Spinocerebellar Ataxia 28 Presenting as Predominantly Generalized Dystonia

Dear Sir,

Spinocerebellar ataxia type 28 (SCA 28) is characterized by young-adult onset slowly progressive gait and limb ataxia, dysarthria, ptosis, and Opthalmoplegia. We report a case of SCA 28 in a 37-year-old gentleman with predominant dystonia, bilateral optic atrophy, and cerebellar ataxia.

CASE REPORT

A 37-year-old South Indian gentleman presented with childhood onset decreased vision, drooping of eyelids, and abnormal posturing of the body for the past 3 years.

At around 10 years of age, he noticed progressive deterioration of vision and a year after which it became static. He was able to perform his daily activities without any visual assistance. He had difficulty with distant vision in the beginning, and later on his near vision was also affected. His mother also noticed progressive bilaterally symmetrical drooping of both the upper eyelids since childhood. There was no history of diplopia or night blindness.

He also complained of abnormal movements of his neck, right upper limb, and trunk for the past 3 years. At first, he noticed a pulling sensation of his neck with intermittent involuntary forced deviation of the head to the right. It was present mainly during sitting and walking. However, it was completely absent if support was given to the head or while resting on a pillow. It was not suppressible nor present during sleep. Over the past few months, he also noted rightward as well as backward tilting of the head due to which he finds it difficult to feed himself. Two years back he started to notice abnormal posturing of the right upper limb while walking. His wife had noticed abnormal elevation of his shoulder with intermittent twisting posture of the right upper extremity while walking. His posturing disappears on placing his hands on his hips. A year back, his wife also noticed sustained rightward curving of the trunk while walking. For the past 3 years, he has noticed swaying sideways while walking. He has difficulty walking on uneven ground and walks with a wide base. This difficulty has been static.

He was born out of a nonconsanguineous marriage and had normal developmental milestones. His brother, who is 33 years old, has drooping of eyelids and decreased movements of the eyeballs in all directions with no history of dystonia or ataxia. He was not available for examination. His father passed away 4 years back due to myocardial infarction, His mother was a healthy woman of 63 years and there was no family history [Figure 1].

Figure 1.

PEDIGREE CHART

On examination, he was found to have bilateral primary optic atrophy [Figure 2] and bilateral ptosis with external ophthalmoplegia. His visual acuity was 6/60 bilateral. The pupils were reacting normally to light. There was no evidence of retinitis pigmentosa. He had dystonic posturing of his neck, right shoulder, and trunk [Video 1] and lingual dyskinesia [Video 1]. He also had cerebellar signs of both the upper and lower limbs [Video 1]. He had brisk reflexes of the lower limbs, and his plantar was bilateral extensor. His magnetic resonance imaging (MRI) revealed cerebellar vermian atrophy [Figure 3]. The possibilities considered were mitochondrial disorders like Kearns-Sayre syndrome (csf lactate , serum lactate, and pyruvate were normal) and spinocerebellar ataxias.

Figure 2.

Fundus photo demonstrating bilateral optic atrophy

Figure 3.

MRI T2 SAGITTAL IMAGE demonstrating cerebellar atrophy

Genetic testing through clinical exome sequencing (Med Genome Labs Ltd) revealed two mutations in the AFG3L2 gene, viz., a single base pair insertion in exon 13 (ENST00000269143.3, c. 1628_1629insT), resulting in a frameshift and premature truncation of the protein four amino acids downstream to codon 543 (p. Lys543AsnfsTer4) and a missense mutation (ENST00000269143.3, c.868A>T) in exon 8 (p. Ser290Cys). Mutations in the AFG3L2 gene are responsible to cause spinocerebellar ataxia 28 (SCA 28, #610246). Both the mutations have not been reported previously reported in the literature. Owing to financial constraints, his mother and brother couldn’t be tested. So, segregation analysis was not performed for the identified mutations.

DISCUSSION

SCA28 is inherited in an autosomal dominant pattern. The clinical features include slowly progressive gait and limb ataxia, dysarthria, nystagmus, ptosis, opthalmoparesis, hyperreflexia of the lower limbs, dystonia or parkinsonism features.[1,2] Bilateral optic atrophy was described only in one study.[3] SCA28 presenting with prominent dystonia is rare.

The AFG3L2 gene encodes a subunit of the mitochondrial metalloprotease AFG3-like protein 2 (AFG3L2). The literature strongly suggests that AFG3L2 variants causative of SCA 28 act through a gain-of-function or dominant-negative mechanism.[4] The novel frameshift mutation results in the truncation of the protein after 547 amino acids, which leads to the loss of the functional M41-protease domain of the AFG3L2 protein where most of the pathogenic mutations are localized.[4]

Practical implications

Clinical evaluation and genetic testing for SCA 28 should be considered in patients with autosomal dominant ataxia syndromes, especially presenting with external ophthalmoplegia and prominent dystonia.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Appendix

APPENDIX 1.

AUTHORS

NAME	LOCATION	ROLE	CONTRIBUTION
Jidhin Raj, MD	Govt. Medical College Kottayam	Author	Design and conceptualized study; Data collection; drafted the manuscript for intellectual content
Jacob George, DM	Govt. Medical College Kottayam	Author	Data collection, revision of manuscript
Manjit P.S, MD	Govt. Medical College Kottayam	Author	Data collection, revision of manuscript
Neethu Suresh, MD	Govt. Medical College Kottayam	Author	Data collection
Ajay Radhakrishnan, MD	Govt. Medical College Kottayam	Author	Data collection
Jiji Rajesh Kumar MD	Government Medical College, Kottayam	Author	Data collection
Lova Satyanarayana Ph.D	MedGenome Labs Ltd., Bangalore	Author	Data collection, revision of manuscript