Microcephaly, Seizures, Spasticity, And Brain Calcifications

A number sign (#) is used with this entry because of evidence that a syndrome of microcephaly, seizures, spasticity, and brain calcifications (MISSBC) is caused by homozygous mutation in the PCDH12 gene (605622) on chromosome 5q31.

Description

MISSBC is an autosomal recessive neurodevelopmental disorder characterized by progressive microcephaly, early-onset seizures, and severely delayed or even absent psychomotor development with profound intellectual disability and spasticity or dystonia. Brain imaging shows midbrain dysplasia and intracerebral calcifications (summary by Aran et al., 2016).

Clinical Features

Tolmie et al. (1987) described a brother and sister with microcephaly with early-onset seizures and spasticity. Silengo et al. (1992) described a male-female sib pair, born of consanguineous parents, who had congenital microcephaly in association with early-onset myoclonic seizures, spasticity, and profound psychomotor retardation without detectable brain malformations. The severity of the neurologic features and their perinatal onset differentiated the syndrome from the more common autosomal recessive microcephaly.

Gross-Tsur et al. (1995) described 5 microcephalic sibs, 4 females and 1 male, who were affected with neonatal generalized tonic-clonic seizures and went on to develop spastic quadriplegia and had essentially no psychomotor development. They were born to consanguineous parents of Arab extraction. All had profound mental retardation, and only 1 patient developed eye contact and a social smile. Chromosome analysis and CT scans were normal in all affected sibs but 1, in whom the CT showed absence of the anterior limbs of the internal capsule and a large caudate. There were 2 unaffected sibs, 1 male and 1 female, in this sibship.

Sibs with the syndrome of microcephaly and severe myoclonic seizures, profound mental retardation, hypertonia, and spasticity were also described by Schinzel and Litschgi (1984). Straussberg et al. (1998) described an infant with the same syndrome born to a consanguineous couple of Palestinian origin. The findings of magnetic resonance imaging were reported. Straussberg et al. (1998) provided follow-up of a second patient who had previously been reported as suffering from Alpers disease (Frydman et al., 1993). The patient was born to first-cousin parents of Palestinian Arabs, the same ethnicity as the first patient of Straussberg et al. (1998). Two sibs had died of the same condition. Myoclonic and tonic-clonic seizures were first noted at the age of 10 days. Spasticity, swallowing difficulties, and frequent aspirations necessitated nasogastric feeding. EEG showed hypsarrhythmia.

Aran et al. (2016) reported 10 patients from 4 consanguineous Palestinian families originating from the same small town with MISSBC. Three of the 10 were affected fetuses, each from a different family, who were terminated after prenatal ultrasound showed microcephaly and hyperechogenic foci in the perithalamic and/or periventricular regions. One fetus had midbrain dysplasia. Postmortem examinations were not performed on the fetuses. Two of the other patients were children, 1 of whom died at age 3 (family A) and the other who was alive but severely disabled at age 5 (family B). These patients had onset of seizures in the first days or weeks of life that were associated with multifocal or asynchronized epileptic discharges on EEG. The patients had axial hypotonia, peripheral dystonia with brisk reflexes, profound developmental disability, and visual impairment. Brain imaging of both children showed midbrain dysplasia; 1 also had hypoplasia of the corpus callosum. Aran et al. (2016) noted that the patients were investigated for possible intrauterine TORCH infections, but all tests were negative, with no evidence for infection. The third family (family C) had been reported by Gross-Tsur et al. (1995); only 1 affected individual was available for study. This was a 26-year-old woman with microcephaly (-7.5 SD), severe visual impairment, and severe psychomotor retardation. Other features included axial hypotonia, peripheral dystonia, and spasticity. Brain imaging was not performed. Her 4 older affected sibs had all died of pulmonary aspiration.

Using CT imaging, Nicolas et al. (2017) determined that 1 of the patients reported by Aran et al. (2016) (patient III-1 from family B) had perithalamic calcifications in the posterior arms of the internal capsules and in the juxtacortical white matter. The findings confirmed that the hyperechogenicity observed by Aran et al. (2016) represented intracranial calcifications. Nicolas et al. (2017) noted that the expression pattern of PCDH12 is similar to that of SLC20A2 (158378), mutation in which causes idiopathic basal ganglia calcification-1 (IBGC1; 213600).

Inheritance

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

Molecular Genetics

In 6 patients from 4 unrelated consanguineous Palestinian families with MISSBC, Aran et al. (2016) identified a homozygous truncating mutation in the PCDH12 gene (R839X; 605622.0001). The mutation was found by whole-genome sequencing and confirmed by Sanger sequencing in the first family, followed by direct sequencing in the subsequent families. It segregated with the disorder in all families. Haplotype analysis indicated a founder effect, and 3 of 83 unrelated healthy individuals from the same town carried the mutation, yielding a carrier rate of 0.018. Analysis of cells derived from 1 carrier indicated that the mutation results in nonsense-mediated mRNA decay and likely a complete loss of function.

Nicolas et al. (2017) identified 4 different heterozygous missense variants in the PCDH12 gene in 4 of 79 patients with brain calcifications who were screened for mutations in the PCDH12 gene. All were found at very low frequencies in the ExAC database; functional studies of the variants, studies of patient cells, and segregation studies among family members were not performed.

History

In 2 ostensibly unrelated Jamaican black families living in Birmingham, England, Bundey and Hill (1975) found 3 cases of severe microcephaly with spastic quadriplegia beginning between 4 and 16 months of age. The authors concluded that Roboz and Pitt (1969) and perhaps others have reported the same condition. The paper by Bundey and Hill (1975) was not published, but the patients were referred to by Bundey and Griffiths (1977). The microcephaly was 'postnatal;' head circumference was normal at birth and at 7 months. There were no neonatal problems. The first abnormalities noted by the parents were unresponsiveness and delayed milestones. On reevaluation of the family, Bundey et al. (1991) concluded that the disorder may represent the Allan-Herndon syndrome (300523).