Marjo S van der Knaap

Publications (126)1009.08 Total impact

• Article: Mutations in DARS Cause Hypomyelination with Brain Stem and Spinal Cord Involvement and Leg Spasticity.

  Ryan J Taft, Adeline Vanderver, Richard J Leventer, Stephen A Damiani, Cas Simons, Sean M Grimmond, David Miller, Johanna Schmidt, Paul J Lockhart, Kate Pope, [......], Monica Juneja, Ishwar C Verma, Prab Prabhakar, Susan Blaser, Julian Raiman, Petra J W Pouwels, Marianna R Bevova, Truus E M Abbink, Marjo S van der Knaap, Nicole I Wolf
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  ABSTRACT: Inherited white-matter disorders are a broad class of diseases for which treatment and classification are both challenging. Indeed, nearly half of the children presenting with a leukoencephalopathy remain without a specific diagnosis. Here, we report on the application of high-throughput genome and exome sequencing to a cohort of ten individuals with a leukoencephalopathy of unknown etiology and clinically characterized by hypomyelination with brain stem and spinal cord involvement and leg spasticity (HBSL), as well as the identification of compound-heterozygous and homozygous mutations in cytoplasmic aspartyl-tRNA synthetase (DARS). These mutations cause nonsynonymous changes to seven highly conserved amino acids, five of which are unchanged between yeast and man, in the DARS C-terminal lobe adjacent to, or within, the active-site pocket. Intriguingly, HBSL bears a striking resemblance to leukoencephalopathy with brain stem and spinal cord involvement and elevated lactate (LBSL), which is caused by mutations in the mitochondria-specific DARS2, suggesting that these two diseases might share a common underlying molecular pathology. These findings add to the growing body of evidence that mutations in tRNA synthetases can cause a broad range of neurologic disorders.
  The American Journal of Human Genetics 05/2013; 92(5):774-80. · 10.60 Impact Factor
• Article: Improvement of White Matter Changes on Neuroimaging Modalities After Stem Cell Transplant in Metachromatic Leukodystrophy.

  Martje E van Egmond, Petra J W Pouwels, Jaap-Jan Boelens, Caroline A Lindemans, Frederik Barkhof, Martijn D Steenwijk, Peter M van Hasselt, Marjo S van der Knaap, Nicole I Wolf
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  ABSTRACT: IMPORTANCE We sought to illustrate improvement of cerebral white matter changes in metachromatic leukodystrophy after treatment with hematopoietic stem cell transplant (HSCT). OBSERVATIONS We conducted serial magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy (1H-MRS) as standard follow-up after HSCT with cord blood in 1 patient with juvenile metachromatic leukodystrophy diagnosed before frank degenerative symptoms developed. We measured MRI and 1H-MRS changes. The white matter changes first increased after HSCT, then decreased in relation to the pre-HSCT MRI and 1H-MRS. CONCLUSIONS AND RELEVANCE Hematopoietic stem cell transplant, if performed early in metachromatic leukodystrophy, can not only stabilize but even improve cerebral white matter abnormalities. Our findings suggest a biological effect of HSCT.
  JAMA neurology. 04/2013;
• Article: A De Novo Mutation in the β-Tubulin Gene TUBB4A Results in the Leukoencephalopathy Hypomyelination with Atrophy of the Basal Ganglia and Cerebellum.

  Cas Simons, Nicole I Wolf, Nathan McNeil, Ljubica Caldovic, Joseph M Devaney, Asako Takanohashi, Joanna Crawford, Kelin Ru, Sean M Grimmond, David Miller, [......], Johanna L Schmidt, Robert S Chudnow, Rudy van Coster, Lieven Lagae, Jill Kisler, Jürgen Sperner, Marjo S van der Knaap, Raphael Schiffmann, Ryan J Taft, Adeline Vanderver
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  ABSTRACT: Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) is a rare hereditary leukoencephalopathy that was originally identified by MRI pattern analysis, and it has thus far defied all attempts at identifying the causal mutation. Only 22 cases are published in the literature to date. We performed exome sequencing on five family trios, two family quartets, and three single probands, which revealed that all eleven H-ABC-diagnosed individuals carry the same de novo single-nucleotide TUBB4A mutation resulting in nonsynonymous change p.Asp249Asn. Detailed investigation of one of the family quartets with the singular finding of an H-ABC-affected sibling pair revealed maternal mosaicism for the mutation, suggesting that rare de novo mutations that are initially phenotypically neutral in a mosaic individual can be disease causing in the subsequent generation. Modeling of TUBB4A shows that the mutation creates a nonsynonymous change at a highly conserved asparagine that sits at the intradimer interface of α-tubulin and β-tubulin, and this change might affect tubulin dimerization, microtubule polymerization, or microtubule stability. Consistent with H-ABC's clinical presentation, TUBB4A is highly expressed in neurons, and a recent report has shown that an N-terminal alteration is associated with a heritable dystonia. Together, these data demonstrate that a single de novo mutation in TUBB4A results in H-ABC.
  The American Journal of Human Genetics 04/2013; · 10.60 Impact Factor
• Article: Deficiency in SLC25A1, Encoding the Mitochondrial Citrate Carrier, Causes Combined D-2- and L-2-Hydroxyglutaric Aciduria.

  Benjamin Nota, Eduard A Struys, Ana Pop, Erwin E Jansen, Matilde R Fernandez Ojeda, Warsha A Kanhai, Martijn Kranendijk, Silvy J M van Dooren, Marianna R Bevova, Erik A Sistermans, [......], Jean-Marc Nuoffer, Rossella Parini, Marie-Hélène Read, Axel Renneberg, René Santer, Thomas Strahleck, Emile van Schaftingen, Marjo S van der Knaap, Cornelis Jakobs, Gajja S Salomons
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  ABSTRACT: The Krebs cycle is of fundamental importance for the generation of the energetic and molecular needs of both prokaryotic and eukaryotic cells. Both enantiomers of metabolite 2-hydroxyglutarate are directly linked to this pivotal biochemical pathway and are found elevated not only in several cancers, but also in different variants of the neurometabolic disease 2-hydroxyglutaric aciduria. Recently we showed that cancer-associated IDH2 germline mutations cause one variant of 2-hydroxyglutaric aciduria. Complementary to these findings, we now report recessive mutations in SLC25A1, the mitochondrial citrate carrier, in 12 out of 12 individuals with combined D-2- and L-2-hydroxyglutaric aciduria. Impaired mitochondrial citrate efflux, demonstrated by stable isotope labeling experiments and the absence of SLC25A1 in fibroblasts harboring certain mutations, suggest that SLC25A1 deficiency is pathogenic. Our results identify defects in SLC25A1 as a cause of combined D-2- and L-2-hydroxyglutaric aciduria.
  The American Journal of Human Genetics 04/2013; 92(4):627-31. · 10.60 Impact Factor
• Article: NUBPL mutations in patients with complex I deficiency and a distinct MRI pattern.

  Sietske H Kevelam, Richard J Rodenburg, Nicole I Wolf, Patrick Ferreira, Roelineke J Lunsing, Leo G Nijtmans, Anne Mitchell, Hugo A Arroyo, Dietz Rating, Adeline Vanderver, Carola G M van Berkel, Truus E M Abbink, Peter Heutink, Marjo S van der Knaap
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  ABSTRACT: OBJECTIVE: To identify the mutated gene in a group of patients with an unclassified heritable white matter disorder sharing the same, distinct MRI pattern. METHODS: We used MRI pattern recognition analysis to select a group of patients with a similar, characteristic MRI pattern. We performed whole-exome sequencing to identify the mutated gene. We examined patients' fibroblasts for biochemical consequences of the mutant protein. RESULTS: We identified 6 patients from 5 unrelated families with a similar MRI pattern showing predominant abnormalities of the cerebellar cortex, deep cerebral white matter, and corpus callosum. The 4 tested patients had a respiratory chain complex I deficiency. Exome sequencing revealed mutations in NUBPL, encoding an iron-sulfur cluster assembly factor for complex I, in all patients. Upon identification of the mutated gene, we analyzed the MRI of a previously published case with NUBPL mutations and found exactly the same pattern. A strongly decreased amount of NUBPL protein and fully assembled complex I was found in patients' fibroblasts. Analysis of the effect of mutated NUBPL on the assembly of the peripheral arm of complex I indicated that NUBPL is involved in assembly of iron-sulfur clusters early in the complex I assembly pathway. CONCLUSION: Our data show that NUBPL mutations are associated with a unique, consistent, and recognizable MRI pattern, which facilitates fast diagnosis and obviates the need for other tests, including assessment of mitochondrial complex activities in muscle or fibroblasts.
  Neurology 04/2013; · 8.31 Impact Factor
• Article: Exome sequencing reveals mutated SLC19A3 in patients with an early-infantile, lethal encephalopathy.

  Sietske H Kevelam, Marianna Bugiani, Gajja S Salomons, Annette Feigenbaum, Susan Blaser, Chitra Prasad, Johannes Häberle, Ivo Baric, Ingrid M C Bakker, Nienke L Postma, Warsha A Kanhai, Nicole I Wolf, Truus E M Abbink, Quinten Waisfisz, Peter Heutink, Marjo S van der Knaap
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  ABSTRACT: To accomplish a diagnosis in patients with a rare unclassified disorder is difficult. In this study, we used magnetic resonance imaging pattern recognition analysis to identify patients with the same novel heritable disorder. Whole-exome sequencing was performed to discover the mutated gene. We identified seven patients sharing a previously undescribed magnetic resonance imaging pattern, characterized by initial swelling with T2 hyperintensity of the basal nuclei, thalami, cerebral white matter and cortex, pons and midbrain, followed by rarefaction or cystic degeneration of the white matter and, eventually, by progressive cerebral, cerebellar and brainstem atrophy. All patients developed a severe encephalopathy with rapid deterioration of neurological functions a few weeks after birth, followed by respiratory failure and death. Lactate was elevated in body fluids and on magnetic resonance spectroscopy in most patients. Whole-exome sequencing in a single patient revealed two predicted pathogenic, heterozygous missense mutations in the SLC19A3 gene, encoding the second thiamine transporter. Additional predicted pathogenic mutations and deletions were detected by Sanger sequencing in all six other patients. Pathology of brain tissue of two patients demonstrated severe cerebral atrophy and microscopic brain lesions similar to Leigh's syndrome. Although the localization of SLC19A3 expression in brain was similar in the two investigated patients compared to age-matched control subjects, the intensity of the immunoreactivity was increased. Previously published patients with SLC19A3 mutations have a milder clinical phenotype, no laboratory evidence of mitochondrial dysfunction and more limited lesions on magnetic resonance imaging. In some, cerebral atrophy has been reported. The identification of this new, severe, lethal phenotype characterized by subtotal brain degeneration broadens the phenotypic spectrum of SLC19A3 mutations. Recognition of the associated magnetic resonance imaging pattern allows a fast diagnosis in affected infants.
  Brain 03/2013; · 9.46 Impact Factor
• Article: Novel Hypomyelinating Leukoencephalopathy Affecting Early Myelinating Structures: Clinical Course in Two Brothers.

  Davide Tonduti, Anna Pichiecchio, Nicole I Wolf, Giada Ariaudo, Marjo S van der Knaap, Stefano Bastianello, Umberto Balottin, Simona Orcesi
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  ABSTRACT: A novel leukoencephalopathy, termed hypomyelinating leukoencephalopathy affecting early myelinating structures (HEMS), was recently described. Here we report on two patients affected by HEMS with a clinical picture characterized by early-onset nystagmus and thereafter progressive cerebellar signs and mild spasticity predominantly affecting the legs. In one patient, who has the longest follow-up described to date, we detected a mild worsening of the clinical and neuroradiologic picture after a long period of stability lasting until age 6 years. The most recent magnetic resonance image, performed at the age of 11 years, showed a more severe neuroradiologic picture characterized by involvement of almost the entire supratentorial white matter, with relative sparing of the subcortical fibers. We also provide spectroscopy results, not previously reported in this disorder, that support the idea of a progressive disease course on neuroimaging. Our findings suggest that HEMS patients should undergo a new magnetic resonance imaging evaluation after a certain interval to look for possible progression of the abnormalities.
  Neuropediatrics 01/2013; · 0.94 Impact Factor
• Article: Hyaluronan accumulation and arrested oligodendrocyte progenitor maturation in vanishing white matter disease.

  Marianna Bugiani, Nienke Postma, Emiel Polder, Nikki Dieleman, Peter G Scheffer, Fraser J Sim, Marjo S van der Knaap, Ilja Boor
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  ABSTRACT: Vanishing white matter disease is a genetic leukoencephalopathy caused by mutations in eukaryotic translation initiation factor 2B. Patients experience a slowly progressive neurological deterioration with episodes of rapid clinical worsening triggered by stress. The disease may occur at any age and leads to early death. Characteristic neuropathological findings include cystic degeneration of the white matter with feeble, if any, reactive gliosis, dysmorphic astrocytes and paucity of myelin despite an increase in oligodendrocytic density. These features have been linked to a maturation defect of astrocytes and oligodendrocytes. However, the nature of the link between glial immaturity and the observed neuropathological features is unclear. We hypothesized that the defects in maturation and function of astrocytes and oligodendrocytes are related. Brain tissue of seven patients with genetically proven vanishing white matter disease was investigated using immunohistochemistry, western blotting, quantitative polymerase chain reaction and size exclusion chromatography. The results were compared with those obtained from normal brain tissue of age-matched controls, from chronic demyelinated multiple sclerosis lesions and from other genetic and acquired white matter disorders. We found that the white matter of patients with vanishing white matter disease is enriched in CD44-expressing astrocyte precursor cells and accumulates the glycosaminoglycan hyaluronan. Hyaluronan is a major component of the extracellular matrix, and CD44 is a hyaluronan receptor. We found that a high molecular weight form of hyaluronan is overabundant, especially in the most severely affected areas. Comparison between the more severely affected frontal white matter and the relatively spared cerebellum confirms that high molecular weight hyaluronan accumulation is more pronounced in the frontal white matter than in the cerebellum. High molecular weight hyaluronan is known to inhibit astrocyte and oligodendrocyte precursor maturation and can explain the arrested glial progenitor maturation observed in vanishing white matter disease. In conclusion, high molecular weight species of hyaluronan accumulate in the white matter of patients with vanishing white matter disease, and by inhibiting glial maturation and proper function, they may be a major determinant of the white matter pathology and lack of repair.
  Brain 01/2013; 136(Pt 1):209-22. · 9.46 Impact Factor
• Source

  Available from: Gert C Scheper

  Article: Pathogenic mutations causing LBSL affect mitochondrial aspartyl-tRNA synthetase in diverse ways.

  Laura van Berge, Josta Kevenaar, Emiel Polder, Agnès Gaudry, Catherine Florentz, Marie Sissler, Marjo S van der Knaap, Gert C Scheper
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  ABSTRACT: The autosomal recessive white matter disorder "leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation" (LBSL) is caused by mutations in DARS2, coding for mitochondrial aspartyl-tRNA synthetase (mtAspRS). Generally, patients are compound heterozygous for mutations in DARS2. Many different mutations have been identified in patients, including several missense mutations. Here we have examined the effects of missense mutations found in LBSL patients on the expression, enzyme activity, localization and dimerization of mtAspRS, which is important for understanding the cellular defect underlying the pathogenesis of the disease. Nine different missense mutations were analyzed and showed various effects on mtAspRS properties. Several mutations have a direct effect on the catalytic activity of the enzyme; others have an effect on protein expression or dimerization. Most mutations have a clear impact on at least one of the studied properties of mtAspRS, probably resulting in a small contribution of the missense variants to the mitochondrial aspartylation activity in the cell.
  Biochemical Journal 12/2012; · 4.90 Impact Factor
• Article: Megalencephalic leukoencephalopathy with subcortical cysts: chronic white matter oedema due to a defect in brain ion and water homoeostasis.

  Marjo S van der Knaap, Ilja Boor, Raúl Estévez
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  ABSTRACT: 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.
  The Lancet Neurology 11/2012; 11(11):973-85. · 23.46 Impact Factor
• Article: Recognizable phenotypes associated with intracranial calcification.

  John H Livingston, Stavros Stivaros, Marjo S VAN DER Knaap, Yanick J Crow
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  ABSTRACT: Aim  In this observational study, we adopted a systematic approach to the radiological phenotyping of disorders associated with intracranial calcification, with the aim of determining if characteristic patterns could be defined as an aid to the future diagnosis of known conditions and the identification of new disorders. Method  A cranial imaging-based scoring system was devised using both computed tomography and magnetic resonance imaging data. Patients were grouped into diagnostic categories where a definitive molecular diagnosis was known, or where the clinical and radiological features suggested a specific diagnosis. For patients in whom the diagnosis was unknown, subgroups were defined according to shared radiological features. Results  Data on 244 scans from 119 patients were analysed. A specific diagnosis was available for 59 patients (31males, 28 females; median age 50mo, range 1wk to 54y). These were as follows (number of patients in brackets): Aicardi-Goutières syndrome (33), cerebroretinal microangiopathy with calcification and cysts (10), band-like calcification with simplified gyration and polymicrogyria (6), COL4A1-related disease (3), Degos disease (2), Krabbe disease (2), Alexander disease (1), mitochondrial disease (1), and tetrasomy 15 (1). In 60 patients the aetiology was unknown. Within this group, subsets demonstrating shared characteristics suggestive of a specific calcification phenotype could be identified. Interpretation  This study confirms the value of a systematic approach to radiological phenotyping of disorders associated with intracranial calcification.
  Developmental Medicine & Child Neurology 11/2012; · 2.92 Impact Factor
• Article: A novel GJC2 mutation associated with hypomyelination and Müllerian agenesis syndrome: coincidence or a new entity?

  Cengiz Yalcinkaya, Ozdem Erturk, Beyhan Tuysuz, Gozde Yesil, Jonathan I M L Verbeke, Britta Keyser, Manfred Stuhrmann, Doris Steinemann, Erik A Sistermans, Marjo S van der Knaap
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  ABSTRACT: In recent years, several new white matter diseases have been identified based on magnetic resonance imaging and clinical findings. For most newly defined disorders the genetic basis has been identified. However, there is still a large group of patients without a specific diagnosis. Hypomyelinating leukodystrophies are the largest group among them. In some disorders characterized by hypomyelination only central nervous system involvement is observed, but in some disorders involvement of other organs is observed as well, such as eyes or teeth. Pelizaeus-Merzbacher-like disease (PMLD) is an autosomal recessive hypomyelinating disorder of the central nervous system characterized by nystagmus, ataxia, and progressive spasticity. The disease is caused by mutations in GJC2, the gene that encodes the gap junction protein connexin 47. Here we describe hypomyelination and Müllerian agenesis syndrome in a girl who is homozygous for a novel mutation in the GJC2 gene. It is an open question whether this is an association by chance or a feature of PMLD not previously noted.
  Neuropediatrics 05/2012; 43(3):159-61. · 0.94 Impact Factor
• Article: Infantile-Onset Alexander Disease : A Genetically Proven Case With Mild Clinical Course in a 6-Year-Old Indian Boy.

  Konanki Ramesh, Suvasini Sharma, Atin Kumar, Gajja S Salomons, Marjo S van der Knaap, Sheffali Gulati
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  ABSTRACT: Alexander disease is an autosomal dominant leukoencephalopathy characterized by developmental delay, macrocephaly, and characteristic neuroimaging abnormalities predominantly involving frontal lobes. We report a 6-year-old Indian boy with infantile-onset Alexander disease, who has an unusually mild clinical course and a de novo p.Leu359Val mutation in the glial fibrillary acidic protein gene.
  Journal of child neurology 05/2012; · 1.59 Impact Factor
• Article: Leukoencephalopathy with thalamus and brainstem involvement and high lactate 'LTBL' caused by EARS2 mutations.

  Marjan E Steenweg, Daniele Ghezzi, Tobias Haack, Truus E M Abbink, Diego Martinelli, Carola G M van Berkel, Annette Bley, Luisa Diogo, Eugenio Grillo, Johann Te Water Naudé, Tim M Strom, Enrico Bertini, Holger Prokisch, Marjo S van der Knaap, Massimo Zeviani
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  ABSTRACT: In the large group of genetically undetermined infantile-onset mitochondrial encephalopathies, multiple defects of mitochondrial DNA-related respiratory-chain complexes constitute a frequent biochemical signature. In order to identify responsible genes, we used exome-next-generation sequencing in a selected cohort of patients with this biochemical signature. In an isolated patient, we found two mutant alleles for EARS2, the gene encoding mitochondrial glutamyl-tRNA synthetase. The brain magnetic resonance imaging of this patient was hallmarked by extensive symmetrical cerebral white matter abnormalities sparing the periventricular rim and symmetrical signal abnormalities of the thalami, midbrain, pons, medulla oblongata and cerebellar white matter. Proton magnetic resonance spectroscopy showed increased lactate. We matched this magnetic resonance imaging pattern with that of a cohort of 11 previously selected unrelated cases. We found mutations in the EARS2 gene in all. Subsequent detailed clinical and magnetic resonance imaging based phenotyping revealed two distinct groups: mild and severe. All 12 patients shared an infantile onset and rapidly progressive disease with severe magnetic resonance imaging abnormalities and increased lactate in body fluids and proton magnetic resonance spectroscopy. Patients in the 'mild' group partially recovered and regained milestones in the following years with striking magnetic resonance imaging improvement and declining lactate levels, whereas those of the 'severe' group were characterized by clinical stagnation, brain atrophy on magnetic resonance imaging and persistent lactate increases. This new neurological disease, early-onset leukoencephalopathy with thalamus and brainstem involvement and high lactate, is hallmarked by unique magnetic resonance imaging features, defined by a peculiar biphasic clinical course and caused by mutations in a single gene, EARS2, expanding the list of medically relevant defects of mitochondrial DNA translation.
  Brain 04/2012; 135(Pt 5):1387-94. · 9.46 Impact Factor
• Source

  Available from: Martijn Kranendijk

  Article: Progress in understanding 2-hydroxyglutaric acidurias.

  Martijn Kranendijk, Eduard A Struys, Gajja S Salomons, Marjo S Van der Knaap, Cornelis Jakobs
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  ABSTRACT: The organic acidurias D: -2-hydroxyglutaric aciduria (D-2-HGA), L-2-hydroxyglutaric aciduria (L-2-HGA), and combined D,L-2-hydroxyglutaric aciduria (D,L-2-HGA) cause neurological impairment at young age. Accumulation of D-2-hydroxyglutarate (D-2-HG) and/or L-2-hydroxyglutarate (L-2-HG) in body fluids are the biochemical hallmarks of these disorders. The current review describes the knowledge gathered on 2-hydroxyglutaric acidurias (2-HGA), since the description of the first patients in 1980. We report on the clinical, genetic, enzymatic and metabolic characterization of D-2-HGA type I, D-2-HGA type II, L-2-HGA and D,L-2-HGA, whereas for D-2-HGA type I and type II novel clinical information is presented which was derived from questionnaires.
  Journal of Inherited Metabolic Disease 03/2012; 35(4):571-87. · 3.58 Impact Factor
• Article: Restricted diffusion in vanishing white matter.

  Hannemieke D W van der Lei, Marjan E Steenweg, Marianna Bugiani, Petra J W Pouwels, Inge M Vent, Frederik Barkhof, Wessel N van Wieringen, Marjo S van der Knaap
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  ABSTRACT: To investigate the occurrence of restricted diffusion in vanishing white matter, the affected structures,the time of occurrence in the disease course, and the histopathologic correlate. Retrospective observational study. Forty-six patients with vanishing white matter. VU University Medical Center. We evaluated all available diffusion-weighted imaging studies in our database and recorded the areas that displayed restricted diffusion in 1 or more patients. We measured the mean apparent diffusion coefficients of these areas in all patients and used the putamen for internal quality control. We recorded age and disease duration during magnetic resonance imaging, and we obtained a magnetic resonance image of a postmortem vanishing white matter brain slice and subsequently performed histopathologic stainings. Areas with decreased apparent diffusion coefficient values were found in the U fibers (n=21 patients), cerebellar white matter (n=18), middle cerebellar peduncle(n=8), pyramids (n=8), genu (n=8) or splenium (n=9) of the corpus callosum, and posterior limb of the internal capsule(n=10). Overall, patients showing restricted diffusion(n=32)were younger and had shorter disease duration. Histopathologic analysis of the brain slice revealed that regions with restricted diffusion had a higher cell density. In vanishing white matter, restricted diffusion can be found in relatively spared regions with high cellularity particularly in young patients with short disease duration.
  Archives of neurology 02/2012; 69(6):723-7. · 6.31 Impact Factor
• Article: Novel infantile-onset leukoencephalopathy with high lactate level and slow improvement.

  Marjan E Steenweg, Adeline Vanderver, Berten Ceulemans, Prab Prabhakar, Luc Régal, Aviva Fattal-Valevski, Lawrence Richer, Barbara Goeggel Simonetti, Frederik Barkhof, Richard J T Rodenburg, Petra J W Pouwels, Marjo S van der Knaap
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  ABSTRACT: To describe a novel pattern of magnetic resonance imaging (MRI) abnormalities as well as the associated clinical and laboratory findings. The MRIs of more than 3000 patients with an unclassified leukoencephalopathy were systematically reviewed.Clinical and laboratory data were retrospectively collected.Setting: University hospital. Seven patients (3 male) shared similar MRI abnormalities and clinical features. Pattern of MRI abnormalities and clinical and laboratory findings. 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. These patients represent a single novel leukoencephalopathy,probably caused by a mitochondrial defect.
  Archives of neurology 02/2012; 69(6):718-22. · 6.31 Impact Factor
• Source

  Available from: Gert C Scheper

  Article: Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation is associated with cell-type-dependent splicing of mtAspRS mRNA.

  Laura van Berge, Stephanie Dooves, Carola G M van Berkel, Emiel Polder, Marjo S van der Knaap, Gert C Scheper
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  ABSTRACT: LBSL (leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation) is an autosomal recessive white matter disorder with slowly progressive cerebellar ataxia, spasticity and dorsal column dysfunction. Magnetic resonance imaging shows characteristic abnormalities in the cerebral white matter and specific brain stem and spinal cord tracts. LBSL is caused by mutations in the gene DARS2, which encodes mtAspRS (mitochondrial aspartyl-tRNA synthetase). The selective involvement of specific white matter tracts in LBSL is striking since this protein is ubiquitously expressed. Almost all LBSL patients have one mutation in intron 2 of DARS2, affecting the splicing of the third exon. Using a splicing reporter construct, we find cell-type-specific differences in the sensitivity to these mutations: the mutations have a larger effect on exon 3 exclusion in neural cell lines, especially neuronal cell lines, than in non-neural cell lines. Furthermore, correct inclusion of exon 3 in the normal mtAspRS mRNA occurs less efficiently in neural cells than in other cell types, and this effect is again most pronounced in neuronal cells. The combined result of these two effects may explain the selective vulnerability of specific white matter tracts in LBSL patients.
  Biochemical Journal 02/2012; 441(3):955-62. · 4.90 Impact Factor
• Article: Characteristics of early MRI in children and adolescents with vanishing white matter.

  Hannemieke D van der Lei, Marjan E Steenweg, Frederik Barkhof, Ton de Grauw, Marc d'Hooghe, Richard Morton, Siddharth Shah, Nicole Wolf, Marjo S van der Knaap
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  ABSTRACT: MRI in vanishing white matter typically shows diffuse abnormality of the cerebral white matter, which becomes increasingly rarefied and cystic. We investigated the MRI characteristics preceding this stage. In a retrospective observational study, we evaluated all available MRIs in our database of DNA-confirmed VWM patients and selected MRIs without diffuse cerebral white matter abnormalities and without signs of rarefaction or cystic degeneration in patients below 20 years of age. A previously established scoring list was used to evaluate the MRIs. An MRI of seven patients fulfilled the criteria. All had confluent and symmetrical abnormalities in the periventricular and bordering deep white matter. In young patients, myelination was delayed. The inner rim of the corpus callosum was affected in all patients. In early stages of VWM, MRI does not necessarily display diffuse cerebral white matter involvement and rarefaction or cystic degeneration. If the MRI abnormalities do not meet the criteria for VWM, it helps to look at the corpus callosum. If the inner rim (the callosal-septal interface) is affected, VWM should be considered.
  Neuropediatrics 02/2012; 43(1):22-6. · 0.94 Impact Factor
• Source

  Available from: J. Paul Taylor

  Article: Archetypal and new families with Alexander disease and novel mutations in GFAP.

  Albee Messing, Rong Li, Sakkubai Naidu, J Paul Taylor, Lital Silverman, Daniel Flint, Marjo S van der Knaap, Michael Brenner
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  ABSTRACT: To describe genetic analyses of the 2 most thoroughly studied, historically seminal multigenerational families with Alexander disease described prior to the identification of GFAP as the related gene, as well as 1 newly discovered family. Clinical histories were obtained and DNA was analyzed from blood, cheek epithelial cells, or fixed paraffin-embedded surgical samples. Affected and unaffected adult members of 3 families and affected children were included. Mutations in GFAP and behavior of mutant protein in cellular transfection assays. Family A contains 4 siblings in whom we found a novel p.Ser247Pro mutation that was paternally inherited. The phenotypes of these siblings include 1 unaffected adult, 1 individual with juvenile-onset disease, and 2 individuals with adult-onset disease. Family B spans 4 generations, including the first described patient with adult-onset disease originally reported in 1968. Analysis of members of the later generations revealed a novel p.Asp417Ala mutation. Family C contains 3 generations. We detected a novel p.Gln426Leu mutation that, to our knowledge, is the farthest C-terminal mutation known. These families display clear evidence of variable phenotypes but do not support recessive inheritance. While germline mosaicism cannot be excluded for 1 family (A), we propose that for genetic counseling purposes the risk of germline mosaicism should be described as less than 1%.
  Archives of neurology 02/2012; 69(2):208-14. · 6.31 Impact Factor