Gaze Palsy, Familial Horizontal, With Progressive Scoliosis 1

A number sign (#) is used with this entry because familial horizontal gaze palsy with progressive scoliosis-1 (HGPPS1) is caused by homozygous or compound heterozygous mutation in the ROBO3 gene (608630) on chromosome 11q24.

Description

HGPPS is an autosomal recessive neurologic disorder characterized by eye movement abnormalities apparent from birth and childhood-onset progressive scoliosis. These features are associated with a developmental malformation of the brainstem including hypoplasia of the pons and cerebellar peduncles and defective decussation of certain neuronal systems. Cognitive function is normal (summary by Bosley et al., 2005).

Genetic Heterogeneity of Familial Horizontal Gaze Palsy With Progressive Scoliosis

See also HGPPS2 (617542), caused by mutation in the DCC gene (120470) on chromosome 18q21.

Clinical Features

Dretakis and Kondoyannis (1974) described 5 children in 2 families who had scoliosis associated with progressive external ophthalmoplegia. One of the families had previously been reported by Dretakis (1970). In a Chinese family living in Jamaica, Crisfield (1974) observed 4 sibs (2 male, 2 female) from a sibship of 11 with severe scoliosis and progressive external ophthalmoplegia. Weakness of trunk muscles and other neurologic disease were not detected. Sharpe et al. (1975) reported further on this Chinese family of Hakka extraction. All 4 sibs had paralysis of horizontal (i.e., lateral) gaze, which developed in the first decade of life. They also showed pendular nystagmus and progressive scoliosis. The oldest developed, in his 20s, bilateral facial myokymia and continuous contracture of the facial muscles. The site of the neurologic lesion was thought to be the supranuclear areas of the pons. Granat et al. (1979) also reported cases.

Jen et al. (2002) reported 2 unrelated consanguineous families with horizontal gaze palsy with progressive scoliosis inherited in an autosomal recessive pattern. All 6 affected individuals (4 males and 2 females) had no horizontal gaze from birth by family report and no horizontal gaze was noted in a 2-week-old affected infant. All affected individuals other than the infant had mild to moderate scoliosis by visual inspection or spine x-ray that was progressive by report.

Jen et al. (2004) carried out high resolution MRI in 8 patients from 4 families with HGPPS. Abnormal flattening of the basis pontis and hypoplasia in the pontine tegmentum were evident on sagittal sections. The structural alterations in caudal pons suggested potential involvement of the abducens nuclei, the medial longitudinal fasciculus, and the pontine paramedian reticular formation. The medulla appeared abnormally butterfly-like, with anterior flattening and an unusual midline cleft. The abducens nerves were visualized bilaterally in the extra-axial space, and orbital MRI demonstrated normal extraocular muscle configuration and size, as well as the presence of apparently normal intraorbital motor nerves to the medial and lateral rectus muscles. Therefore, Jen et al. (2004) concluded that the absence of bulging of abducens nuclei into the fourth ventricle observed in HGPPS patients likely represents hypoplasia rather than absence of the abducens nuclei. These findings distinguish HGPPS from other congenital eye movement disorders in which absence or aberrant motor nerves are associated with hypoplastic extraocular muscles but normal brain structure. Somatosensory evoked potential studies in all 4 HGPPS patients available for study showed abnormally reversed lateralization of these responses, indicating uncrossed ascending dorsal column-medial lemniscal sensory pathways. Similarly, motor evoked potential studies in these patients demonstrated abnormally ipsilateral muscle responses, reflecting uncrossed descending corticospinal motor pathways. Uncrossed corticospinal and dorsal column-medial lemniscal pathways and the abnormal midline cleft in the medulla observed in these patients suggested the absence of pyramidal and internal arcuate decussations and a role for the HGPPS gene in hindbrain axon pathway crossing and morphogenesis.

Bosley et al. (2005) reported detailed clinical features of 11 patients from 5 families with HGPPS confirmed by genetic analysis; 4 of the families had been reported by Jen et al. (2004). All affected individuals had no horizontal smooth pursuit, saccades, optokinetic nystagmus, or vestibuloocular responses. Horizontal ductions were absent in all but 1 patient, who had small amplitude dysconjugate eye movements to the left. Vertical versions were normal, except for saccadic smooth pursuit in 5 patients. Convergence was present in all patients to varying degrees, and small to moderate amplitude pendular nystagmus was seen in 8 patients from 3 families. Bosley et al. (2005) emphasized that all patients came to medical attention because of severe childhood-onset thoracolumbar scoliosis and that horizontal gaze palsy was present at birth.

Inheritance

Jen et al. (2002) proposed autosomal recessive inheritance for this disorder based on their 2 consanguineous families with equal involvement of both sexes and the absence of affected individuals in earlier generations. They noted that because the disorder shows similarities to the Kearns-Sayre syndrome (530000), it had been thought to represent a mitochondrial cytopathy with mitochondrial inheritance.

Jen et al. (2004) identified and reported 8 additional consanguineous HGPPS families. The phenotypes were consistent with linkage to the 11q23-q25 locus, affected individuals were homozygous in the candidate region, and, in all cases, homozygous mutations in ROBO3 were identified.

Mapping

By genomewide linkage analysis in 2 families with horizontal gaze palsy with progressive scoliosis, Jen et al. (2002) mapped the disease locus to a 30-cM interval on chromosome 11q23-q25 (combined maximum multipoint lod score of 5.46 near marker GATA140F03).

Molecular Genetics

In 10 HGPPS index patients, Jen et al. (2004) identified 10 different mutations (608630.0001-608630.0010) in the ROBO3 gene. Each of the mutations was found in homozygosity and included 1 nonsense, 1 splice site, 2 frameshift, and 6 missense mutations, 4 of which resulted in nonconservative changes to amino acid residues that are evolutionarily conserved. Jen et al. (2004) found that ROBO3 is required for hindbrain axon midline crossing, explaining the horizontal gaze palsy in this condition.

In 2 unrelated children with sporadic HGPPS, born of nonconsanguineous parents, Chan et al. (2006) identified compound heterozygosity for 2 different 2-bp deletions (608630.0011 and 608630.0012) and a missense and a nonsense mutation (608630.0013 and 608630.0014) in the ROBO3 gene, respectively. The mother of 1 of the patients, who was heterozygous for a 2-bp deletion (see 608630.0011), had mild scoliosis that did not require treatment.

History

The family reported by Crisfield (1974) and Sharpe et al. (1975) is of genetic fame, having been that in which hemoglobin Constant Spring (141850.0001) was first identified. The anomalous hemoglobin and the neurologic lesion segregated independently.