2009 Vienna - European Society of Human Genetics

Molecular basis of Mendelian disorders
Groupe Hospitalier Necker, Service de Génétique Médicale, Paris, France,
20 CHU de Rennes, Département de Médecine de l’Enfant et de l’Adolescent,
Rennes, France, 21 CHRU de Montpellier, Montpellier, Montpellier, France, 22 Université
Montpellier1 et Montpellier2, Institut des Neurosciences, Montpellier,
France, 23 CNRS, UMR6214, INSERM, U771, Angers, France.
We report the results of molecular screening in 980 patients carried out
as part of their work-up for suspected hereditary optic neuropathies.
Among these patients, 588 (60%) had a family history of hereditary
optic atrophy whereas the remaining 392 (40%) patients had no obvious
family history of the disease. All the patients were investigated for
Leber’s hereditary optic neuropathy (LHON) and autosomal dominant
optic atrophy (ADOA), by searching for the ten primary LHON-causing
mtDNA mutations and examining the entire coding sequences of the
OPA1 and OPA3 genes, the two genes currently identified in ADOA.
Molecular defects were identified in 440 patients (45% of screened
patients). Among these, 295 patients (67%) had an OPA1 mutation,
131 patients (30%) had an mtDNA mutation, and 14 patients (3%),
belonging to three unrelated families, had an OPA3 mutation. Interestingly,
OPA1 mutations were found in 157 (40%) of the 392 apparently
sporadic cases of optic atrophy. The eOPA1 locus-specific database
now contains a total of 204 OPA1 mutations, including 77 novel OPA1
mutations reported here. The statistical analysis of this large set of
mutations has led us to propose a diagnostic strategy that should help
with the molecular work-up of optic neuropathies. Our results highlight
the importance of investigating LHON-causing mtDNA mutations as
well as OPA1 and OPA3 mutations in cases of suspected hereditary
optic neuropathy, even in absence of a family history of the disease.
P12.083
synergistic effect of spastin gene mutations in a Hungarian
patient with hereditary spastic paraplegia (HsP)
A. Gal1 , K. Mede2 , V. Remenyi1 , S. Wiess3 , U. Goelnitz3 , M. J. Molnar1 ;
1Clinical and Research Centre for Molecular Neurology, Budapest, Hungary,
2 3 Vasary Kolos Hospital, Esztergom, Hungary, Centogene GmbH, Institute of
Molecular Diagnostics, Rostock, Germany.
Hereditary spastic paraplegia (HSP) is a group of genetically heterogeneous
disorders characterized by progressive spasticity of the lower
limbs. Mutations in the SPG4 gene, which encodes spastin protein, are
responsible for up to 45% of autosomal dominant cases.
Here we present a Hungarian family, in which the 31 year old proband
has pronounced progressive spastic paraparesis, increased deep tendon
reflexes and pyramidal sings in the lower limbs. She suffers from
urinary incontinence. The proband was born with club feet. Her 58 year
old mother’s symptoms started at age 48 with mild walking problems.
She has mild spastic paraparesis, increased deep tendon reflexes and
pyramidal signs in the lower limbs. DNA analysis by direct sequencing
of all exons in SPG1, SPA2, SPG3a and SPG4 genes revealed the
following: the proband is compound heterozygous for the sequence
variants C131T (S44L) and C1684T (R562Term) in the spastin (SPG4)
gene. In her mother only the C1684T (R562Term) mutation was detected.
The C1684T substitution has been previously described as a
pathogenic mutation. Although the S44L amino acid change has been
described in the literature as a pathogenic mutation more current data
suggest this change is a harmless polymorphism (rs28939368) if it occurs
alone. In the presence of a disease causing mutation it may act as
a modifier, leading to an earlier age of onset.
We can conclude that in the proband the coexistence of S44L and
R562Term resulted in the severity clinical symptoms and early age of
onset.
P12.084
Frequency of sPG42 in Autosomal-Dominant spastic Paraplegia
(AD-HsP)
N. Schlipf 1 , R. Schüle 2,3 , C. Beetz 4 , A. K. Erichsen 5 , S. Forlani 6,7 , S. Otto 8 , S.
Klebe 9 , S. Klimpe 10 , K. Karle 11 , C. Tallaksen 5 , G. Stevanin 6,7 , A. Brice 6,7 , O.
Rieß 1 , L. Schöls 2,11 , P. Bauer 1 ;
1 Department of Medical Genetics, Institute of Human Genetics, Tübingen, Germany,
2 Department of Neurology, University of Tübingen, Tübingen, Germany,
3 Research Division for Clinical Neurogenetics, Department of Neurodegenerative
Disease, Hertie-Institute for Clinical Brain Research, Tübingen, Germany,
4 Institute for Clinical Chemistry and Laboratory Diagnostics, University Hospital
Jena, Jena, Germany, 5 Ullevål University Hospital, Oslo, Norway, 6 INSERM,
U679, Paris, France, 7 Université Pierre et Marie Curie - Paris 6, URM S679,
Paris, France, 8 Department of Neurology, Ruhr-University Bochum, Bochum,
Germany, 9 Department of Neurology, University of Schleswig Holstein, Kiel,
Germany, 10 Department of Neurology, University of Mainz, Mainz, Germany,
11 Research Division for Clinical Neurogenetics, Department of Neurodegenerative
Disease, Hertie-Institute for Clinical Brain Research, Tübingen, Germany.
Background: Hereditary spastic paraplegia (HSP) represents a neurodegenerative
disorder resulting in progressive spasticity of the
lower limbs. The most frequent causes of autosomal dominant HSP
(AD-HSP) are mutations in the SPAST-gene (SPG4 locus). However,
roughly 60% of the patients remain SPG4 mutation-negative despite a
family history compatible with autosomal dominant inheritance. Mutations
in the gene for acetyl-CoA transporter (SLC33A1) have recently
been reported to cause autosomal dominant hereditary spastic paraplegia
(HSP) type SPG42.
Objective: We wanted to determine the relative frequency of SPG42/
SLC33A1 mutations in index patients of AD-HSP families for whom
SPG4 mutations had been excluded.
Methods: We screened a large cohort of 263 SPG4 mutation-negative
patients for variations in SPG42/SLC33A1 by high resolution melting
(HRM) combined with direct sequencing.
Results: Currently, aberrant melting curves were identified in 32 cases
(12%). Subject to future investigation will be, for each resulting aberrant
HRM curve the direct sequencing of the corresponding sample
due to assess a variation. Further a multiplex ligation dependent probe
amplification assay (MLPA) targeting SPG42 will investigate copy
number variations.
P12.085
Only rarely is thin corpus callosum (tcc) present in sPG11
- clinical heterogeneity and genetic data in a large international
cohort
A. Rolfs 1 , U. Goelnitz 2 , S. Weiss 2 , D. Friday 2 , P. Bauer 3 , K. Boycott 4 , J. Girouard
5 , P. Huan-Kee 6 , B. Lindvall 7 , I. Navarro Vera 8 , A. Summers 9 , L. Velsher 9 ,
M. Wittstock 10 ;
1 Albrecht-Kossel Institute for Neuroregeneration, Rostock, Germany, 2 Centogene
GmbH, Rostock, Germany, 3 Department of Human Genetics, University
of Tübingen, Tübingen, Germany, 4 Children´s Hospital of Eastern Ontario, Dept
of Genetics, Ottawa, ON, Canada, 5 CHA, Hopital Enfant-Jesus, Quebec, QC,
Canada, 6 Singapore Baby & Child Clinic, Mount Elizabeth Medical Centre,
Singapore, Singapore, 7 Muscle centre, Dept of Neurology, Örebro, Sweden,
8 Centro de Analisis Geneticos, c/Santa Teresa 45, Zaragoza, Spain, 9 North
York General Hospital, Toronto, ON, Canada, 10 Dept of Neurology, University of
Rostock, Rostock, Germany.
Spatacsin mutations cause an autosomal - recessive (AR) form of
spastic paraplegia, SPG type 11 (SPG11). Typically SPG11 is been
diagnosed in cases with slight ataxia, thin corpus callosum (TCC),
mental impairment, pyramidal signs, increased deep tendon reflexes
and only rarely neuropathy. In a cohort of 251 patients with AR-HSP we
analysed SPG11 gene by sequencing the gene including the exon-intron
boundaries and deletion screening by MLPA. We have been able
to detect 88 mutated alleles in 44 patients from 37 non-related families.
Patients are from Canada (N=11), Arabian countries (N=4), Scandinavia
(N=3), East-Europe (N=9), Latin-America (N=2), 8 from Singapore,
UK, Denmark, Spain, Germany, Austria and Croatia, resp. We found
64 different mutations (37 are not described): splice mutations 22/88
(25%), small deletions/insertions 38/88 (43%), large deletions (exon
11, 24, 27, 29, 31, 32, 34) 10/88 (11%), missense/nonsense mutations18/88
(20%). For 38 patients we got clinical data including MRI
results (35 cases). Age at onset ranged from 8 to 38 years with a mean
of 22.0+/-9.6. Onset was characterized by gait disorders (21/38, 55%),
polyneuropathy (7/38, 18%), dementia, dystonia, tremor and dysarthria
(each in three patients). Interestingly only in 15/35 (42%) a TCC has
been demonstrable. This low frequency of TCC is in contrast to other
reports and raises the question of the specificity of TCC for SPG11.
Mutations within the exons 24 - 34 are correlated with a more severe
phenotype. Our data demonstrate a great phenotypic variability and a
high percentage of large deletions within the SPG11 gene