Cone Rod Dystrophy in SCA1: Case Report and Review of Literature

Mini Review

J Ophthalmol & Vis Sci. 2016; 1(1): 1002.

Cone Rod Dystrophy in SCA1: Case Report and Review of Literature

Rashmi V1,2*

¹Neuro-Ophthalmology, W K Kellogg Eye Center, University of Michigan, USA

²Department of Neuro Ophthalmology, Shroff Eye Center, India

*Corresponding author: Verma Rashmi, Department of Neuro Ophthalmology, Shroff Eye Center, New Delhi, India

Received: January 24, 2016; Accepted: February 15, 2016; Published: February 22, 2016

Abstract

The Spinocerebellar Ataxias (SCAs) are a genetically and clinically diverse group of autosomal dominant disorders (labeled SCA1 through 36). Ophthalmic manifestations have been reported with many of them, but cone rod dystrophy has been reported predominantly with SCA7. Only 2 isolated cases in the US and recently members of a French family have been reported to have cone rod dysfunction with SCA1.We report hereby, an additional case of cone-rod dystrophy in a member of a family with genetically identified SCA1 in the United States.

Our patient presented with bilateral painless progressive vision loss with gait and balance difficulty. Family history was positive for ataxia in brother, father, 2 cousins and paternal aunt. Detailed clinical and electrophysiological studies including HVF, Multifocal ERG, Full field ERG and VEP were carried out. A diagnosis of cone rod dystrophy was made. The MRI was normal for age with no cerebellar or brain stem atrophy. Records of his brother, which showed positive genetic testing for SCA1, were retrieved and included after permission from him. The patient’s genetic testing further revealed SCA1. To our knowledge from a thorough Pubmed search, only 2 isolated cases in the US and recently members of a French family have been diagnosed to have cone rod dystrophy associated with SCA1. A complete neuro-ophthalmic exam including dilated fundus exam and electrophysiological testing in patients affected with unexplained visual loss in SCA1 might help in early diagnosis of cone rod dystrophy and in reporting more of such associations.

Keywords: SCA1; Ataxia; Ophthalmic manifestations; Cone rod dystrophy; Maculopathy

Background

The Spinocerebellar Ataxias (SCA’s) are a genetically and clinically diverse group of Autosomal Dominant (AD) disorders characterized by a slowly progressive cerebellar syndrome in association with various oculomotor, retinal, pyramidal, extra-pyramidal, sensory and cognitive/behavioral symptoms that vary with the underlying affected gene. The SCA’s are classified according to the genetic loci of the tri-nucleotide repeat and have been numbered according to their chronology of identification: SCA1 through SCA36. SCA 1, 2, 3, 6 and 7 comprise 80% of the SCA’s. They typically present in middle age, with slowly progressive in coordination of gait, often associated with appendicular ataxia, dysmetria, intentional tremors, gait difficulties, dysarthria and visual problems (difficulty focusing, diplopia, slowed/ dysmetric saccades). Atrophy of the cerebellum occurs frequently, causing the person to retain full mental capacity but progressively and irreversibly lose control of all motor functions. Brain imaging, in the form of MRI, helps rule out other diseases and localize the abnormality, usually atrophy of the cerebellum and brainstem. Recognition and discrimination of SCA’s are important for proper diagnosis and evaluation.

The common underlying mutational mechanism in all SCA’s is expanded CAG repeat encoding a tract of glutamine amino acids (Polyglutamine or Poly-Q tract) at different gene loci. In this inherited autosomal dominant disorder, the Poly-Q tract is increased from a normal level (maximum 35-40 repeat units) to a disease causing level and passed on to approximately 50% of the offspring. The age of onset varies inversely with length of Poly-Q tract repeats. The SCA’s exhibit genetic anticipation wherein the polyglutamine expansion lengthens when passed down to the progeny, resulting in earlier age of onset and more severe disease phenotype for individuals who inherit the disease allele.

SCA1

SCA1 was the first dominantly-inherited ataxia for which the locus and gene defect were identified [1]. Manifestations of SCA1 include severe four limb ataxia with dysarthria, causing most patients to be wheelchair-bound within 15-20 years of onset of disease. SCA1 is caused by poly-Q encoding CAG repeat expansions (39-83 repeats; normal alleles have 6-38 repeats) resulting in the SCA1 disease protein, Ataxin-1 mapped to chromosome 6p23) to have an abnormally long stretch of the amino acid glutamine and misfolded, resulting in neuronal degeneration and dysfunction in the cerebellum, brainstem and spinocerebellar tracts [2,3]. Ophthalmic manifestations include saccadic dysmetria in the form of hypermetric or slow saccades, gazeevoked and rebound nystagmus and reduced smooth pursuit gain [4]. Optic atrophy and consequently abnormal visual evoked potentials have been described in SCA1 [5]. Recently, 2 cases in the United States and members of a family in France have been reported to have cone rod dysfunction with SCA1 [6-8].

SCA7

SCA7 is relatively rare, autosomal dominant and the poly-Q encoding CAG repeat expansions (Greater than 36 repeats in disease, less than 20 repeats in health) occur within the ATXN7 gene mapped to chromosome 3p12-13 manifesting as gait imbalance, progressing to appendicular ataxia, and eventually leading to wheelchair confinement. Until recently, SCA7 was the only inherited ataxia reportedly associated with a cone-rod dystrophy manifesting as reduced visual acuity, dyschromatopsia, and photosensitivity, followed by progressive loss in peripheral vision and night blindness [9,10]. The ophthalmoscopic exam may initially have a normalappearing macula, progressing to retinal pigment epithelial mottling, eventually developing into a ‘‘bull’s-eye’’ maculopathy. However, Electroretinogram (ERG) demonstrating loss of photopic function or Ocular Coherence Tomography (OCT) showing thinning of the macula and Retinal Nerve Fiber Layer (RNFL) may help in diagnosing the macular and retinal dysfunction prior to the appearance of the maculopathy [11,12].

Methods

The patient, a 60 year old male, presenting with painless progressive bilateral vision loss, underwent clinical assessment including a dilated fundus exam, Humphrey Visual Field (HVF), fundus color and auto fluorescence photography, OCT maculae, VEP, Multifocal Electroretinography (multifocal ERG) and full-field ERG. He also underwent a brain MRI and a complete neurologic exam. Details of previous genetic examinations of his brother were extracted from medical charts after prior permission. After informed consent, DNA from the patient was analyzed for SCA1 gene mutation.

Results

The patient reported painless progressive bilateral vision loss for the past 2 years. Ocular history was significant for failed vision screening test at work 2 years earlier, which led to uneventful cataract surgery and subsequent YAG laser capsulotomy both eyes. Vision however failed to improve with actual further worsening of vision both eyes. Past medical history was significant only for hypertension, well controlled with single medication. However, in depth history revealed that he had balance difficulty for several years. His family history was positive for worsening ataxia in his brother, father (died at age 80), 2 cousins and a paternal aunt. His brother had tested positive for SCA1 in the past. His neurologic exam revealed normal strength and tone in all extremities, normal sensation and 2+ reflexes. However, he was found to manifest mild parkinsonian symptoms with a parkinsonian gait and postural instability.

Best-corrected visual acuity at distance was 20/60 in both eyes (OU). Near vision was J7 OU with a +3.00D reading add. Farnsworth D-15 was abnormal OU, consistent with congenital protanomalia. He was orthophoric in all directions of gaze; ocular motility was full but showed saccadic dysmetria. Pupils were equal, round and reactive with no afferent pupillary defect. Intraocular pressure by applanation was 16 mm Hg both eyes. Slit lamp exam of anterior segment revealed well centered posterior chamber implants and posterior vitreous detachments in both eyes. HVF 24-2 showed central scotomas both eyes (Figure 1). The dilated fundus exam revealed mild temporal pallor of both optic discs and subtle speckled macular pigmentary changes in both eyes (Figure 2 & 3). The multifocal ERG demonstrated a loss of P1 amplitude in the central 10 degrees in each eye (Figure 4A & 4B). Full field ERG showed relatively greater loss of cone-mediated responses compared to rod-mediated responses (Figure 5). The OCT of maculae revealed foveal atrophy and foveal cavitation, more in the right eye (Figure 6A & 6B). VEP latencies were essentially normal except for the delays at the small 7 minute checks.