Skip to main content

Conference Program

Subpage Hero

Loading

Novel bi-allelic variants in GJC2 associated Pelizaeus-Merzbacker-like disease in three patients at a single center in North India: Case series 

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Clinical- Pediatric
  • Secondary Categories:
    • Clinical- Pediatric
Introduction:
GJC2 encodes for connexin 47 (Cx47), also known as gap junction protein γ2 (GJC2), which is responsible for oligodendrocyte differentiation & myelination. Biallelic recessive variants in GJC2 is responsible for a severe hypomyelinating disorder, Pelizaeus-Merzbacker-like disease (PMLD) also called as Hypomyelinating disorder type 2 (HLD2). The disease is characterized by early infantile nystagmus, hypotonia, delayed development, dysarthria and seizures. The hypotonia gradually changes to spasticity in childhood. MRI is suggestive of diffuse areas of white matter (WM) hypomyelination seen as T2 hyperintensities with cerebellar atrophy. 

Other allelic disorders with homozygous or compound heterozygous GJC2 mutations are GJC2 related hereditary spastic paraparesis designated as SPG44 and recently described subclinical leukodystrophy. SPG44 is milder form of disease, having late onset spasticity, hyperreflexia, intention tremor with no signs of nystagmus. 

Pelizaeus-Merzbacker disease (PMD), X linked recessive disorder is a very close differential to PMLD.

 

Methods:
Case description: We describe two families presenting to a single center in city of Prayagraj, North India. First family: 6-year-old male child, born out of non-consanguineous marriage with normal birth & antenatal history, presented with delayed development, ataxia, tremors & titubation of head. No nystagmus seen, but brisk reflexes & hypertonia present. MRI done was suggestive of WM hypomyelination & thin corpus callosum.

Second family: 9m old girl child born of third-degree consanguineous marriage, presented with complaint of nystagmus since 3m of age, head titubation & developmental delay. Microcephaly with hypertonia & brisk reflexes present. MRI brain & EEG at 8m of age was normal. The couple’s elder girl child had expired at age of 8.5yr with similar complaints of ataxia, delayed development & nystagmus with MRI brain showing hypomyelination of white matter. On review of previous papers, relative macrocephaly, brisk reflexes & hypertonia documented. Differentials of PLP like disorder, Canavan’s disease was kept. The couple has a surviving well 5yr old boy. 

Results:
For the first family, in view of male child with characteristic clinical features and hypomyelination in MRI, whole exome sequencing (WES) done to rule out PMD. Novel homozygous likely pathogenic variant c.814T>C (p. Try272His) in Exon 2 of GJC2 gene found (PM1, PM2, PM5, PP3) with no variants in PLP1 gene.

For the second family, in view of two girl siblings affected with similar features and a normal male child, Pelizaeus-Merzbacker-like disease (PMLD) suspected.  Due to financial constraints, WES could not be done for the elder sibling. But for the second affected child WES was done and it revealed novel likely pathogenic homozygous c.270del (p. Ser91ArgfsTer119), frameshift mutation causing premature stop codon at codon119 (PVS1, PM2). Both varaints have not been previously described in ClinVar.

With no treatments are available, both families advised for multidisciplinary care involving physiotherapy, occupational therapy, speech therapy, nutritionist, developmental pediatrician and specialists like ophthalmologists & ENT for vision & hearing assessment. 

 

 

Conclusion:
Clinical distinction between PMD and PMLD is very difficult hence, in both the families, genetic testing helped in ending the diagnostic odyssey. Moreover, in low to middle income countries like India, these investigations are an out of pocket expenditure for the families. The ease of availability and affordability of exome sequencing has transformed genomics. Importance of thorough clincal history & examination can be highlighted in these cases leading to appropriate investigations & management with judicious use of monetary funds. The importance of risk of recurrence of such autosomal recessive disorders can be highlighted in the second family. Genetic counselling with emphasis on prenatal testing (chorionic villus sampling or amniocentesis) is especially important in our country with high rates of consanguinity. The option of continuing or discontinuing the preganancy must be made by the family after proper genetic counselling.

 

Agenda

Sponsors