Mehmo Syndrome

A number sign (#) is used with this entry because of evidence that MEHMO syndrome (mental retardation, epileptic seizures, hypogonadism and hypogenitalism, microcephaly, and obesity) is caused by hemizygous mutation in the EIF2S3 gene (300161) on chromosome Xp22.

Clinical Features

Steinmuller et al. (1998) described a previously unrecognized X-chromosomal mental retardation syndrome and referred to it by the acronym MEHMO, which was derived from the clinical hallmarks: mental retardation, epileptic seizures, hypogonadism and hypogenitalism, microcephaly, and obesity. Life expectancy of the patients was less than 2 years.

Leshinsky-Silver et al. (2002) provided evidence that MEHMO is an X-linked mitochondrial disorder. They described an Ethiopian Jewish boy with MEHMO and lactic acidosis, whose muscle biopsy revealed markedly reduced activities of respiratory chain enzymes of complex I (see 602694), III (see 516020), and IV (see 516030), whereas complex II (see 600857) (exclusively encoded by nuclear DNA) was not affected. The skeletal muscle histology showed abundant fatty infiltration and mitochondrial proliferation. Electron microscopy showed concentric arrangement of the cristae in huge mitochondria, irregular lamellar arrangement, and electron dense bodies. The family history of 2 male sibs of the mother who died in the first year of life suggested X-linked MEHMO syndrome. The multiple deficiencies of mtDNA encoded respiratory chain complexes with normal levels of nuclear encoded mitochondrial enzymes and the morphology of the mitochondria suggested that a nuclear defect located in the Xp22.13-p21.1 region leads to abnormal mitochondrial function.

Borck et al. (2012) reported 3 males from a consanguineous family of Moroccan Jewish ancestry with X-linked syndromic intellectual disability with features of MEHMO. They had delayed psychomotor development since infancy, microcephaly (-3.8 to -4.8), short stature, ataxic gait, lower limb spasticity with hyperreflexia, and Achilles tendon shortening. Dysmorphic facial features included flat and broad nasal tip, temporal narrowing, long face with long chin, large ears, long philtrum, open mouth, and widely spaced teeth. Brain imaging showed thin corpus callosum and enlarged ventricles. Two brothers had growth hormone deficiency. Each patient had unique additional features, including cleft lip and palate in 1, seizures in a second, and hypogonadism and obesity in the third. One boy had behavioral abnormalities, including aggression, head banging, and attention deficit-hyperactivity disorder. Carrier females in the family were unaffected.

Moortgat et al. (2016) reported 2 teenaged maternal half brothers, born of unrelated Belgian parents, with X-linked syndromic severe mental retardation. They showed global developmental delay, axial hypotonia, and spastic quadriparesis since birth. Each also had poor overall growth, progressive microcephaly (up to -8.5 SD), and poor or absent speech. They were either unable to walk or could only walk with aid. Dysmorphic features included strabismus and large ears. Other features included growth hormone deficiency, delayed puberty, hypogonadism, and evidence of pancreatic dysfunction, including hypoglycemia and pancreatitis. Brain imaging showed reduced white matter and thin corpus callosum. One patient developed seizures at age 9 months and had autistic features; the other patient did not have seizures or autism. One patient died at age 17 years from severe respiratory disease and multiorgan failure. A male infant in a second family of Spanish origin had poor growth, microcephaly, micrognathia, micropenis, and generalized hypertonia with no visual contact. He developed hypoglycemia soon after birth. He had severe global developmental delay and never achieved head control. He had onset of seizures at age 10 months and died at age 12 months. Three other male family members reportedly had a similar phenotype with early death.

Skopkova et al. (2017) described 3 additional patients with MEHMO: 2 boys, aged 1.5 and 5 years, from nonconsanguineous Slovakian families, and a 5-year-old boy from a nonconsanguineous US family of northern European origin. Both Slovakian boys had severe intellectual disability, microcephaly, epileptic seizures resistant to treatment, hypogonadism, hypogenitalism, and central obesity. Both had onset of diabetes at 10 months of age. Neither achieved head control, had any social interactions, or was able to make any voluntary movements. Brain imaging showed myelination delay. The other child had microcephaly, hypospadias and cryptorchidism, developmental delay, and obesity. He did not have epileptic seizures, and an electroencephalogram was normal.

Heterogeneity

DeLozier-Blanchet et al. (1999) suggested that the disorder described by Steinmuller et al. (1998) was the same as the disorder reported by DeLozier-Blanchet et al. (1989). However, Skopkova et al. (2017) excluded mutation in the EIF2S3 gene in the family reported by DeLozier-Blanchet et al. (1989).

Inheritance

The transmission pattern of MEHMO in the family reported by Borck et al. (2012) was consistent with X-linked recessive inheritance.

Mapping

By haplotype and 2-point linkage analyses in the large 3-generation family with MEHMO, Steinmuller et al. (1998) assigned the disease locus to Xp22.13-p21.1, in a region flanked by CYBB (300481) and DXS365.

Molecular Genetics

In 3 males from a consanguineous family of Morocco Jewish ancestry with X-linked syndromic mental retardation with features of MEHMO, Borck et al. (2012) identified a hemizygous missense mutation in the EIF2S3 gene (I222T; 300161.0001). The mutation, which was found by a combination of linkage analysis and exome sequencing, segregated with the disorder in the family. Female carriers were unaffected. In vitro functional expression assays in yeast and in human cells showed that the mutation impaired binding to EIF2B (see, e.g., EIF2B1, 606686) and disrupted EIF2 complex formation, resulting in defects in translation initiation.

In affected members of 2 unrelated families with an X-linked mental retardation syndrome, Moortgat et al. (2016) identified 2 different hemizygous mutations in the EIF2S3 gene: a missense mutation (I259M; 300161.0002), resulting in a slightly less severe phenotype, and a frameshift mutation (300161.0003), resulting in a more severe phenotype with death in infancy. Functional studies of the variant and studies of patient cells were not performed.

In affected members of 4 families with MEHMO, including the original family reported by Steinmuller et al. (1998), Skopkova et al. (2017) identified mutations in the EIF2S3 gene: a frameshift mutation (300161.0004) in 3 families, and a missense mutation (S108R; 300161.0005) in 1 patient who had a milder form of the syndrome.

Animal Model

Moortgat et al. (2016) found that morpholino knockdown of eif2s3 in zebrafish resulted in morphologic defects, including morphants being shorter with a curved tail, smaller head, and small eyes compared to wildtype. Morphants also showed hypomotility.