Gian Nicola Gallus

Mitochondria, oxidative stress and neurodegeneration

Mitochondria are involved in ATP supply to cells through oxidative phosphorylation (OXPHOS), synthesis of key molecules and response to oxidative stress, as well as in apoptosis. They contain many redox enzymes and naturally occurring inefficiencies of oxidative phosphorylation generate reactive oxygen species (ROS). CNS functions depend heavily on efficient mitochondrial function, since brain tissue has a high energy demand. Mutations in mitochondrial DNA (mtDNA), generation and presence of ROS and environmental factors may contribute to energy failure and lead to neurodegenerative diseases. Many rare metabolic disorders have been associated with mitochondrial dysfunction. More than 300 pathogenic mtDNA mutations involve proteins that regulate OXPHOS and mitochondrial structural integrity, and have also been described in neurodegenerative diseases with autosomal inheritance. Mitochondria may have an important role in ageing-related neurodegenerative disorders like Parkinsons disease (PD), Alzheimers disease (AD), Huntingtons disease (HD) and amyotrophic lateral sclerosis (ALS). In primary mitochondrial and neurodegenerative disorders, there is strong evidence that mitochondrial dysfunction occurs early and has a primary role in pathogenesis. In the present review, we discuss several mitochondrial diseases as models of neurodegeneration.

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.

Two novel HTRA1 mutations in a European CARASIL patient

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a hereditary, nonhypertensive cause of recurrent lacunar stroke and cognitive decline associated with alopecia, spondylosis deformans, and lumbago.1 The disease has been linked to mutations in the HTRA1 gene, encoding for serine protease HTRA1, loss of which causes dysregulation of transforming growth factor-β signaling.2

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.

Spastic paraplegia in ‘dominant optic atrophy plus’ phenotype due to OPA1 mutation

Sir, We read the papers by Yu-Wai-Man et al. (2010) and Marelli et al. (2011) with much interest. The authors described three families with dominant optic atrophy plus phenotype due to OPA1 mutations presenting spastic paraplegia among the extra-ocular neurological features. Two families, reported by Yu-Wai-Man et al . (2010), harboured a deletion c.876-878del(TGT) and a nonsense GTPase mutation c.899C>T, respectively, both resulting in premature termination codons. The affected members presented neuropathy in addition to spastic paraplegia and dominant optic atrophy. Marelli et al. (2011) described a third family in which a missense mutation c.1652G>A in the dynamin domain was associated with Behr syndrome. We report here, a patient in whom a deletion c.2708_2711delTTAG of OPA1 was associated with dominant optic atrophy, spastic paraplegia, Duane retraction syndrome, migraine with atypical aura, patent foramen ovale and muscle fibre abnormalities. Considering the previous reports, we extend the mutations of OPA1 as possibly responsible for dominant optic atrophy plus phenotypes presenting spastic paraplegia, and identify some features shared by patients with optic atrophy plus and spastic pyramidal involvement. The proband, a 28-year-old Italian female belonging to a family from Sicily, has suffered from loss of central vision due to optic atrophy since childhood. She was referred to our unit for the onset, appeared a few years earlier, of slowly progressive …

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.

A novel heteroplasmic tRNASer(UCN) mtDNA point mutation associated with progressive external ophthalmoplegia and hearing loss

Abstract We sequenced all mitochondrial tRNA genes from a patient with sporadic external ophthalmoplegia (PEO) and 5% COX-negative fibers in muscle biopsy, who had no detectable large mtDNA deletions. Direct sequencing showed a heteroplasmic mutation at nucleotide 7506 in the dihydrouridine stem of the tRNA Ser(UCN) gene. RFLP analysis confirmed that 30% of muscle and 20% of urinary epithelium mtDNA harbored the mutation, which was absent in other tissues of the proband as well as in mtDNA of his mother and 100 patients with various encephalomyopathies. Several point mutations on mitochondrial tRNA genes have been reported in PEO patients without large-scale rearrangements of mtDNA but no point mutations have hitherto been found in the gene coding for tRNA Ser(UCN) .

A second MNGIE patient without typical mitochondrial skeletal muscle involvement

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disease caused by mutations in the gene encoding thymidine phosphorylase (TYMP). Clinically, MNGIE is characterized by gastrointestinal dysmotility, cachexia, ptosis, ophthalmoparesis, peripheral neuropathy and leukoencephalopathy. Most MNGIE patients have signs of mitochondrial dysfunction in skeletal muscle at morphological and enzyme level, as well as mitochondrial DNA depletion, multiple deletions and point mutations. A case without mitochondrial skeletal muscle involvement and with a TYMP splice-acceptor site mutation (c. 215–1 G>C) has been reported. Here, we describe an Italian patient with the same mutation and without mitochondrial skeletal muscle involvement, suggesting a possible genotype–phenotype correlation.

Chronic progressive external ophthalmoplegia: A new heteroplasmic tRNALeu(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 patients 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.

The first cerebrotendinous xanthomatosis family from Argentina: a new mutation in CYP27A1 gene.

Cerebrotendinous xanthomatosis (CTX) is a treatable, autosomal recessive, lipid storage disorder characterized by diarrhea and cataracts, usually appearing in the first decade of life, followed by growth of tendon xanthomas and progressive neurologic disability.1 The typical brain findings include MRI signal abnormalities mainly in the globus pallidus and dentate nuclei.2 The disease is caused by deficiency of the mitochondrial enzyme, sterol 27-hydroxylase, resulting in impaired primary bile acid synthesis, decreased chenodeoxycholic acid production, and cholestanol accumulation in virtually every tissue.3 The main blood chemistry abnormalities include high plasma levels of cholestanol with normal to low cholesterol. Different mutations of the CYP27A1 gene have been described.4 Early diagnosis is crucial as treatment with chenodeoxycholic acid (CDCA) may improve symptoms.5 Here we report the cases of two Argentinian siblings with a novel mutation of the CYP27A1 gene associated with clinical variants, including absence of tendon xanthomas. ### Case 1 (male, 17 years). The first clinical manifestation was chronic diarrhea from birth and growth retardation. Episodes of febrile seizures occurred at 1 and 3 years, followed by photosensitive epileptic syndrome. Posterior subcapsular cataracts were found at 3 years and removed at 8 years of age. Mild mental retardation, attention deficit, and hyperactivity were reported at school age. At 17 …