Sensory Ataxic Neuropathy, Dysarthria, And Ophthalmoparesis Research Articles

MITOCHONDRIAL DISEASES (Posters): P.188Novel POLG mutations and variable clinical phenotypes in 5 Chinese patients with mitochondrial diseases

POLG related mitochondrial disorders has rarely been reported in China. Here we report 5 unrelated Chinese patients (2 males and 3 females) with mitochondrial disease caused by POLG gene mutations. Two of them had a dominant family history and 3 were sporadic cases. The ages of onset were from 15 to 40 years old, with disease course ranging from 1 to 26 years. Clinically, 1 case were conformed with SANDO (sensory ataxic neuropathy, dysarthria and ophthalmoparesis) syndrome, 2 cases with autosomal dominant progressive external ophthalmoplegia (PEO), 1 case with autosomal recessive PEO, and 1 case with sensory axonal neuropathy and mental retardation. Laboratory examination revealed normal or mild elevation of serum creatine kinase level. Electromyography revealed myopathic or neurogenic pattern. Nerve conduction studies showed decreased amplitude of nerve action potential in 3 cases, with sensory nerve predominantly involved. Mitochondrial abnormality appeared in 4 patients who underwent muscle biopsies. Sural nerve biopsy revealed chronic axonal neuropathy in the patient with sensory axonal neuropathy and mental retardation. Genetic test revealed compound heterozygous POLG mutations in 3 sporadic patients and single heterozygous mutations in 2 dominant inherited patients. c.914G>A (p.S305N), c.924G>T (p.Q308H), c.1613A>T (p.E538V), c.1612G>T (p.E538*), c.1790 G>A (p.R597Q) and c.3002delG. were novel mutations. Novel mutations found in this study expanded the mutational spectrum of POLG.

The wide POLG-related spectrum: An integrated view

The aims of this study were to describe the spectrum of recessively inherited POLG-related disorders, to report new POLG mutations and to discuss genotype-phenotype correlations in order to propose a strategy for diagnosis. Twenty eight patients diagnosed with two POLG mutations at 12 tertiary European centers of adult neurology were studied. Exhaustive phenotypic data, brain MRI, muscle analysis, mitochondrial DNA and POLG analysis findings were collected. Five distinct phenotypes were observed: Sensory Ataxic Neuropathy, Dysarthria and Ophthalmoparesis (SANDO), autosomal recessive Progressive External Ophthalmoplegia (arPEO), Spino Cerebellar Ataxia with Epilepsy (SCAE), Mitochondrial Neuro Gastro Intestinal Encephalopathy (MNGIE)-like phenotype and Sensory Ataxic Neuropathy with Ophthalmoparesis but without dysarthria which we propose to name SANO. An increasing gradient of functional severity was appreciated from PEO with the best prognosis, to SANO, SANDO and finally SCAE respectively. Four new missense mutations were found. Regarding genotype/phenotype correlations, P587L mutation was associated with SANO rather than with SANDO (p<0.005) and W748S mutation was associated with SANDO or SCAE (with more severe disease progression), rather than with SANO or PEO (p<0.004). Distinguishing between various phenotypes can have important diagnosis and prognosis implications. POLG mutations should be priority searched for in cases of SANDO or SANO. Mitochondrial respiratory chain and mitochondrial DNA studies should be considered in the case of negative POLG analysis or other phenotypes.

Sensori-neural hearing loss in Sensory ataxic neuropathy, dysarthria and ophthalmoparesis (SANDO): A Case Report

Objective To report a case of bilateral sensorineural hearing loss in a patient with sensory ataxic neuropathy, dysarthria and ophthalmoparesis (SANDO). Method Case report and review of literature on mitochondrial disorders to facilitate understanding of the type of hearing loss. Case report We present a 37 year old lady diagnosed with SANDO, who was seen in the ENT department with a history of progressive hearing loss for 6 months. Audiogram showed bilateral trough shaped sensorineural hearing loss, dipping at 1 KHz. Earlier, this patient had presented to the neurology department with classical neurological signs of progressive sensory ataxia. Diagnosis of SANDO was confirmed by muscle biopsy and mitochondrial studies. Conclusion This is the first case report on SANDO documenting associated hearing loss in ENT literature. Further studies are required to explain the pattern of hearing loss in these patients

ATAXIA WITH OPHTHALMOPLEGIA OR SENSORY NEUROPATHY IS FREQUENTLY CAUSED BY POLG MUTATIONS

Progress in molecular genetics unraveled the genetic basis of many subtypes of hereditary ataxias. Dominantly inherited forms are most frequently caused by CAG repeat expansions in the SCA1, SCA2, SCA3, SCA6, and SCA7 genes, whereas intronic GAA repeat expansions in the FRDA gene lead to Friedreich ataxia, the most common autosomal recessive ataxia in the Western world.1 Patients with ataxia who are negative for these mutations remain a major diagnostic challenge since genetic heterogeneity of ataxias is immense and includes a large number of extremely rare disorders.2 Phenotypic characteristics indicating the responsible gene are highly warranted to guide cost-intensive and time-intensive genetic screening. Patients with sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (SANDO) have been reported to carry mutations in the gene coding for DNA polymerase gamma ( POLG ).3–5 To analyze the indicative value of the SANDO phenotype for genetic diagnostics, we screened a cohort of ataxia patients with either external ophthalmoplegia or sensory neuropathy for POLG mutations. ### Methods. Twenty-six patients from 23 nonconsanguineous families with cerebellar ataxia plus sensory neuropathy or external ophthalmoplegia were included in this study. The whole coding region including intron-exon boundaries of the POLG gene was screened by direct sequencing. Primer sequences are noted in table e-1 on the Neurology ® Web site at www.neurology.org. Sensory neuropathy was clinically diagnosed in patients with reduced vibration sense, hyporeflexia at least of lower …

Molecular analysis of ANT1, TWINKLE and POLG in patients with multiple deletions or depletion of mitochondrial DNA by a dHPLC-based assay

ANT1, TWINKLE and POLG genes affect mtDNA stability and are involved in autosomal dominant PEO, while mutations in POLG are responsible for numerous clinical presentations, including autosomal recessive PEO, sensory ataxic neuropathy, dysarthria and ophthalmoparesis (SANDO), spino-cerebellar ataxia and epilepsy (SCAE) or Alpers syndrome. In this study, we report on the mutational analysis of ANT1, TWINKLE and POLG genes in 15 unrelated patients, using a dHPLC-based protocol. This series of patients illustrates the large array of clinical presentations associated with mtDNA stability defects, ranging from isolated benign PEO to fatal Alpers syndrome. A total of seven different mutations were identified in six of 15 patients (40%). Six different recessive mutations were found in POLG, one in TWINKLE while no mutation was identified in ANT1. Among the POLG mutations, three are novel and include two missense and one frameshift changes. Seventeen neutral changes and polymorphisms were also identified, including four novel neutral polymorphisms. Overall, this study illustrates the variability of phenotypes associated with mtDNA stability defects, increases the mutational spectrum of POLG variants and provides an efficient and reliable detection protocol for ANT1, TWINKLE and POLG mutational screening.

Sensory ataxic neuropathy due to a novel C10Orf2 mutation with probable germline mosaicism

The authors describe siblings with progressive external ophthalmoplegia (PEO) due to a novel heterozygous A to G transition at nucleotide 955 of C10Orf2 (Twinkle). The mutation was not identified in parents' blood, hair follicles, buccal mucosa, or urinary epithelium, indicating germ line mosaicism. One sibling presented with sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (SANDO), a phenotype previously associated with the POLG1 gene, highlighting the clinical overlap in autosomal PEO.

SANDO: another presentation of mitochondrial disease

Purpose To describe a unique mitochondrial syndrome that may present with the combination of ocular manifestations, sensory symptoms, and speech dysfunction. Design Case report. Methods Case report and review of the literature. Results A 43-year-old man presented with a Sensory Ataxic Neuropathy, Dysarthria, and Ophthalmoparesis (SANDO). Nerve conduction studies showed a sensory ganglionopathy. Skeletal muscle biopsy revealed ragged red fibers, and polymerase chain reaction analysis of the tissue demonstrated multiple mitochondrial DNA deletions. Conclusion Mitochondrial disease should be considered in cases of external ophthalmoplegia, especially if a sensory ganglionopathy and dysarthria are present.

Recessive POLG mutations presenting with sensory and ataxic neuropathy in compound heterozygote patients with progressive external ophthalmoplegia

Autosomal recessive progressive external ophthalmoplegia is a mitochondrial disease characterized by accumulation of multiple large-scale deletions of mitochondrial DNA. We previously reported missense mutations in POLG, the gene encoding the mitochondrial DNA polymerase gamma in two nuclear families compatible with autosomal recessive progressive external ophthalmoplegia. Here, we report a novel POLG missense mutation (R627W) in a sporadic patient and we provide genetic support that all these POLG mutations are actually causal and recessive. The novel patient presented with sensory ataxic neuropathy and has the clinical triad of sensory ataxic neuropathy, dysarthria and ophthalmoparesis (SANDO). This is the first finding of a genetic cause of Sensory Ataxic Neuropathy, Dysarthria and Ophthalmoparesis and it implies that this disorder may actually be a variant of autosomal recessive progressive external ophthalmoplegia. Sensory neuropathy is the initial feature in Belgian compound heterozygote autosomal recessive progressive external ophthalmoplegia patients, all carrying the POLG A467T mutation, which occurs at a frequency of 0.6% in the Belgian population.