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

2. 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)

3. 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

4. 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

5. 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 (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

6. 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

7. 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

8. PMD

10. 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.

14. 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

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

16. 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

17. 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

18. 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.

19. 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.

20. 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

21. 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

22. 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

23. 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

24. 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

25. 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

26. 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 (c Del) 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 (c Del)

27. Thank you for your attention