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M Rio,
G Royer,
S Gobin,
Mc de Blois,
C Ozilou,
A Bernheim,
M Nizon, A Munnich,
J-P Bonnefont,
S Romana,
M Vekemans,
C Turleau,
V Malan
[show abstract]
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ABSTRACT: Although discordant phenotypes in monozygotic twins with developmental disorder are not an exception, underlying genetic discordance is rarely reported. Here, we report on the clinical and cytogenetic details of 4-year-old female monozygotic twins with discordant phenotypes. Twin 1 exhibited global developmental delay, overweight and hyperactivity. Twin 2 had an autistic spectrum disorder. Molecular karyotyping in twin 1 identified a 2p25.3 deletion, further confirmed by FISH analysis on leukocytes. Interestingly, array-CGH was normal in twin 2 but FISH analysis using the same probe as twin 1 showed mosaicism with 1/3 of cells with a 2p25.3 deletion, 1/3 of cells with a 2p25.3 duplication, and 1/3 of normal cells. Genotyping with microsatellite markers confirmed the monozygosity of the twins. We propose that the chromosome imbalance may be due to a mitotic non-allelic recombination occurring during blastomeric divisions of a normal zygote. Such event will result in three distinct cell populations, whose proportion in each embryo formed after separation from the zygote may differ, leading to discordant chromosomal anomalies between twins. We also discuss that the MYTL1L and the SNTG2 genes within the reported region could probably relate to the phenotypic discordance of the monozygotic twins.
Clinical Genetics 10/2012; · 3.13 Impact Factor
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C Thauvin-Robinet,
S Thomas,
M Sinico,
B Aral,
L Burglen,
N Gigot,
H Dollfus,
S Rossignol,
M Raynaud,
C Philippe, [......],
N Elkhartoufi,
L Faivre, A Munnich,
N Boddaert,
L Van Maldergem,
F Encha-Razavi,
S Lyonnet,
M Vekemans,
E Escudier,
T Attié-Bitach
Clinical Genetics 10/2012; · 3.13 Impact Factor
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Z Assouline,
M Jambou,
M Rio,
C Bole-Feysot,
P de Lonlay,
C Barnerias,
I Desguerre,
C Bonnemains,
C Guillermet,
J Steffann, A Munnich,
J P Bonnefont,
A Rötig,
A S Lebre
[show abstract]
[hide abstract]
ABSTRACT: Isolated complex I deficiency is a frequent cause of respiratory chain defects in childhood. In this study, we report our systematic approach with blue native PAGE (BN-PAGE) to study mitochondrial respiratory chain assembly in skin fibroblasts from patients with Leigh syndrome and CI deficiency. We describe five new NDUFS4 patients with a similar and constant abnormal BN-PAGE profile and present a meta-analysis of the literature. All NDUFS4 mutations that have been tested with BN-PAGE result in a constant and similar abnormal assembly profile with a complete loss of the fully assembled complex I usually due to a truncated protein and the loss of its canonical cAMP dependent protein kinase phosphorylation consensus site. We also report the association of abnormal brain MRI images with this characteristic BN-PAGE profile as the hallmarks of NDUFS4 mutations and the first founder NDUFS4 mutations in the North-African population.
Biochimica et Biophysica Acta 02/2012; 1822(6):1062-9. · 4.66 Impact Factor
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M Barth,
V Serre,
L Hubert,
Y Chaabouni,
N Bahi-Buisson,
M Cadoudal,
D Rabier,
S Nguyen The Tich,
M Ribeiro,
D Ricquier, A Munnich,
D Bonneau,
P de Lonlay,
L Christa
[show abstract]
[hide abstract]
ABSTRACT: Background: Aromatic amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive disorder resulting in a combined dopamine and serotonin deficiency. About 50% of the cases set in the neonatal period. Here, we report an atypical clinical presentation with moderate symptoms. Patient: At 10months old, the patient presented paroxysmal eye movements without seizures, and feeding difficulties which were attributed to gastroesophageal reflux. She was investigated at the age of 7years, because of orofacial dyspraxia, hypomimie, axial hypotonia and focal segmental dystonia, bilateral ptosis, without evidence for cognitive impairment. Results: HVA [110nM; (reference value (rv): 202-596)] and HIAA (12nM; rv: 87-366) decreased, OMD (520nM; rv: 5-60) and 5-HTP (56nM; rv: 2-16) increased in CSF. We confirmed the diagnosis of AADC deficiency because the activity in plasma was low: 4pmol/min/ml; rv: 16-137. The kinetic analysis revealed a sixfold increase in the apparent affinity for L-dopa (4.26mM; control=0.71), but the V (max) was unchanged (37.5pmol dopamine/min/ml; control=39.1), suggesting a modification in the substrate binding-site. Molecular analysis revealed two heterozygous mutations in the DDC gene: c1040G > A; pR347Q already described, and a novel mutation c478C > T, pR160W. Conclusion: (1) CSF neurotransmitters metabolites suggested a moderate AADC deficiency; (2) The initial velocity saturation curve for L-dopa displayed a cooperative ligand binding behavior, in keeping with the modifications of the three-dimensional structure, induced by the amino acid substitutions (3) The treatment combination of L-dopa with pyridoxine dramatically improved the quality of life, the fatigability, and the paroxysmal eye movements.
JIMD reports. 01/2012; 3:25-32.
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Anna-Maja Molin,
J Andrieux,
D A Koolen,
V Malan,
M Carella,
L Colleaux,
V Cormier-Daire,
A David,
N de Leeuw,
B Delobel, [......],
A Receveur,
M Rio,
L Ronsbro Darling,
C Rosenberg,
J Sá,
L Vallee,
C Vincent-Delorme,
L Zelante,
M-L Bondeson,
G Annerén
[show abstract]
[hide abstract]
ABSTRACT: Congenital deletions affecting 3q11q23 have rarely been reported and only five cases have been molecularly characterised. Genotype-phenotype correlation has been hampered by the variable sizes and breakpoints of the deletions. In this study, 14 novel patients with deletions in 3q11q23 were investigated and compared with 13 previously reported patients.
Clinical data were collected from 14 novel patients that had been investigated by high resolution microarray techniques. Molecular investigation and updated clinical information of one cytogenetically previously reported patient were also included.
The molecular investigation identified deletions in the region 3q12.3q21.3 with different boundaries and variable sizes. The smallest studied deletion was 580 kb, located in 3q13.31. Genotype-phenotype comparison in 24 patients sharing this shortest region of overlapping deletion revealed several common major characteristics including significant developmental delay, muscular hypotonia, a high arched palate, and recognisable facial features including a short philtrum and protruding lips. Abnormal genitalia were found in the majority of males, several having micropenis. Finally, a postnatal growth pattern above the mean was apparent. The 580 kb deleted region includes five RefSeq genes and two of them are strong candidate genes for the developmental delay: DRD3 and ZBTB20.
A newly recognised 3q13.31 microdeletion syndrome is delineated which is of diagnostic and prognostic value. Furthermore, two genes are suggested to be responsible for the main phenotype.
Journal of Medical Genetics 12/2011; 49(2):104-9. · 6.36 Impact Factor
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Clinical Genetics 10/2011; 80(4):403-5. · 3.13 Impact Factor
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F Lamazou,
J Steffann,
N Frydman,
P Burlet,
N Gigarel,
S Romana,
J-P Bonnefont,
M Lelorch,
L Hesters,
R Fanchin,
V Kerbrat,
M Vekemans, A Munnich,
R Frydman
[show abstract]
[hide abstract]
ABSTRACT: Preimplantation genetic diagnosis (PGD) is authorized in France since 1999. After 10 years, technical results are encouraging. With the development of new technologies, our team is able to diagnosis the large majority of chromosome translocations and 75 monogenic diseases. However, PGD remains limited because of the growing augmentation of demands causing an increasing delay for the first procedure of more than 18 months. Since 2006, 19 couples asked for a PGD with HLA typing. In January 2011, 11 couples have already been included in our PGD program. The birth of the first child after PGD with HLA typing offers new perspectives of treatment for these couples.
Journal de Gynécologie Obstétrique et Biologie de la Reproduction 09/2011; 40(7):682-6. · 0.42 Impact Factor
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British Journal of Dermatology 09/2011; 166(3):678-81. · 3.67 Impact Factor
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A Boutron,
C Acquaviva,
C Vianey-Saban,
P de Lonlay,
H Ogier de Baulny,
N Guffon,
D Dobbelaere,
F Feillet,
F Labarthe,
D Lamireau,
A Cano,
T Billette de Villemeur, A Munnich,
J M Saudubray,
D Rabier,
O Rigal,
M Brivet
[show abstract]
[hide abstract]
ABSTRACT: Deficiency of mitochondrial trifunctional protein (MTP) is caused by mutations in the HADHA and HADHB genes, which have been mostly delineated at the genomic DNA level and have not been always elucidated.
To identify mutations in a French cohort of 52 MTP deficient patients and the susceptibility of mutations generating premature termination codons (PTCs) to the nonsense mRNA mediated decay (NMD).
Mutation screening in fibroblasts was performed at the cDNA level and real-time RT-PCR was used to compare the levels of the different PTC-bearing mRNAs before and after a treatment of fibroblasts by emetine, a translation inhibitor.
A mutation detection rate of 100% was achieved. A total of 22 novel mutations were identified, including a large-sized genomic deletion in HADHB gene. A high proportion of all identified mutations were non-sense, frameshift and splicing mutations, generating (PTCs), distributed essentially on HADHA coding regions. We could demonstrate that the majority of mutations resulting in PTCs conform to the established rules governing the susceptibility to NMD.
Our results emphasize the value of cDNA analysis in the characterization of HADHA and HADHB mutations and further strengthen the model of haploinsufficiency as a major pathomechanism in MTP defects.
Molecular Genetics and Metabolism 04/2011; 103(4):341-8. · 3.19 Impact Factor
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A S Lebre,
M Rio,
L Faivre d'Arcier,
D Vernerey,
P Landrieu,
A Slama,
C Jardel,
P Laforêt,
D Rodriguez,
N Dorison, [......],
B Funalot,
N Villeneuve,
V Valayannopoulos,
P de Lonlay,
I Desguerre,
F Brunelle,
J P Bonnefont,
A Rötig, A Munnich,
N Boddaert
[show abstract]
[hide abstract]
ABSTRACT: To identify a consistent pattern of brain MRI imaging in primary complex I deficiency. Complex I deficiency, a major cause of respiratory chain dysfunction, accounts for various clinical presentations, including Leigh syndrome. Human complex I comprises seven core subunits encoded by mitochondrial DNA (mtDNA) and 38 core subunits encoded by nuclear DNA (nDNA). Moreover, its assembly requires six known and many unknown assembly factors. To date, no correlation between genotypes and brain MRI phenotypes has been found in complex I deficiencies.
The brain MRIs of 30 patients carrying known mutation(s) in genes involved in complex I were retrospectively collected and compared with the brain MRIs of 11 patients carrying known mutations in genes involved in the pyruvate dehydrogenase (PDH) complex as well as 10 patients with MT-TL1 mutations.
All complex I deficient patients showed bilateral brainstem lesions (30/30) and 77% (23/30) showed anomalies of the putamen. Supratentorial stroke-like lesions were only observed in complex I deficient patients carrying mtDNA mutations (8/19) and necrotising leucoencephalopathy in patients with nDNA mutations (4/5). Conversely, the isolated stroke-like images observed in patients with MT-TL1 mutations, or the corpus callosum malformations observed in PDH deficient patients, were never observed in complex I deficient patients.
A common pattern of brain MRI imaging was identified with abnormal signal intensities in brainstem and subtentorial nuclei with lactate peak as a clue of complex I deficiency. Combining clinico-biochemical data with brain imaging may therefore help orient genetic studies in complex I deficiency.
Journal of Medical Genetics 10/2010; 48(1):16-23. · 6.36 Impact Factor
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L Galmiche,
F Jaubert,
F Sauvat,
S Sarnacki,
O Goulet,
Z Assouline,
V Vedrenne,
A-S Lebre,
N Boddaert,
N Brousse,
D Chrétien, A Munnich,
A Rötig
[show abstract]
[hide abstract]
ABSTRACT: Chronic intestinal pseudo-obstruction (CIPO) is a severe disease of the digestive tract motility. In pediatric population, CIPO remains of unknown origin for most patients. Chronic intestinal pseudo-obstruction is also a common feature in the course of mitochondrial oxidative phosphorylation disorders related for some patients to mutations in TYMP, POLG1, mtDNA tRNA(leu(UUR)) or tRNA(lys) genes. We hypothesized that CIPOs could be the presenting symptom of respiratory chain enzyme deficiency and thus we investigated oxidative phosphorylation in small bowel and/or colon smooth muscle of primary CIPO children.
We studied eight children with CIPO and 12 pediatric controls. We collected clinical, radiological and pathological data and measured respiratory chain enzymatic activity in isolated smooth muscle of the small bowel and/or the colon. We also sequenced TYMP, POLG, mtDNA tRNA(leu(UUR)) and tRNA(lys) genes.
Neither pathological nor radiological data were in favor of a mitochondrial dysfunction. No respiratory chain enzyme deficiency was detected in CIPO children. In myogenic CIPO, respiratory enzymes and citrate synthase activities were increased in small bowel and/or colon whereas no abnormality was noted in neurogenic and unclassified CIPO. Levels of enzyme activities were higher in control small bowel than in control colon muscle. Sequencing of TYMP, POLG, mtDNA tRNA(leu(UUR)) and tRNA(lys) genes and POLG gene did not reveal mutation for any of the patients.
The normal enzymatic activities as the lack of radiological and genetic abnormalities indicate that, at variance with adult patients, oxidative phosphorylation deficiency is not a common cause of childhood CIPO.
Neurogastroenterology and Motility 09/2010; 23(1):24-9, e1. · 3.41 Impact Factor
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M Rio,
A S Lebre,
P de Lonlay,
V Valayannopoulos,
I Desguerre,
J-L Dufier,
D Grévent,
M Zilbovicius,
C Tréguier,
F Brunelle,
C de Baracé,
J Kaplan,
M A Espinase-Berrod,
C Sainte-Rose,
S Puget,
A Rotig, A Munnich,
N Boddaert
Neurology 07/2010; 75(1):93. · 8.31 Impact Factor
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N Boddaert,
I Desguerre,
N Bahi-Buisson,
S Romano,
V Valayannopoulos,
Y Saillour,
D Seidenwurm,
D Grevent,
L Berteloot,
A-S Lebre,
M Zilbovicius,
S Puget,
R Salomon,
T Attie-Bitach, A Munnich,
F Brunelle,
P de Lonlay
[show abstract]
[hide abstract]
ABSTRACT: OBJECTIFS: To propose a MRI cerebellar algorithm that may be applied to guide genetic/malformative or biochemical investigations for patients with cerebellar ataxia.
Cerebral MRI of 158 patients with cerebellar ataxia and no supratentorial abnormality were examined according to a new categorization system based on posterior fossa imaging. The clinical and radiological findings were confronted to biochemical and/or genetic results using the MR cerebellar algorithm. Seven groups of cerebellar MRI pattern were described: vermian dysgenesis (n=27), cerebellar hypoplasia (n=15), hemispheric cerebellar dysgenesis (n=6), unilateral hemispheric atrophy (n=5), global cerebellar atrophy (n=84), signal abnormalities (n=11) and normal MRI (n=10). Cerebellar hypoplasia, vermian dysgenesis and hemispheric cerebellar dysgenesis groups were classified as malformative disorders. Global atrophy and signal abnormality groups were classified as metabolic disorders.
In the vermian dysgenesis group, a specific genetic diagnosis was obtained in eight children (8/27) and all of the mutated genes (AHI1 (JBS3), CEP290 (JBS5), TMEM67 (JBS6), and RPGRIP1L (JBS7)) are involved in primary cilia function. In the group of pontocerebellar hypoplasia specific genetic diagnosis was obtained in one patient (PCH2) (1/15). Thus, nine of 42 children classified as malformative disorder had a molecular diagnosis. Global atrophy and signal abnormality groups were classified as metabolic disorders, specific biochemical was obtained in 46/95 children. In global atrophy group, respiratory chain deficiency was diagnosed in 18 children (18/84). In 21 children a congenital disorders of glycosylation type 1a (CDG Ia) was diagnosed (21/84) and infantile neuroaxonale dystrophy (INAD) was diagnosed in one child. In signal abnormalities group, specific biochemical diagnosis was obtained in six out of 11 children, five children with respiratory chain deficiency and one child with sulphite oxidase deficiency. In hemispheric cerebellar dysgenesis and normal MRI groups, no biological diagnosis was found for any of the patients. In the group of unilateral hemispheric atrophy, we hypothesized a clastic prenatal injury.
The proposed MR cerebellar algorithm was useful to guide genetic/malformative or biochemical investigations, allowing an etiological diagnosis in 55 children.
Journal of Neuroradiology 04/2010; 37(4):220-30. · 1.21 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Hypohidrotic ectodermal dysplasia (HED) is characterized by abnormal development of the eccrine sweat glands, hair and teeth. The X-linked form of the disease, caused by mutations in the EDA gene, represents the majority of HED cases. Autosomal dominant and recessive forms occasionally occur and result from mutations in at least two other genes: EDAR and EDARADD. EDARADD interacts with the TAB2/TRAF6/TAK1 complex, which is necessary for NF-kappaB activation by EDAR.
To determine frequency of EDARADD, TRAF6, TAB2 and TAK1 mutations in HED.
We have screened 28 familial or sporadic HED cases with no mutations in the EDA and EDAR genes for EDARADD, TRAF6, TAB2 and TAK1 mutations.
We identified one EDARADD 6-bp homozygous in-frame deletion (c.402-407del, p.Thr135-Val136del) in a patient born to consanguineous parents. Functional studies showed that the p.Thr135-Val136del impaired the EDAR-EDARADD interaction and then severely inhibited NF-kappaB activity. In the remaining 27 patients, we failed to find causative mutations in EDARADD, or in TRAF6, TAB2 or TAK1.
Our study demonstrates that EDARADD mutations are not a frequent cause of HED, while mutations in TRAF6, TAB2 and TAK1 may not be implicated in this disease.
British Journal of Dermatology 03/2010; 162(5):1044-8. · 3.67 Impact Factor
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C Jung,
N Dagoneau,
G Baujat,
M Le Merrer,
A David,
M Di Rocco,
B Hamel,
A Mégarbané,
A Superti-Furga,
S Unger, A Munnich,
V Cormier-Daire
[show abstract]
[hide abstract]
ABSTRACT: Stüve-Wiedemann syndrome (SWS, OMIM 601559) is a severe autosomal recessive condition caused by mutations in the leukemia inhibitory receptor (LIFR) gene. The main characteristic features are bowing of the long bones, neonatal respiratory distress, swallowing/sucking difficulties and dysautonomia symptoms including temperature instability often leading to death in the first years of life. We report here four patients with SWS who have survived beyond 36 months of age with no LIFR mutation. These patients have been compared with six unreported SWS survivors carrying null LIFR mutations. We provide evidence of clinical homogeneity of the syndrome in spite of the genetic heterogeneity.
Clinical Genetics 03/2010; 77(3):266-72. · 3.13 Impact Factor
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M Willems,
D Geneviève,
G Borck,
C Baumann,
G Baujat,
E Bieth,
P Edery,
C Farra,
M Gerard,
D Héron,
B Leheup,
M Le Merrer,
S Lyonnet,
D Martin-Coignard,
M Mathieu,
C Thauvin-Robinet,
A Verloes,
L Colleaux, A Munnich,
V Cormier-Daire
[show abstract]
[hide abstract]
ABSTRACT: Microcephalic osteodysplastic primordial dwarfism type II (MOPD II, MIM 210720) and Seckel syndrome (SCKL, MIM 210600) belong to the primordial dwarfism group characterised by intrauterine growth retardation, severe proportionate short stature, and pronounced microcephaly. MOPD II is distinct from SCKL by more severe growth retardation, radiological abnormalities, and absent or mild mental retardation. Seckel syndrome is associated with defective ATR dependent DNA damage signalling. In 2008, loss-of-function mutations in the pericentrin gene (PCNT) have been identified in 28 patients, including 3 SCKL and 25 MOPDII cases. This gene encodes a centrosomal protein which plays a key role in the organisation of mitotic spindles. The aim of this study was to analyse PCNT in a large series of SCKL-MOPD II cases to further define the clinical spectrum associated with PCNT mutations. Among 18 consanguineous families (13 SCKL and 5 MOPDII) and 6 isolated cases (3 SCKL and 3 MOPD II), 13 distinct mutations were identified in 5/16 SCKL and 8/8 MOPDII including five stop mutations, five frameshift mutations, two splice site mutations, and one apparent missense mutation affecting the last base of exon 19. Moreover, we demonstrated that this latter mutation leads to an abnormal splicing with a predicted premature termination of translation. The clinical analysis of the 5 SCKL cases with PCNT mutations showed that they all presented minor skeletal changes and clinical features compatible with MOPDII diagnosis. It is therefore concluded that, despite variable severity, MOPDII is a genetically homogeneous condition due to loss-of-function of pericentrin.
Journal of Medical Genetics 08/2009; 47(12):797-802. · 6.36 Impact Factor
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F Molinari,
A Kaminska,
G Fiermonte,
N Boddaert,
A Raas-Rothschild,
P Plouin,
L Palmieri,
F Brunelle,
F Palmieri,
O Dulac, A Munnich,
L Colleaux
[show abstract]
[hide abstract]
ABSTRACT: Neonatal epileptic encephalopathies with suppression bursts (SBs) are very severe and relatively rare diseases characterized by neonatal onset of seizures, interictal electroencephalogram (EEG) with SB pattern and very poor neurological outcome or death. Their etiology remains elusive but they are occasionally caused by metabolic diseases or malformations. Studying an Arab Muslim Israeli consanguineous family, with four affected children presenting a severe neonatal epileptic encephalopathy, we have previously identified a mutation in the SLC25A22 gene encoding a mitochondrial glutamate transporter. In this report, we describe a novel SLC25A22 mutation in an unrelated patient born from first cousin Algerian parents and presenting severe epileptic encephalopathy characterized by an EEG with SB, hypotonia, microcephaly and abnormal electroretinogram. We showed that this patient carried a homozygous p.G236W SLC25A22 mutation which alters a highly conserved amino acid and completely abolishes the glutamate carrier's activity in vitro. Comparison of the clinical features of patients from both families suggests that SLC25A22 mutations are responsible for a novel clinically recognizable epileptic encephalopathy with SB.
Clinical Genetics 08/2009; 76(2):188-94. · 3.13 Impact Factor
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V Valayannopoulos,
L Hubert,
J F Benoist,
S Romano,
J B Arnoux,
D Chrétien,
J Kaplan,
F Fakhouri,
D Rabier,
A Rötig,
A S Lebre, A Munnich,
Y de Keyzer,
P de Lonlay
[show abstract]
[hide abstract]
ABSTRACT: An adult patient with methylmalonic aciduria due to defective cobalamin synthesis (CblA) responsive to vitamin B(12) presented suddenly with severe visual impairment ascribed to optic atrophy followed by a fatal multiorgan failure and lactic acidosis but low methylmalonic acid in plasma and urine. Multiple deficiency of oxidative phosphorylation was found in the patient's liver. We suggest that patients with B(12)-sensitive methylmalonic aciduria who have a milder clinical course should be carefully monitored for long-term complications.
Journal of Inherited Metabolic Disease 05/2009; 32(2):159-62. · 3.58 Impact Factor
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N. Brahimi,
M. Jambou,
E. Sarzi,
V. Serre,
N. Boddaert,
S. Romano,
P. de Lonlay,
A. Slama, A. Munnich,
A. Rötig,
J.P. Bonnefont,
A.S. Lebre
[show abstract]
[hide abstract]
ABSTRACT: Deoxyguanosine kinase (dGK) deficiency is a frequent cause of mitochondrial DNA depletion associated with a hepatocerebral phenotype. In this study, we describe a new splice site mutation in the DGUOK gene and the clinical, radiologic, and genetic features of these DGUOK patients. This new DGUOK homozygous mutation (c.444-62C>A) was identified in three patients from two North-African consanguineous families with combined respiratory chain deficiencies and mitochondrial DNA depletion in the liver. Brain MRIs are normal in DGUOK patients in the literature. Interestingly, we found subtentorial abnormal myelination and moderate hyperintensity in the bilateral pallidi in our patients. This new mutation creates a cryptic splice site in intron 3 (in position −62) and is predicted to result in a larger protein with an in-frame insertion of 20 amino acids. In silico analysis of the putative impact of the insertion shows serious clashes in protein conformation: this insertion disrupts the α5 helix of the dGK kinase domain, rendering the protein unable to bind purine deoxyribonucleosides. In addition, a common haplotype that segregated with the disease in both families was detected by haplotype reconstruction with 10 markers (microsatellites and SNPs), which span 4.6 Mb of DNA covering the DGUOK locus. In conclusion, we report a new DGUOK splice site mutation that provide insight into a critical protein domain (dGK kinase domain) and the first founder mutation in a North-African population.
Molecular Genetics and Metabolism 03/2009; · 3.19 Impact Factor
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Agnès Atale,
Patrizia Bonneau-Amati,
Agnès Rötig,
Alain Fischer,
Stéphanie Perez-Martin,
Pascale de Lonlay,
Patrick Niaudet,
L De Parscau,
C Mousson,
C Thauvin-Robinet, A Munnich,
F Huet,
L Faivre
[show abstract]
[hide abstract]
ABSTRACT: Out of a series of 30 French patients with Pearson syndrome, we report on two patients with an atypical presentation, which include growth deficiency, pancytopaenia, tubulopathy and absence of exocrine pancreas dysfunction. Patient 1, a 4-year-old boy with a past history of pancytopaenia and transient metabolic acidosis at 13 months of age, presented at 2(1/2) years of age with severe tubulopathy of de Toni-Debré-Fanconi type, growth retardation, metabolic lactic acidosis and mild cytolysis. Despite normal exocrine pancreatic function, study of mitochondrial DNA revealed a 3.5 kb deletion. Patient 2 had a personal history of pancytopaenia requiring blood transfusions at 11 months of age and presented with severe intractable proximal and distal tubulopathy at 2 years of age. Exocrine pancreatic deficiency could not be evidenced and post-mortem studies revealed a 4.9 kb deletion of the mitochondrial DNA. A review of the literature revealed three patients presenting with Pearson syndrome and tubulopathy with normal pancreatic function and highlights delay in diagnosis in those three patients. The series of 30 French patients with Pearson syndrome also revealed that tubulopathy was present in 7/30 cases (23%), with variable outcome. In conclusion, Pearson syndrome should be screened for in children presenting with the association of growth retardation, anaemia/pancytopaenia, lactic acidosis and tubulopathy, even in the absence of exocrine pancreatic deficiency.
European journal of medical genetics 12/2008; 52(1):23-6. · 1.57 Impact Factor
