Genotype-phenotype and OCT correlations in Autosomal Dominant Optic Atrophy related to OPA1 gene mutations: Report of 13 Italian families.

Mutations in OPA1 are responsible of 32-89% cases of Autosomal Dominant Optic Atrophy (ADOA). OPA1 ADOA usually presents in childhood with bilateral, progressive visual loss due to retinal ganglion cells neurodegeneration, but environmental factors are supposed to influence onset and phenotype. Sixty Italian OPA1 mutations carriers (fifty-two symptomatic), belonging to thirteen families, underwent neuro-ophthalmologic evaluation. Visual acuity (n=60) and Optical Coherence Tomography (OCT) (n=12) were compared in missense mutations (OPA-M) versus haploinsufficiency-inducing mutations (OPA-H) and correlated with age. Presence of plus phenotypes was investigated. We found four known mutations, the most common being missense c.1034G>A, and a new missense mutation, c1193A>C, the latter in a 54-yrs old female with late-onset phenotype. Visual acuity, colour sensitivity, and optic disc atrophy were sensitive indicators of disease. OCT RNFL thickness was reduced in OPA1 compared to controls. OPA-M showed worst visual acuity than OPA-H, but not more frequent plus-phenotype, observed only in four OPA-H patients. In both groups, visual acuity worsened with age. Our data confirm worst vision in OPA-M, but not increased plus-phenotype. Since most patients belonged to nine families from south-eastern Sicily (a famous region for the cult of St. Lucy, patron of the blinds) local genetic and environmental factors might have accounted for the low occurrence of plus-phenotypes.

Polyneuropathy in cerebrotendinous xanthomatosis and response to treatment with chenodeoxycholic acid.

Polyneuropathy has been reported in cerebrotendinous xanthomatosis (CTX), although its nature and possible association with certain genotypes and phenotypes are unclear. The effect of chronic administration of chenodeoxycholic acid (CDCA) on peripheral nerve conduction parameters is still debated. We report clinical, laboratory, and electrophysiological findings in 35 CTX patients. Twenty-six subjects (74.2 %) showed peripheral nerve abnormalities. Polyneuropathy was predominantly axonal (76.9 % of patients) and generally mild. No correlation was found between its presence and clinical or biochemical data. In polyneuropathic patients, CDCA treatment improved electrophysiological conduction parameters, irrespective of the duration of therapy. Improvement mainly concerned nerve conduction velocities, whereas most nerve amplitudes remained unchanged. This means that CDCA treatment did not influence the number of axons activated by maximum electrical stimulation but increased the conduction of the still-excitable fibers. Our findings may suggest that CDCA treatment promotes myelin synthesis in nerve fibers with residual unaffected axons. The effect of therapy may therefore depend largely on the extent of irreversible structural damage to axons.

High frequency of OPA1 mutations causing high ADOA prevalence in south-eastern Sicily, Italy.

Optic atrophy type 1 (OPA1) gene mutation causes autosomal dominant optic atrophy (ADOA, MIM #165500). Prevalence of ADOA ranges from 1:50,000 in most populations to 1:12,000 in Denmark. Seventy members of nine families were analysed for the presence of OPA1 gene mutations by polymerase chain reaction (PCR) and direct sequencing. We identified three OPA1 gene mutations in 48 patients with variable signs of optic atrophy. Two mutations, c.784-21_784-22insAluYb8 and c.876_878delTGT, were found in two different families. The third mutation, c.869G>A, was found in 28 patients from seven families. The haplotype analysis data suggested that the c.869G>A mutation is a founder mutation. Our main result suggests a higher ADOA prevalence in south-eastern Sicily than previously found in Denmark. This is because of not only the founder effect but also to the presence of three different mutations in the geographical area of the study. Our hypothesis is that a combination of social pressure because of blindness and migration factors is involved. In fact, in Siracusa, a provincial capital in south-eastern Sicily, St. Lucy, the patron saint of the blind was born and died.

Clinical relevance and neurophysiological correlates of spasticity in cerebrotendinous xanthomatosis.

Cerebrotendinous xanthomatosis (CTX) is a rare neurometabolic disease due to defective activity of sterol 27-hydroxylase, with plasma and tissue cholestanol storage. Clinical phenotype is characterized by both systemic manifestations and neurological signs. Therapy with chenodeoxycholic acid (CDCA) suppresses abnormal bile acid synthesis. The purpose of the study was to assess the frequency and clinical relevance of spasticity in the CTX phenotype and to study the usefulness of transcranial magnetic stimulation (TMS) in detecting corticospinal tract damage and monitoring the effects of replacement therapy. Twenty-four CTX patients underwent clinical evaluation including general disability scores, pyramidal and cerebellar function scales, assessment of serum cholestanol and TMS. Nine patients who started CDCA therapy at baseline received clinical and neurophysiological follow up. All patients showed signs of pyramidal damage which were relevant for clinical disability in 18 out of 24 cases (75%), resulting in spastic paraparesis. TMS revealed corticospinal alterations even in subjects with mild clinical signs of corticospinal tract involvement. After CDCA treatment, serum cholestanol decreased to normal concentrations in all patients. Clinical picture was unchanged in seven out of nine cases; in two others pyramidal signs disappeared. A reduction in abnormal neurophysiological parameters was found. Spastic paraparesis is the most frequent and relevant neurological feature in CTX patients. Replacement treatment with CDCA can prevent the progression of pyramidal damage, especially if started early in the course of the disease. TMS represents a sensitive indicator of corticospinal tract dysfunction and subclinical improvements in pyramidal function after CDCA therapy.

Four novel CYP27A1 mutations in seven Italian patients with CTX.

BACKGROUND AND PURPOSE: Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disease, because of sterol 27-hydroxylase deficiency. Clinical manifestations of CTX are tendon xanthomas, juvenile cataracts, osteoporosis, diarrhoea and multiple progressive neurological dysfunctions. More than 300 patients with CTX have been reported to date worldwide and about fifty different mutations identified in CYP27A1 gene. This study describes the clinical and laboratory findings of seven new patients. METHODS: We report the molecular and clinical characterization of seven new Italian patients with CTX carrying four novel mutations. RESULTS: We identified four novel mutations located in different exons, in particular in the region of exons 2-5 of the CYP27A1 gene. Phenotypical expression did not differ from classical CTX presentation except for absence of tendon xanthomas in two patients.

Chronic progressive external ophthalmoplegia: a new heteroplasmic tRNA(Leu(CUN)) mutation of mitochondrial DNA.

We sequenced all genes of mitochondrial tRNAs of a patient with chronic progressive external ophthalmoplegia with 5% ragged red fibres and 15% COX-negative fibres but without macrorearrangements of mitochondrial DNA (mtDNA). Direct sequencing showed a novel heteroplasmic G>A substitution in position 12316 of tRNA(Leu(CUN)) gene. This change destroys a highly conserved G-C base coupling in tRNA TpsiC branch. By RFLP analysis we could demonstrate different degrees of heteroplasmy in different patient's tissues. This alteration, absent in a population of 110 patients with different encephalomyopathies, can be considered pathogenic: it is the tenth tRNA(Leu(CUN)) pathogenic mutation described up to date.

Clinical and molecular diagnosis of cerebrotendinous xanthomatosis with a review of the mutations in the CYP27A1 gene.

Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disease due to defective activity of the mitochondrial enzyme sterol 27-hydroxylase. In 1991, sterol 27-hydroxylase gene (CYP27A1) was localised on the long arm of chromosome 2 [1]. Clinical characteristics of CTX are diarrhoea, cataracts, tendon xanthomas and neurological manifestations including dementia, psychiatric disturbances, pyramidal and/or cerebellar signs, and seizures. More than 300 patients with CTX have been reported to date worldwide and about 50 different mutations identified in the CYP27A1 gene. Almost all mutations lead to the absence or inactive form of the sterol 27-hydroxylase. In this review, according with the aims of this section of the journal, we describe the different pathogenetic mutations in the CYP27A1 gene and the main clinical and pathogenetic aspects that may help clinical neurologists in the diagnosis of CTX.