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Three siblings with variable degrees of neuromuscular involvement and congenital sideroblastic anemia: A peculiar
Mai Abd El Salam1, Khaled Salama1, Yasmeen M M Selim1
1Department of Pediatrics (Pediatric Hematology Unit), Kasr Alainy Faculty of Medicine, Cairo University, Cairo, Egypt.
Insights
Genetic testing identified a novel SLC25A38 variant causing sideroblastic anemia type-2 and a GMPPB variant in siblings with complex neurological symptoms. This highlights the value of exome sequencing for diagnosing rare inherited disorders.
Area of Science:
- Genetics
- Hematology
- Neurology
Background:
- Congenital sideroblastic anemias (CSAs) are inherited bone marrow disorders characterized by ineffective erythropoiesis.
- Some CSA cases present with complex phenotypes, including neurological manifestations.
Purpose of the Study:
- To perform detailed clinical and genetic characterization of three siblings with CSA.
- To identify the genetic basis of complex phenotypes in a familial CSA case.
Main Methods:
- Clinical evaluation of affected siblings.
- Allogenic hematopoietic stem-cell transplantation in elder siblings.
- Whole-exome sequencing for genetic variant identification.
Main Results:
- Identified a novel homozygous nonsense variant in SLC25A38 (c.559C>T; p.(Arg187*)) causing autosomal-recessive sideroblastic anemia type-2.
- Identified a homozygous pathogenic variant in GMPPB (c.458C>T; p.(Thr153Ile)) causing autosomal-recessive muscular dystrophy-dystroglycanopathy type B14.
- Two siblings presented with limb-girdle myopathy and global developmental delay; hematopoietic stem cell transplantation stabilized hematological features.
Conclusions:
- Whole-exome sequencing is crucial for diagnosing familial cases with complex phenotypes and neurological symptoms.
- This study identified novel genetic variants in SLC25A38 and GMPPB, expanding the genetic landscape of CSA and related disorders.
- Therapeutic strategies include hematopoietic stem cell transplantation and trial therapy with acetylcholine esterase inhibitors for neurological symptoms.
Introduction:
Congenital sideroblastic anemias (CSAs) are a group of inherited bone-marrow disorders manifesting with erythroid hyperplasia and ineffective erythropoiesis.
Methods:
We describe a detailed clinical and genetic characterization of three siblings with CSA.
Results:
Two of them had limb-girdle myopathy and global developmental delay. The two elder siblings performed allogenic hematopoietic stem-cell transplantation 5 and 3 years prior with stabilization of the hematological features. Exome sequencing in the non-transplanted sibling revealed a novel homozygous nonsense variant in SLC25A38 gene NM_017875.2:c.559C > T; p.(Arg187*) causing autosomal-recessive sideroblastic anemia type-2, and a second homozygous pathogenic previously reported variant in GMPPB gene NM_013334.3:c.458C > T; p.(Thr153Ile) causing autosomal-recessive muscular dystrophy-dystroglycanopathy type B14. With the established diagnosis, hematopoietic stem cell transplantation is now being scheduled for the youngest sibling, and a trial therapy with acetylcholine esterase inhibitors was started for the two neurologically affected patients with partial clinical improvement.
Conclusion:
This family emphasizes the importance of whole-exome sequencing for familial cases with complex phenotypes and vague neurological manifestations.
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