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Two de novo intronic mutations of GLS gene leading to Glutaminase Deficiency/ Autosomal Recessive Developmental and Epileptic Encephalopathy 71 (AR-DEE71)

Biochemical/Metabolic and Therapeutics
  • Primary Categories:
    • Metabolic Genetics
  • Secondary Categories:
    • Metabolic Genetics
Introduction


Developmental and epileptic encephalopathies (DEEs) often manifest in the neonatal period with severely impaired neurologic function causing severe hypotonia, respiratory insufficiency and either seizures or burst suppression on EEG. DEEs present a diagnostic challenge due to their rarity, the need for extensive and highly specialized testing, and their poor prognosis. They are often caused by mutations in genes crucial for brain development and function. Among these genes, GLS stands out due to its vital role in CNS leading to autosomal recessive DEE type 71.

Case Presentation


Proband is a 6-week-old Female, born at 38+1/7 weeks by elective C-section for IUGR to a 27 yo, G2P1 mother of Bengali descent without consanguinity. She was initially vigorous with APGARs of 6 at 1 and 5 minutes. Growth parameters were weight 2nd%ile, length 5th%ile, and HC 12th%ile for age. She had severe hypotonia with hyperreflexia, poor suck/swallow, and hypoventilation with frequent, severe apneic events.

Physical examination was notable for minor dysmorphic features including a narrow bifrontal diameter, mildly posteriorly rotated ears, over-folded upper helices, broad nasal bridge, microretrognathia as well as hypoplastic nipples, a deep sacral dimple, clenched hands without contractures, and left partial simian crease.

Diagnostic Workup
 

  • EEG: burst suppression pattern without seizures which did not respond to standard vitamin challenges

  • MRI: structurally normal brain with mild ventriculomegaly, punctate left periventricular stroke, and non-diagnostic spectrographic profile

  • Newborn screen including SMA was normal

  • Extensive metabolic testing from the serum, urine, and CSF were unremarkable with the exception of the serum amino acid profile which showed a markedly elevated glutamine (1317) with smaller elevations in alanine and proline suggested to be the result of hyperammonemia or lactic acidemia

  • Methylation studies for PWS, microarray, and poly A expansion for PHOX2B were negative

  • Rapid Whole Exome Sequencing (rWES) and Mitochondrial genome sequencing with deletion analysis were negative

  • Rapid whole genome sequencing (rWGS) Trio: Two de novo intronic mutations in GLS gene:

    • c.736-1 G>C:p.? in intron 4 of the GLS gene (NM_014905.4) - Likely Pathogenic Variant (VLP)

    • c.605+3 A>G:p.? in intron 3 of the GLS gene (NM_014905.4) - Variant of uncertain significant (VUS)

      • Phase undetermined, as both variants are de novo and not near each other. Neither variant has nearby informative SNPs to suggest parent of origin.








Treatment and Management


Supportive care.



 

Outcome and Follow-Up


At the time of writing this abstract, at 6 weeks of age, she is requiring persistent ventilatory support pending tracheostomy and gastrostomy placement.

Discussion
Glutaminase deficiency is associated with three distinct clinical phenotypes:

1. Infantile Cataract, Skin abnormalities, Glutamate excess, and Impaired Intellectual Development (CASGID - AD) associated with a gain of function, undetectable glutamine, and no respiratory insufficiency or hypotonia.

2. Global Developmental Delay, Progressive Ataxia, and Elevated Glutamine (GDPAG – AR) with early onset developmental delay and ataxia in mid- to late childhood. One or both alleles of the GLS gene typically carry a GCA trinucleotide repeat in the 5’UTR allowing residual glutaminase activity leading to elevated plasma glutamine with normal ammonia.

3. Developmental and Epileptic Encephalopathy 71 (DEE71 - AR) characterized by seizures, hypotonia, brain abnormalities, and respiratory insufficiency/failure with elevated plasma Glutamine.

Based on triad of hypotonia, respiratory insufficiency/failure and burst suppression in the setting of an elevated plasma glutamine, the reported de novo intronic VUS in this patient likely represents a VLP in trans phase with the de novo intronic VLP, leading to a compound heterozygous state compatible with the AR-DEE71 phenotype. 

Conclusion


This is the first report of de novo intronic mutations in a patient with clinical features of Glutaminase deficiency/DEE71, emphasizing the diagnostic utility of WGS in critically ill infants with undiagnosed epileptic encephalopathies. 

Agenda

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