Microcephaly, Epilepsy, And Diabetes Syndrome

A number sign (#) is used with this entry because of evidence that microcephaly, epilepsy, and diabetes syndrome (MEDS) is caused by homozygous or compound heterozygous mutation in the IER3IP1 gene (609382) on chromosome 18q21.

Description

MEDS is an autosomal recessive neurodevelopmental disorder characterized by microcephaly, simplified gyral pattern, severe epilepsy, and infantile diabetes (summary by Poulton et al., 2011).

Clinical Features

De Wit et al. (2006) and Poulton et al. (2011) reported a male infant, born of consanguineous Moroccan parents, with a syndromic form of microcephaly. His head circumference was 2.5 SD below the mean at birth, and progressed to 3 SD below the mean at age 2 months. He had developmental delay, hypotonia, seizures, obesity, diabetes mellitus, and presumed hypogonadism. Brain MRI showed a simplified gyral pattern and EEG showed hypsarrhythmia. The diabetes and seizures were difficult to control and he died at age 18 months. Poulton et al. (2011) reported another consanguineous family in Argentina with a similar disorder. The index case had microcephaly with simplified gyral pattern, refractory seizures, and infantile diabetes mellitus. He died at age 27 months. Postmortem examination of an older affected sib showed extreme microcephaly with extreme gyral simplification. Microscopy showed reduced numbers of neurons in the cortex, hypomyelination, and apoptosis. The pancreas showed few and small islets with few insulin-positive beta cells.

Abdel-Salam et al. (2012) reported 4 patients from 2 unrelated consanguineous Egyptian families with MEDS. All presented soon after birth with neonatal permanent diabetes mellitus and severely delayed psychomotor development. Several patients had neonatal jaundice. Within the first months of life, all patients developed seizures, including myotonic and tonic-clonic, associated with polyspikes and slow waves with a burst-suppression pattern on EEG. Physical examination in the first years of life showed microcephaly (range -3.6 to -9 SD) associated with variable dysmorphic features, such as short forehead, bitemporal narrowing, anteverted nares, puffy cheeks, deep philtrum, tented upper lip, narrow palate, and gingival hypertrophy. Brain imaging showed simplified gyration pattern, cortical atrophy, and hypoplastic or agenesis of the corpus callosum with variable cerebellar vermis hypoplasia. All patients had skeletal anomalies, including osteopenia, slender bones with thin cortices, and sometimes pathologic fractures. More variable additional features included a boy with hirsutism, undescended testes, and hypoplastic scrotum, and a girl with optic atrophy. Laboratory studies showed abnormal liver enzymes in some patients and microalbuminuria in all. Three of the children were more severely affected, with almost no developmental progress and severe axial hypotonia necessitating gastric feeding in 2. These 3 children died before age 5 years, including 2 who had recurrent respiratory infections and died of pneumonia. The fourth child had normal muscle tone and primitive reflexes, visual fixation, and social smile at age 2 months. Abdel-Salam et al. (2012) noted the phenotypic overlap with Wolcott-Rallison syndrome (226980), which is caused by mutation in the EIF2AK3 gene (604032).

Shalev et al. (2014) reported a boy, born of unrelated parents, with MEDS. Bitemporal narrowing was noted on prenatal ultrasound at 23 weeks' gestation, and the patient showed microcephaly (-4 SD) at birth. He developed intractable generalized seizures associated with hypsarrhythmia around age 2 months, and soon after was diagnosed with diabetes mellitus. He had essentially no psychomotor development, cortical blindness, and lack of social smiling. Brain imaging showed a simplified gyral pattern. At age 4 years, physical examination showed retractile testes, coarse facies with large cheeks, long palpebral fissures, small mouth, thick philtrum, overfolded helices, hypertrichosis, and tapered fingers. He had no speech or voluntary motor activity, but diabetes was well controlled. He also had recurrent respiratory infections and died at age 8 years.

Inheritance

MEDS is an autosomal recessive disorder (Poulton et al., 2011).

Molecular Genetics

By homozygosity mapping followed by candidate gene sequencing in 2 consanguineous families with MEDS, Poulton et al. (2011) identified different homozygous mutations in the IER3IP1 gene (V21G, 609382.0001 and L78P, 609382.0002). Poulton et al. (2011) concluded that the disorder was due to abnormally increased apoptosis.

In 4 patients from 2 unrelated consanguineous Egyptian families with MEDS, Abdel-Salam et al. (2012) identified homozygosity for the L78P mutation in the IER3IP1 gene. The mutation, which was found by whole-exome sequencing, segregated with the disorder in the families. Functional studies of the variant were not performed.

In a boy with MEDS, Shalev et al. (2014) identified compound heterozygous mutations in the IER3IP1 gene: V21G and c.79delT (609382.0003). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the family. The V21G mutation was inherited from the unaffected father, who was of mixed Libyan-Tangier origin, whereas the c.79delT mutation was inherited from the unaffected mother, who was of mixed Ashkenazi Jewish/Spanish/French origin. Functional studies of the variants were not performed.