Phenotype and sarcoglycan expression in Tunisian LGMD 2C patients sharing the same del521-T mutation.

 

Kefi M, Amouri R, Driss A, Ben Hamida C, Ben Hamida M, Kunkel LM, Hentati F.

 

Limb-girdle muscular dystrophy type 2C is an autosomal recessive muscular disorder caused by mutations in the gene encoding the gamma-sarcoglycan subunit. This gamma-sarcoglycanopathy is prevalent in Tunisia where only one homozygous mutation a 521-T deletion has been identified. The aim of this study was to carry out a comparative clinical and immunocytochemical analysis of Tunisian patients sharing the same gamma-sarcoglycan gene mutation. One hundred and thirty-two patients were classified as severe, moderate or mild according to a calculated severity score. Heterogeneous phenotypes between siblings were encountered in 75% of the families. The severity of the disease was not found to be related to the age of onset. Immunohistochemical studies of muscle biopsy showed a total absence of gamma-sarcoglycan, a normal or slightly reduced alpha and delta-sarcoglycans whereas the expression of beta-sarcoglycan was variable. The residual sarcoglycan expression was not related to the clinical phenotype. In conclusion, the phenotypic variability in sarcoglycanopathies in Tunisia seems to involve a modifying gene controlling the course of the disease.

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2: Parkinsonism Relat Disord. 2003 Jun;9(5):247-51. 

 

Autosomal recessive parkinsonism linked to parkin gene in a Tunisian family. Clinical, genetic and pathological study.

 

Gouider-Khouja N, Larnaout A, Amouri R, Sfar S, Belal S, Ben Hamida C, Ben Hamida M, Hattori N, Mizuno Y, Hentati F.

 

Service de Neurologie, Institut National de Neurologie, La Rabta, Tunis 1007, Tunisia. neziha.khouja@rns.tn

 

OBJECTIVES: To report clinical, pathological and genetic findings in a Tunisian kindred with autosomal recessive juvenile parkinsonism (AR-JP) linked to parkin gene. BACKGROUND: AR-JP has been mapped to chromosome 6q and is caused by several mutations of the parkin gene (Park 2). Pathological features in AR-JP are characterized by neuronal loss in substantia nigra (SN) without Lewy bodies (LB). PATIENTS AND METHODS: Three affected siblings with juvenile Parkinson's disease were studied. Pathological examination of the brain was performed in one of them. Linkage studies and mutation analysis of the parkin gene were performed. RESULTS: Clinical picture was characterized by the association of rest tremor, bradykinesia and rigidity. Parkinsonian signs markedly improved with levodopa treatment in the three siblings. Dystonia was observed in one patient and diurnal fluctuations of parkinsonian signs in another one. Linkage analysis showed homozygous haplotypes in patients as compared to unaffected individuals and mutation analysis of the parkin gene revealed a homozygous two-base AG deletion in exon 2 (101-102). Pathological examination of the brain in one patient showed marked loss of pigmented neurons with extraneuronal free melanin in the lateral and medial parts of the SN associated to a slight spongiosis and astrocytic gliosis. In the locus coeruleus, there was also loss of pigmented neurons without gliosis. No LB or neurofibrillary tangles were found neither by traditional nor by histo-immunological stainings. CONCLUSION: This Tunisian kindred with AR-JP linked to a micro-deletion of the parkin gene shows clinical similarities with the previously reported Japanese and European families. Pathological features of this kindred are compared to what has been reported in AR-JP families linked to large exonic deletions of this gene.

 

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3: Clin Chem. 2002 Mar;48(3):577-9. 

 

Serum vitamin E and lipid-adjusted vitamin E assessment in Friedreich ataxia phenotype patients and unaffected family members.

 

Feki M, Belal S, Feki H, Souissi M, Frih-Ayed M, Kaabachi N, Hentati F, Ben Hamida M, Mebazaa A.

 

Laboratory of Biochemistry, Rabta Hospital, 1007 Tunis, Tunisia.

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4: Nat Genet. 2002 Jan;30(1):21-2. Epub 2001 Dec 17.

 

Ganglioside-induced differentiation-associated protein-1 is mutant in Charcot-Marie-Tooth disease type 4A/8q21.

 

Baxter RV, Ben Othmane K, Rochelle JM, Stajich JE, Hulette C, Dew-Knight S, Hentati F, Ben Hamida M, Bel S, Stenger JE, Gilbert JR, Pericak-Vance MA, Vance JM.

 

Center for Human Genetics, Institute of Genomic Sciences and Policy, Research Park Building II Room 105, Box 2903, Duke University Medical Center, Durham, North Carolina 27710, USA.

 

We previously localized and fine-mapped Charcot Marie Tooth 4A (CMT4A), the autosomal recessive, demyelinating peripheral neuropathy, to chromosome 8. Through additional positional cloning, we have identified a good candidate gene, encoding ganglioside-induced differentiation-associated protein-1 (GDAP1). We found three different mutations in four different Tunisian families-two nonsense and one missense mutation. How mutations in GDAP1 lead to CMT4A remains to be understood.

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5: Nat Genet. 2001 Oct;29(2):160-5. 

 

The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis.

 

Yang Y, Hentati A, Deng HX, Dabbagh O, Sasaki T, Hirano M, Hung WY, Ouahchi K, Yan J, Azim AC, Cole N, Gascon G, Yagmour A, Ben-Hamida M, Pericak-Vance M, Hentati F, Siddique T.

 

Department of Neurology, Northwestern University Medical School, Chicago, Illinois, USA.

 

Amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS) are neurodegenerative conditions that affect large motor neurons of the central nervous system. We have identified a familial juvenile PLS (JPLS) locus overlapping the previously identified ALS2 locus on chromosome 2q33. We report two deletion mutations in a new gene that are found both in individuals with ALS2 and those with JPLS, indicating that these conditions have a common genetic origin. The predicted sequence of the protein (alsin) may indicate a mechanism for motor-neuron degeneration, as it may include several cell-signaling motifs with known functions, including three associated with guanine-nucleotide exchange factors for GTPases (GEFs).

 

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6: Eur J Neurol. 2001 Sep;8(5):477-81. 

 

Effect of vitamin E supplementation in patients with ataxia with vitamin E deficiency.

 

Gabsi S, Gouider-Khouja N, Belal S, Fki M, Kefi M, Turki I, Ben Hamida M, Kayden H, Mebazaa R, Hentati F.

 

Ataxia with vitamin E (Vit E) defciency (AVED) is an autosomal recessive disorder caused by mutations of the alpha tocopherol transfer protein gene. The Friedreich ataxia phenotype is the most frequent clinical presentation. In AVED patients, serum Vit E levels are very low in the absence of intestinal malabsorption. As Vit E is a major antioxidant agent, Vit E deficiency is supposed to be responsible for the pathological process. Twenty-four AVED patients were fully investigated (electromyography, nerve conduction velocity (NVC) studies, somatosensory evoked potentials, cerebral computed tomography scan, sural nerve biopsy, genetic studies) and supplemented with Vit E (800 mg daily) during a 1-year period. Clinical evaluation was mainly based on the Ataxia Rating Scale (ARS) for cerebellar ataxia assessment and serum Vit E levels were monitored. Serum Vit E levels normalized and ARS scores decreased moderately but significantly suggesting clinical improvement. Better results were noted with mean disease duration < or = 15 years. Reflexes remained abolished and posterior column disturbances unchanged. Vitamin E supplementation in AVED patients stabilizes the neurological signs and can lead to mild improvement of cerebellar ataxia, especially in early stages of the disease.

 

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7: Neuromuscul Disord. 2001 Jan;11(1):27-34. 

 

Linkage of a new locus for autosomal recessive axonal form of Charcot-Marie-Tooth disease to chromosome 8q21.3.

 

Barhoumi C, Amouri R, Ben Hamida C, Ben Hamida M, Machghoul S, Gueddiche M, Hentati F.

 

We report the clinical and genetic linkage analysis of a large Tunisian family with thirteen affected patients suffering from Charcot-Marie-Tooth disease with pyramidal involvement. The inheritance is autosomal recessive. The clinical phenotype is consistent in all patients. It is characterized by onset during the first decade, a progressive course and distal atrophy in all four limbs, associated with a mild pyramidal syndrome. Nerve biopsy in two patients showed severe axonal neuropathy. Genetic linkage excluded known loci of different genetic forms of Charcot-Marie-Tooth disease, familial spastic paraplegia and familial amyotrophic lateral sclerosis. A significant lod score was obtained with marker D8S286, confirming linkage to chromosome 8q21.3. The clinical syndrome observed in this family seems to correspond to a new genetic form of autosomal recessive Charcot-Marie-Tooth disease.

 

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8: Neurology. 2000 Nov 14;55(9):1388-90. 

 

Novel mutations in spastin gene and absence of correlation with age at onset of symptoms.

 

Hentati A, Deng HX, Zhai H, Chen W, Yang Y, Hung WY, Azim AC, Bohlega S, Tandan R, Warner C, Laing NG, Cambi F, Mitsumoto H, Roos RP, Boustany RM, Ben Hamida M, Hentati F, Siddique T.

 

Department of Neurology, Northwestern Institute of Neurosciences, Northwestern University Medical School, Chicago, IL 60611, USA.

 

Autosomal dominant hereditary spastic paraplegia is genetically heterogeneous, with at least five loci identified by linkage analysis. Recently, mutations in spastin were identified in SPG4, the most common locus for dominant hereditary spastic paraplegia that was previously mapped to chromosome 2p22. We identified five novel mutations in the spastin gene in five families with SPG4 mutations from North America and Tunisia and showed the absence of correlation between the predicted mutant spastin protein and age at onset of symptoms.

 

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9: Neuromuscul Disord. 2000 Jun;10(4-5):240-6. 

 

A new locus for autosomal recessive limb-girdle muscular dystrophy in a large consanguineous Tunisian family maps to chromosome 19q13.3.

 

Driss A, Amouri R, Ben Hamida C, Souilem S, Gouider-Khouja N, Ben Hamida M, Hentati F.

 

Autosomal recessive limb-girdle muscular dystrophies represent a genetically heterogeneous group of diseases characterized by a progressive involvement of skeletal muscles. They show a wide spectrum of clinical courses, varying from very mild to severe. Eight loci responsible for autosomal recessive limb-girdle muscular dystrophies have been mapped and six defective genes identified. In this study, we report the clinical data, muscle biopsy findings and results of genetic linkage analysis in a large consanguineous Tunisian family with 13 individuals suffering from autosomal recessive limb-girdle muscular dystrophy. Clinical features include variable age of onset, proximal limb muscle weakness and wasting predominantly affecting the pelvic girdle, and variable course between siblings. CK rate was usually high in younger patients. Muscle biopsy showed dystrophic changes with normal expression of dystrophin and various proteins of the dystrophin-associated protein complex (sarcoglycan sub-units, dystroglycan, and sarcospan). Genetic linkage analysis excluded the known limb-girdle muscular dystrophies loci as well as ten additional candidate genes. A maximum LOD score of 4.36 at &theta;=0.00 was obtained with marker D19S606, mapping this new form of autosomal recessive limb-girdle muscular dystrophy to chromosome 19q13.3.