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PubMed This is a summary of 16 peer-reviewed journal articles Updated
Neurology

Diagnosis, POLG Genetics, and Look-Alikes

At a Glance

SANDO diagnosis combines the symptom pattern with neurologic examination, nerve conduction studies, brain MRI, and POLG genetic testing. A normal MRI does not exclude SANDO, and genetic results help distinguish it from CIDP, CANVAS, Friedreich ataxia, and Miller Fisher syndrome.

The diagnosis of SANDO syndrome is a multi-step process that combines physical examinations, electrical nerve tests, and advanced imaging [1]. Identifying specific pathogenic mutations in the POLG gene is a critical step to confirm the diagnosis and distinguish SANDO from its “look-alikes” [2][3].

The Diagnostic Toolset

To build a case for SANDO, your neurology team will look for evidence of damage in three specific areas: your sensory nerves, your brain, and your eye muscles [2].

Electrical and Imaging Tests

  • EMG and Nerve Conduction Studies (NCS): These tests measure how well your nerves send signals. In SANDO, these studies typically reveal a sensory axonal neuropathy, meaning the main body of the sensory nerves is damaged [1][4]. Unlike some other conditions, the motor nerves (which control strength) are often relatively preserved [5].
  • Brain MRI: An MRI scan may show specific patterns of change in the brain. Some patients with SANDO have “bilateral lesions”—changes appearing on both sides—in the thalamus (the brain’s relay station) or the cerebellum (the balance center) [2]. However, a normal MRI does not rule out the syndrome [2].
  • Muscle Biopsy: While less common today, a muscle biopsy can show “secondary multiple mtDNA deletions” [4]. This means the POLG mutation has caused the DNA inside your mitochondria to break or become missing in multiple places [6].

The Genetics: Understanding POLG

SANDO is a genetic condition caused by mutations in the POLG gene [4]. The classic SANDO phenotype is usually inherited in an autosomal recessive pattern, meaning you typically need two mutated copies of the gene—one from each parent—to develop the syndrome [7][8]. However, autosomal dominant variants of POLG disease also exist, which can complicate family testing.

Researchers have identified specific mutations (like p.A467T and p.W748S) that appear frequently in POLG disease registries [4]. However, having a common variant does not predict your specific symptoms, severity, or disease timeline [3]. This is because POLG mutations can cause a wide spectrum of diseases, and scientists do not yet fully understand why one person develops SANDO while another develops a different mitochondrial disorder [6][9].

It is highly recommended to speak with a genetic counselor. A counselor can help you understand whether your variants are truly pathogenic (disease-causing) versus a “Variant of Uncertain Significance” (VUS), discuss reproductive options, and explain the implications for testing your relatives.

Differentiating the “Look-Alikes”

Because the symptoms of SANDO—balance issues, slurred speech, and eye weakness—are seen in other diseases, it is common for patients to be misdiagnosed initially [1].

Condition Why it looks like SANDO How it is different
CIDP (Chronic Inflammatory Demyelinating Polyneuropathy) Causes nerve damage and balance loss [10]. CIDP is an autoimmune disease with “demyelinating” features on nerve tests. It often responds to immune-modulating treatments. Do not abruptly stop CIDP treatments without your neurologist’s guidance, even if SANDO is suspected [11].
CANVAS Causes sensory ataxia and balance issues [5]. CANVAS is a clinical syndrome often associated with a different gene expansion (RFC1). It frequently includes a chronic cough and vestibular (inner-ear) failure [5][12].
Friedreich Ataxia Causes coordination and speech changes [13]. Usually appears in younger people and is caused by the FXN gene. It typically lacks the eye-muscle paralysis (ophthalmoparesis) seen in SANDO [13].
Miller Fisher Syndrome Causes the “triad” of ataxia, eye weakness, and loss of reflexes [14]. This is an acute (sudden) autoimmune reaction that often follows an infection. SANDO is a lifelong, slowly progressive genetic condition [15].

Distinguishing SANDO from these conditions is vital because the treatments are entirely different. Genetic confirmation ensures you receive the correct monitoring and avoid harmful medications like valproate [16].

Common questions in this guide

What tests are used to diagnose SANDO syndrome?
Doctors typically combine a neurologic examination with EMG and nerve conduction studies, brain MRI, and POLG genetic testing. SANDO often shows damage to the sensory nerves while motor nerves are relatively preserved; MRI may show changes in the thalamus or cerebellum, but a normal MRI does not rule it out. Muscle biopsy is used less often and may show multiple mitochondrial DNA deletions.
What does a POLG mutation mean for a SANDO diagnosis?
A pathogenic POLG variant is a disease-causing change in the gene linked to SANDO. Classic SANDO is usually autosomal recessive, so a person generally has two altered copies, one inherited from each parent; other POLG disorders can follow a dominant pattern. A genetic counselor can explain whether a result is pathogenic or a variant of uncertain significance.
Can a normal brain MRI rule out SANDO?
No. Some people with SANDO have MRI changes in both sides of the thalamus or cerebellum, but the scan can be normal. Doctors use MRI together with symptoms, nerve studies, and genetic results rather than using it alone.
How is SANDO different from CIDP and CANVAS?
CIDP is an autoimmune nerve disorder that usually shows demyelination on nerve studies and may improve with immune-modulating treatment. CANVAS is often linked to an RFC1 gene expansion and may include chronic cough and inner-ear balance failure. SANDO is associated with POLG variants and typically shows sensory axonal nerve damage.
What other conditions can look like SANDO?
Friedreich ataxia and Miller Fisher syndrome can resemble SANDO because they may cause poor coordination, speech changes, or eye weakness. Friedreich ataxia is linked to the FXN gene and usually begins younger, while Miller Fisher syndrome is a sudden autoimmune illness often following an infection. The time course, examination, nerve studies, and genetic testing help doctors separate these conditions.
What should I ask about POLG testing and my family's risk?
Ask whether testing included full POLG sequencing, whether each variant is considered disease-causing, and whether an RFC1 expansion test is appropriate. A certified genetic counselor can discuss uncertain results, testing for relatives, reproductive options, and what the findings may mean for your family. Do not stop treatment for a suspected look-alike such as CIDP without your neurologist's guidance.

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References

References (16)
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    Protein molecular modeling shows residue T599 is critical to wild-type function of POLG and description of a novel variant associated with the SANDO phenotype.

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    MRI findings in SANDO variety of the ataxia-neuropathy spectrum with a novel mutation in POLG (c.3287G>T): A case report.

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This page is for informational purposes only and does not constitute medical advice. A neurologist and genetic counselor should interpret your POLG results and guide testing or treatment decisions.

Guide contents Sensory ataxic neuropathy-dysarthria-ophthalmoparesis syndrome
Research & Literature
02 Symptoms and Emergency Warning Signs 04 Day-to-Day Management and Your Care Team