Alternative titles; symbolsGLUTAMINE SYNTHASE DEFICIENCY, CONGENITAL SYSTEMICCongenital glutamine deficiency is a severe autosomal recessive disorder characteriz...
Alternative titles; symbols
Congenital glutamine deficiency is a severe autosomal recessive disorder characterized by onset at birth of encephalopathy, lack of normal development, seizures, and hypotonia associated with variable brain abnormalities (summary by Haberle et al., 2011).
▼ Clinical Features
Haberle et al. (2005) described 2 presumably unrelated newborns of consanguineous Turkish ancestry who had congenital glutamine synthetase deficiency with severe brain malformations resulting in multiorgan failure and neonatal death. Glutamine was largely absent from their serum, urine, and cerebrospinal fluid. The first infant died on day 2. He had shortness of limbs, flexion contractures of elbows and knees, camptodactyly, ulnar deviation in hands, flat nasal root, short nose, anteverted nares, thin lips, and low-set ears. The second patient died in week 4. She showed generalized muscular hypotonia, enteropathy with voluminous diarrhea, necrolytic migratory erythema of the skin, and also had broad nasal root and low-set ears.
Haberle et al. (2011) reported a child, born of consanguineous Sudanese parents, with congenital glutamine deficiency. At birth, he showed generalized hypotonia, lower limb hyperreflexia, and soon developed seizures. He had severe developmental delay, apnea, recurrent respiratory infections, and episodes of bradycardia. He developed a transient severe epidermolytic rash. Laboratory studies showed hyperammonemia and decreased glutamine in serum and CSF. Brain MRI showed hypomyelination, thinning of the corpus callosum, and mild brain atrophy with prominent cortical sulci. He was alive, but severely handicapped, at age 3 years.
▼ Molecular Genetics
Haberle et al. (2005) detected homozygous mutations in the GLUL gene in each of 2 Turkish patients with a systemic glutamine deficiency. One patient carried an arg324-to-cys substitution (R324C; 138290.0001), and the other an arg341-to-cys substitution (R341C; 138290.0002). Neither mutation was found in 160 control alleles, including 60 alleles from Turkish persons. Parental heterozygosity suggested an autosomal recessive mode of inheritance and confirmed segregation of mutations in both families. Both mutations were found in heterozygosity in the parents.
In a Sudanese boy with congenital glutamine deficiency, Haberle et al. (2011) identified a homozygous mutation in the GLUL gene (R324S; 138290.0003).