C10ORF2

Spinocerebellar Ataxia, Infantile-Onset

Clinical Characteristics
Ocular Features: 

Ocular problems begin by about age 7 years when various degrees of ophthalmoplegia appear.  By the second decade damage to the optic nerves is evident (optic atrophy) leading to severe vision loss.

Systemic Features: 

This mitochondrial DNA depletion syndrome allows normal development in the first year of life.  By 10-18 months of age, muscle weakness and coordination become evident.  Deep tendon reflexes are diminished or absent.  The muscle deficits are relentlessly progressive and by teenage years most individuals are wheelchair-bound.  Generalized seizures are common.  Facial and limb dyskinesia of an athetoid nature is evident to a variable degree.  A sensory polyneuropathy develops in many patients.  Cerebellar atrophy is evident on neuroimaging.

Neurosensory hearing loss may become evident late in the first decade of life.  The amount of hearing loss is progressive, leading eventually to profound deafness.  Some patients experience a complete loss of vestibular caloric responses. 

Most individuals live to adulthood but a severe form of this disease in which liver damage and encephalopathy occur limits the lifespan to about 5 years.

Genetics

This infantile-onset form of spinocerebellar atrophy results from homozygous or compound heterozygous mutations in the C10ORF2 gene (10q24) which encodes the so-called Twinkle and Twinky mitochondrial proteins. Since the Twinkle protein is involved in the production and maintenance of mitochondrial DNA, its malfunction leads to reduced quantities of mtDNA in the liver and CNS but not in skeletal muscle.

Mutations in the C10ORF2 gene affecting the Twinkle protein may be responsible for an autosomal dominant progressive ophthalmoplegia (609286) in which ptosis and cataracts are often found but the more extensive muscle and sensory deficits are often missing.  This is one of the better examples of seemingly unique, allelic phenotypes resulting from different mutations in the same gene.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment has been reported but physical therapy, assistive hearing devices, and low vision aids might be helpful in selected patients.

References
Article Title: 

Infantile onset spinocerebellar ataxia caused by compound heterozygosity for Twinkle mutations and modeling of Twinkle mutations causing recessive disease

Pierce SB, Gulsuner S, Stapleton GA, Walsh T, Lee MK, Mandell JB, Morales A, Klevit RE, King MC, Rogers RC. Infantile onset spinocerebellar ataxia caused by compound heterozygosity for Twinkle mutations and modeling of Twinkle mutations causing recessive disease. Cold Spring Harb Mol Case Stud. 2016 Jul;2(4):a001107. doi: 10.1101/mcs.a001107.

PubMed ID: 
27551684

External Ophthalmoplegia, C10ORF2 and mtDNA Mutations

Clinical Characteristics
Ocular Features: 

Ptosis and external ophthalmoplegia are found in almost all patients.  These have a variable onset with some patients not symptomatic until midlife or later.  External ophthalmoplegia may be the only symptom.  Onset in late adolescence has also been reported.  Cataracts often occur.

Systemic Features: 

About half (52%) of patients have fatigue and weakness.  Ataxia and peripheral neuropathy with paresthesias are sometimes present. Some patients report bulbar symptoms of dysphagia, dysarthria and dysphonia.  Skeletal muscle biopsies show typical ragged red fibers and evidence of mitochondrial dysfunction with cytochrome c oxidase (COX) deficiency.  Late onset of typical features of parkinsonism including a resting tremor, rigidity, and bradykinesia is seen in some patients.  Several individuals have reported major depression and/or bipolar disorder. Myopathy (33%) with muscle wasting and respiratory difficulties can occur.   As many as 24% of patients have cardiac abnormalities consisting primarily of conduction defects.

Genetics

This an autosomal dominant disorder secondary to mutations in the C10ORF2 (Twinkle) gene (10q24) in association with mitochondrial DNA depletion.  It accounts for approximately 35% of autosomal dominant cases of external ophthalmoplegia.

At least two additional mutations cause similar external ophthalmoplegia syndromes: PEOA1 (157640, 258450), and PEOA2 (609283).

The same gene may have mutations that are responsible for spinocerebellar ataxia, infantile-onset (271245), a more generalized and progressive neurodegenerative disease transmitted in an autosomal recessive pattern.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No effective treatment is known.

References
Article Title: 

The clinical, histochemical, and molecular spectrum of PEO1(Twinkle)-linked adPEO

Fratter C, Gorman GS, Stewart JD, Buddles M, Smith C, Evans J, Seller A, Poulton J, Roberts M, Hanna MG, Rahman S, Omer SE, Klopstock T, Schoser B, Kornblum C, Czermin B, Lecky B, Blakely EL, Craig K, Chinnery PF, Turnbull DM, Horvath R, Taylor RW. The clinical, histochemical, and molecular spectrum of PEO1(Twinkle)-linked adPEO. Neurology. 2010 May 18;74(20):1619-26.

PubMed ID: 
20479361
Subscribe to RSS - C10ORF2