vertical 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

Spastic Paraplegia 7

Clinical Characteristics
Ocular Features: 

Many but not all individuals have significant visual loss due to optic atrophy.  Other ocular signs include supranuclear palsy, ptosis, and nystagmus.  Older individuals with advanced disease may have progressive external ophthalmoplegia.

Systemic Features: 

There is a great deal of clinical heterogeneity between families and not all individuals have severe neurological disease.  Progressive neurological signs (primarily abnormal gait) are often present in late childhood or early adolescence but may occur late in life.  Clinical features include muscle atrophy and weakness with spasticity (more pronounced in the lower limbs), ataxia, pyramidal signs, dysphagia, and cerebellar dysarthria.  Hyperreflexia and extensor plantar responses are often present.  Cognitive deficits are manifest as deficits in attention and higher levels of reasoning.  Some patients have a mild peripheral neuropathy with decreased vibratory sense.  Many patients have significant dysfunction of the bladder sphincter.  Adults may lose their mobility and are confined to a wheelchair.

Some patients develop scoliosis and pes cavus.  The MRI often shows cerebellar and mild frontal cortical atrophy.

Genetics

This type of spastic paraplegia results from mutations in the paraplegin gene, SPG7 (16q24.3).  It is usually transmitted in an autosomal recessive pattern although heterozygous patients with symptoms have been reported. Evidence suggests that the symptoms arise from a defect in mitochondrial respiration.

Patients with spastic paraplegia 15 (270700) have a similar neurological phenotype plus a flecked retina.  Congenital cataracts are part of the phenotype of spastic paraplegia 46 (614409).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Treatment is symptomatic.  Physical, speech, and occupational therapy may be helpful in selected patients.  Low vision aids may be of benefit in some individuals, at least early in the disease.

References
Article Title: 

Mutations in the SPG7 gene cause chronic progressive external ophthalmoplegia through disordered mitochondrial DNA maintenance

Pfeffer G, Gorman GS, Griffin H, Kurzawa-Akanbi M, Blakely EL, Wilson I, Sitarz K, Moore D, Murphy JL, Alston CL, Pyle A, Coxhead J, Payne B, Gorrie GH, Longman C, Hadjivassiliou M, McConville J, Dick D, Imam I, Hilton D, Norwood F, Baker MR, Jaiser SR, Yu-Wai-Man P, Farrell M, McCarthy A, Lynch T, McFarland R, Schaefer AM, Turnbull DM, Horvath R, Taylor RW, Chinnery PF. Mutations in the SPG7 gene cause chronic progressive external ophthalmoplegia through disordered mitochondrial DNA maintenance. Brain. 2014 Apr 10. [Epub ahead of print].

PubMed ID: 
24727571

A clinical, genetic, and biochemical characterization of SPG7 mutations in a large cohort of patients with hereditary spastic paraplegia

Arnoldi A, Tonelli A, Crippa F, Villani G, Pacelli C, Sironi M, Pozzoli U, D'Angelo MG, Meola G, Martinuzzi A, Crimella C, Redaelli F, Panzeri C, Renieri A, Comi GP, Turconi AC, Bresolin N, Bassi MT. A clinical, genetic, and biochemical characterization of SPG7 mutations in a large cohort of patients with hereditary spastic paraplegia. Hum Mutat. 2008 Apr;29(4):522-31.

PubMed ID: 
18200586
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