A 26 year old presents with a suspected mild movement disorder

Can you solve the case?

Review the case background and choose from the test options below

How quickly can you reach a diagnosis?
Begin

A 26 year old presents with a suspected mild movement disorder

Can you solve the case?

Review the case background and choose from the test options below

How quickly can you reach a diagnosis?
Begin

Clinical and family history

Ataxia symptoms

Experiences tremors when performing fine motor movements along with general fine motor clumsiness that worsens when ill or fasting. Mild hypotonia observed in all four limbs with mild upper and lower extremity ataxia

Dystonia symptoms

Walks somewhat unstably with lurching, abnormal gait. Walks on toes with feet turned inwards. Exhibits reduced or absent reflexes in upper and lower extremities

Anxiety symptoms

Describes anxiety in social and certain daily situations. Reports some difficulty in maintaining focus and attention when reading and sometimes in conversation

Ataxia and dystonia symptoms trace back to 5 years of age

Summary of testing performed

  • Cranial MRI identified symmetric white matter abnormality
  • Cranial MRS identified abnormal Cho/Cr and NAA/Cho ratios
  • Abnormal fibroblast mitochondrial oxidative phosphorylation
  • No evidence for hypomethylation

Family history

  • The family history was significant for tremor and similar clumsiness during illness or fasting

Ataxia symptoms

Experiences tremors when performing fine motor movements along with general fine motor clumsiness that worsens when ill or fasting. Mild hypotonia observed in all four limbs with mild upper and lower extremity ataxia

Dystonia symptoms

Walks somewhat unstably with lurching, abnormal gait. Walks on toes with feet turned inwards. Exhibits reduced or absent reflexes in upper and lower extremities

Anxiety symptoms

Describes anxiety in social and certain daily situations. Reports some difficulty in maintaining focus and attention when reading and sometimes in conversation

Ataxia and dystonia symptoms trace back to 5 years of age

Summary of testing performed

  • Cranial MRI identified symmetric white matter abnormality
  • Cranial MRS identified abnormal Cho/Cr and NAA/Cho ratios
  • Abnormal fibroblast mitochondrial oxidative phosphorylation
  • No evidence for hypomethylation

Family history

  • The family history was significant for tremor and similar clumsiness during illness or fasting

What’s the next step?

Based on the clinical information provided, impairment of the cerebellum and basal ganglia are suspected. The early age of onset is consistent with a genetic etiology.

Based on the clinical information provided, impairment of the cerebellum and basal ganglia are suspected. The early age of onset is consistent with a genetic etiology.

Which one of the following tests would you order?

Chromosomal Microarray Analysis

You’ve ordered a Chromosomal Microarray Analysis that provides genome-wide analysis of copy number variants (CNVs) but will miss smaller sequence variants.

This is a logical choice given its acceptance as a first-tier tool when a possible chromosomal abnormality is suspected.

But the results are negative.

You’ve ordered a Chromosomal Microarray Analysis that provides genome-wide analysis of copy number variants (CNVs) but will miss smaller sequence variants.

This is a logical choice given its acceptance as a first-tier tool when a possible chromosomal abnormality is suspected.

But the results are negative.

Which one of the following tests would you order next?

DYT1 DNA Test

You’ve ordered a DYT1 DNA Test that uses PCR to specifically test the TOR1A gene for presence of the GAG 948 deletion.

This is a logical choice given the patient’s dystonia symptoms.

But the results are negative.

You’ve ordered a DYT1 DNA Test that uses PCR to specifically test the TOR1A gene for presence of the GAG 948 deletion.

This is a logical choice given the patient’s dystonia symptoms.

But the results are negative.

Which one of the following tests would you order next?

FXN Repeat Expansion Test

You’ve ordered repeat expansion testing for FXN, the causal gene for Friedreich’s ataxia. PCR in combination with sizing by fluorescent capillary electrophoresis and agarose gel electrophoresis is used to determine the size of the GAA repeat. Other sequence variants in the FXN gene will be missed.

This is a logical choice given the patient’s early onset ataxia symptoms.

But the results are negative – both FXN alleles fall within the normal range.

You’ve ordered repeat expansion testing for FXN, the causal gene for Friedreich’s ataxia. PCR in combination with sizing by fluorescent capillary electrophoresis and agarose gel electrophoresis is used to determine the size of the GAA repeat. Other sequence variants in the FXN gene will be missed.

This is a logical choice given the patient’s early onset ataxia symptoms.

But the results are negative – both FXN alleles fall within the normal range.

Which one of the following tests would you order next?

SCA Repeat Expansion Tests

You’ve ordered repeat expansion testing for common spinocerebellar ataxia (SCA) genes. The exact genes tested differs by laboratory, but the test you order covers ATXN1 (SCA1), ATXN2, (SCA2), ATXN3 (SCA3), CACNA1A (SCA6) and ATXN7 (SCA7). PCR in combination with fluorescent capillary electrophoresis is used for fragment size analysis.

This is a logical choice given the patient’s ataxia symptoms.

But the results are negative – all alleles fall within their normal range.

You’ve ordered repeat expansion testing for common spinocerebellar ataxia (SCA) genes. The exact genes tested differs by laboratory, but the test you order covers ATXN1 (SCA1), ATXN2, (SCA2), ATXN3 (SCA3), CACNA1A (SCA6) and ATXN7 (SCA7). PCR in combination with fluorescent capillary electrophoresis is used for fragment size analysis.

This is a logical choice given the patient’s ataxia symptoms.

But the results are negative – all alleles fall within their normal range.

Which one of the following tests would you order next?

Exome Sequencing

You’ve ordered exome sequencing which provides a broad, phenotype-driven analysis of the exonic regions of all genes. You’ve chosen to add on mitochondrial genome sequencing.

Exome plus mitochondrial genome sequencing is a good choice for investigation of a broader set of genes than is possible with targeted gene or panel testing, but is unlikely to identify smaller deletions and duplications.

Although a number of deleterious variants are identified, along with many variants of uncertain significance (VUS), none are able to fully explain the patient’s phenotype.

You’ve ordered exome sequencing which provides a broad, phenotype-driven analysis of the exonic regions of all genes. You’ve chosen to add on mitochondrial genome sequencing.

Exome plus mitochondrial genome sequencing is a good choice for investigation of a broader set of genes than is possible with targeted gene or panel testing, but is unlikely to identify smaller deletions and duplications.

Although a number of deleterious variants are identified, along with many variants of uncertain significance (VUS), none are able to fully explain the patient’s phenotype.

Which one of the following tests would you order next?

Genomic Unity® Testing

You’ve ordered Genomic Unity® Testing which uniquely uses a whole genome sequencing (WGS) methodology that provides comprehensive sequence, deletion/duplication, copy number variant, mitochondrial variant and tandem repeat expansion analysis.

Testing identifies two FXN GAA alleles of normal size, and no other pathogenic FXN variants, ruling out Friedreich’s ataxia. The most common spinocerebellar ataxias are similarly ruled out by normal size alleles of ATXN1 (SCA1), ATXN2 (SCA2), ATXN3 (SCA3), CACNA1A (SCA6), ATXN7 (SCA7), ATXN8OS (SCA8), ATXN10 (SCA10), PPP2R2B (SCA12), TBP (SCA17) and NOP56 (SCA36).

Further analysis of the data identifies compound heterozygous variants in the POLR3A gene: a multi-exon deletion and a pathogenic sequence variant in the noncoding region of the gene. The findings are consistent with a spastic ataxia diagnosis.

Congratulations, you’ve solved the case!

You’ve ordered Genomic Unity® Testing which uniquely uses a whole genome sequencing (WGS) methodology that provides comprehensive sequence, deletion/duplication, copy number variant, mitochondrial variant and tandem repeat expansion analysis.

Testing identifies two FXN GAA alleles of normal size, and no other pathogenic FXN variants, ruling out Friedreich’s ataxia. The most common spinocerebellar ataxias are similarly ruled out by normal size alleles of ATXN1 (SCA1), ATXN2 (SCA2), ATXN3 (SCA3), CACNA1A (SCA6), ATXN7 (SCA7), ATXN8OS (SCA8), ATXN10 (SCA10), PPP2R2B (SCA12), TBP (SCA17) and NOP56 (SCA36).

Further analysis of the data identifies compound heterozygous variants in the POLR3A gene: a multi-exon deletion and a pathogenic sequence variant in the noncoding region of the gene. The findings are consistent with a spastic ataxia diagnosis.

Congratulations, you’ve solved the case!

Interested to explore the results of other testing for comparison?

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