Growth Retardation, Impaired Intellectual Development, Hypotonia, And Hepatopathy

A number sign (#) is used with this entry because of evidence that growth retardation, impaired intellectual development, hypotonia, and hepatopathy (GRIDHH) is caused by compound heterozygous mutation in the IARS gene (IARS1; 600709) on chromosome 9q22.

Description

GRIDHH is an autosomal recessive multisystem disorder characterized by poor overall growth, impaired intellectual development, hypotonia, and variable liver dysfunction. Additional features, such as seizures and hearing loss, may also be present (summary by Kopajtich et al., 2016).

Clinical Features

Kopajtich et al. (2016) reported 3 unrelated patients with a similar multisystem disorder characterized by intrauterine and postnatal growth retardation, including small head circumference (-3 to -5 SD), hypotonia, and delayed psychomotor development with variable severity of impaired intellectual development. The patients were 18, 19, and 3 years old at the time of last examination. An 18-year-old German male was the most severely affected: he had moderate to severe intellectual disability, no expressive speech, and spasticity. Brain MRI showed white matter changes consistent with hypomyelination. A 19-year-old Japanese female had mild intellectual disability, sensorineural hearing loss, and several well-controlled seizures; brain imaging was normal. A 3-year-old Austrian male had mild developmental delay and normal brain imaging. All 3 patients had variable liver involvement: the German patient had only biochemical evidence of intermittent and mild hepatic synthesis defects, whereas the other 2 patients had abnormal liver enzymes associated with steatosis and fibrosis in early childhood. The 3-year-old boy had recurrent episodes of severe liver dysfunction with cholestasis; he was also found to carry a heterozygous variant in the ABCB11 gene (603201), which may have contributed to the liver phenotype. Liver function as well as microcephaly improved in the Japanese patient. All patients showed mild mitochondrial complex I deficiency in fibroblasts, muscle, or liver. The most severely affected patient also had complex IV deficiency in muscle. All patients also had zinc deficiency and showed an improvement with zinc supplementation; however, a beneficial effect of zinc supplementation could not be demonstrated in the yeast or zebrafish models. The cause of zinc deficiency in the patients may have been related to chronic liver disease.

Orenstein et al. (2017) reported a boy, born to unrelated Arab parents, with intrauterine growth delay, liver dysfunction, and neurodevelopmental disabilities. The patient presented with neonatal liver failure and cholestasis. He had a strikingly round face, full cheeks, increased fat in the genitalia area, and soft, translucent, hyperelastic skin with joint laxity. He also had a duplicated left collecting system and mild bilateral hydronephrosis as well as growth hormone resistance. He was treated with growth hormone from the age of 19 months; by the age of 4 years, his weight and length were within normal limits, but his head circumference was 2.5 SD below the mean. Neuropsychologic evaluation demonstrated mild developmental delay. He did not have zinc deficiency.

Inheritance

The transmission pattern of GRIDHH in the families reported by Kopajtich et al. (2016) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 3 unrelated patients with GRIDHH, Kopajtich et al. (2016) identified compound heterozygous mutations in the IARS gene (600709.0001-600709.0006). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Yeast growth studies confirmed that each patient carried 1 loss-of-function allele and 1 hypomorphic allele.

In a boy, born of unrelated Arab parents, with GRIDHH, Orenstein et al. (2017) identified compound heterozygous missense mutations in the IARS gene (600709.0007-600709.0008). The mutations, which were found by whole-exome sequencing, segregated with the phenotype in the family. Yeast complementation studies showed that, similar to the previously reported cases, one allele caused impaired function and the other caused loss of function.

Animal Model

Kopajtich et al. (2016) found that iars was ubiquitously expressed in zebrafish during early embryonic development. It localized to the somites and developing brain regions after gastrulation, especially in the tectum region of the brain, pineal gland, and hindbrain. Morpholino knockdown of the iars gene in zebrafish embryos resulted in a delay in embryonic development, with embryos showing altered brain configuration and severe shortening of the posterior body axis in a concentration-dependent manner. Zinc treatment did not result in a phenotypic rescue.