Microcephaly, Seizures, And Developmental Delay

A number sign (#) is used with this entry because of evidence that microcephaly, seizures, and developmental delay (MCSZ) is caused by homozygous or compound heterozygous mutation in the PNKP gene (605610) on chromosome 19q13.

Description

Microcephaly, seizures, and developmental delay is an autosomal recessive neurodevelopmental disorder with onset in infancy. There is a range of phenotypic severity: some patients have a disease course consistent with early infantile epileptic encephalopathy (EIEE), whereas others have more well-controlled seizures and a protracted course associated with cerebellar atrophy and peripheral neuropathy (Shen et al., 2010 and Poulton et al., 2013).

For a general phenotypic description and a discussion of genetic heterogeneity of EIEE, see EIEE1 (308350).

Clinical Features

Shen et al. (2010) reported 6 unrelated kindreds, including 3 consanguineous families of Arabic Palestinian origin and 1 each of Arabic, Turkish, and mixed European ancestry, with microcephaly, infantile-onset seizures, and developmental delay, which the authors abbreviated as MCSZ. There were 11 affected individuals ranging in age from 1 month to 21 years. Microcephaly was progressive and without neuronal migration or structural abnormalities, consistent with primary microcephaly. However, 5 patients had a slightly simplified gyral pattern, 5 had enlarged ventricles, and 6 had a thin corpus callosum. All patients had microcephaly at birth; some were noted to have microcephaly on prenatal ultrasound. Onset of treatment-resistant seizures occurred before 6 months of age, and most seizures were of the complex partial type. Two patients had surgical resection, and 4 had placement of a vagal stimulator to control seizures. All had severe intellectual disability and delayed motor milestones with absent speech or speech limited to a few words. Most patients had behavioral problems with hyperactivity. A seventh family of mixed European origin with a slightly less severe phenotype was also identified. The patients were aged 8 years and 18 months. The older girl walked at 14 months, spoke at 18 months, and conversed at the level of a 3.5-year-old. She had moderate seizure control. Cells from 1 affected individual showed sensitivity to irradiation in culture, reflecting a deficiency in nonhomologous end-joining of DNA. In addition, patients' cells were significantly impaired in their ability to repair hydrogen-peroxide induced free radical DNA damage, and also showed a delayed ability to repair camptothecin-induced damage compared to controls. Despite the laboratory evidence of damage in DNA repair mechanisms, none of the patients had an apparent immunodeficiency, and none had developed cancer.

Clinical Variability

Poulton et al. (2013) reported 2 brothers, born of consanguineous Dutch parents from an isolated population, with early-childhood onset of a neurodegenerative disorder. Both patients showed microcephaly (-3.25 to -3.5 SD) and global developmental delay from infancy. One patient developed febrile seizures at 2.5 years of age. At age 9 years, he had severe microcephaly (-6 SD), short stature (-4 SD), and ataxic gait. The disorder was progressive: in his teens, he became wheelchair-bound, showed severe cerebellar atrophy on brain imaging, and developed a sensorimotor axonal polyneuropathy characterized by loss of reflexes, hypotonia, and muscular atrophy. The patient's younger brother had similar features, with delayed development, progressive microcephaly (-4.75 SD), loss of independent walking, severe progressive cerebellar atrophy, and signs of a demyelinating polyneuropathy. He developed seizures at age 12 months. The seizure frequency decreased over time in both patients. Poulton et al. (2013) emphasized the neurodegenerative character of the disorder in these patients, and suggested that the phenotype was distinct from that reported by Shen et al. (2010).

Inheritance

The transmission pattern of MCSZ in the families reported by Shen et al. (2010) was consistent with autosomal recessive inheritance.

Molecular Genetics

By genomewide linkage analysis followed by candidate gene sequencing of a region on chromosome 19q13 in families with EIEE10, Shen et al. (2010) identified homozygous or compound heterozygous mutations in the PNKP gene (605610.0001-605610.0004), resulting in a loss of protein function.

In 2 Dutch brothers, born of consanguineous parents, with a somewhat protracted course of MCSZ, Poulton et al. (2013) identified a homozygous truncating mutation in the PNKP gene (605610.0002). Patient fibroblasts showed increased susceptibility under stress conditions compared to controls. The same mutation had been found by Shen et al. (2010) in patients with a more severe epilepsy phenotype.