1. NGS panel - Genetic testing for oculomotor apraxia

Oculomotor apraxia

June 28, 2017

Clinical features

Ataxia with oculomotor apraxia (AOA) is a rare inherited disease characterized by childhood onset of slowly progressive cerebellar ataxia, followed by oculomotor apraxia and a severe primary motor peripheral axonal motor neuropathy. There are 2 major subtypes of AOA, type 1 and type 2, which are clinically similar but are caused by mutations in different genes. AOA1 is primarily caused by mutations in APTX, while AOA2 is caused by mutations in the SETX gene. 1

The major clinical features of AOA1 include the following:

  • Cerebellar ataxia, oculomotor apraxia, and areflexia
  • Childhood onset
  • Slow progression leading to severe motor handicap
  • Severe peripheral neuropathy developing with the course of the disease
  • Absence of extra-neurologic findings common in ataxia-telangiectasia
  • Long survival
  • Family history consistent with autosomal recessive inheritance.

Laboratory findings commonly observed in AOA1-affected patients include the following:

  • Decreased serum concentration of albumin
  • Increased serum concentration of total cholesterol
  • Normal serum concentration of alpha-fetoprotein
  • Nerve biopsy confirms axonal neuropathy.

Ataxia with oculomotor apraxia type 2 (AOA2) is clinically characterized by onset between age three and 30 years, cerebellar atrophy, axonal sensorimotor neuropathy, oculomotor apraxia, and elevated serum concentration of alpha-fetoprotein (AFP). Serum alpha-fetoprotein concentration higher than 20 ng/mL were reported in >95% of affected individuals6. According to a recent large research study, AOA2 accounted for 8% of all autosomal recessive cerebellar ataxia1,7.

Ataxia with oculomotor apraxia type 3 (AOA3) was reported in a Saudi family in association with a pathogenic missense variant in PIK3R5. The disorder is clinically and biochemically overlapping with AOA2.

Ataxia with oculomotor apraxia type 4 (AOA4) was recently described in a cohort of nine Portuguese families associated with pathogenic variants in PNKP1, 5. Age of onset and clinical features are very similar to AOA1.


Overview of genes included in Oculomotor apraxia panel, autosomal dominant offered by CENTOGENE

Gene
(OMIM)
(chr.locus) Protein
(Function)
Frequency of mutations Associated/allelic disorders
APTX
(606350)
9p21.1 Aprataxin 23/46 (46,5%) for AOA1 and AOA2 1,2
13/204 (6%) 3
Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia (208920)
PIK3R5
(611317)
17p13.1 Phosphoinositide-3-kinase regulatory subunit 5 Reported in Saudi families 4 Ataxia-oculomotor apraxia 3 (615217)
PNKP
(605610)
19q13.33 Polynucleotide kinase 3'-phosphatase Reported in 9 Portugeese families 5 Ataxia-oculomotor apraxia 4 (616267);
Microcephaly, seizures, and developmental delay (613402)
SETX
(608465)
9q34.13 Senataxin 100% for AOA2 6 Amyotrophic lateral sclerosis 4, juvenile (602433);
Spinocerebellar ataxia, autosomal recessive 1 (606002)

There is no cure for ataxia oculomotor apraxia, however physical therapy may be helpful, mostly for disabilities resulting from peripheral neuropathy.

CENTOGENE offers full gene sequencing and deletion/duplication analysis for the Oculomotor apraxia panel genes (APTX, PIK3R5, PNKP, SETX).


Differential diagnosis

The differential diagnosis of ataxia oculomotor apraxia-related disorders – depending on the major symptoms in the initial case – includes the following diseases:

  • Friedreich ataxia (FRDA)
  • Ataxia with vitamin E deficiency (AVED)
  • Ataxia with coenzyme Q10 deficiency
  • Spinocerebellar ataxia type 2 (SCA2)
  • Spinocerebellar ataxia with axonal neuropathy (SCAN1)
  • Ataxia-telangiectasia.

Testing strategy

CENTOGENE offers advanced, fast and cost-effective strategy to test large NGS panels and diagnose complex phenotypes based on the PCR-free whole genome sequencing and NGS technology. This approach offers an unparalleled advantage by reducing amplification/capture biases and provides sequencing of entire gene at a more uniform coverage.

To confirm/establish the diagnosis, CENTOGENE offers the following testing strategy for oculomotor apraxia using NGS Panel Genomic targeted towards this specific phenotype:

Step 1: Whole genome sequencing from a single filter card. The sequencing covers the entire genic region (coding region, exon/intron boundaries, intronic and promoter) for all the genes included in the Oculomotor apraxia panel. Copy Number Variants analysis derived from NGS data is also included.

Step 2: If no mutation is identified after analysis of the Oculomotor apraxia panel, based on the approval and consent, we further recommend to continue the bioinformatics analysis of the data obtained by whole genome sequencing to cover genes that are either implicated in an overlapping phenotype or could be involved in a similar pathway but not strongly clinically implicated based on the current information in literature.


Referral reasons

The following individuals are candidates for Oculomotor apraxia panel testing:

  • Individuals with a family history of ataxia oculomotor apraxia and presentation of the most common symptoms including cerebellar ataxia, oculomotor apraxia, and areflexia
  • Individuals without a positive family history, but with symptoms resembling ataxia oculomotor apraxia
  • Individuals with a negative but suspected family history of ataxia oculomotor apraxia, in order to perform proper genetic counseling.

Test utility

Sequencing, deletion/duplication of the Oculomotor apraxia panel genes should be performed in all individuals suspected of having ataxia oculomotor apraxia and suspected phenotypes. In parallel, other genes reported to be related with this clinical phenotype should also be analyzed for the presence of mutations, due to the overlap in many clinical features caused by those particular genes.

Confirmation of a clinical diagnosis through genetic testing can allow for genetic counseling and may direct medical management. Genetic counseling can provide a patient and/or family with the natural history of ataxia oculomotor apraxia and related disorders and identify at-risk family members, provide disease risks as well as appropriate referral for patient support and/or resources.


More information on CENTOGENE´s Oculomotor apraxia panel can be found in our genetic test catalogue.