OMIM ID:
Spinocerebellar Ataxia, Infantile-Onset
Alternate Names
Defective Genes
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
Inheritance
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
In order for autosomal recessive disorders to be expressed, offspring generally must inherit two mutations, one from each carrier parent. Carriers with only one mutation, such as the parents, do not have clinical disease. Note that carrier parents can expect that 1 in 4 children (25%) will inherit both mutations and have the disorder, 2 in 4 children (50%) will be carriers like their parents, while 1 in 4 children (25%) inherit neither mutation.
In order for autosomal recessive disorders to be expressed, offspring generally must inherit two mutations, one from each carrier parent. Carriers with only one mutation, such as the parents, do not have clinical disease. Note that carrier parents can expect that 1 in 4 children (25%) will inherit both mutations and have the disorder, 2 in 4 children (50%) will be carriers like their parents, while 1 in 4 children (25%) inherit neither mutation.