CLINICAL, RADIOLOGICAL AND GENETIC ASPECTS OF LEUKODYSTROPHIES

ESETISMERTETÉS CLINICAL, RADIOLOGICAL AND GENETIC ASPECTS OF LEUKODYSTROPHIES LÁSZLÓ A1, ELPELEG ON2, HORVÁTH K3, JAKOBS C4, KÓBOR J1, GAL A5, BARSI P...
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ESETISMERTETÉS CLINICAL, RADIOLOGICAL AND GENETIC ASPECTS OF LEUKODYSTROPHIES LÁSZLÓ A1, ELPELEG ON2, HORVÁTH K3, JAKOBS C4, KÓBOR J1, GAL A5, BARSI P6, KELEMEN A6, SARACZ J7, SVÉKUS A8, TEGZES A9, VÖRÖS E10 1 University of Szeged, A. Szent-Györgyi Medical Centre, Department of Pediatrics, Szeged 2Metabolic Disorders Unit, Shaare Zedek Medical Centre Jerusalem, Jerusalem 3Radiological Clinic, Semmelweis University, Budapest 4Metabolic Unit of Department Clinical Chemistry, University Medical Centre, Amsterdam, Nederland 5Institute of Human Genetics, Hamburg-Eppendorf, Germany 6Semmelweis University, Department of Neurology, Budapest 7Pál Heim Hospital, Department of Child’s Neurology, Budapest 8Kálmán Pándy, County Hospital, Department of Pediatrics, Gyula 9 Bethesda Hospital, Department of Neurology, Budapest 10University of Szeged, Department of Radiology, Szeged

LEUKODYSTROPHIÁK KLINIKAI, RADIOLÓGIAI ÉS GENETIKAI VONATKOZÁSAI László A, MD, PhD, DsC; Elpeleg ON, MD; Horváth K, MD; Jakobs C, MD; Kóbor J, MD; Gal A, MD; Barsi P, MD; Kelemen A, MD; Saracz J, MD; Svékus A, MD; Tegzes A, MD; Vörös E, MD Ideggyogy Sz 2010;63(7–8):266–273. The authors summarize the pathomechanism of the myelination process, the clinical, radiological and the genetical aspects of the leukodystrophies, as in 18q deletion syndrome, adrenoleukodysrtophy, metachromatic leukodystrophy, Pelizaeus-Merzbacher leukodystrophy, Alexander disease and olivo-ponto-cerebellar atrophy (OPCA).

A szerzôk összefoglalják a leukodystrophiák klinikai, radiológiai és genetikai vonatkozásait 18q deletiós szindrómában, adrenoleukodystrophiában, Canavan-kórban, metachromatikus leukodystrophiában, Pelizaeus–Merzbacher-leukodystrophiában, Alexander-kórban és olivoponto-cerebellaris atrophiában.

Keywords: different types of leukodystrophies, clinical, radiological and genetic aspects

Kulcsszavak: különbözô típusú leukodystrophiák, klinikai, radiológiai és genetikai aspektusok

Correspondence: Aranka LÁSZLÓ MD, PhD, DSc, University of Szeged, Albert Szent-Györgyi Medical Centre Department of Pediatrics; 6720 Szeged, Korányi fasor 14–15. Hungary. Phone: (36-62) 545-331, fax: (36-62) 545-329 Érkezett: 2008. november 19.

Elfogadva: 2009. március 18.

www.elitmed.hu

T

he inherited leukodystrophies are a complex group of diseases caused by different enzyme deficiencies leading to lysosomal, peroxisomal or mitochondrial disfunctions, with abnormal formation or breakdown of the myelin1. The different leukodystrophies can be presented with different phenotypic expression. The leukodystrophies may be unclassified or classified2, 3. The lysosomal leu-

kodystrophies can be classified as metachromatic-, ortochromatic and infantile gangliosidosis type I, as peroxisomal originated, infantile and other type of adrenoleukodystrophy4. Leukodystrophic changes can be seen in amino and organic acid disorders, with different types of white matter alteration5. The delayed myelination appears to be peculiar to the 18q deletion syndrome,

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because the gene for myelin basic protein has been localized to the distal end of the long arm of chromosome 18. This is the major protein participating in the myelination process of CNS and the nerves6, 7 . Defective biosynthesis of proteolipid protein in Pelizeus-Merzbacher disease, an X-linked neurologic disorder of the myelin metabolism, is caused by mutation in the gene encoding proteolipid protein8. Poor myelination was seen in the peripheral white matter, including the centrum semiovale, in the 18q deletion syndrome case of Ono et al.9. Canavan disease (CD) is a progressive infantile type neurodegenerative autosomal recessively inherited leukodystrophy characterized by rapidly severe developmental delay, lack of interest, spasticity, megalencephaly, blindness, with early death of spongy degeneration of the brain involving loss of the axons’ myelin. Biochemical defect is associated with reduced activity of the enzyme N-acetylL-aspartate-amido-hydrolase (aspartoacylase = ASPA) which is responsible for the break-down a particular chemical in the brain, hydrolyzes Nacetyl-aspartic acid (NAA) to acetate and aspartate. Urinary NAA is a biochemical marker for the diagnosis of Canavan disease10. The X-linked adrenoleukodystrophy (X-ALD), as a rare and fatal neurodegenerative disorder that affected boys. The genetic defect and biochemical abnormalities have now been defined, that is with peroxisomal original defect of beta-oxidation of very long chain fatty acids (VLCFAs). Androstenedion and DHEAS serum concentrations are subnormal in all adreno-myeloneuropathic patients and may therefore serve as sensitive markers of the adrenal function11. Metachromatic leukodystrophy (MLD) is an autosomal recessive neurodegenerative lysosomal disease caused by a defect of the enzyme arylsulfatase A (ARSA) that disrupts the degradation of sulfatides (Sulf) in neurons and glial cells. According to the ARSA deficiency earlier we reported an infant patient with MLD12. Pelizaeus-Merzbacher leukodystrophy (PML) is an X-linked recessive disorder. The gene defect is mutation troubles of proteo-lipid protein (PLP) gene13. Gao et al. published fluorescens in situ hybridisation (FISH) or real-time PCR methods for these analyses14, 15. Alexander disease is a rare but very severe devastating neurological disorder. De novo dominant mutations in the glial fibrillar acid protein (GFAP) gene have recently been associated with nearly all cases of Alexander disease. Li et al. published de

novo paternal inheritance mutation including 17 different missense mutations and one insertion mutation16. The Alexander disease mutation of GFAP causes filament disorganisation and decreased solubility of GFAP17. Olivo-ponto-cerebellar atrophy can be manifested in dysarthria, followed by impaired balance of gait, mild limb ataxia, and saccadic eye movement. The postmortem examination revealed neuronal loss restricted to the olivo-ponto-cerebellar system, being more severe in the pontine nucleus. Mild neuronal loss was also found in the anterior vermis and inferior olivary nucleus. Alpha-synuclein immunohistochemistry demonstrated widespread occurrence of glial cytoplasmic inclusions in the central nervous system18. Our aim was to publish the clinical, biochemical and genetical aspects and MRI diagnostic values of our different types leukodystrophic patients. These data are summarised in Table 1.

Patients, methods and results CASE REPORTS

18 q deletion syndrome Our working group earlier published a case of a male patient in association with 18q21.3-qter deletion and typical symptoms of the Lesch-Nyhan syndrome but without any hypoxantine-guaninephosphoribosyl-transferase (HGPRT) deficiency, but hyperuricemia and hyperserotoninemia19. Cytogenetic analysis showed deletion of the long arm of chromosome del 18q21.3-qter (Figure 1.). The karyotype of the mother proved normal, while in the father a pericentric inversion of chromosome 9 was demonstrated. Electrophysiological investigations: The sensory evoked potentials (SEP) in 1995 showed delayed peripheral and central nerve conductive velocities corresponding to demyelination-like syndromes. Brainstem auditory evoked potentials (BAEPs) showed delayed absolute and interpeak latencies (Kiss JG). SPECT detected a left frontal hyperperfusion focus and under it a temporoparietal hypoperfusic field. There was no lateral difference in the activity distribution in the basal ganglia, thalamus and cerebellar hemisphere (Buga K). On the basis of MRI findings, the actual brain maturity of this patient was delayed with several additional focal myelination abnormalities (Figure 2.).

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Table 1. Genetical aspects of leukodystrophies Sign

Gene locus

Enzyme defect

Mutations

Clinical, radiological aspects

Male (27 years). Dg: atypical Lesch-Nyhan syndrome

18q21.3-qter deletion20 Myeline basic protein gene 23–25

HGPRT normal activity



Father

46; XY pericentric inversion of chrom 9 46; XX

uric acid 400 µmol/l demyelination EEG: normal SPECT: left sided hypoperfusion SEP: delayed peripheral and central nerve conductive velocities (demyelination-like) uric acid nephrolith

Mother

healthy person

Male infant (7 months-5y). Dg: Canavandisease See: Table 2

17(17p13-pter) ASPA gene: 6 exons and 5 introns11, 30, 31, 33

asparto-acylase (ASPA)

914(A305E)

hyperpyruvataemia (192 µmol/l) lactic acidosis (5.2 mmol/l) arylsulfatase A (45.8 µmol/mg prot/h; normal range: 60-86) beta-galactosidase (237.76 nmol/mg prot/h; normal range) EEG: no specific pathological signs MRI of L1, L2: parieto-occipital dysmyelination (“tigroid” patterns)

L1, L2 adult males (37 years, 32 years). Dg: adrenoleukodystrophy

XLR (X-linked recessive) PEX26 gene36 ABCD1 gene37

peroxysomal defect of VLCFA (very long chain fatty acids)

P1 male infant (2 years). Dg: PelizaeusMerzbacher leukodystrophy (PML) Mother

proteo-lipidprotein gene (PLP)5,13–15 duplications/ deletions of PLP gene

guanine-adenine transition (c986-G/A) codon change TGT→TAT gene carrier

somatomental retardation tetraparetic stage MRI: nearly total cerebral demyelination

1 y. 10 months male infant. Dg: Alexanderleukodystrophy

GFAP (glial fibrillar acid protein) gene15–17, 19

A to G transition at nucleotid position 1026 → E371G (subst glycine for glutamic acid)

cranial MRI: extensive leukoencephalopathy

21 y. female. Dg: olivo-pontocerebellar atrophy (OPCA)

alpha-synuclein+ cytoplasmatic inclusions18

reduction of GABA in tissues and cerebrospinal fluid (CSF)18

Canavan disease A seven months-old Hungarian male infant showed progressive cerebral laesion, spastic muscle tone and tonic epileptic myotonic attacks. His symptoms were started after 6th life week. EEG registered no specific pathological patterns (Kóbor J). Laboratory findings: electrolytes, liver and renal functions

truncal ataxia, dysarthria EEG normal, regular alpha type CT slightly wider IV. ventricle, CSF: oligloclonal gammopathy, MRI: olivo-ponto-cerebellar atrophy

were normal, but hyperuricaemia (329 µmol/l), hyperpyruvataemia (192 µmol/l) and lactate acidosis (5.2 mmol/l) were detected. Specific enzyme investigations excluded the homozygosity for metachromatic (MLD) and ortochromatic leukodystrophy (OLD). Biochemical investigations: highly elevated urinary excretion of N-acetyl-aspartic acid (165 nmol/mol/creatinine, while in controls 6.6-

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Figure 1. 46; XY, 18q21.3-qter deletion. Chromosome set of the propositus with 18q deletion Figure 2. 18q deletion MRI. On the long TR/long TE scans, the genu corporis callosi and the frontal white matter, mainly on the left side, were hypointense. The globus pallidus and the thalamus were also slightly hypointense symmetrically. In the periventricular white matter on the left side, focal areas of hyperintensity could be seen temporooccipito-parietally. The posterior limb of the internal capsules also displayed an increased signal intensity. The lateral ventricles and the temporoparietal subarachnoid space were slightly dilated (Vörös E)

35.4) was proven, indicating Canavan disease (Jakobs C). Cranial MRI revealed diffuse spongy leukodystrophy suspecting to Canavan disease (Figure 3.). Sural nerve, muscle and skin biopsies gave no pathologic information, neurogenic muscular atrophy, mitochondrial myopathy (no ragged red fibers), peripheral demyelination were excluded.

Figure 3. Cranial MRI of Canavan patient. An MRI of the brain (T2) of a 7 month-old with Canavan disease, which revealed diffuse leukodystrophy suspecting to Canavan disease. The sagital T1, axial T2, coronal flair and inversion recovery showed mildly dilated ventricular system, including the IV. chamber. The hemispherial and cerebellar white material have been swollen showing pathologically increased T2 and low T1 signs, narrow periventricular border. Corpus callosum and capsula interna seemed to be intact, but most part of the swollen pons revealed pathological signs. Thalamus has been mildly affected, as bilateral globus pallidus have been severely affected, while putamen, caudatus and the cortex were unaffected, cortex (Vörös E) MOLECULAR GENETIC INVESTIGATIONS

Genomic DNA was extracted from peripheral blood by standard methods. Two oligonucleotide primers were used: CDP1 (CTCTTGATGGGAAGACGATC) and CDP2 (ACACCGTGTAAGATGTAAGC) corresponding two positions 791-810 and 974-955 in the cDNA respectively. Direct sequencing of the PCR product was performed by fluorescent dideoxy-chain termination reaction and ABI 377 automatic sequencer apparatus. Our Hungarian Canavan infant (patient 1.) has been proven to be homozygous for the 914 (A305E) mutation, while our Israelian woman patient (patient 2.) has been proven to be gene carrier for Y231X mutation. Patient 3. (patient 2’s sister) has a silent mutation nt 693 C to A (A of ATG = 1) at the amino acid level Tyr 231 to Tyr, without any pathogenic mutations. She was allowed to follow on her gravidity (Table 2., Elpeleg ON). ADRENOLEUKODYSTROPHIC PATIENTS

Among the investigated four leukodystrophic two adult male patients (L/1 37 years, L/2 32 years.) had

Table 2. Mutations of Aspartoacylase (ASPA) gene for Canavan disease Patient

Age (years)

Mutation of ASPA gene

Genotype

1. (male)

at the dg.: seven months, at present: five years 33 years 31 years fetus (chorionic villi)

914 (A305E)

homozygote

Y231X nt 693 C to A (A of ATG=1) Tyr 231 to Tyr

gene carrier without any pathogenetic mutation

2. (female) 3. (pregnant woman) prenatal diagnosis

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field, dysmyelination in the posterior periventricular region (Figure 4.). Metachromatic and orthrochromatic leukodystrophies were excluded by specific enzyme investigations according to the normal aryl-sulphatase-A and N-acetylβD-glucosidase activities from the leukocytes’ homogenate. Pelizaeus-Merzbacher leukodystrophy (PML) is caused by different mutations of proteo-lipid-protein (PLP). Our two year old male infant patient was investigated because of somatomental retardation, in tetraparetic stage. Previously the diagnosis was detected in Bethesda Childrens’ Hospital (Tegzes A), with SSCP (single strand conformation polymorphism) has been analysed from the exon 7th of PLP (proteolipid protein) gene. The Amplicon 2 pattern showed aberrant migration. The direct sequenation of 33rd of codon two nucleotid guaFigure 4. Cranial MRI of adrenoleukodystophic patient. See in text. The MRI demon- nin-adenin transition (c986-GA) strated a parieto-occipital dysmyelination. On T2 there was a very high signal inten- which caused codon change from sity at the parieto-occipital field, dysmyelinatio in the posterior periventicular region TGT to TAT. His mother has been proven gene carrier for this mutation (Gal A). The cranial MRI showed nearly total loss of cerebral myelination (Figure 5., Barsi P). Biochemical investigation: MLD was excluded according to the normal arylsulphatase-A activity (95 nmol/mg protein/h. Beta-glycosidase activity was found to be 7.62 nmol/mg protein/h (heterozygous genotype), the total hexosaminidase activity was 1606 nmol/ mg protein/h (normal activity). The aryl-sulphatase B fraction was 368 nmol/mg protein/h (also norFigure 5. Pelizaeus-Merzbacher leukodystrophy. The mal), while the A enzyme activity was 1238=77.1% cranial MRI showed nearly total loss of cerebral myelin- nmol/mg protein/h (signing heterozygous genoisation (Barsi P) type). Alexander leukodystrophy is a progressive usualbeen proven to be adrenoleukodystrophy (ALD) ly fatal neurological disorder defined by the abunaccording to the parieto-occipital typical localiza- dant presence in astrocytes of protein aggregates tion of the demyelination process. L/1 patient’s called Rosenthal fibers20. Alexander disease is MRI demonstrated that was tipical localization for caused by different mutations of glial fibrillar acid adrenal leukodystrophy without any affection of the proteine (GFAP) gene Kyllerman et al. and Kawai thalamus and peripheral white material. The cap- et al. reported a new missense mutation, and A to G sula interna and externa, corpus callosum may be transition at nucleotid position 1026 in exon 6, leadaffected, the most frequent regions are the bilateral ing to the substitution of glycine for glutamic acid occipital ones. On T2 there was a very high signal at amino acid position 371 (E371G) in a Japan intensity in two cases at the total parieto-occipital infant with Alexander disease20, 21.

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One year and 10 month of age male patient’s MRI showed an extensive leukoencephalopathy. Only some of the occipital U-fibres are spared. There are also slight signal changes in the basal ganglia. There is a periventricular rim of low signal intensity on the T2-weighted images and high signal intensity on the T1-weighted imaged. There are signal abnormalities in areas of the brain stem, the hilus of the dentate nucleus and the cerebellar white matter. These images are diagnostic for Alexander disease (Figure 6.). Olivo-ponto cerebellar atrophy (OPCA): A 18 year female patient had a mild hearing loss on both sides at age three years and MRI scan taken at that time showed no pathology. She was sent to Heim Pal Hospital, Neurological Department (Saracz J). Neurological examination did not reveal any signs of pathological deterioration, apart from a bilateral sensorineural hypacusis. Her EEG examination gave a regular α-type registration, without any pathological components. She tried to use hearing aid, after which that her hearing status worsened. From her 16 y. age severe ataxia has developed. OPCA was diagnosed by typical cranial MRI findings (Figure 7., Barsi P, 2006). Gabapentin was ordered according to Gazulla and Benavente’s publication22.

Figure 6. Alexander disease. 1 y 10 month-of age male patient’s MRI showed an extensive leukoencephalopathy. Only some of the occipital U-fibres are spared. There are also slight signal changes in the basal ganglia. There is a periventricular rim of low signal intensity on the T2-weighted images and high signal intensity on the T1-weithted imaged. There are signal abnormalities in areas of the brain stem, the hilus of the dentate nucleus and the cerebellar white matter. These images are diagnostic for Alexander disease (van der Knaap MS)

of chromosome 18. Some similar cases have been reported24–26. In a case involving the 18q deletion syndrome, delayed myelination in the white matter

Discussion Rodichok and Miller reported evoked potential findings in a patient with 18q deletion syndrome (18q22.3-qter), the deletion included the locus for myelin basic protein (MBP)23. We noticed delayed myelination and severe alterations on electrophysiological investigations by SEP and BAEP. MRI examination revealed a delayed myelination over all the brain, apart from the corpus callosum and the frontal gray matter, in which the myelination was at a more advanced stage. Focal hyperintensities were thought to be consequences of the gliotic processes. We hypothetized that there should be an uric acid splitting regulator gene at the end of the 18q chromosome. Since Grouchy et al. published the first case with Figure 7. MRI of olivo-ponto-cerebellar atrophy (OPC) (18 y female patient) (Barpartial monosomy of the long arm si P)

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was demonstrated by MRI27, 28. A similar situation was reported in a Japanese boy10. Cytogenetic investigation revealed a deletion of 18q21.3-qter. Diffusion-weighted MRI shows absent or lowgrade myelin edema in adrenomyeloneuropathy, L2-hydroxyglutaric aciduria, non-ketotic hyperglycinemia, van der Knaap disease and vanishing white matter disease and medium grade in metachromatic leukodystrophy29. The human aspartoacetylase gene 17(17p13-ter) consists of 6 exons and 5 introns11, 30. The predominant Jewish mutations are the missense mutation on exon 6 (Glu 285 Ala) and a nonsense mutation on exon 5 (Tyr 231 X, tyrosine > termination codon). These mutations can be found in 98% of all Jewish patients with Canavan-disease. Among our Canavan disease loaded families an A305E homozygous mutation, an Y231X heterozygous mutation and from the chorionic villi homogenate Thy 281 Thyr non-pathogen mutation were detected (Table 2.). Sistermans et al. described the results of the mutation analysis in 17 European, non-Jewish patients31. Ten different mutations were found, of which four had not been described before (H21P, A57T, R168H, P181T). The other common mutation (Ala 305 Glu) is found in 40-48% of nonJewish patients. According to genetic studies, among Ashkenasi-Jews the carrier frequency is between 1/35 and 1/5932. Hess published a missense point mutation on exon 6, causing substitution of glutamic acid to alanine in position 285 of aspartoacylase (Gly 285 Ala)33. Elpeleg et al. found the C854 mutation in 36/36 mutant alleles of Israelian CD patients of Ashkenazi-Jewish origin, among the screened 879 healthy subjects the carrier rate was 1:5934. This mutation is the common non-Jewish mutation through Europe accounting for about 40% of the mutated alleles. Salomons et al. published

improved molecular diagnosis for CD. The purified polymerase chain reaction product were directly sequenced and aligned with the asparto-acylase (ASPA gene)35. Prenatal molecular diagnosis of adrenoleukodystrophy was published by Huang et al.36 Furuki et al. recently isolated PEX26 as the pathogenic gene for PBD of CG837. Mutation c.459+1G>A is more frequent in countries situated at the western edges of Europe. Mutation p.P426L is most prevalent in countries assembled in a cluster containing the Netherlands, Germany, and Austria38. Di Rocco et al. reported three cases with infantile-onset lysosomal storage disorders showing white matter hypomyelination39. Vianello et al. published X-linked adrenoleukodystrophy with olivopontocerebellar atrophy40. Olivopontocerebellar atrophy (OPCA) is a degenerative disease of the nervous system (NS) which currently has no known cure. The neuronal depopulation it brings about produces a number of neurochemical alterations, including a reduction in levels of gamma-aminobutyric acid (GABA) in tissues and in cerebrospinal fluid (CSF). Gazulla et Benavente discussed how such effects are due to the increased levels of GABA in the NS triggered by the drug22.

Conclusion The authors discuss the different type of leukodystrophies caused by specific enzyme deficiencies and the molecular genetic diagnostic methods of the specific mutations. The cranial MRI gives the most important diagnostic helpness as the first step of diagnostic protocoll in the neurometabolic and familiar hereditary neurological disorders.

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