Sensory Neuronopathy in Patients with Recessive Polymerase γ Mutations
Abstract & Commentary
By Russell L. Chin, MD, Associate Professor of Clinical Neurology, Weill Cornell Medical College. Dr. Chin reports no financial relationships relevant to this field of study.
Synopsis: Detailed neuropathological investigation of patients with sensory neuronopathy and polymerase γ mutations revealed evidence of posterior column atrophy in spinal cord sections and marked neuronal cell loss with severe mitochondrial biochemical abnormalities (involving respiratory chain complexes I and IV) in the dorsal root ganglia.
Source: Lax NZ, et al. Sensory neuronopathy in patients harbouring recessive polymerase γ mutations. Brain 2012;135:62-71.
In this study, 12 patients with autosomal recessive poly- merase γ (POLG) mutations were studied. Eleven of the patients underwent clinical and neurophysiological assessment. Two patients expired and had extensive neuropathological studies of the spinal cord (both patients) and dorsal root ganglia (one patient). Age of disease onset was typically in the second or third decade with a few reporting onset in their early 40s. Five had documented peripheral neuronopathy at presentation with sensory ataxia. Three had features of pure sensory neuropathy (SN) with two also showing evidence of motor involvement. Clinically progressive external opthalmoplegia and ptosis were a common finding in all patients.
Electrodiagnostic studies revealed sensory or mixed sensorimotor findings. Macro-EMG in two patients showed increased fiber density and median macro motor unit potential amplitude, consistent with motor neuronopathy. Four patients also showed evidence of proximal myopathy.
Muscle biopsies, obtained in 11 patients, revealed secondary mitochondrial DNA changes with evidence of mitochondrial DNA deletions in association with focal cytochrome c oxidase (COX) deficiency. Analysis of the spinal cord revealed severe myelin loss in the posterior columns (particularly in the fasciculus gracilis), diminished complex I activity in the posterior horn neurons, and a reduction in the posterior horn interneuron population.
Dorsal root ganglion (DRG) cell density was reduced significantly and the neurons also were smaller when compared with controls. Immunohistochemistry demonstrated reduced expression of protein subunits comprising complexes I and IV of the respiratory chain. Mitchondrial DNA copy number analysis showed DRG neurons with dramatically reduced MT-ND4 and MT-ND1 copy numbers, suggesting a decrease in the number of wild-type mitochondrial and also absolute mitochondrial DNA copy number.
The investigators conclude that neuronal dysfunction and death in the dorsal root ganglia results in loss of their central axonal branches and ascending fibers in the posterior fasciculus and posterior horn neurons in the spinal cord. In this study, SN was not the sole clinical feature, and the age of onset and additional features (chronic progressive external opthalmoplegia, ptosis, dysarthria and epilepsy) were clues to a mitochondrial process.
Commentary
The mitochondrial genome is maintained and replicated by the POLG protein. The catalytic domain of this protein is encoded by the POLG gene located on chromosome 15q25. Numerous mutations have been mapped to this gene and are associated with a broad spectrum of neurodegenerative diseases (http://tools.niehs.nih.gov/polg), including Alpers-Huttenlocher syndrome in infancy, mitochondrial encephalopathy with lactic acidosis and stroke-like episodes, and mitochondrial recessive ataxic syndrome. SN has been reported as part of the SANDO clinical triad (sensory ataxia associated with dysarthria and opthalmoparesis) and also as a presenting feature of the mitochondrial disease.1
SN (or ganglionopathy) refers to primary disease of sensory cell bodies in the dorsal root ganglia.2 These are some of the longest nerves in the body (> 2 m in tall individuals) with the nerve extending from periphery to the cell bodies (near the intervertebral foramen), entering the spinal cord (specifically the fasciculus gracilis) via the posterior roots, and ascending to its first synapse at the cranio-cervical junction.
Well-recognized causes of SN include paraneoplastic disease (e.g., anti-Hu antibodies associated small cell bronchogenic carcinoma), antimitotic treatments (e.g., cisplatin, carboplatin, oxaliplatin), HIV infection, Sjögren syndrome, vitamin B6 toxicity, anti-disialosyl antibodies (e.g., GD1b antibodies), and celiac disease. A significant percentage of SN cases remain idiopathic. A non-length dependent distribution of sensory loss (with upper limb, trunk, or facial involvement) and almost pure and severe electrophysiologic sensory involvement are characteristic of SN. Patients may have diffuse sensory loss with resulting ataxia and pseudoatheoid movements. Tendon reflexes are reduced or absent.3
The molecular mechanisms behind SN are poorly understood and pathologic data are limited given the absence of simple, non-traumatic methods of studying the DRG. Primary degeneration of sensory nerves has been demonstrated pathologically in paraneoplastic and HIV-related SN. In Sjögren's syndrome, mononuclear inflammatory cell infiltrates around individual sensory ganglion cells undergoing degeneration have been noted. GD1b antibodies are reported to bind to the surface of sensory ganglion neurons and paranodal myelin in the ventral and dorsal roots.4
The DRG findings in this study provide welcome and intriguing information that could advance our understanding of the mechanisms of SN associated with other (more common) conditions, for which treatment options are currently limited.
References
1. Fadic R, et al. Sensory ataxic neuropathy as the presenting feature of a novel mitochondrial disease. Neurology 1997;49:239-245.
2. Camdessanché JP, et al. The pattern and diagnostic criteria of sensory neuronopathy: A case-control study. Brain 2009;132:1723-1733.
3. Kuntzer T, et al. Clinical features and pathophysiological basis of sensory neuronopathies (ganglionopathies). Muscle Nerve 2004;30:255-268.
4. Griffin JW, et al. Ataxic sensory neuropathy and dorsal root ganglionitis associated with Sjögren's syndrome. Ann Neurol 1990;27:304-315.
Detailed neuropathological investigation of patients with sensory neuronopathy and polymerase γ mutations revealed evidence of posterior column atrophy in spinal cord sections and marked neuronal cell loss with severe mitochondrial biochemical abnormalities (involving respiratory chain complexes I and IV) in the dorsal root ganglia.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
- Award-winning Medical Content
- Latest Advances & Development in Medicine
- Unbiased Content