Alternative titles; symbolsMICROCEPHALY, SEIZURES, SPASTICITY, AND BRAIN CALCIFICATIONS; MISSBC▼ DescriptionDiencephalic-mesencephalic junction dysplasia syndrom...
Alternative titles; symbols
Diencephalic-mesencephalic junction dysplasia syndrome-1 (DMJDS1) is an autosomal recessive neurodevelopmental disorder characterized by progressive microcephaly, severely delayed or even absent psychomotor development with profound intellectual disability, and spasticity or dystonia. Some patients may have seizures and/or visual impairment. Brain imaging shows a characteristic developmental malformation of the midbrain; subtle intracranial calcifications may also be present (summary by Aran et al., 2016 and Guemez-Gamboa et al., 2018).
Genetic Heterogeneity of Diencephalic-Mesencephalic Junction Dysplasia Syndrome
See also DMJDS2 (618646), caused by mutation in the GSX2 gene (616253) on chromosome 4q12.
▼ 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.
Zaki et al. (2012) reported 2 unrelated consanguineous Egyptian families (family 1592 and 1846) each containing 2 sibs with DMJD. The patients, who ranged from 7 months to 4 years of age, had severely impaired development from infancy, postnatal progressive microcephaly (down to -8.7 SD), axial hypotonia, spastic quadriparesis, dysphagia, and early-onset seizures that were difficult to control. The patients were nonambulatory and had no language. Dysmorphic features included strabismus, bushy eyebrows, hairy forehead, broad prominent nasal root, long flat philtrum, thin upper lip, posteriorly rotated ears, and short neck. Some patients had recurrent unexplained fever and vasomotor instability. Brain imaging showed abnormal morphology of the midbrain consistent with diencephalic-mesencephalic dysplasia, as well as enlarged ventricles, and hypoplasia of the corpus callosum. The authors proposed the term 'butterfly sign' to reflect the MRI appearance of the brainstem. Diffusion tensor imaging, performed in 2 sibs (family 1592), showed defects in corticopontine/corticospinal tract fibers and reduced axonal volume, suggesting a defect in axonal pathfinding. There was no evidence of cortical migration defects, such as polymicrogyria or lissencephaly. In the patients from these 2 families, Guemez-Gamboa et al. (2018) identified homozygous mutations in the PCDH12 gene (605622.0002 and 605622.0003; see MOLECULAR GENETICS). A third family (family 1825) with a similar phenotype was also described by Zaki et al. (2012); however, Guemez-Gamboa et al. (2018) excluded PCDH12 mutations in that family, suggesting genetic heterogeneity of the phenotype.
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.
Guemez-Gamboa et al. (2018) reported 14 patients from 8 unrelated families with DMJDS1. Two of the families had been reported by Zaki et al. (2012). The patients presented with progressive microcephaly (-1.5 to -8.7 SD), profoundly impaired development, hypotonia, inability to stand or walk, absence of fine motor skills, and no language. The phenotype was dominated by severe pyramidal tract signs, including spasticity, hyperreflexia, and extensor plantar responses, as well as axial hypotonia. More variable features included cranial nerve defects, such as strabismus, poor visual tracking, and dysphagia, recurrent unexplained fever in early childhood, vasomotor instability, ataxia, and autistic features. About half of patients had early-onset seizures associated with focal and generalized abnormalities on EEG. Most patients had dysmorphic features, including bitemporal narrowing, low-set ears, broad prominent nasal bridge, long flat philtrum, broad chin, and thin upper lip. Brain imaging showed a characteristic malformation of the brainstem, including DMJD and a 'butterfly-like' contour of the midbrain, thin corpus callosum, enlarged ventricles, and disrupted corticospinal tract projections. Six of 7 patients had subtle intracranial calcifications.
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).
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.
In 14 patients from 8 unrelated families with DMJDS1, Guemez-Gamboa et al. (2018) identified 5 different homozygous nonsense or frameshift mutations in exon 1 of the PCDH12 gene (see, e.g., 605622.0002-605622.0004). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Expression of 3 of the mutations in HEK293 cells resulted in no protein expression, consistent with a loss of function. Most of the families were consanguineous and of Egyptian or Turkish origin; 2 families had previously been reported by Zaki et al. (2012). Reprogrammed induced neural cells derived from fibroblasts from family 1 showed undetectable PCDH12 protein levels and had impaired neurite length compared to controls.
Associations Pending Confirmation
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.
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).