gaze palsy

Neurodegeneration with Ataxia, Dystonia, and Gaze Palsy, Childhood-Onset

Clinical Characteristics
Ocular Features: 

Vertical gaze palsy has its onset between 7 and 15 years of age.   Nystagmus and oculomotor apraxia are often present.

Systemic Features: 

Onset of unsteadiness, gait ataxia, and cognitive decline are evident in the first or second decades of life.  Dysdiadokinesis, dysarthria, dysmetria, dystonia, athetotic movements, signs of Parkinsonism with tremor may also be present.  Some patients have a mild hearing loss.  Tissue from muscle biopsies are normal.  Brain imaging reveals cerebellar atrophy in some families and iron deposition in the basal ganglia in others.

Many patients are wheelchair-bound eventually.

Genetics

Homozygous mutations in the SQSTM1 gene (5q35.3) are responsible for this condition. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported but physical therapy, speech therapy, and special education may be of benefit.

References
Article Title: 

Absence of the Autophagy Adaptor SQSTM1/p62 Causes Childhood-Onset Neurodegeneration with Ataxia, Dystonia, and Gaze Palsy

Haack TB, Ignatius E, Calvo-Garrido J, Iuso A, Isohanni P, Maffezzini C, Lonnqvist T, Suomalainen A, Gorza M, Kremer LS, Graf E, Hartig M, Berutti R, Paucar M, Svenningsson P, Stranneheim H, Brandberg G, Wedell A, Kurian MA, Hayflick SA, Venco P, Tiranti V, Strom TM, Dichgans M, Horvath R, Holinski-Feder E, Freyer C, Meitinger T, Prokisch H, Senderek J, Wredenberg A, Carroll CJ, Klopstock T. Absence of the Autophagy Adaptor SQSTM1/p62 Causes Childhood-Onset Neurodegeneration with Ataxia, Dystonia, and Gaze Palsy. Am J Hum Genet. 2016 Sep 1;99(3):735-43.

PubMed ID: 
27545679

Arthrogryposis, Perthes Disease, and Upward Gaze Palsy

Clinical Characteristics
Ocular Features: 

Upward gaze is restricted and attempts to do so are associated with exotropia.

Systemic Features: 

Arthrogryposis with restricted joint mobility is present in both proximal and distal joints, including hips, elbows, hands, and knees.  It is usually evident early in infancy when parents note "tight joints".  Other joint deformities present to some degree are "trigger finger" deformities found in the middle fingers and thumbs.  Hip pain and difficulty walking as early as 3 years of age can be signs of avascular necrosis of the femoral head (Perthes disease).   

Pyloric stenosis can lead to severe, recurrent vomiting.  Pulmonic stenosis is commonly present and there are often cardiac septal defects as well as valvular malfunctions.  Bronchial asthma is a feature.

Genetics

One extended consanguineous Saudi family with three affected females has been reported.  No similar findings are present in the parents and the condition is most likely transmitted as an autosomal recessive.  A homozygous mutation in NEK9 (14q24) has been associated with this condition.

Heterozygous mutations in the same gene have been identified in 3 patients with nevus comedonicus (617025).  

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Flexion deformities may be at least partially alleviated by surgery and is especially beneficial for digital function.  Pyloric stenosis and cardiac valve disease may respond to surgery.

References
Article Title: 

Mutations in NEK9 Cause Nevus Comedonicus

Levinsohn JL, Sugarman JL; Yale Center for Mendelian Genomics, McNiff JM, Antaya RJ, Choate KA. Somatic Mutations in NEK9 Cause Nevus Comedonicus. Am J Hum Genet. 2016 May 5;98(5):1030-7.

PubMed ID: 
27153399

Accelerating matchmaking of novel dysmorphology syndromes through clinical and genomic characterization of a large cohort

Shaheen R, Patel N, Shamseldin H, Alzahrani F, Al-Yamany R, ALMoisheer A, Ewida N, Anazi S, Alnemer M, Elsheikh M, Alfaleh K, Alshammari M, Alhashem A, Alangari AA, Salih MA, Kircher M, Daza RM, Ibrahim N, Wakil SM, Alaqeel A, Altowaijri I, Shendure J, Al-Habib A, Faqieh E, Alkuraya FS. Accelerating matchmaking of novel dysmorphology syndromes through clinical and genomic characterization of a large cohort. Genet Med. 2016 Jul;18(7):686-95.

PubMed ID: 
26633546

Gaze Palsy, Familial Horizontal, with Progressive Scoliosis 1

Clinical Characteristics
Ocular Features: 

Horizontal ophthalmoplegia is the ocular hallmark of this condition.  It is often present at birth with complete lack of horizontal gaze but in other individuals develops sometime in the first decade of life.  Horizontal smooth pursuit, saccades, optokinetic nystagmus, and vestibuloocular responses are lacking.  Vertical pursuit movements are usually intact except for smooth pursuit which is often saccadic.  Pendular nystagmus (usually horizontal) may be present and head shaking accompanies the nystagmus in some patients.  Many patients are orthophoric but some have a mild esotropia and/or vertical deviation.  The degree of convergence is variable.  Amblyopia does not usually occur and vision has been described as normal or near normal in spite of the presence of nystagmus.  Fusion and some degree of stereoacuity are generally present.  Compensatory head motion can effectively mask the horizontal palsy.  The ophthalmoplegia is progressive according to descriptions of some patients.

Some individuals are considered to have Duane retraction syndrome or congenital esotropia before the scoliosis becomes apparent.

Systemic Features: 

Progressive thoracolumbar scoliosis begins early in the first decade of life and may be evident by 2 years of life.  MRI reveals hypoplasia of the pons and cerebellar peduncles and electrophysiology studies provides evidence of abnormal (uncrossed) corticospinal and dorsal column-medial lemniscus pathways.  Cranial nerves VI and III seem to be intact.

Neuroimaging in some patients reveals medullary and pontine atrophy with hypoplasia of facial colliculi.

Genetics

Homozygous mutations in the ROBO3 gene (11q24.2) are responsible for this autosomal recessive disorder.  The ROBO3 protein product is important for normal midline axon crossing in the brainstem. Consanguinity is common among parents.

see Gaze Palsy, Familial Horizontal, with Progressive Scoliosis 2 (617542) for another condition with somewhat similar features.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Scoliosis may require surgical stabilization.  Physical therapy can be beneficial.

References
Article Title: 

Mutations in a human ROBO gene disrupt hindbrain axon pathway crossing and morphogenesis

Jen JC, Chan WM, Bosley TM, Wan J, Carr JR, R?ob U, Shattuck D, Salamon G, Kudo LC, Ou J, Lin DD, Salih MA, Kansu T, Al Dhalaan H, Al Zayed Z, MacDonald DB, Stigsby B, Plaitakis A, Dretakis EK, Gottlob I, Pieh C, Traboulsi EI, Wang Q, Wang L, Andrews C, Yamada K, Demer JL, Karim S, Alger JR, Geschwind DH, Deller T, Sicotte NL, Nelson SF, Baloh RW, Engle EC. Mutations in a human ROBO gene disrupt hindbrain axon pathway crossing and morphogenesis. Science. 2004 Jun 4;304(5676):1509-13.

PubMed ID: 
15105459
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