In 2 sisters, aged 7 and 10 years, Harbord et al. (1990) described developmental delay and a nonprogressive cerebellar ataxia with similar neurophysiologic and neuroradiologic findings of an extensive neuronal migration defect. There were no dysmorphic features, metabolic ... In 2 sisters, aged 7 and 10 years, Harbord et al. (1990) described developmental delay and a nonprogressive cerebellar ataxia with similar neurophysiologic and neuroradiologic findings of an extensive neuronal migration defect. There were no dysmorphic features, metabolic abnormalities, chromosomal defects or evidence of prenatal environmental toxins. Harbord et al. (1990) considered that these sibs had an autosomal recessive neuronal migration defect that had not previously been recorded. It appeared that other recognized causes of neuronal migration defects such as the Miller-Dieker syndrome (247200), the Norman-Roberts syndrome (257320), the Neu-Laxova (256520) and Joubert syndrome (213300) could be excluded on the basis of clinical and radiologic features. The absence of muscle disease differentiated these patients from children with migration defects associated with congenital muscular dystrophy, e.g., Fukuyama type (253800). Piao et al. (2002) studied 2 consanguineous Palestinian pedigrees with an autosomal recessive form of bilateral frontoparietal polymicrogyria (BFPP) using linkage analysis. The first pedigree was originally reported by Straussberg et al. (1996) and was described as having pachygyria, but improved magnetic resonance imaging (MRI) clearly showed that the core disorder was polymicrogyria. The parents were first cousins and 3 of 4 children were affected. They all had normal prenatal and perinatal history and normal head growth but showed gross developmental delay and moderate mental retardation. At ages 14, 9, and 7.5 years they could speak a few words and walk independently. All 3 developed medically refractory seizures. All 3 had esotropia, increased muscle tone, mild truncal ataxia, and finger dysmetria, without dysmorphic features or other congenital anomalies. They also had strabismus. The second pedigree came from the same village as the first, although there was no known relationship between the 2 families. The proposita, a 13-year-old girl, was the first child of healthy Palestinian parents who were first cousins. The course and physical findings were similar to those in the affected members of the first pedigree. A younger son was also affected in the second pedigree. Chang et al. (2003) reported 19 patients from 10 kindreds with apparent autosomal recessive bilateral frontoparietal polymicrogyria. Included were the 2 families reported previously by Piao et al. (2002), and the family reported by Harbord et al. (1990). Eight of the 10 families were consanguineous. Clinical features included motor and cognitive developmental delay, esotropia, strabismus, pyramidal signs, and seizures. Brain MRI of all patients showed bilateral symmetric polymicrogyria, most often in a frontoparietal distribution, although in some patients it was diffuse. All patients also had enlarged ventricles, reduced white matter volume, patchy white matter signal changes, and hypoplasia of the cerebellum and brainstem. Chang et al. (2003) noted that several of the patients had previously been reported as having 'cobblestone lissencephaly,' a 'neuronal migration abnormality,' pachygyria, or 'lissencephaly with cerebellar hypoplasia,' but reinterpretation or repeats of the imaging showed that these patients had findings consistent with BFPP. Jansen and Andermann (2005) reviewed the clinical and radiologic features as well as the genetics of the various forms of polymicrogyria. Piao et al. (2005) reported 6 unrelated families with BFPP confirmed by genetic analysis; 4 were consanguineous. Affected individuals demonstrated considerable clinical homogeneity, with moderate to severe mental retardation, motor developmental delay, seizures, cerebellar ataxia, and dysconjugate gaze. Brain imaging showed bilateral polymicrogyria with anterior to posterior gradient, patchy white matter changes, and brainstem and cerebellar hypoplasia. By contrast, no GPR56 mutations were identified in 5 additional patients with BFPP but who showed fewer diagnostic criteria than for typical GPR56-related BFPP, lacking white matter changes and cerebellar hypoplasia. In addition, no GPR56 mutations were identified in 7 additional patients with bilateral frontal, perisylvian, or generalized polymicrogyria. The findings indicated that the phenotype of BFPP is specific.
Piao et al. (2004) identified splice site, frameshift, and missense mutations in the GPR56 gene (see, e.g., 604110.0001-604110.0008) in 12 families with bilateral frontoparietal polymicrogyria of various ethnic origins. All missense mutations affected regions of the protein predicted ... Piao et al. (2004) identified splice site, frameshift, and missense mutations in the GPR56 gene (see, e.g., 604110.0001-604110.0008) in 12 families with bilateral frontoparietal polymicrogyria of various ethnic origins. All missense mutations affected regions of the protein predicted to represent the extracellular portion of GPR56; 4 mutations affected the extracellular N terminus of the protein, and 1 the extracellular loop between transmembrane domains 4 and 5.