Skew deviation and ocular tilt reaction as presenting feature of CACNA1A mutation.

We report the case of a 9-year-old girl with aggravation of childhood left head tilt without diplopia. She had right hypertropia and right incyclotorsion, which was compatible with skew deviation and ocular tilt reaction (OTR). She had ataxia, epilepsy, and cerebellar atrophy. Her OTR and neurologic dysfunctions were secondary to a channelopathy caused by CACNA1A mutation.

Sensory ataxic neuropathy with dysarthria and ophthalmoparesis (SANDO) in late life due to compound heterozygous POLG mutations.

Missense mutations in the gene for polymerase gamma 1 (POLG1) cause a number of phenotypically heterogeneous mitochondrial diseases, most commonly progressive external ophthalmoplegia, and are characterized by the accumulation of multiple, large-scale deletions of mitochondrial DNA. The triad of sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (SANDO) has been demonstrated in a small subset of patients with POLG1 mutations. We report a sporadic case of an 80-year-old compound heterozygote man who presented with SANDO and was found to have three known pathogenic mutations in the POLG1 gene (p.T251I/p.P587L/p.G848S). To our knowledge, none of these mutations have been demonstrated previously in SANDO. This patient's late presentation illustrates that a mitochondrial disorder should be considered regardless of age if the clinical symptoms warrant.

Familial cold-induced transient diplopia.

BACKGROUND: The major precipitants of intermittent diplopia secondary to a phoria breakdown include fatigue and illness. PURPOSE: To describe cold-induced vertical diplopia in a mother and daughter. METHODS: Retrospective report. RESULTS: Mother and daughter both developed vertical diplopia after exposure to cold ambient temperatures. These symptoms remained stable over many years. Ocular motility examination suggested that the diplopia resulted from breakdown of a small vertical phoria. CONCLUSIONS: Familial cold-induced vertical diplopia is a rare disorder of unclear etiology that need not be associated with underlying systemic disease.

Clinical characterisation and molecular analysis of Wagner syndrome.

AIM: To detail the clinical findings in a British family with molecularly characterised Wagner syndrome. BACKGROUND: Only in the last year has the specific genetic defect in Wagner syndrome been identified, and the background literature of the molecular genetics is outlined. Clinical and laboratory findings in a second case of Wagner syndrome are included to highlight difficulties that can be encountered when identifying pathogenic mutations for disorders arising in complex genes. METHODS: Mutation screening was performed using PCR and RT-PCR. RESULTS: A heterozygous mutation was found converting the donor splice site of exon 8 of the chondroitin sulphate proteoglycan 2 (CSPG2). This is the same mutation that has been reported in the original Wagner pedigree. The main clinical features of Wagner syndrome are vitreous syneresis, thickening and incomplete separation of the posterior hyaloid membrane, chorioretinal changes accompanied by subnormal electroretinographic responses, an ectopic fovea and early-onset cataract. A clinical feature present in this family, but previously undescribed, is anterior uveitis without formation of synechiae. Wagner syndrome has a progressive course, resulting in loss of vision even in the absence of retinal detachment. CONCLUSION: On a background of considerable confusion regarding the distinction between Wagner syndrome and predominantly ocular Stickler syndrome, it is now apparent the that two conditions are both clinically and genetically distinct. This report summarises the clinical findings in Wagner syndrome and extends the phenotypic characteristics.

[Familial mitochondrial chronic progressive external ophthalmoplegia. Five families with differing genetics]. / Familiäre mitochondriale chronisch progressive externe Ophthalmoplegie. Fünf Familien mit unterschiedlicher Genetik.

UNLABELLED: Chronic progressive external ophthalmoplegia (CPEO) is considered the most frequent form of mitochondrial encephalomyopathies. Most cases occur sporadically. We investigated 18 consecutive patients with CPEO. Thirteen cases were sporadic and five cases were familial. In one family with maternal inheritance the mitochondrial point mutation A3243G was identified. In index patients of three other families multiple deletions of mitochondrial DNA were found. One of these families showed autosomal recessive inheritance. In the two other pedigrees a definitive determination of the mode of inheritance was impossible. The fifth family revealed autosomal dominant or maternal inheritance. In their index patient no alteration of mitochondrial DNA could be identified (including sequencing of hot spots for mitochondrial mutations). CONCLUSIONS: CPEO was familial in 28% of our patients. There are three different modes of inheritance: (i) maternal transmission associated with mitochondrial point mutations as it is known for other mitochondrial disorders, (ii) autosomal recessive, and (iii) autosomal dominant inheritance. In contrast to sporadic cases with single mitochondrial deletions autosomal inheritance can be associated with multiple deletions of mitochondrial DNA. They are due to so far unknown nuclear mutations.

Familial intermittent diplopia: a report of two cases.

The presence of sufficient muscle balance and bifovial fixation to prevent a break in fusion resulting in diplopia, even under conditions of hypoxia, fatigue, stress, and peripheral gaze, has been of concern in aviation medicine since 1917. Considerable resources are still expended obtaining, reporting, and storing test results, using procedures that undoubtedly exceed the skills of many examiners, when denials are rare, few inflight breaks in fusion have ever been reported, and most known cases of diplopia are from the history. We have recently examined a 54-yr-old employee with a 5-yr history of several daily episodes of incapacitating diplopia, and we have information about his 48-yr-old brother who has a similar history. When asymptomatic, both have normal vision test results. Detection was from the histories; the diagnosis remains uncertain. The ease of concealment, rare test value, and prevalent examiner skills are of concern. The importance of the history is reaffirmed.

Azorean disease of the nervous system.

We studied a family of Portuguese ancestry from the Azores who suffered a progressive neurologic disease characterized by gait ataxia, features similar to Parkinson's disease in some patients, limitation of eye movements, widespread fasciculations of muscles, loss of reflexes in the lower limbs, followed by nystagmus, mild cerebellar tremor and extensor plantar responses. Two post-mortem examinations revealed loss of neurons and gliosis in the substantia nigra, nuclei pontis (and in the putamen in one case) as well as in the nuclei of the vestibular and other cranial nerves, columns of Clarke and anterior horns, in the spinal cord there were also loss of fibers in the fasciculi gracilis and mild changes in the pyramidal tracts. Comparison of the disease in this family with the findings reported in three families of similar ancestry, previously thought to have different disorders, suggests that they may all represent a single genetic entity with variable expression.