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M Philippart

Publications and source records attributed to M Philippart.

At least 19 recordsLinked to original sources
PubMed2004

Leukoencephalopathy, cerebral calcifications, and cysts: new observations.

We describe three cases of the rare syndrome of leukoencephalopathy, brain calcifications, and cysts. Conventional MRI, proton spectroscopy, and diffusion-weighted imaging yielded additional information on the disease. Imaging findings favor increased water content rather than a demyelinating process in the pathophysiology of this disease. Clinical features of Coats disease and consanguinity were also encountered.

Adolescent↗
PubMed2003

Membrane phospholipids and high-energy metabolites in childhood ataxia with CNS hypomyelination.

BACKGROUND: Childhood ataxia with CNS hypomyelination (CACH) is a leukodystrophy with extreme rarefaction of white matter caused by mutations in one of the five subunits of the translation initiation factor 2B (eIF2B). METHODS: Seven children with this disease and nine age-matched control subjects were studied with proton-decoupled phosphorus magnetic resonance (MR) spectroscopy. RESULTS: In patients with CACH, cerebral concentrations of high-energy phosphate metabolites were abnormal. Of the metabolites involved in biosynthesis and catabolism of membrane phospholipids, glycerophosphorylethanolamine was reduced (0.24 +/- 0.18 mmol/kg brain vs 0.44 +/- 0.14; p < 0.02), and phosphorylethanolamine was increased (2.32 +/- 0.53 vs 1.53 +/- 0.22; p < 0.01), whereas the choline-containing phosphorylated metabolites were unchanged. Nucleoside triphosphate (NTP) was reduced (2.44 +/- 0.34 mmol/kg brain tissue vs 3.09 +/- 0.58; p < 0.01), phosphocreatine was elevated (4.11 +/- 0.63 vs 3.27 +/- 0.33; p < 0.01), and inorganic phosphate was reduced (0.77 +/- 0.32 vs 1.06 +/- 0.26; p < 0.05). Intracellular pH was elevated in patients (7.03 +/- 0.04 vs 6.99 +/- 0.02; p < 0.02). CONCLUSIONS: The authors found an altered energy state of the residual cell population investigated. Together with previously identified replacement of white matter by CSF, the present findings raise the possibility that the genetic defect in eIF2B may result in impairment of myelin membrane synthesis or myelin membrane transport in the in vivo CACH brain. Ethanolamine metabolites constitute the plasmalogens, and the present findings may include a defect in plasmalogen metabolism.

Adolescent↗
PubMed2001

Pheno/genotypic correlations of neuronal ceroid lipofuscinoses.

The neuronal ceroid lipofuscinoses (NCL) are a large group of autosomal recessive lysosomal storage disorders with both enzymatic deficiency and structural protein dysfunction. Previously, diagnosis of NCL was based on age at onset and clinicopathologic (C-P) findings, classified as 1) infantile (INCL), 2) late infantile (LINCL), 3) juvenile (JNCL), and 4) adult (ANCL). Most patients with NCL have progressive ocular and cerebral dysfunction, including cognitive/motor dysfunction and uncontrolled seizures. After reviewing 319 patients with NCL, the authors found that 64 (20%) did not fit into this classification of NCL. With research progress, four additional forms have been recognized: 5) Finnish, 6) Gypsy/Indian, and 7) Turkish variants of LINCL and 8) northern epilepsy, also known as progressive epilepsy with mental retardation. These eight NCL forms resulted from 100 different mutations on genes CLN1to CLN8 causing different phenotypes (http://www.ucl.ac.uk/ncl). The genes CLN1 and CLN2 encode lysosomal palmitoyl protein thioesterase and tripeptidyl peptidase 1. The function of CLN3, CLN5, and CLN8 gene-encoded products is unknown, although their predicted amino acid sequences suggest they have a transmembrane topology. The diagnosis of NCL is based on C-P findings, enzymatic assay, and molecular genetic testing. Before biochemical and genetic tests are conducted, ultrastructural studies (i.e., blood [buffy coat] or punch biopsies [skin, conjunctiva]) must be performed to confirm the presence and nature of lysosomal storage material (fingerprint or curvilinear profiles or granular osmiophilic deposits). The recognition of variable onset from infancy to middle age supersedes the traditional emphasis on age-related NCL forms.

Age of Onset↗
PubMed2001

MeCP2 mutations in children with and without the phenotype of Rett syndrome.

BACKGROUND: Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the X-linked methyl CpG binding protein 2 (MeCP2) gene. METHODS: One hundred sixteen patients with classical and atypical RTT were studied for mutations of the MeCP2 gene by using DHPLC and direct sequencing. RESULTS: Causative mutations in the MeCP2 gene were identified in 63% of patients, representing a total of 30 different mutations. Mutations were identified in 72% of patients with classical RTT and one third of atypical cases studied (8 of 25). The authors found 17 novel mutations, including a complex gene rearrangement found in one individual involving two deletions and a duplication. The duplication was identical to a region within the 3' untranslated region (UTR), and represents the first report of involvement of the 3' UTR in RTT. The authors also report the identification of MeCP2 mutations in two males; a Klinefelter's male with classic RTT (T158M) and a hemizygous male infant with a Xq27-28 inversion and a novel 32 bp frameshift deletion [1154(del32)]. Studies examining the relationship between mutation type, X-inactivation status, and severity of clinical presentation found significant differences in clinical presentation between different types of mutations. Mutations in the amino-terminus were significantly correlated with a more severe clinical presentation compared with mutations closer to the carboxyl-terminus of MeCP2. Skewed X-inactivation patterns were found in two asymptomatic carriers of MeCP2 mutations and six girls diagnosed with either atypical or classical RTT. CONCLUSION: This patient series confirms the high frequency of MeCP2gene mutations causative of RTT in females and provides data concerning the molecular basis for clinical variability (mutation type and position and X-inactivation patterns).

Adolescent↗
PubMed2001

Rett and Angelman's syndromes: models of arrested development.

Rett and Angelman's syndromes have emerged slowly from their initial classifications as degenerative disorders and static encephalopathies; the terms development and developmental arrest have been used for 200 years. An attempt has been made to trace the genesis and the various contexts of these seminal concepts. Both disorders give frozen-framed expression of developmental levels not easily appreciated in normal children who progress from day to day. Although close in developmental level, about 9 and 15 months with a scatter of a few months, these disorders may actually overlap in a few instances. These syndromes illustrate how a slightly more advanced brain function may appear to be a big gap and how difficult it is to differentiate between a failure to progress further, which is easily confused with regression, and an apparent loss of skills actually never acquired. Learning to see the infant brain behind the aging body and how it adjusts within the constraints of its fixed low level of neural organization is the best basis for diagnosis and treatment. Identifying shortcomings and special risks is more rewarding than ill-conceived attempts to modify anatomic destiny.

Angelman Syndrome↗
PubMed2001

Impaired temporo-occipital blood flow in an atypical CLN1 case with late infantile onset and granular osmiophilic deposits.

A 5-year-old boy presented with frequent absences. Speech began to regress. He became ataxic, barely able to walk. Studies with Xe-133 and hexamethylpropylene amine oxime single-photon emission computed tomography revealed sharply decreased cerebral blood flow, especially in the occipital area. Landau-Kleffner syndrome was suspected but a sleep electroencephalogram showed few abnormalities. He was started on clorazepate and diltiazem. A skin biopsy to rule out possible CLN2 revealed, instead of the predicted curvilinear profiles, granular osmiophilic deposits, consistent with infantile neuronal ceroid lipofuscinosis (CLN1). The family reported increased seizure frequency and consulted with a colleague, who advised them to resume valproate and discontinue diltiazem. The boy died shortly thereafter. Decreased cerebral blood flow is a new finding in CLN1 with delayed onset. Calcium-channel blockers improve cerebral blood flow and perhaps delay clinical regression.

Age of Onset↗
PubMed1998

Angelman syndrome: correlations between epilepsy phenotypes and genotypes.

We compared epilepsy phenotypes with genotypes of Angelman syndrome (AS), including chromosome 15q11-13 deletions (class I), uniparental disomy (class II), methylation imprinting abnormalities (class III), and mutation in the UBE3A gene (class IV). Twenty patients were prospectively selected based on clinical cytogenetic and molecular diagnosis of AS. All patients had 6 to 72 hours of closed-circuit television videotaping and digitized electroencephalogrpahic (EEG) telemetry. Patients from all genotypic classes had characteristic EEGs with diffuse bifrontally dominant high-amplitude 1- to 3-Hz notched or triphasic or polyphasic slow waves, or slow and sharp waves. Class I patients had severe intractable epilepsy, most frequently with atypical absences and myoclonias and less frequently with generalized extensor tonic seizures or flexor spasms. Epileptic spasms were recorded in AS patients as old as 41 years. Aged-matched class II, III, and IV patients had either no epilepsy or drug-responsive mild epilepsy with relatively infrequent atypical absences, myoclonias, or atonic seizures. In conclusion, maternally inherited chromosome 15q11-13 deletions produce severe epilepsy. Loss-of-function UBE3A mutations, uniparental disomy, or methylation imprint abnormalities in AS are associated with relatively mild epilepsy. Involvement of other genes in the chromosome 15q11-13 deletion, such as GABRB3, may explain severe epilepsy in AS.

Adolescent↗
PubMed1998

Mutations in the palmitoyl-protein thioesterase gene (PPT; CLN1) causing juvenile neuronal ceroid lipofuscinosis with granular osmiophilic deposits.

A subtype of neuronal ceroid lipofuscinosis (NCL) is well recognized which has a clinical course consistent with juvenile NCL (JNCL) but the ultrastructural characteristics of infantile NCL (INCL): granular osmiophilic deposits (GROD). Evidence supporting linkage of this phenotype, designated vJNCL/GROD, to the INCL region of chromosome 1p32 was demonstrated (pairwise lod score with D1S211 , Z max = 2.63, straight theta = 0.00). The INCL gene, palmitoyl-protein thioesterase (PPT ; CLN1), was therefore screened for mutations in 11 vJNCL/GROD families. Five mutations in the PPT gene were identified: three missense mutations, Thr75Pro, Asp79Gly, Leu219Gln, and two nonsense mutations, Leu10STOP and Arg151STOP. The missense mutation Thr75Pro accounted for nine of the 22 disease chromosomes analysed and the nonsense mutation Arg151STOP for seven. Nine out of 11 patients were shown to combine a missense mutation on one disease chromosome with a nonsense mutation on the other. Mutations previously identified in INCL were not observed in vJNCL/GROD families. Thioesterase activity in peripheral blood lymphoblast cells was found to be markedly reduced in vJNCL/GROD patients compared with controls. These results demonstrate that this subtype of JNCL is allelic to INCL and further emphasize the correlation which exists between genetic basis and ultrastructural changes in the NCLs.

Age of Onset↗
PubMed1997

Genetic linkage analysis of a variant of juvenile onset neuronal ceroid lipofuscinosis with granular osmiophilic deposits.

A number of variant forms of the neuronal ceroid lipofuscinoses (NCL) have been described and remain unmapped. The genes for infantile (CLN1), juvenile (CLN3) and Finnish-variant late-infantile (CLN5) have previously been mapped to chromosome regions 1p32, 16p12 and 13q21.1-32 respectively. The locus for a variant form of juvenile onset NCL characterised by cytosomal granular osmiophilic deposits (GROD) has been excluded from the CLN3 region of chromosome 16. This study describes the outcome of genetic linkage analysis in four families with this variant at the loci for the CLN1 and CLN5 genes. Using highly informative microsatellite markers tightly linked to the CLN5 locus we have excluded the JNCL variant with GROD from this region. Marker typing across the CLN1 region suggests that JNCL with GROD may be an allelic variant of infantile NCL.

Adolescent↗
PubMed1997

The value of positron emission tomography in the diagnosis and monitoring of late infantile and juvenile lipopigment storage disorders (so-called Batten or neuronal ceroid lipofuscinoses).

Positron Emission Tomography (PET) with 2-deoxy-2 [18F]-fluoro-D-glucose provides a measure of functional brain activity, particularly in the dendritic field. In CLN3 (juvenile neuronal ceroid lipofuscinosis or juvenile Batten disease, with fingerprint inclusions) hypometabolism slowly spreads from calcarine to anterior areas, sparing subcortical structures and brainstem. In CLN2 (late infantile neuronal ceroid lipofuscinosis or Jansky-Bielschowsky disease, with curvilinear inclusions) degeneration is rapid with generalized cortical and subcortical hypometabolism. This is associated with rapidly progressive cerebral atrophy on anatomical neuroimaging. A 4-year-old child with CLN2 scanned with PET 13 months after the clinical onset showed hypometabolism, severe in the thalamus and mild in cortical areas. Three other patients with CLN2 had severe generalized hypometabolism and brain atrophy. Longitudinal PET studies in CLN may provide key insights into degenerative processes.

Blood Glucose↗
PubMed1996

Brainstem frequency-following responses in Rett syndrome.

The brainstem frequency-following response (FFR) is a short-latency evoked response that reflects waveform properties of periodic auditory stimuli. Unlike neural activity evoked by transient stimuli, the FFR originates in phase-locked neurons that provide unique information concerning the early processing of auditory inputs. FFRs elicited by a pure tone were recorded from 9 Rett syndrome patients (age 26-55 years, mean = 34.4 years) and compared with those of 18 normal infants (age 2-10 months, mean = 5.0 months), and 113 young adult (age 18-30 years, mean = 22.2 years) controls. The Rett syndrome pattern indicated considerable intersubject latency variability and poor intrasubject repeat reliability except for brief FFR components which were consistently synchronized. The pattern observed in Rett syndrome was similar in certain respects to that observed in infants, but both patterns differed from those of adults, who showed larger amplitudes and consistent waveform synchrony. Clinical and neuropathologic data indicate developmental arrest rather than a neurodegenerative process in Rett syndrome. The present results are consistent with this interpretation. Neurophysiologic studies may identify markers that are distinctive in Rett syndrome and make it possible to monitor changes with age and disease process.

Adolescent↗
PubMed1995

New Spielmeyer-Vogt variant with granular inclusions and early brain atrophy.

Three females in 2 families were originally diagnosed with Spielmeyer-Vogt disease (SVD). The clinical course was different from SVD, with vision well preserved until age 10 years, and learning rather than visual difficulties the marker at the onset. Later, regression was unusually rapid, including global dementia, blindness, aphasia, and finally loss of self-feeding and ambulation between ages 12-18 years. MRI scan in patient 3 documented brain atrophy between ages 8-10 years. Position Emission Tomography (PET) scanning with fluorodeoxyglucose in patients 2 and 3 showed diffusely decreased or absent cortical glucose metabolism, comparable at ages 12 and 18 years, respectively, to the results found in the oldest typical SVD case tested at age 29 years. Fine granular inclusions, instead of the expected fingerprint inclusions, were demonstrated by electron microscopy of lymphocytes, conjunctiva, and skin. Usual markers on chromosome 16p12 were not present in the first family tested. The clinical course, with nonspecific initial behavior difficulties, late onset of visual decline followed by fast global regression, progressive brain atrophy, decreased cortical glucose utilization as shown by PET scanning, and granular tissue inclusions, suggest a genetic variant of SVD.

Adult↗
PubMed1995

Tay-Sachs disease with atypical chronic course and limited brain storage: alpha-locus hexosaminidase genetic compound.

A 19-year-old Irish-Jewish male had a slow neurologic regression starting at age 4 1/2 years with stuttering. The chronic course resembled that of Spielmeyer-Vogt (juvenile ceroid-lipofuscinosis) disease. The brain was atrophic with neuronal losses and huge compound inclusions in the remaining neurons. Lipid NANA was within normal limits in gray and white matter and GM2 gangliosides were moderately elevated at 11.5% lipid NANA. Beta-hexosaminidase A activity was reduced, secondary to a compound mutation at the alpha-locus. Lysosomal hydrolase activities and lipid composition showed nonspecific abnormalities. Exhaustive tissue extraction ruled out the possibility of tightly bound gangliosides to account for the relatively low GM2 ganglioside concentration. The extract contained unidentified chromogenic substances interfering with the resorcinol reaction. The similarly affected patient's sister lived to age 26 years and her brain was even more atrophic. No biochemical abnormality to account for progressive neuronal losses and relative lack of GM2 ganglioside storage was found.

Adult↗
PubMed1994

Spielmeyer-Vogt (Batten, Spielmeyer-Sjögren) disease. Distinctive patterns of cerebral glucose utilization.

We have studied seven patients with Spielmeyer-Vogt disease (SV), aged 11-29 years, using PET and 2-deoxy-2[18F]fluoro-D-glucose. Five patients showed a distinctive age-related progression with decreased metabolic activity starting in the calcarine area and spreading rostrally to the entire cortex, leaving normal uptake only in the basal ganglia and brainstem of the oldest patients. Calcarine hypometabolism was mild in the youngest patient. All patients, including the youngest when the study was repeated 2 years later, had significantly decreased calcarine metabolic activity (P = 0.002). Two patients had PET patterns markedly different from the five others, with significantly decreased metabolic activity in most brain areas. Both patients may represent a new SV variant. An adult pathological control with congenital amaurosis showed normal cerebral metabolic activity in all areas. Two patients had older sisters, one now deceased, the other not available for study, who presented a rapid regression associated with epilepsy. Phenytoin and carbamazepine probably caused increased seizure activity and faster regression. The younger siblings treated with phenobarbital monotherapy had few seizures and maintained motor functions 5-8 years longer compared with their respective sisters. While the clinical course made obvious that some areas, such as the macula, are damaged before others, the progression from the calcarine area to the more anterior regions (but sparing the basal ganglia) provides unexpected insights into selective vulnerability of neurons that will allow a more precise way of monitoring individual patients.

Adolescent↗
PubMed1994

Neuropathology of Rett syndrome: case report with neuronal and mitochondrial abnormalities in the brain.

Neuronal changes in the brain of a Rett syndrome patient were examined in a frontal lobe biopsy performed at age 3 years and in the postmortem brain at age 15 years. In the brain biopsy, frontal cortex contained numerous scattered pyramidal neurons with cytoplasmic vacuolation and increased cytoplasmic density, with no neuronophagia or inflammation detected; electron microscopy showed these neurons to have large, lucent-appearing mitochondria, very abundant ribosomal content, and some lipofuscin granules. Postmortem brain 12 years later showed scattered neurons in frontal cortex, substantia nigra, and cerebellar folia, with increased electron density of the cytoplasm, stacks of ribosomal endoplasmic reticulum, and large amounts of disorganized membranous material, including autophagic-type organelles. Mitochondria of these neurons contained electron-dense, finely granular matrix inclusions; in the substantia nigra, some spherical mitochondrial inclusions completely filled the matrix space. Golgi preparations of (autopsy) frontal cortex and cerebellar folia showed truncation and thickening of dendrites and a degenerate appearance of cortical pyramidal neurons, similar to changes found in aged brain. Synaptophysin immunohistochemistry indicated that the density of synapses was not greatly altered compared to controls in frontal cortex and cerebellum. The patient also had a second genetic defect, severe combined immunodeficiency with thymic aplasia, which may be X-linked.

Adolescent↗
PubMed1993

Rett syndrome associated with tuberous sclerosis in a male and in a female: evidence for arrested motor and mental development.

Two sporadic cases of tuberous sclerosis presented with flexion spasms in a male and early intractable seizures evolving into a Lennox-Gastaut syndrome in a female. Early hypotonia and lack of substantial motor development are key features of the Rett syndrome, more easily overlooked than hand-wringing. Clumsy self-feeding and immature ambulation were the highest achievements in the second case now aged 36 years. Immaturity rather than degeneration, dementia, or assumed tissue destruction, is the capital feature of many disorders of early brain development leading to profound motor as well as mental retardation. Studying unusual clinical combinations is more likely to shed light on the underlying etiology than focusing on procrustean syndrome definitions.

Developmental Disabilities↗
PubMed1991

Difference in early development of presumed monozygotic twins with Rett syndrome.

Normal early development has generally been insisted on as an essential criterion for the diagnosis of Rett syndrome. A new set of monozygotic female twins is reported. Twin 1 was considered to be abnormal from birth while delay was not suspected in twin 2 until she was about one year old. Some regression occurred during the second year in both twins, who are now clinically indistinguishable from each other at age 4 years. Other than a slight difference in head circumference at birth, no environmental factor which could account for the clinical difference has been identified.

Child, Preschool↗