R Schiffmann

Publications (68)503.6 Total impact

• Article: GFAP mutations, age at onset, and clinical subtypes in Alexander disease.

  M Prust, J Wang, H Morizono, A Messing, M Brenner, E Gordon, T Hartka, A Sokohl, R Schiffmann, H Gordish-Dressman, [......], M Nakagawa, R Pedersen, A Reddy, Y Sawaishi, M Schneider, E Sherr, Y Takiyama, K Wakabayashi, J R Gorospe, A Vanderver
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  ABSTRACT: To characterize Alexander disease (AxD) phenotypes and determine correlations with age at onset (AAO) and genetic mutation. AxD is an astrogliopathy usually characterized on MRI by leukodystrophy and caused by glial fibrillary acidic protein (GFAP) mutations. We present 30 new cases of AxD and reviewed 185 previously reported cases. We conducted Wilcoxon rank sum tests to identify variables scaling with AAO, survival analysis to identify predictors of mortality, and χ(2) tests to assess the effects of common GFAP mutations. Finally, we performed latent class analysis (LCA) to statistically define AxD subtypes. LCA identified 2 classes of AxD. Type I is characterized by early onset, seizures, macrocephaly, motor delay, encephalopathy, failure to thrive, paroxysmal deterioration, and typical MRI features. Type II is characterized by later onset, autonomic dysfunction, ocular movement abnormalities, bulbar symptoms, and atypical MRI features. Survival analysis predicted a nearly 2-fold increase in mortality among patients with type I AxD relative to those with type II. R79 and R239 GFAP mutations were most common (16.6% and 20.3% of all cases, respectively). These common mutations predicted distinct clinical outcomes, with R239 predicting the most aggressive course. AAO and the GFAP mutation site are important clinical predictors in AxD, with clear correlations to defined patterns of phenotypic expression. We propose revised AxD subtypes, type I and type II, based on analysis of statistically defined patient groups.
  Neurology 09/2011; 77(13):1287-94. · 8.31 Impact Factor
• Article: Elevated CSF N-acetylaspartylglutamate in patients with free sialic acid storage diseases.

  F Mochel, U F H Engelke, J Barritault, B Yang, N H McNeill, J N Thompson, A Vanderver, N I Wolf, M A Willemsen, F W Verheijen, F Seguin, R A Wevers, R Schiffmann
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  ABSTRACT: To investigate body fluids of patients with undiagnosed leukodystrophies using in vitro (1)H-NMR spectroscopy (H-NMRS). We conducted a cross-sectional study using high-resolution in vitro H-NMRS on CSF and urine samples. We found a significant increase of free sialic acid in CSF or urine in 6 of 41 patients presenting with hypomyelination of unknown etiology. Molecular genetic testing revealed pathogenic mutations in the SLC17A5 gene in all 6 patients. H-NMRS revealed an increase of N-acetylaspartylglutamate in the CSF of all patients with SLC17A5 mutation (range 13-114 micromol/L, reference <12 micromol/L). In patients with undiagnosed leukodystrophies, increased free sialic acid in CSF or urine is a marker for free sialic acid storage disorder and facilitates the identification of the underlying genetic defect. Because increase of N-acetylaspartylglutamate in CSF has been observed in other hypomyelinating disorders, it can be viewed as a marker of a subgroup of hypomyelinating disorders.
  Neurology 01/2010; 74(4):302-5. · 8.31 Impact Factor
• Article: Proposed high-risk screening protocol for Fabry disease in patients with renal and vascular disease.

  C Auray-Blais, D S Millington, S P Young, J T R Clarke, R Schiffmann
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  ABSTRACT: Fabry disease is a complex, multisystemic and clinically heterogeneous disease with prominent urinary excretion of globotriaosylceramide (Gb(3)), the principal substrate of the deficient enzyme, alpha-galactosidase A. Some measure of specific treatment is possible with enzyme replacement therapy, which can be applied safely and effectively to Fabry patients. Incidence estimations of Fabry disease vary widely from 1:55 000 to 1:3000 male births. The true incidence is likely to be higher than originally thought, owing to the existence of milder variants of the disease. The main complications of Fabry disease are a 100-fold increased risk of ischaemic stroke, cardiac disease, a wide variety of arrhythmias, valvular dysfunction and cardiac vascular disease, as well as progressive renal failure usually associated with significant proteinuria. These clinical manifestations are non-specific and are often mistaken for symptoms of other disorders, thus complicating the confirmation of diagnosis. Other clinical features of the disease are often absent (angiokeratoma), subtle (corneal opacities and hypohidrosis), or unaccompanied by specific physical findings (acroparaesthesias) indicating the true nature of the underlying disease. We propose the hypothesis that alpha-galactosidase A deficiency is a modifiable cardiovascular risk factor in the general population. This hypothesis may be tested by a non-invasive high-risk screening protocol for Fabry patients with ischaemic strokes and a variety of cardiac, and renal complications. These patients would benefit from diagnosis, appropriate treatment, follow-up and surveillance. Early detection of Fabry patients would also benefit affected relatives, many of whom do not have a clear diagnosis of their clinical condition.
  Journal of Inherited Metabolic Disease 02/2009; 32(2):303-8. · 3.58 Impact Factor
• Article: Cerebellar ataxia with elevated cerebrospinal free sialic acid (CAFSA).

  F Mochel, F Sedel, A Vanderver, U F H Engelke, J Barritault, B Z Yang, B Kulkarni, D R Adams, F Clot, J H Ding, C R Kaneski, F W Verheijen, B W Smits, F Seguin, A Brice, M T Vanier, M Huizing, R Schiffmann, A Durr, R A Wevers
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  ABSTRACT: In order to identify new metabolic abnormalities in patients with complex neurodegenerative disorders of unknown aetiology, we performed high resolution in vitro proton nuclear magnetic resonance spectroscopy on patient cerebrospinal fluid (CSF) samples. We identified five adult patients, including two sisters, with significantly elevated free sialic acid in the CSF compared to both the cohort of patients with diseases of unknown aetiology (n = 144; P < 0.001) and a control group of patients with well-defined diseases (n = 91; P < 0.001). All five patients displayed cerebellar ataxia, with peripheral neuropathy and cognitive decline or noteworthy behavioural changes. Cerebral MRI showed mild to moderate cerebellar atrophy (5/5) as well as white matter abnormalities in the cerebellum including the peridentate region (4/5), and at the periventricular level (3/5). Two-dimensional gel analyses revealed significant hyposialylation of transferrin in CSF of all patients compared to age-matched controls (P < 0.001)--a finding not present in the CSF of patients with Salla disease, the most common free sialic acid storage disorder. Free sialic acid content was normal in patients' urine and cultured fibroblasts as were plasma glycosylation patterns of transferrin. Analysis of the ganglioside profile in peripheral nerve biopsies of two out of five patients was also normal. Sequencing of four candidate genes in the free sialic acid biosynthetic pathway did not reveal any mutation. We therefore identified a new free sialic acid syndrome in which cerebellar ataxia is the leading symptom. The term CAFSA is suggested (cerebellar ataxia with free sialic acid).
  Brain 01/2009; 132(Pt 3):801-9. · 9.46 Impact Factor
• Article: Sensitivity and specificity of decreased CSF asialotransferrin for eIF2B-related disorder.

  A Vanderver, Y Hathout, J Maletkovic, E S Gordon, M Mintz, M Timmons, E P Hoffman, L Horzinski, F Niel, A Fogli, O Boespflug-Tanguy, R Schiffmann
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  ABSTRACT: This is a study estimating diagnostic accuracy of CSF asialotransferrin to transferrin ratio measurement in eIF2B related disorders by using clinical evaluation and EIF2B mutation analysis as the reference standard. eIF2B-related disorder is a relatively common leukodystrophy with broad phenotypic variation that is caused by mutations in any of the five EIF2B genes. There is a need for a simple and clinically valid screening tool for physicians evaluating patients with an unclassified leukodystrophy. CSF two-dimensional gel (2DG) electrophoresis analyses to measure asialotransferrin to transferrin ratios were performed in 60 subjects including 6 patients with documented EIF2B gene mutations, patients with other types of leukodystrophy, and patients with no leukodystrophy. All six patients with mutation proven eIF2B-related disease showed low to nearly undetectable amounts of asialotransferrin in their CSF when compared to 54 unaffected controls by CSF 2DG analyses in this study. eIF2B-like patients, with clinically similar presentations but no mutations in EIF2B1-5, were distinguished from patients with mutations in EIF2B1-5 by this biomarker. Patients with mutations in EIF2B1-5 had asialotransferrin/transferrin ratio levels significantly different from the group as a whole (p < 0.001). Using 8% asialotransferrin/transferrin ratio as a cutoff, this biomarker has a 100% sensitivity (95% CI = 52-100%) and 94% specificity (95% CI = 84-99%). Decreased asialotransferrin/transferrin ratio in the CSF of patients with eIF2B-related disorder is highly sensitive and specific. This rapid (<48 hours) and inexpensive diagnostic tool for eIF2B-related disorders has the potential to identify patients with likely eIF2B-related disorder for mutation analysis.
  Neurology 06/2008; 70(23):2226-32. · 8.31 Impact Factor
• Article: Uniparental disomy of chromosome 1 causing concurrent Charcot-Marie-Tooth and Gaucher disease Type 3.

  W S Benko, K S Hruska, N Nagan, O Goker-Alpan, P S Hart, R Schiffmann, E Sidransky
  Neurology 04/2008; 70(12):976-8. · 8.31 Impact Factor
• Article: Hypomyelination with atrophy of the basal ganglia and cerebellum: follow-up and pathology.

  M S van der Knaap, T Linnankivi, A Paetau, A Feigenbaum, K Wakusawa, K Haginoya, W Köhler, M Henneke, A Dinopoulos, P Grattan-Smith, K Brockmann, R Schiffmann, S Blaser
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  ABSTRACT: Hypomyelination with atrophy of the basal ganglia and cerebellum is a recently defined disorder. Only a few patients have been described. We report on 11 additional patients and new MRI findings and provide histopathologic confirmation of the MRI interpretation. We reviewed the patients' clinical history and present findings. We scored the MRI abnormalities. The histopathology of one patient was re-examined. The patients' early psychomotor development was normal or delayed, followed by increasing extrapyramidal movement abnormalities, ataxia, and spasticity. Mental capacities were variably affected. MRI showed hypomyelination with, on follow-up, evidence of further myelin loss and variable white matter atrophy. The putamen was small or, more often, absent; the head of the caudate nucleus was decreased in size. In contrast, the thalamus and globus pallidus remained normal. Cerebellar atrophy was invariably present. Histopathology confirmed the myelin deficiency, probably related to both lack of deposition and low-grade further loss. The degeneration of putamen was subtotal. The cerebellar cortex was affected, particularly the granular layer. Hypomyelination with atrophy of the basal ganglia and cerebellum is a syndrome diagnosed by distinctive MRI findings. Histopathology confirms hypomyelination, low-grade further myelin loss, subtotal degeneration of the putamen, and cerebellar cortical atrophy. All known patients are sporadic, and the mode of inheritance is unclear.
  Neurology 08/2007; 69(2):166-71. · 8.31 Impact Factor
• Article: Xeroderma pigmentosum, trichothiodystrophy and Cockayne syndrome: a complex genotype-phenotype relationship.

  K H Kraemer, N J Patronas, R Schiffmann, B P Brooks, D Tamura, J J DiGiovanna
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  ABSTRACT: Patients with the rare genetic disorders, xeroderma pigmentosum (XP), trichothiodystrophy (TTD) and Cockayne syndrome (CS) have defects in DNA nucleotide excision repair (NER). The NER pathway involves at least 28 genes. Three NER genes are also part of the basal transcription factor, TFIIH. Mutations in 11 NER genes have been associated with clinical diseases with at least eight overlapping phenotypes. The clinical features of these patients have some similarities but also have marked differences. NER is involved in protection against sunlight-induced DNA damage. While XP patients have 1000-fold increase in susceptibility to skin cancer, TTD and CS patients have normal skin cancer risk. Several of the genes involved in NER also affect somatic growth and development. Some patients have short stature and immature sexual development. TTD patients have sulfur deficient brittle hair. Progressive sensorineural deafness is an early feature of XP and CS. Many of these clinical diseases are associated with developmental delay and progressive neurological degeneration. The main neuropathology of XP is a primary neuronal degeneration. In contrast, CS and TTD patients have reduced myelination of the brain. These complex neurological abnormalities are not related to sunlight exposure but may be caused by developmental defects as well as faulty repair of DNA damage to neuronal cells induced by oxidative metabolism or other endogenous processes.
  Neuroscience 05/2007; 145(4):1388-96. · 3.38 Impact Factor
• Article: Neuropathic and cerebrovascular correlates of hearing loss in Fabry disease.

  M Ries, H J Kim, C K Zalewski, M A Mastroianni, D F Moore, R O Brady, J M Dambrosia, R Schiffmann, C C Brewer
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  ABSTRACT: Fabry disease, OMIM 301500, is a progressive multisystem storage disorder due to the deficiency of alpha-galactosidase A (GALA). Neurological and vascular manifestations of this disorder with regard to hearing loss have not been analysed quantitatively in large cohorts. We conducted a retrospective cross sectional analysis of hearing loss in 109 male and female patients with Fabry disease who were referred to and seen at the Clinical Center of the National Institutes of Health, Bethesda, MD, USA on natural history and enzyme replacement study protocols. There were 85 males aged 6-58 years (mean 31 years, SD 13) and 24 females aged 22-72 years (mean 42 years, SD 12). All patients underwent a comprehensive audiological evaluation. In addition, cerebral white matter lesions, peripheral neuropathy, and kidney function were quantitatively assessed. HL(95), defined as a hearing threshold above the 95th percentile for age and gender matched normal controls, was present in 56% [95% CI (42.2-67.2)] of the males. Prevalence of HL(95) was lower in the group of patients with residual GALA enzyme activity compared with those without detectable activity (33% versus 63%) HL(95) was present in the low-, mid- and high-frequency ranges for all ages. Male patients with HL(95) had a higher microvascular cerebral white matter lesion load [1.4, interquartile range (IQR) 0-30.1 +/- versus 0, IQR 0-0], more pronounced cold perception deficit [19.4 +/- 5.5 versus 13.5 +/- 5.5 of just noticeable difference (JND) units] and lower kidney function [creatinine: 1.6 +/- 1.2 versus 0.77 +/- 0.2 mg/dl; blood urea nitrogen (BUN): 20.1 +/- 14.1 versus 10.3 +/- 3.28 mg/dl] than those without HL(95) (P < 0.001). Of the females, 38% had HL(95). There was no significant association with cold perception deficit, creatinine or BUN in the females. Word recognition and acoustic reflexes analyses suggested a predominant cochlear involvement. We conclude that hearing loss involving all frequency regions significantly contributes to morbidity in patients with Fabry disease. Our quantitative analysis suggests a correlation of neuropathic and vascular damage with hearing loss in the males. Residual GALA activity appears to have a protective effect against hearing loss.
  Brain 01/2007; 130(Pt 1):143-50. · 9.46 Impact Factor
• Article: Myeloperoxidase predicts risk of vasculopathic events in hemizgygous males with Fabry disease.

  C R Kaneski, D F Moore, M Ries, G C Zirzow, R Schiffmann
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  ABSTRACT: Fabry disease results in a global vasculopathy leading to early-onset stroke and renal and cardiac failure. We found that random myeloperoxidase in serum and plasma was significantly elevated in 73 consecutive male patients with Fabry disease. Random serum myeloperoxidase level in men predicted the risk of a Fabry vasculopathy-related event in subsequent years. Long-term enzyme replacement therapy did not reduce myeloperoxidase level or eliminate the risk of vasculopathic events.
  Neurology 01/2007; 67(11):2045-7. · 8.31 Impact Factor
• Article: Peripheral and central hypomyelination with hypogonadotropic hypogonadism and hypodontia.

  M Timmons, M Tsokos, M Abu Asab, S B Seminara, G C Zirzow, C R Kaneski, J D Heiss, M S van der Knaap, M T Vanier, R Schiffmann, K Wong
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  ABSTRACT: We identified four unrelated patients (three female, one male) aged 20 to 30 years with hypomyelination, pituitary hypogonadotropic hypogonadism, and hypodontia. Electron microscopy and myelin protein immunohistochemistry of sural nerves showed granular debris-lined clefts, expanded abaxonal space, outpocketing with vacuolar disruption, and loss of normal myelin periodicity. Reduced galactocerebroside, sphingomyelin, and GM1-N-acetylglucosamine and increased esterified cholesterol were found. This is a clinically homogeneous progressive hypomyelinating disorder. The term 4H syndrome is suggested.
  Neurology 01/2007; 67(11):2066-9. · 8.31 Impact Factor
• Article: Skin abnormalities as an early predictor of neurologic outcome in Gaucher disease.

  W M Holleran, S G Ziegler, O Goker-Alpan, M J Eblan, P M Elias, R Schiffmann, E Sidransky
  Clinical Genetics 05/2006; 69(4):355-7. · 3.13 Impact Factor
• Article: Alexander disease: ventricular garlands and abnormalities of the medulla and spinal cord.

  M S van der Knaap, V Ramesh, R Schiffmann, S Blaser, M Kyllerman, A Gholkar, D W Ellison, J P van der Voorn, S J M van Dooren, C Jakobs, F Barkhof, G S Salomons
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  ABSTRACT: Alexander disease is most commonly associated with macrocephaly and, on MRI, a leukoencephalopathy with frontal preponderance. The disease is caused by mutation of the GFAP gene. Clinical and MRI phenotypic variation have been increasingly recognized. The authors studied seven patients with Alexander disease, diagnosed based on mutations in the GFAP gene, who presented unusual MRI findings. The authors reviewed clinical history, MRI abnormalities, and GFAP mutations. All patients had juvenile disease onset with signs of brainstem or spinal cord dysfunction. None of the patients had a macrocephaly. The MRI abnormalities were dominated by medulla and spinal cord abnormalities, either signal abnormalities or atrophy. One patient had only minor cerebral white matter abnormalities. A peculiar finding was the presence of a kind of garland along the ventricular wall in four patients. Three patients had an unusual GFAP mutation, one of which was a duplication mutation of two amino acids, and one an insertion deletion. Signal abnormalities or atrophy of the medulla or spinal cord on MRI are sufficient to warrant DNA analysis for Alexander disease. Ventricular garlands constitute a new sign of the disease. Unusual phenotypes of Alexander disease are found among patients with late onset and protracted disease course.
  Neurology 03/2006; 66(4):494-8. · 8.31 Impact Factor
• Article: Golli-MBP copy number analysis by FISH, QMPSF and MAPH in 195 patients with hypomyelinating leukodystrophies.

  C Vaurs-Barriere, M-N Bonnet-Dupeyron, P Combes, F Gauthier-Barichard, X T Reveles, R Schiffmann, E Bertini, D Rodriguez, P Vago, J A L Armour, P Saugier-Veber, T Frebourg, R J Leach, O Boespflug-Tanguy
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  ABSTRACT: The inherited disorders of CNS myelin formation represent a heterogeneous group of leukodystrophies. The proteolipoprotein (PLP1) gene has been implicated in two X-linked forms, Pelizaeus-Merzbacher disease (PMD) and spastic paraplegia type 2, and the gap junction protein alpha12 (GJA12) gene in a recessive form of PMD. The myelin basic protein (MBP) gene, which encodes the second most abundant CNS myelin protein after PLP1, presents rearrangements in hypomyelinating murine mutants and is always included in the minimal region deleted in 18q- patients with an abnormal hypomyelination pattern on cerebral MRI. In this study, we looked at the genomic copy number at the Golli-MBP locus in 195 patients with cerebral MRI suggesting a myelin defect, who do not have PLP1 mutation. Although preliminary results obtained by FISH suggested the duplication of Golli-MBP in 3 out of 10 patients, no abnormal gene quantification was found using Quantitative Multiplex PCR of Short Fluorescent fragments (QMPSF), Multiplex Amplifiable Probe Hybridization (MAPH), or another FISH protocol using directly-labelled probes. Pitfalls and interest in these different techniques to detect duplication events are emphasised. Finally, the study of this large cohort of patients suggests that Golli-MBP deletion or duplication is rarely involved in inherited defects of myelin formation.
  Annals of Human Genetics 02/2006; 70(Pt 1):66-77. · 2.57 Impact Factor
• Article: Divergent phenotypes in Gaucher disease implicate the role of modifiers.

  O Goker-Alpan, K S Hruska, E Orvisky, P S Kishnani, B K Stubblefield, R Schiffmann, E Sidransky
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  ABSTRACT: Gaucher disease is classified into neuronopathic and non-neuronopathic forms with wide phenotypic variation among patients sharing the same genotype. While homozygosity for the common L444P allele usually correlates with the neuronopathic forms, how a defined genotype leads to a phenotype remains unknown. The genetic and epigenetic factors causing phenotypic differences were approached by a clinical association study in 32 children homozygous for the point mutation L444P. Direct sequencing and Southern blots were utilised to establish the genotype and exclude recombinant alleles. Glucocerebrosidase activity was measured in lymphoblast and fibroblast cell lines. Residual enzyme activity was highly variable and did not correlate with the observed clinical course. There was also a wide spectrum of phenotypes. Average age at diagnosis was 15 months, and slowed saccadic eye movements were the most prevalent finding. The most severe systemic complications and highest mortality occurred in splenectomised patients before the advent of enzyme replacement therapy (ERT). On ERT, as morbidity and mortality decreased, developmental and language deficits emerged as a major issue. Some trends related to ethnic background were observed. The wide clinical spectrum observed in the L444P homozygotes implicates the contribution of genetic modifiers in defining the phenotype in Gaucher disease.
  Journal of Medical Genetics 07/2005; 42(6):e37. · 6.36 Impact Factor
• Source

  Available from: nih.gov

  Article: Parkinsonism among Gaucher disease carriers.

  O Goker-Alpan, R Schiffmann, M E LaMarca, R L Nussbaum, A McInerney-Leo, E Sidransky
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  ABSTRACT: An association between Gaucher disease and Parkinson disease has been demonstrated by the concurrence of Gaucher disease and parkinsonism in rare patients and the identification of glucocerebrosidase mutations in probands with sporadic Parkinson disease. Using a different and complementary approach, we describe 10 unrelated families of subjects with Gaucher disease where obligate or confirmed carriers of glucocerebrosidase mutations developed parkinsonism. These observations indicate that mutant glucocerebrosidase, even in heterozygotes, may be a risk factor for the development of parkinsonism. Understanding the relationship between altered glucocerebrosidase and the development of parkinsonian manifestations will provide insights into the genetics, pathogenesis, and treatment of Parkinson disease.
  Journal of Medical Genetics 01/2005; 41(12):937-40. · 6.36 Impact Factor
• Article: The effect of genotype on the natural history of eIF2B-related leukodystrophies.

  A Fogli, R Schiffmann, E Bertini, S Ughetto, P Combes, E Eymard-Pierre, C R Kaneski, M Pineda, M Troncoso, G Uziel, R Surtees, D Pugin, M-P Chaunu, D Rodriguez, O Boespflug-Tanguy
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  ABSTRACT: Recessive mutations in the five eucaryotic initiation factor 2B (eIF2B) subunits have been found in leukodystrophies of variable age at onset and severity. To evaluate the clinical spectrum of eIF2B-related disorders and search for a phenotype-genotype correlation. Ninety-three individuals (78 families) with an undetermined leukodystrophy were selected on MRI-based criteria of childhood ataxia with central hypomyelination/vanishing white matter (CACH/VWM) for EIF2B genes analysis. Eighty-nine percent of individuals with MRI criteria of CACH/VWM have a mutation in one of the eIF2B beta to epsilon subunits. For 83 individuals (68 families), 46 distinct mutations (90% missense) in four of the five eIF2B subunits (beta, gamma, delta, epsilon) were identified. Sixty-four percent were in the epsilon subunit, a R113H substitution was found in 71% of eIF2B epsilon-mutated families. A large clinical spectrum was observed from rapidly fatal infantile to asymptomatic adult forms. Disease severity was correlated with age at onset (p < 0.0001) but not with the type of the mutated subunit nor with the position of the mutation within the protein. Mutations R113H in the epsilon subunit and E213G in the beta subunit were significantly associated with milder forms. The degree of eIF2B dysfunction, which is involved in the regulation of protein synthesis during cellular stress, may play a role in the clinical expression of eIF2B-related disorders.
  Neurology 06/2004; 62(9):1509-17. · 8.31 Impact Factor
• Article: Five patients with a recently described novel leukoencephalopathy with brainstem and spinal cord involvement and elevated lactate.

  S V Serkov, I N Pronin, O V Bykova, O I Maslova, N V Arutyunov, T I Muravina, V N Kornienko, L M Fadeeva, H Marks, C Bönnemann, R Schiffmann, M S van der Knaap
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  ABSTRACT: Recently, a novel leukoencephalopathy syndrome was described in eight patients with a distinct pattern of MRI abnormalities. Here we describe the clinical, laboratory, and MRI findings in five new, unrelated patients. The clinical picture was homogeneous with onset in childhood, a slowly progressive course, variable mental deficits, signs of pyramidal and cerebellar dysfunction and sometimes dorsal column dysfunction. In two patients, a minor head trauma was followed by neurological deterioration and fever. No underlying metabolic defect was found. In two patients serum lactate was elevated, but no evidence of a mitochondrial defect was found. MRI showed variably extensive, diffuse, or spotty cerebral white matter abnormalities and a selective involvement of particular brainstem tracts. The tracts involved included the pyramidal tracts, sensory tracts, superior and inferior cerebellar peduncles, and intraparenchymal trajectories of the trigeminal nerve. In four patients spinal MRI was performed and revealed involvement of tracts over the entire length depicted. Single voxel proton MRS in three patients revealed increased lactate within the abnormal white matter. The uniform and highly characteristic MRI findings, in combination with the similarities in clinical and MRS findings, provide evidence for a distinct nosological entity.
  Neuropediatrics 03/2004; 35(1):1-5. · 0.94 Impact Factor
• Article: Gaucher disease with parkinsonian manifestations: does glucocerebrosidase deficiency contribute to a vulnerability to parkinsonism?

  N Tayebi, J Walker, B Stubblefield, E Orvisky, M E LaMarca, K Wong, H Rosenbaum, R Schiffmann, B Bembi, E Sidransky
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  ABSTRACT: Among the phenotypes associated with Gaucher disease, the deficiency of glucocerebrosidase, are rare patients with early onset, treatment-refractory parkinsonism. Sequencing of glucocerebrosidase in 17 such patients revealed 12 different genotypes. Fourteen patients had the common "non-neuronopathic" N370S mutation, including five N370S homozygotes. While brain glucosylsphingosine levels were not elevated, Lewy bodies were seen in the four brains available for study. The shared clinical and neuropathologic findings in this subgroup suggest that the deficiency in glucocerebrosidase may contribute to a vulnerability to parkinsonism.
  Molecular Genetics and Metabolism 07/2003; 79(2):104-9. · 3.19 Impact Factor
• Article: The neurogenetics of mucolipidosis type IV.

  G Altarescu, M Sun, D F Moore, J A Smith, E A Wiggs, B I Solomon, N J Patronas, K P Frei, S Gupta, C R Kaneski, O W Quarrell, S A Slaugenhaupt, E Goldin, R Schiffmann
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  ABSTRACT: Mucolipidosis type IV (MLIV) is an autosomal recessive disease caused by mutations in the MCOLN1 gene that codes for mucolipin, a member of the transient receptor potential (TRP) gene family. To comprehensively characterize the clinical and genetic abnormalities of MLIV. Twenty-eight patients with MLIV, aged 2 to 25 years, were studied. Ten returned for follow-up every 1 to 2 years for up to 5 years. Standard clinical, neuroimaging, neurophysiologic, and genetic techniques were used. All patients had varying degrees of corneal clouding, with progressive optic atrophy and retinal dystrophy. Twenty-three patients had severe motor and mental impairment. Motor function deteriorated in three patients and remained stable in the rest. All had a constitutive achlorhydria with elevated plasma gastrin level, and 12 had iron deficiency or anemia. Head MRI showed consistent characteristic findings of a thin corpus callosum and remained unchanged during the follow-up period. Prominent abnormalities of speech, hand usage, and swallowing were also noted. Mutations in the MCOLN1 gene were present in all patients. Correlation of the genotype with the neurologic handicap and corpus callosum dysplasia was found. MLIV is both a developmental and a degenerative disorder. The presentation as a cerebral palsy-like encephalopathy may delay diagnosis.
  Neurology 09/2002; 59(3):306-13. · 8.31 Impact Factor