Immunodeficiency, Developmental Delay, And Hypohomocysteinemia

A number sign (#) is used with this entry because of evidence that immunodeficiency, developmental delay, and hypohomocysteinemia (IMDDHH) is caused by heterozygous mutation in the NFE2L2 gene (600492) on chromosome 2q31.

Description

IMDDHH is a multisystem disorder characterized by immunodeficiency, mildly delayed psychomotor development, poor overall growth from infancy, and hypohomocysteinemia. Additional features, such as congenital heart defects and liver involvement, are more variable (summary by Huppke et al., 2017).

Clinical Features

Huppke et al. (2017) reported 4 unrelated children, between 1.8 and 14 years, with a similar multisystem disorder characterized by failure to thrive, poor overall growth with short stature, immunodeficiency, and variable neurodevelopmental abnormalities. The patients presented in infancy with growth retardation and recurrent infections, such as respiratory and skin infections. Immunologic workup in 3 patients showed hypogammaglobulinemia and IgA deficiency with decreased switched memory B cells and poor polysaccharide response, and 1 patient was suspected to have a defect in natural killer cell (NK) function. All had delayed psychomotor development, although it was typically mild intellectual disability with speech delay and learning disabilities or delayed acquisition of fine motor skills; IQ testing in 1 patient was 74. Other features were variable. Three patients had cardiac defects, including atrial septal defect, cardiomyopathy, and thickened bicuspid aortic valve. One patient had absence seizures, intermittent tremor, and hoarse voice, and another had mild nonspecific dysmorphic features. Some patients had evidence of possible liver damage. Three patients had low blood homocysteine levels, 2 had low plasma cysteine, and all had low creatinine. Brain imaging, performed in 3 patients, showed periventricular and subcortical T2-weighted white matter abnormalities. Special studies, including magnetic resonance spectroscopy (MRS), performed in 1 patient showed decreased N-acetylaspartylglutamate and creatine, as well as myelin deficits.

Clinical Management

Based on cellular studies, Huppke et al. (2017) treated patient 1 with luteolin and ascorbic acid. After 6 months, liver enzymes had normalized, but there was no effect on homocysteine levels. The mother reported a positive effect, with fewer infections and improved physical and school performance.

Molecular Genetics

In 4 unrelated patients with IMDDHH, Huppke et al. (2017) identified 4 different de novo heterozygous missense mutations in the NFE2L2 gene (600492.0001-600492.0004). All mutations affected 1 of 2 motifs (ETGE or DLG) in the N-terminal Neh2 domain that facilitates the binding of inhibitory KEAP1 (606016) molecules. Fibroblasts derived from 1 patient showed increased levels of mutant NFE2L2 and increased expression of multiple genes, including those involved in the stress response. The strongest increase in expression was seen for AKR1C1 (600449) and AKR1B10 (604707). Patient erythrocytes showed increased activity of G6PD (305900) and GSR (138300), indicating downstream activation of NFE2L2 target genes in vivo. Patient cells also showed an imbalance in cytosolic redox balance, with a more reducing, i.e., more negative, resting state redox balance compared to controls. Treatment of patient cells with the antioxidant luteolin reduced the NFE2L2 levels by up to 90%, while treatment with ascorbic acid was less consistently effective. Overall, the findings suggested that the mutations increased NFE2L2 levels in the absence of stress and caused constitutive chronic activation of stress response genes, consistent with a gain-of-function effect.