Complete deletion of the aprataxin gene: ataxia with oculomotor apraxia type 1 with severe phenotype and cognitive deficit

Abstract

Ataxia with oculomotor apraxia type 1 (AOA1) is a recently described autosomal-recessive neurodegenerative condition of childhood onset. It is caused by mutations in the APTX gene, which encodes the protein aprataxin. Clinical features include gait and limb ataxia, dysarthria, oculomotor apraxia, mild peripheral neuropathy and progression of neurological deficits.¹ Some patients manifest parkinsonian symptoms or mental retardation, although the latter has been reported predominantly in Japanese patients.² We report a patient with homozygous deletion of APTX, who presented with behavioural changes (social withdrawal), and subsequent rapid progression of neurological symptoms associated with severe cognitive decline. We suggest that complete deletion of APTX is associated with a more severe phenotype than that associated with point mutations.

BACKGROUND

Ataxia with oculomotor apraxia type 1 (AOA1) is a recently described autosomal-recessive neurodegenerative condition of childhood onset. It is caused by mutations in the APTX gene, which encodes the protein aprataxin. Clinical features include gait and limb ataxia, dysarthria, oculomotor apraxia, mild peripheral neuropathy and progression of neurological deficits.¹ Some patients manifest parkinsonian symptoms or mental retardation, although the latter has been reported predominantly in Japanese patients.² We report a patient with homozygous deletion of APTX, who presented with behavioural changes (social withdrawal), and subsequent rapid progression of neurological symptoms associated with severe cognitive decline. We suggest that complete deletion of APTX is associated with a more severe phenotype than that associated with point mutations.

CASE PRESENTATION

The patient is the second child of first-cousin Pakistani parents, and has two healthy brothers who are neurologically and cognitively normal. Prenatal, delivery and early neonatal history were unremarkable. Early developmental milestones were met at the appropriate times and social development was normal. At age 5 years, she began to withdraw from social contact in school and became very shy. She also demonstrated difficulties in acquiring new language. She was then noticed to become more unsteady while walking and, by 5.5 years, she began to fall. At age 6.5 years, her movements became slower and she required a walker for ambulation. She also had difficulty initiating speech, and became severely dysarthric. At 7 years of age, she became wheelchair-bound and was unable to stand independently. There was also deterioration of her fine motor skills and she required assistance with feeding, dressing and most activities of daily living. Neurological exam at 7 years 4 months revealed oculomotor apraxia, which was most marked on lateral gaze. There was difficulty initiating saccadic movements, and she needed to blink or turn her head in order to initiate lateral eye movement. Her cranial nerve exam was otherwise normal. Global muscle tone was normal, but there was intermittent dystonic posturing of the feet. Muscle bulk was slightly reduced in the lower limbs. Manual muscle strength testing revealed normal strength of the upper extremities and proximal lower extremities. There was weakness of the tibialis anterior, extensor hallucis longus and peronei bilaterally. Cerebellar exam revealed multiple abnormalities, including dysmetria, bradykinesia, dysdiadochokinesis and a marked intention tremor. Deep tendon reflexes were reduced in the upper extremities, and absent at the knees and ankles. Plantar response was extensor. Sensation was normal to light touch, pain, vibration and proprioception. There was marked truncal instability, and continuous choreiform movements of the trunk, shoulders, hands and feet. Electromyography and nerve conduction tests carried out at age 5.5 years were normal. Magnetic resonance imaging of the brain revealed marked cerebellar atrophy but no other abnormalities.

INVESTIGATIONS

Neurocognitive testing was performed at age 6 years 11 months. Standardised tests and age-appropriate norms were used to evaluate the patient’s overall intellectual function, academic skills, vocabulary, visual-perceptual skills, visual-motor skills, learning, memory and problem solving (table 1).

Table 1. Neuropsychological profile.

Test name	Normative mean (SD)	Patient’s performance	Qualitative description	Age equivalent**
WPPSI-III FSIQ*	100 (15)	69	Impaired
WPPSI-III VIQ	100 (15)	77	Borderline
Vocabulary	10 (3)	N/A	N/A
Information	10 (3)	6	Below average	4:10
Word reasoning	10 (3)	5	Borderline	4:1
WPPSI-III PIQ	100 (15)	73	Borderline
Block design	10 (3)	3	Impaired	3:7
Picture concepts	10 (3)	7	Below average	5:4
Matrix reasoning	10 (3)	7	Below average	5:4
Picture completion	10 (3)	6	Below average	4:10
WPPSI-III PSI	100 (15)	64	Impaired
Coding	10 (3)	2	Impaired	4:1
Symbol search	10 (3)	5	Borderline	4:7
WCJ-III achievement
Letter-word identification	100 (15)	82	Below average	6:1
Spelling	100 (15)	N/A	N/A
Word attack	100 (15)	84	Below average	6:3
Calculation	100 (15)	N/A	N/A	A
Applied problems	100 (15)	82	Below average	5:5
Peabody Picture Vocabulary Test	100 (15)	73	Borderline	4:8
Expressive Vocabulary Test	100 (15)	75	Borderline	4:8
CELF-3—Concepts and directions	10 (3)	5	Borderline
Children Memory Scale
Dot locations—Learning	10 (3)	N/A	N/A
Dot locations—Delayed recall	10 (3)	N/A	N/A
Faces—Immediate recognition	10 (3)	6	Below average
Faces—Delayed recognition	10 (3)	4	Borderline
Stories—Immediate recall	10 (3)	N/A	N/A
Stories—Delayed Recall	10 (3)	N/A	N/A
Stories—Delayed recognition	10 (3)	N/A	N/A
Beery Visual-motor Integration	100 (15)	7	Borderline	5:2
Beery Motor Coordination	100 (15)	1	Impaired	2:11
Beery Visual-Perceptual Test	100 (15)	19	Below average	5:7
Children’s Category Test	50 (10)	N/A	N/A

WPPSI-III, Wechsler Preschool and Primary Scale of Intelligence—Third Edition; WCJ-III, Woodcock Johnson Tests of Academic Achievement—version III; CELF-3, Clinical Evaluation of Language Fundamentals—version 3

*American norms are reported for the WPPSI-III. The VIQ and FSIQ were pro-rated because the Vocabulary subtest could not be completed.

**Age equivalents are in the format Year:Month. For example, 5:2 indicates 5 years, 2 months.

The assessment clearly revealed widespread cognitive impairment affecting all domains of function. Overall intellectual ability was impaired (2^nd percentile), with equally weak non-verbal and verbal skills. Receptive and expressive vocabulary were poorly developed, as were early academic skills (eg letter and number recognition). Visual-perceptual matching, visual learning and visual memory were all impaired for her age. Evaluation of verbal learning, verbal memory and higher-level problem-solving skills was discontinued as it was too challenging.

PCR amplification and Southern blotting of the aprataxin (APTX) gene exons 1 to 8 were performed according to standard methods. FISH analysis of the 9p13.3 region surrounding the APTX gene revealed no evidence of microdeletion.

DISCUSSION

We describe a patient with homozygous deletion of the APTX gene, who presents with rapid cognitive and neurological decline. Deletion of the APTX gene has been previously reported in a single family with two affected members; however, these patients were described as having no cognitive deficit, and the neurological symptoms were not assessed as being more severe compared with the classical phenotype.³ Although ataxia is the presenting symptom in the vast majority of reported cases, our patient presented with behavioural changes (withdrawal from previously normal social contact) and difficulties with language acquisition. Subsequent neurocognitive testing revealed severe global impairment, suggesting that cognitive deficit is progressive in some patients. Cognitive impairment is not a universal feature of AOA1, but seems to be predominant in Japanese patients.² AOA1 patients of European origin have been reported with varying degrees of cognitive deficit, with no clear genotype–phenotype correlation.¹ The rapid neurological deterioration of our patient (18 months from ataxia onset to becoming wheelchair-bound) is striking compared with previously reported cases, in which the average loss of ambulation occurred 7–11 years post-onset of ataxia.¹ Homozygosity for truncating mutations has previously been associated with earlier onset of ataxia compared with missense mutations, but disease progression is not accelerated.^1,2

The APTX gene encodes aprataxin, a member of the histidine triad (HIT) superfamily, and plays an important role in DNA repair. In a series of elegant experiments, it has been demonstrated that aprataxin resolves abortive DNA ligation intermediates that are caused by reactive oxygen species.⁴ Failure of this process results in accumulation of unrepaired DNA-adenylates and subsequent cellular dysfunction. These investigators postulated that neuronal accumulation of these toxic metabolites forms the basis for the neurological deterioration in AOA1. Other studies subsequently demonstrated that fibroblasts from patients with AOA1 are hypersensitive to reactive oxygen species, with increased numbers of single-stranded DNA breaks and cell death compared with controls.⁵

As the enzymatic activity of aprataxin has been proven necessary for maintaining DNA single-strand break repair, complete absence of this enzyme would render cells highly susceptible to oxidative damage. The unusual clinical features of our patient suggest that deletion of the APTX gene is associated with a severe phenotype of AOA1, which is probably due to progressive accumulation of toxic unrepaired DNA-adenylates associated with oxidative damage. We suggest that complete deletion of the APTX gene does confer a more severe neurological and neurocognitive phenotype compared with AOA1 resulting from point mutations

LEARNING POINTS

• Ataxia with oculomotor apraxia (AOA) type 1 is a recessive disorder characterised by cerebellar ataxia, dysarthria, mild neuropathy and rarely mental retardation or Parkinsonism.

• AOA type 1 is caused by mutations in Aprataxin (APTX).

• Here a case of AOA type 1 with unusually severe and rapid cognitive decline due to APTX deletion is described.