Megalencephaly and leukodystrophy with mild clinical course: a report on 12 new cases

doi:10.1016/S0387-7604(98)00002-3

Brain and Development

Volume 20, Issue 3, April 1998, Pages 142-153

https://doi.org/10.1016/S0387-7604(98)00002-3 Get rights and content

Abstract

Twelve patients with early infancy onset megalencephaly and leukodystrophy with a mild clinical course are reported. The neuroradiological, clinical, and genetic aspects of this recently recognized familial leukodystrophy syndrome were reviewed. Five were affected siblings, and all patients had consanguineous parents. Macrocephaly, a slowly progressive delay in motor development and mild mental deterioration constitute the clinical triad of the disease, showing characteristic age-related onset. The clinical findings outlined remarkably slight functional deterioration despite severe lesions on magnetic resonance imaging (MRI), especially in the initial period. Characteristically, mental function is preserved for years after onset of the motor deficit. The MRI lesions do not reflect the progress of disease. The disease probably has an autosomal recessive mode of inheritance even though no metabolic defect has been detected to date. In a more severe variant of the mentioned disease, there is more progressive and severe neurological dysfunction, including ataxia and spastic quadriparesis, leading to an inability to walk independently after 10 years of age. In mild variants, however, disease severity varies from macrocephaly with near-normal pyschomotor development to mild motor and/or mental dysfunction. Seizures were observed in both types but response to drugs was good. The 12 patients reported here confirm the specific and distinguishing clinical and radiological features of the previously reported 51 cases with this new syndrome, while adding some information regarding identification of the disease.

Introduction

The combination of leukoencephalopathy and megalencephaly with infancy onset is generally a progressive neurological disorder. Canavan's disease, Alexander's disease, a variant of l-2-OH-glutaric aciduria, and GM₁ gangliosidosis are the most familiar causative diseases 1, 2, 3, 4, 5, 6. In these leukodystrophies, neurological deterioration occurs in months, and leads to death in a few months or years. Recent reports have described a distinct form of infantile leukoencephalopathy and megalencephaly with a mild clinical course 7, 8, 9, 10, 11. This could be considered as a new syndrome [12]. No metabolic defect was detected and an autosomal recessive inheritance was suggested in this new leukodystrophy. However, clinical features suggested the presence of two variants of this new syndrome. Here, we present 12 new patients, the first Turkish cases, with clinical and magnetic resonance imaging (MRI) features.

Section snippets

Patients

Twelve patients with megalencephaly presenting in the first year of life and diffuse leukoencephalopathy alone or with subcortical cystic cavitations on cranial MRI were followed prospectively together with a normal biochemical study of blood and urine. The mean follow-up period was 3.1±2.3 (mean±SD) years, or from 0.5 to 7.5 years. A detailed clinical and developmental history was obtained on all patients, periodically. Neurological and mental examinations, including IQ test, were documented

Clinical profiles

Clinical characteristics of the patients are summarized in Table 1. Five of them were affected siblings. The mean age at first consultation was 2.8±1.9 years (range 0.5–6 years). Five patients were female. The mean age at last visit was 6.2±3.2 years (range 2–10 years). Unfortunately, one of the patients (case 1) died due to pneumonia at the age of 4.5 years. Other cases were followed to the present day. Physical examination showed no abnormalities, including no organomegaly or cutaneous signs.

Discussion

The presented cases are typical examples of the recently recognized new syndrome with specific clinical and MRI features distinguishing it from other progressive neurological diseases with megalencephaly and leukodystrophy. First, in most of the patients, the triad of macrocephaly, motor developmental delay, and mental deterioration shows a characteristic age-related onset. Second, MRI appearance is characteristic with diffuse and homogenous white matter disease with parenchymal swelling, a

Acknowledgements

The authors are grateful to Dr. A.H. Van Gennip, Dr. R.B.H. Schutgens, R.J.A. Wanders, and Dr. P. Vreken from Academic Medical Center (Emma Children's Hospitals Amc), University of Amsterdam, The Netherlands for organic acid analysis. This study has been partly funded by the Turkish Child Neurology Association.

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By the age of 13–19, patients are usually wheelchair-bound [van der Knaap et al., 2012]. Cognitive skills are normal or mildly decreased [Goutières et al., 1996; Singhal et al., 1996; Topcu et al., 1998; van der Knaap et al., 1995]. Most individuals have occasional epileptic seizures that are usually easily controlled with medication [van der Knaap et al., 1995], but status epilepticus can occur [Mejaski-Bosnjak et al., 1997; Singhal et al., 1996].
Megalencephalic leukoencephalopathy with subcortical cysts (MLC) (MIM #604004) is a rare autosomal recessive neurological disorder characterized by macrocephaly, motor and cognitive decline, ataxia, spasticity and occasional seizures. Magnetic resonance imaging (MRI) shows diffusely abnormal and swollen white matter of the cerebral hemispheres and subcortical cysts in the anterior temporal and frontoparietal region. Mutations in MLC1(22q13.33) and GLIALCAM have been identified in patients with MLC. Mutations in MLC1 account for approximately 75% of the cases.
MLC was suspected in eighteen Iranian patients from sixteen families based on positive clinical findings including macrocephaly beginning in the first year, neurocognitive deterioration, seizure or loss of consciousness after minor head trauma. All except two were born to consanguineous parents. Brain MRI images were compatible with MLC and confirmed the diagnosis. Sequencing of entire coding region of MLC1 was performed for seventeen patients and mutations in MLC1 were detected in all of them. Eight novel mutations and seven previously reported mutations were identified. This report shows that MLC is relatively common in Iranian population, as expected for rare diseases with high inbreeding, with a surprisingly high frequency of novel mutations.
Megalencephalic leukoencephalopathy with subcortical cysts protein-1 modulates endosomal pH and protein trafficking in astrocytes: Relevance to MLC disease pathogenesis
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Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare leukodystrophy caused by mutations in the gene encoding MLC1, a membrane protein mainly expressed in astrocytes in the central nervous system. Although MLC1 function is unknown, evidence is emerging that it may regulate ion fluxes. Using biochemical and proteomic approaches to identify MLC1 interactors and elucidate MLC1 function we found that MLC1 interacts with the vacuolar ATPase (V-ATPase), the proton pump that regulates endosomal acidity. Because we previously showed that in intracellular organelles MLC1 directly binds Na, K-ATPase, which controls endosomal pH, we studied MLC1 endosomal localization and trafficking and MLC1 effects on endosomal acidity and function using human astrocytoma cells overexpressing wild-type (WT) MLC1 or MLC1 carrying pathological mutations. We found that WT MLC1 is abundantly expressed in early (EEA1⁺, Rab5⁺) and recycling (Rab11⁺) endosomes and uses the latter compartment to traffic to the plasma membrane during hyposmotic stress. We also showed that WT MLC1 limits early endosomal acidification and influences protein trafficking in astrocytoma cells by stimulating protein recycling, as revealed by FITC-dextran measurement of endosomal pH and transferrin protein recycling assay, respectively. WT MLC1 also favors recycling to the plasma-membrane of the TRPV4 cation channel which cooperates with MLC1 to activate calcium influx in astrocytes during hyposmotic stress. Although MLC disease-causing mutations differentially affect MLC1 localization and trafficking, all the mutated proteins fail to influence endosomal pH and protein recycling. This study demonstrates that MLC1 modulates endosomal pH and protein trafficking suggesting that alteration of these processes contributes to MLC pathogenesis.
Congenital genetic inborn errors of metabolism presenting as an adult or persisting into adulthood: Neuroimaging in the more common or recognizable disorders
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Megancephalic leukoencephalopathy with subcortical cysts (MLC) is a rare, autosomal recessive vacuolating myelinopathy that was described by van der Knaap et al207 in 1995 and is sometimes referred to as “van der Knaap disease.”208-212 Genetic analyses have mapped the defect to the MLC-1 gene at chromosome 22q, although a small subset of patients with MLC with MRI findings of MLC may test negative for the genetic defect.207-212 MLC is usually characterized by macrocephaly that presents in infancy, often with mild neurologic symptoms at presentation such as mild motor delay; the symptoms gradually worsen over years with deterioration to poor ambulation, falls, ataxia, spasticity, and increasing seizures.207-210
Numerous congenital-genetic inborn errors of metabolism (CIEMs) have been identified and characterized in detail within recent decades, with promising therapeutic options. Neuroimaging is becoming increasingly utilized in earlier stages of CIEMs, and even in asymptomatic relatives of patients with a CIEM, so as to monitor disease progress and treatment response. This review attempts to summarize in a concise fashion the neuroimaging findings of various CIEMs that may present in adulthood, as well as those that may persist into adulthood, whether because of beneficial therapy or a delay in diagnosis. Notably, some of these disorders have neuroimaging findings that differ from their classic infantile or earlychildhood forms, whereas others are identical to their early pediatric forms. The focus of this review is their appearance on routine magnetic resonance imaging sequences, with some basic attention to the findings of such CIEMs on specialized neuroimaging, based on recent or preliminary research. The general classes of disorders covered in this complex review are: peroxisomal disorders (adrenoleukodystrophy), lysosomal storage disorders (including metachromatic leukodystrophy, Krabbe or globoid cell leukodystrophy, Fabry, Niemann-Pick, GM1, GM2, Gaucher, mucopolysaccharidoses, and Salla diseases), mitochondrial disorders (including mitochondrial encephalomyopathy with lactic acidosis and strokelike episodes, myoclonic epilepsy with ragged red fibers, Leigh disease, and Kearns-Sayre syndrome), urea cycle disorders, several organic acidemias (including phenylketonuria, maple syrup urine disease, 3-hydroxy-3-methylglutaryl colyase deficiency, glutaric acidurias, methylmalonic academia, proprionic academia, 3-methylglucatonic aciduria, and 2-hydroxyglutaric acidurias), cytoskeletal or transporter molecule defects (including Alexander or fibrinoid leukodystrophy, proteolipid protein-1 defect or Pelizaeus Merzbacher, Wilson, and Huntington diseases), and several neurodegenerative disorders of brain iron accumulation. Additionally, an arbitrary “miscellaneous” category of 5 recognizable disorders that may present in or persist into adulthood is summarized, which include megalencephalic leukoencephalopathy with subcortical cysts (megancephalic leukoencephalopathy with subcortical cysts or van der Knaap disease), polymerase-III gene defect (“4H syndrome”), childhood ataxia with central nervous system hypomyelination (“vanishing white matter disease”), striopallidodentate calcinosis (“Fahr disease”), and Cockayne syndrome.
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Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare and genetically heterogeneous cerebral white matter disease. Clinically, it is characterized by macrocephaly, developmental delay, and seizures. We explore the clinical spectrum, neuroimaging characteristics, and gene involvement in the first patients with megalencephalic leukoencephalopathy with subcortical cysts described from Egypt.
Six patients were enrolled from three unrelated families. Patient inclusion criteria were macrocephaly, developmental delay, normal urinary organic acids, and brain imaging of diffuse cerebral white matter involvement. Direct sequencing of the MLC1 gene in patients' families and GliaCAM in one questionable case was performed using BigDye Terminator cycle sequencing.
Clinical heterogeneity, both intra- and interfamilial, was clearly evident. Developmental delays ranged from globally severe or moderate to mild delay in achieving walking or speech. Head circumference above the ninety-seventh percentile was a constant feature. Neuroimaging featured variability in white matter involvement and subcortical cysts. However, findings of posterior fossa changes and brain stem atrophy were frequently (66.6%) identified in these Egyptian patients. Discrepancy between severe brain involvement and normal mental functions was evident, particularly in patients from the third family. MLC1 mutations were confirmed in all patients. Deletion/insertion mutation in exon 11 (c.908-918delinsGCA, p.Val303 Gly fsX96) was recurrent in two families, whereas a missense mutation in exon 10 (c.880 C > T, p.Pro294Ser) was identified in the third family.
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2012, The Lancet Neurology
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Some patients have a borderline macrocephaly,2,15 but more often the macrocephaly is striking.1 Most children are mildly delayed in achieving unsupported walking and their gait is unstable.1,2,13,14 After several years, patients with MLC develop slowly progressive cerebellar ataxia and, to a lesser degree, spasticity.1,2,13,14
Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is characterised by chronic white matter oedema. The disease has an infantile onset and leads to slow neurological deterioration in most cases, but, surprisingly, some patients recover. The first disease gene, MLC1, identified in 2001, is mutated in 75% of patients. At that time, nothing was known about MLC1 protein function and the pathophysiology of MLC. More recently, HEPACAM (also called GLIALCAM) has been identified as a second disease gene. GlialCAM serves as an escort for MLC1 and the chloride channel CLC2. The defect in MLC1 has been shown to hamper the cell volume regulation of astrocytes. One of the most important consequences involves the potassium siphoning process, which is essential in brain ion and water homoeostasis. An understanding of the mechanisms of white matter oedema in MLC is emerging. Further insight into the specific function of MLC1 is necessary to find treatment targets.
Genetic demyelinating diseases
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Les leucodsytrophies de l’adulte constituent un vaste champ diagnostique.
Une approche multidisciplinaire est indispensable pour arriver à un diagnostic : clinique, neuroradiologique, biochimique et moléculaire.
On estime que moins d’un tiers des leucodystrophies débutant à l’âge adulte ont un diagnostic étiologique.
Une meilleure connaissance neuroradiologique permet de dégager des phénotypes IRM (imagerie par résonance magnétique) orientant vers des diagnostics étiologiques précis.
Les leucodystrophies cavitaires sont représentées par le childhood ataxia with central nervous system hypomyelination (CACH)/Vanishing white matter (VWM) syndrome et la leucoencéphalopathie mégalencéphale avec kystes sous-corticaux (MLC).
Une atteinte médullaire cordonale postérieure oriente vers une leucoencéphalopathie avec atteinte du tronc cérébral et de la moelle avec augmentation de lactate (LBSL).
Diagnosis of leukodystrophies in adults is difficult.
Diagnosis requires a collaborative approach including clinical, neuroradiological, biochemical, and genetic analyses.
Less than thirty percent of adult-onset leukodystrophies have a precise diagnosis.
Improved neuroradiological knowledge is making it possible to determine MRI (magnetic resonance imaging) phenotypes that point towards specific causes and specific diagnoses.
The cavitary leukodystrophies include childhood ataxia with central nervous system hypomyelination/vanishing white matter (CACH/VWM) syndrome and megalencephalic leukoencephalopathy with subcortical cysts (MLC).
Damage to the posterior spinal cord suggests leukoencephalopathy with damage to the brainstem and cord marrow and is accompanied by elevated lactate (LBSL).

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Original articleMegalencephaly and leukodystrophy with mild clinical course: a report on 12 new cases

Abstract

Introduction

Section snippets

Patients

Clinical profiles

Discussion

Acknowledgements

Brain Dev

Pediatr Neurol

J Pediatr

Pediatr Neurol

Pediatr Neurol

Alexander's disease: clues to diagnosis

J Child Neurol

Clinical and magnetic resonance imaging features of l-2-hydroxyglutaric acidemia: report of three cases in comparison with Canavan disease

J Child Neurol

Leukoencephalopathy, megalencephaly, and mild clinical course. A recent individualized familial leukodystrophy. Report on five new cases

J Child Neurol

Original article
Megalencephaly and leukodystrophy with mild clinical course: a report on 12 new cases