrome, the most common genetic cause of mental retardation, results in characteristic physical and neuropsychological findings, including mental retardation and deficits in language and memory. This study was undertaken to confirm previously reported abnormalities of regional brain volumes in Down's syndrome by using high-resolution magnetic resonance imaging (MRI), determine whether these volumetric abnormalities are present from childhood, and consider the relationship between neuroanatomic abnormalities and the cognitive profile of Down's syndrome. METHOD: Sixteen children and young adults with Down's syndrome (age range=5-23 years) were matched for age and gender with 15 normal comparison subjects. High-resolution MRI scans were quantitatively analyzed for measures of overall and regional brain volumes and by tissue composition. RESULTS: Consistent with prior imaging studies, subjects with Down's syndrome had smaller overall brain volumes, with disproportionately smaller cerebellar volumes and relatively larger subcortical gray matter volumes. Also noted was relative preservation of parietal lobe gray and temporal lobe white matter in subjects with Down's syndrome versus comparison subjects. No abnormalities in pattern of brain asymmetry were noted in Down's syndrome subjects. CONCLUSIONS: The results largely confirm findings of previous studies with respect to overall patterns of brain volumes in Down's syndrome and also provide new evidence for abnormal volumes of specific regional tissue components. The presence of these abnormalities from an early age suggests that fetal or early postnatal developmental differences may underlie the observed pattern of neuroanatomic abnormalities and contribute to the specific cognitive and developmental deficits seen in individuals with Down's syndrome.     

Neurophysiological and radiological findings in myotonic dystrophy patients

Somatosensory evoked potentials (SEPs) and brainstem auditory evoked potentials (BAEPs) were recorded in 10 patients with myotonic dystrophy and in 20 sex and age-matched healthy controls. In all patients a brain MRI examination was also performed. In our results, the significantly longer absolute peak latencies of the SEPs and the abnormal increasing of the later components of the BAEPs suggest an involvement of the afferent sensory and central auditory pathways. Brain MRI showed white matter hyperintense lesions (WMHL) in eight patients (80%). No correlations were found between individual abnormal electrophysiological parameters or severity of WMHL and age, age at onset, disease duration or muscular impairment. The total number (SEP + BAEP) of electrophysiological abnormalities significantly correlated with muscular impairment ( p < 0.05) and MRI changes ( p < 0.05), suggesting a strict pathogenetic linkage between muscular and nervous system alterations in this disease.     

Diffuse cerebral hypomyelination with cerebellar atrophy and hypoplasia of the corpus callosum

Three unrelated Japanese patients who presented with ataxia and mild mental retardation were examined in this study. Early development was normal in two patients and slightly delayed in one. All could walk independently, but were unstable due to cerebellar ataxia. They had mild intellectual retardation and displayed slow, progressive, and mild clinical courses. Two patients lost the ability to walk at 12 and 25 years of age. Brain MRI of the three patients revealed diffuse cerebral hypomyelination, moderate cerebellar cortical atrophy, and hypoplasia of the corpus callosum, which were seen in other diffuse hypomyelination syndrome. No known abnormalities were found in biochemical and genetic studies. Auditory brainstem responses and nerve conduction studies were normal. A definite diagnosis could not be made because of the lack of hypodontia, hypogonadism, cataracts, or basal ganglia atrophy. Based on common MRI findings and the relatively mild clinical courses, we believe that these patients may have another subset form of diffuse hypomyelination syndrome involving the cerebral white matter and cerebellum.     

Congenital muscular dystrophy associated with calf hypertrophy, microcephaly and severe mental retardation in three Italian families: evidence for a novel CMD syndrome

We describe four Italian patients (aged 3, 4, 12, and 13 years ) affected by a novel autosomal form of recessive congenital muscular dystrophy. These patients were from three non-consanguineous families and presented an almost identical phenotype. This was characterized by hypotonia at birth, joint contractures associated with severe psychomotor retardation, absent speech, inability to walk and almost no interest in their surroundings. In addition, all patients had a striking enlargement of the calf and quadriceps muscles. Ophthalmologic examination revealed no structural ocular abnormalities in any of the children; one patient had severe myopia. In all cases a magnetic resonance imaging of the brain showed an abnormal posterior cranial fossa with enlargement of the cisterna magna and variable hypoplasia of the vermis of the cerebellum. Abnormality of the white matter was also present in all patients, in the form of patchy signal most evident in the periventricular areas. Serum CK was grossly elevated in all. The muscle biopsy from all cases showed dystrophic changes compatible with congenital muscular dystrophy. Immunofluorescence studies showed mild to moderate partial deficiency of laminin 2 chain. Linkage analysis in the only informative family excluded the known loci for congenital muscular dystrophy, including laminin 2 chain on chromosome 6q2, the Fukuyama congenital muscular dystrophy locus on 9q3 and the muscle-eye-brain disease on chromosome 1p3. We propose that this represent a novel severe variant of congenital muscular dystrophy, with associated central nervous system involvement.     

New pattern of brain MRI lesions in isolated complex I deficiency

We describe a boy presenting at the end of the first year of life with severely delayed motor development and only mild mental retardation. Neurological examination revealed axial hypotonia, mild ataxia and pyramidal signs. Elevated lactate and protein in cerebrospinal fluid were the most prominent laboratory abnormalities. Brain MRI showed severe supratentorial white matter changes. Cerebellar white matter appeared normal whereas the signal of the atrophic cerebellar cortex was markedly increased. In vivo 1H-magnetic resonance spectroscopy of the parietooccipital white matter region showed a distinct resonance of lactate. By means of biochemical analysis of respiratory chain enzymes in fibroblasts, the diagnosis of an isolated complex I deficiency could be established in our patient.     

Pattern and significance of white matter abnormalities in myotonic dystrophy type 1: an MRI study

We reviewed the brain MRI of 66 patients with the adult form of myotonic dystrophy type 1 (DM1) to evaluate the extent and significance of white matter involvement and to look for a pattern of MRI abnormalities suggestive of DM1. White matter lesions (WMLs) and large Virchow Robin spaces (VRSs) were rated by semiquantitative methods and the signal intensity of white matter superior and posterior to the trigones (WMPST) by reference to standard images. Disease duration was correlated positively with WML and negatively with VRS scores. Patients were divided into four groups according to increasing severity of WMPST involvement: group A with mild WMPST hyperintensity, group B with large VRSs and mild or moderate WMPST hyperintensity, group C with moderate WMPST hyperintensity or mild WMPST hyperintensity with small WMLs, group D with severe WMPST hyperintensity or moderate WMPST hyperintensity with small WMLs. Disease duration, muscular impairment, lobar WMLs and brain atrophy significantly increased from groups A and B (not significantly different) to C and from C to D, while convexity VRSs significantly decreased from group B to C and from C to D. Lobar white matter involvement in DM1 seems progressive during the disease and may be characterized initially by large VRSs or mild WMPST hyperintensity, then by small WMLs or moderate WMPST hyperintensity, and finally by more extensive and confluent WMLs or diffuse white matter hyperintensity and by brain atrophy. Received: 2 May 2001, Received in revised form: 19 February 2002, Accepted: 22 February 2002     

Merosin negative congenital muscular dystrophy: a short report

We report a rare case of an infant with congenital muscular dystrophy who presented at birth with marked generalized hypotonia and normal mental development. Creatinine phosphokinase (CPK) level was markedly raised; however no white matter abnormalities were detected by brain imaging techniques. Immunohistochemical staining for merosin (laminin alpha 2) was negative, thereby confirming merosin-deficient congenital muscular dystrophy.     

A severe case of dentatorubro-pallidoluysian atrophy (DRPLA) with microcephaly, very early onset of seizures, and cerebral white matter involvement

We report a severe case of Dentatorubro-pallidoluysian atrophy (DRPLA) presenting with microcephaly, developmental delay, severe epilepsy, and progressive mental deterioration with a very early onset of disease. The case is notable for the early detection of white matter changes by brain MRI. Neuroradiological findings from the case were compared to those of previously reported patients with disease onset before 10 years of age.