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Quantitative proton MRS of Pelizaeus-Merzbacher disease - Evidence of dys- and hypomyelination

Universitätsmedizin Göttingen, Göttingen, Lower Saxony, Germany
Neurology (Impact Factor: 8.3). 10/2005; 65(5):701-6. DOI: 10.1212/01.wnl.0000174642.32187.20
Source: PubMed

ABSTRACT Pelizaeus-Merzbacher disease (PMD) is a rare X-linked recessive neurologic disorder caused by a mutation in the proteolipid protein (PLP) gene on chromosome Xq22. The associated depletion of PLP and severe reduction of other major myelin proteins results in dysmyelination. MRI reveals loss of T1 contrast between gray and affected white matter and T2 hyperintensities of white matter due to elevated water content.
In vivo proton magnetic resonance spectroscopy (MRS) was used to determine cerebral metabolite patterns in five patients with genetically proven PMD. Absolute metabolite concentrations were obtained in cortical gray matter, affected white matter, and basal ganglia and compared to age-matched control values.
In comparison to age-matched controls, MRS of affected white matter resembled the metabolite pattern of cortical gray matter, as indicated by increased concentrations of N-acetylaspartate and N-acetylaspartylglutamate (tNAA), glutamine (Gln), myo-inositol (Ins), and creatine and phosphocreatine. Most remarkably, the concentration of choline-containing compounds was reduced. Parietal gray matter and basal ganglia appeared normal but showed a tendency for elevated tNAA, Gln, and Ins.
Magnetic resonance spectroscopy (MRS)-detected alterations are consistent with enhanced neuroaxonal density, astrogliosis, and reduction of oligodendroglia. These disturbances in cellular composition are in close agreement with the histopathologic features characteristic of dys- and hypomyelination. The proton MRS profile of Pelizaeus-Merzbacher disease (PMD) differs from the pattern commonly observed in demyelinating disorders and allows PMD to be distinguished from other leukodystrophies.

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    ABSTRACT: Pelizaeus-Merzbacher disease (PMD) is a rare X-linked dysmyelination disorder of the central nervous system (CNS). PMD is caused by mutations in the PLP1 gene located at Xq22 and encoding the major myelin component in CNS, proteolipid protein 1 (PLP1). The disease is clinically heterogeneous. Phenotypes are generally categorized into classic and connatal forms. Connatal PMD has more rapid progression with early death, while patients with classic PMD generally survive to adulthood. Both forms of the disease are caused by point mutations as well as rearrangements - multiplication (mainly duplication) and deletion of the PLP1 gene. We present a case of a male patient affected by the classic form of PMD with benign course, except severe dysarthria with the characteristic laryngeal stridor, which is more typical for connatal form of the disease. The diagnosis has been confirmed at the molecular level. The patient has duplication of all 7 exons of the PLP1 gene. This duplication was inherited from the patient's mother, who is an unaffected carrier of the mutation. The patient's family pedigree analysis revealed the interfamilial variability of the phenotype among affected male relatives.
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    ABSTRACT: Within the last 15 years, several new leukoencephalopathies have been recognized. However, more than half of children with cerebral white matter abnormalities still have no specific diagnosis. Our aim was to classify unknown leukoencephalopathies and to identify new diseases among them. During the study, three subgroups of patients were delineated and examined further. First, we evaluated 38 patients with unknown leukoencephalopathy. Brain MRI findings were grouped into seven categories according to the predominant location of the abnormalities. The largest subgroups were myelination abnormalities (n=20) and periventricular white matter abnormalities (n=12). Six patients had uniform MRI findings with signal abnormalities in hemispheric white matter and in selective brain stem and spinal cord tracts. Magnetic resonance spectroscopy (MRS) showed elevated lactate and decreased N-acetylaspartate in the abnormal white matter. The patients presented with ataxia, tremor, distal spasticity, and signs of dorsal column dysfunction. This phenotype - leukoencephalopathy with brain stem and spinal cord involvement and elevated white matter lactate (LBSL) - was first published elsewhere in 2003. A new finding was development of a mild axonal neuropathy. The etiopathogenesis of this disease is unknown, but elevated white matter lactate in MRS suggests a mitochondrial disorder. Secondly, we studied 22 patients with 18q deletions. Clinical and MRI findings were correlated with molecularly defined size of the deletion. All patients with deletions between markers D18S469 and D18S1141 (n=18) had abnormal myelination in brain MRI, while four patients with interstitial deletions sparing that region, had normal myelination pattern. Haploinsufficiency of myelin basic protein is suggested to be responsible for this dysmyelination. Congenital aural atresia/stenosis was found in 50% of the cases and was associated with deletions between markers D18S812 (at 18q22.3) and D18S1141 (at q23). Last part of the study comprised 13 patients with leukoencephalopathy and extensive cerebral calcifications. They showed a spectrum of findings, including progressive cerebral cysts, retinal telangiectasias and angiomas, intrauterine growth retardation, skeletal and hematologic abnormalities, and severe intestinal bleeding, which overlap with features of the previously reported patients with "Coats plus" syndrome and "leukoencephalopathy with calcifications and cysts", suggesting that these disorders are related. All autopsied patients had similar neuropathologic findings showing calcifying obliterative microangiopathy. Our patients may represent an autosomally recessively inherited disorder because there were affected siblings and patients of both sexes. We have started genealogic and molecular genetic studies of this disorder. Väitöskirjan tavoitteena oli selvittää, millaisia uusia sairauksia löytyy lapsipotilailta, joilla magneettikuvaus paljastaa muutoksia aivojen valkeassa aineessa. Valkean aineen sairaudet ovat harvinaisia, usein perinnöllisiä ja oireiltaan eteneviä. Useita uusia sairauksia on tunnistettu magneettikuvauksen yleistyttyä viimeksi kuluneen 15 vuoden aikana, mutta edelleen yli puolet muutoksista jää vaille selitystä. Kartoitimme tuntemattomia aivojen valkean aineen muutoksia 43 potilaallamme, joiden muutokset oli todettu lapsuusiällä, vuosien 1990-2005 välisenä aikana. Seurasimme potilaiden oireiden kehitystä ja aivomuutoksia sekä mittasimme aivokudoksen aineenvaihduntaa magneettispektroskopialla. Tutkittavien joukosta erottui kaksi uutta taudinkuvaa. Kuudella potilaalla oli aivorungon sekä selkäytimen valkean aineen hermoratojen muutoksia ja aivokudokseen kertyi maitohappoa. Heillä oli tasapainovaikeuksia, alaraajojen jäykkyyttä, vapinaa ja asento- sekä värinätunnon heikentymistä. Oireiden alkamisikä vaihteli leikki-iästä murrosikään. Samanlaisia potilaita kuvattiin kirjallisuudessa ensimmäisen kerran vuonna 2003 nimellä LBSL (Leukoencephalopathy with Brainstem and Spinal cord involvement and elevated white matter Lactate). Syyskuussa 2006 potilaita oli raportoitu maailmanlaajuisesti yhteensä 20, suomalaiset potilaat mukaan lukien. Harvinaisuudestaan huolimatta tämä sairaus näyttää kuuluvan yleisimpiin ns. uusiin aivojen valkean aineen sairauksiin Suomessa ja tautia sairastavia löytyy todennäköisesti enemmän, kun tämä suhteellisen lieväoireinen sairaus tulee tunnetuksi. Toisen ryhmän muodostivat potilaat, joilla valkean aineen muutosten lisäksi todettiin laajoja aivokalkkeutumia. Osalla heistä oli poikkeavuuksia myös silmien verkkokalvon verisuonissa, luuston rakenteessa ja verenkuvassa. Perehdyimme lisäksi aiemmin samanlaiseen sairauteen menehtyneiden suomalaisten potilaiden neuropatologisiin löydöksiin, joissa havaittiin muutoksia ensisijaisesti aivojen pienissä verisuonissa. Kirjallisuudessa on aiemmin kuvattu yksittäisiä tai muutaman potilaan aineistoja, yhteensä alle 20 potilasta, jotka todennäköisesti edustavat samaa oireyhtymää. Oma 13 potilaan sarjamme on suurin kuvatuista ja kattaa koko oirekirjon. Jatkotutkimusten tavoitteena on tunnistaa edellä mainittujen perinnöllisten sairauksien taustalla olevat geenivirheet. Kolmannen tutkimusryhmän muodostivat 22 potilasta, joilla oli todettu kromosomin 18 pitkän haaran osittainen häviämä eli deleetio. Puuttuvan alueen koko tutkittiin molekyyligeneettisesti. Aivojen valkea aine kehittyi poikkeavasti vain niillä potilailla, joiden kromosomista 18 puuttuva alue sisälsi aivojen valkean aineen tärkeän proteiinin (MBP) geenin. Tulos vahvisti aikaisempia päätelmiä MBP:n osuudesta 18q- oireyhtymässä todettuun valkean aineen poikkeavuuteen.
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