Pelizaeus Merzbacher & Pelizaeus Merzbacher like Disease Parvaneh Karimzadeh MD Professor of Pediatric Neurology Shahid Behehsti University of Medical Sciences Mofid Children Hospital

Pelizaeus Merzbacher Disease Described clinically by pelizaeus in 1885 and later by Merxbacher in 1910 Zeman predicted the role of proteolipid protein (PLP) in 1964 X-linked recessive The gene localized to the long arm of the X chromosome (Xq21.2-q22)

Pelizaeus Merzbacher Disease(PMD) PMD is linked to the PLP1 gene Genetic description has been complicated by the discovery a form of X-linked spastic paraplegia and PMD are allelic condition

Clinical Manifestation of PMD Hypomyelinating is the major pathologic defect in PMD The MRI pattern is highly suggestive Slowly progressive Before 3 months of age Pendular eye movement Head shaking Hypotonia, dystonia, cerebellar ataxia Mental retardation, choreathetosis Pyramidal sign

Clinical Manifestation of PMD Divided into 3 types Type 1 classic form Type 2 , neonatal progressive type with presentation shortly after birth : sever hypotonia, stridor, feeding difficulty can mimic SMA- no abnormality in Ant-horn Cell death may occur Type 3Transitional form (combination of type 1 and 2 ) Fourth type of PMD , Spastic paraplegia type 2 (X-linked type of spastic paraplegia) is an allelic variant of PMD with PLP gene defect that presents with spasticity in the lower extremities and slow progression

MRI Three pattern Diffuse alteration in hemispheric white matter and corticospinal tract Diffuse alteration in hemispheric white matter with a normal corticospinal tract Patchy changes in the white matter of the cerebral hemisphere

The T1 weighted images show low intensity of all unmyelinated white matter structures; whereas, these structures have high signal intensity in T2 Mutation in PLP1 that encodes the essential intrinsic membrane protein of CNS myelin is the main cause of PMD

PMD

Case Report A 10-month-old girl was referred for evaluation of neurodevelopmental delay The product of the first pregnancy of consanguineous parents Full term by C/S without any history of birth problems (such as asphyxia, hypoxia, icter,…… Motor development evaluation showed the ability of rolling, but head control was incomplete Head nodding ,Hypotonicity,Pendular bilateral nystagmus since neonatal period No history of seizure.

Abnormal signal intensity in the white matter (hyperintensity in T2,FLAIR and low signal intensity in T1 weighted images) An arrest of myelination it is compatible with a younger chronological age Abnormal findings :diffuse hypersignal in the cerebral & cerebellar white matter, genu of the corpus callosum, basal ganglia especially globus pallidus and ventrolateral thalamic nuclei

Gene sequencing Whole exon sequencing of PLP1 gene showed normal sequences in the patient’s blood sample A homozygote deletion c902-918 del in exon2 of GJA12 was found by the sequencing method This frame shift deletion changed the amino acid frame in GJA12 gene

Pelizaeus Merzbacher like Disease Clinically resembles PMD (Classic) but mutation of the PLP1 gene is not detected Nystagmus, ataxia, hypotonia, later spasticity MRI findings : diffuse alteration in white matter and calcification in basal ganglia and dentate nucleus In most cases, no gene has been identified, but in a small subset of them (less than 10%) mutation in GJC2 (so called GJA12) codon for Connexin 46.6 (Cx47) has been found

pelizaeus merzbacher like Disease Mutation of the gap junction protein alpha12 (GJA12) gene is known as one of the autosomal recessive PMLD forms Few patients with the mutation of GJA12 have been reported Their clinical phenotypes are overall compatible with the clinical manifestations of the mild forms of PLP1-related disorders, but better cognition and earlier signs of axonal degeneration is prominent

This form of PMLD is expressed as autosomal recessive Mutations in GJA12 that encodes gap junction protein (Connexin 46.6) This gene encodes Connexin 46.6 that has a cardinal role in central and peripheral myelination Their phenotypes include nystagmus, developmental delay and progressive spasticity.

pelizaeus merzbacher like Disease Another form of PMLD transmitted by an X- linked pattern Gene locus is located on the outer part of the PLP gene location on the X chromosome.

pelizaeus merzbacher like Disease Another form of PMLD Mutations in the thyroid hormone transporter gene MCT8 Express initially as a PMLD Unusual improvement of magnetic resonance imaging white matter signal deposited The interest of determining both free T3 and free T4 to screen for MCT8 mutations in patients under 3 years with PMLD

PMLD Uhlenberg et al 2004 described a consanguineous Turkish family with PMLD Inherited autosomal recessive Nystagmus, developmental delay, ataxia, choreathetose and dysarthria with progressive spasticity – presenting in early infancy He noted that this form of PMLD accompanied with mild peripheral neuropathy Sensory and motor NCV of the lower limb were reduced Heterozygous individuals had no neurologic symptoms They identified 5 different mutations in the GJA12 gene in these patients

PMLD Bugiani et al in 2006 reported 12 patients with PMLD from the family of Saudi Arabia Phenotype of PMD 11 of 12 had mild mental retardation The course tended to be slowly progressive No had dystonia, choreathetose and seizure Brain MRI showed diffused cerebral hypomyelination in white matter

PMLD Wolf et al in 2007 Reported 2 sibling with PMLD born of consanguineous Pakistani parents Pheotype PMD Brain MRI showed T2 weighted hyperintensities consistent with hypomyelination in this 2 sibs identified a homozygous 34-bp deletion in the GJA12 gene

PMLD Silviati et al in 2007 reported another pakistani girl with PMLD She developed Phenotype of PMD Brain MRI showed diffused white matter hypomyelination Silviati indipendently identified the same 34 -bp deletion in this girl

PMLD Henneke et al in 2008 Identified 11 mutations in the GJA12 gene in affected members of 14(7.7%) of 182 families with a PMLD The phenotype was similar to that observed in patients with classic PMD Patients with GJA12 had better cognition and earlier signs of axonal degeneration The authors concluded that GJA12 mutations are not a common cause for PMLD

Conclusion Our patient had a mutation in GJA12 gene and her clinical findings were very similar to other PMLD cases She had a new mutation (c902-918Del) that had not been reported in previous studies With respect to our case and recent reports from other Middle East countries, we think GJA12 gene mutations are common in this area, but we found a new mutation (c902-918 Del)

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