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Articles by P Coutinho
Total Records ( 2 ) for P Coutinho
  C Goizet , A Boukhris , A Durr , C Beetz , J Truchetto , C Tesson , M Tsaousidou , S Forlani , L Guyant Marechal , B Fontaine , J Guimaraes , B Isidor , O Chazouilleres , D Wendum , D Grid , F Chevy , P. F Chinnery , P Coutinho , J. P Azulay , I Feki , F Mochel , C Wolf , C Mhiri , A Crosby , A Brice and G. Stevanin
 

Thirty-four different loci for hereditary spastic paraplegias have been mapped, and 16 responsible genes have been identified. Autosomal recessive forms of spastic paraplegias usually have clinically complex phenotypes but the SPG5, SPG24 and SPG28 loci are considered to be associated with ‘pure’ forms of the disease. Very recently, five mutations in the CYP7B1 gene, encoding a cytochrome P450 oxysterol 7- hydroxylase and expressed in brain and liver, have been found in SPG5 families. We analysed the coding region and exon–intron boundaries of the CYP7B1 gene by direct sequencing in a series of 82 unrelated autosomal recessive hereditary spastic paraplegia index patients, manifesting either a pure (n = 52) or a complex form (n = 30) of the disease, and in 90 unrelated index patients with sporadic pure hereditary spastic paraplegia. We identified eight, including six novel, mutations in CYP7B1 segregating in nine families. Three of these mutations were nonsense (p.R63X, p.R112X, p.Y275X) and five were missense mutations (p.T297A, p.R417H, p.R417C, p.F470I, p.R486C), the last four clustering in exon 6 at the C-terminal end of the protein. Residue R417 appeared as a mutational hot-spot. The mean age at onset in 16 patients was 16.4 ± 12.1 years (range 4–47 years). After a mean disease duration of 28.3 ± 13.4 years (10–58), spasticity and functional handicap were moderate to severe in all cases. Interestingly, hereditary spastic paraplegia was pure in seven SPG5 families but complex in two. In addition, white matter hyperintensities were observed on brain magnetic resonance imaging in three patients issued from two of the seven pure families. Lastly, the index case of one family had a chronic autoimmune hepatitis while his eldest brother died from cirrhosis and liver failure. Whether this association is fortuitous remains unsolved, however. The frequency of CYP7B1 mutations were 7.3% (n = 6/82) in our series of autosomal recessive hereditary spastic paraplegia families and 3.3% (n = 3/90) in our series of sporadic pure spastic paraplegia. The recent identification of CYP7B1 as the gene responsible for SPG5 highlights a novel molecular mechanism involved in hereditary spastic paraplegia determinism.

  M Anheim , B Monga , M Fleury , P Charles , C Barbot , M Salih , J. P Delaunoy , M Fritsch , L Arning , M Synofzik , L Schols , J Sequeiros , C Goizet , C Marelli , I Le Ber , J Koht , J Gazulla , J De Bleecker , M Mukhtar , N Drouot , L Ali Pacha , T Benhassine , M Chbicheb , A M'Zahem , A Hamri , B Chabrol , J Pouget , R Murphy , M Watanabe , P Coutinho , M Tazir , A Durr , A Brice , C Tranchant and M. Koenig
 

Ataxia with oculomotor apraxia type 2 (AOA2) is an autosomal recessive disease due to mutations in the senataxin gene, causing progressive cerebellar ataxia with peripheral neuropathy, cerebellar atrophy, occasional oculomotor apraxia and elevated alpha-feto-protein (AFP) serum level. We compiled a series of 67 previously reported and 58 novel ataxic patients who underwent senataxin gene sequencing because of suspected AOA2. An AOA2 diagnosis was established for 90 patients, originating from 15 countries worldwide, and 25 new senataxin gene mutations were found. In patients with AOA2, median AFP serum level was 31.0 µg/l at diagnosis, which was higher than the median AFP level of AOA2 negative patients: 13.8 µg/l, P = 0.0004; itself higher than the normal level (3.4 µg/l, range from 0.5 to 17.2 µg/l) because elevated AFP was one of the possible selection criteria. Polyneuropathy was found in 97.5% of AOA2 patients, cerebellar atrophy in 96%, occasional oculomotor apraxia in 51%, pyramidal signs in 20.5%, head tremor in 14%, dystonia in 13.5%, strabismus in 12.3% and chorea in 9.5%. No patient was lacking both peripheral neuropathy and cerebellar atrophy. The age at onset and presence of occasional oculomotor apraxia were negatively correlated to the progression rate of the disease (P = 0.03 and P = 0.009, respectively), whereas strabismus was positively correlated to the progression rate (P = 0.03). An increased AFP level as well as cerebellar atrophy seem to be stable in the course of the disease and to occur mostly at or before the onset of the disease. One of the two patients with a normal AFP level at diagnosis had high AFP levels 4 years later, while the other had borderline levels. The probability of missing AOA2 diagnosis, in case of sequencing senataxin gene only in non-Friedreich ataxia non-ataxia-telangiectasia ataxic patients with AFP level ≥7 µg/l, is 0.23% and the probability for a non-Friedreich ataxia non-ataxia-telangiectasia ataxic patient to be affected with AOA2 with AFP levels ≥7 µg/l is 46%. Therefore, selection of patients with an AFP level above 7 µg/l for senataxin gene sequencing is a good strategy for AOA2 diagnosis. Pyramidal signs and dystonia were more frequent and disease was less severe with missense mutations in the helicase domain of senataxin gene than with missense mutations out of helicase domain and deletion and nonsense mutations (P = 0.001, P = 0.008 and P = 0.01, respectively). The lack of pyramidal signs in most patients may be explained by masking due to severe motor neuropathy.

 
 
 
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