Afif Hentati

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

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).

Hereditary spastic paraplegia: Advances in genetic research

Hereditary spastic paraplegia (HSP) is a diverse group of inherited disorders characterized by progressive lower-extremity spasticity and weakness. Insight into the genetic basis of these disorders is expanding rapidly. Uncomplicated autosomal dominant, autosomal recessive, and X-linked HSP are genetically heterogeneous: different genes cause clinically indistinguishable disorders. A locus for autosomal recessive HSP is on chromosome 8q. Loci for autosomal dominant HSP have been identified on chromosomes 2p, 14q, and 15q. One locus (Xq22) has been identified for X-linked, uncomplicated HSP and shown to be due to a proteolipoprotein gene mutation in one family. The existence of HSP families for whom these loci are excluded indicates the existence of additional, as yet unidentified HSP loci. There is marked clinical similarity among HSP families linked to each of these loci, suggesting that gene products from HSP loci may participate in a common biochemical cascade, which, if disturbed, results in axonal degeneration that is maximal at the ends of the longest CNS axons. Identifying the single gene defects that cause HSPs distal axonopathy may provide insight into factors responsible for development and maintenance of axonal integrity. We review clinical, genetic, and pathologic features of HSP and present differential diagnosis and diagnostic criteria of this important group of disorders. We discuss polymorphic microsatellite markers useful for genetic linkage analysis and genetic counseling in HSP. NEUROLOGY 1996;46: 1507-1514

Linkage of a commoner form of recessive amyotrophic lateral sclerosis to chromosome 15q15-q22 markers

ABSTRACT Autosomal recessive familial amyotrophic lateral sclerosis (RFALS) is a rare form of ALS that usually presents at an early age with slow progression of symptoms. RFALS is clinically and genetically heterogeneous and the locus of RFALS type 3 was mapped to 2q33 (ALS2) in a single family. We now report linkage of a more-common form of RFALS to chromosome 15q15-q22 markers (ALS5) and show further genetic locus heterogeneity in RFALS. ALS5 is the locus for most families with RFALS and appears to be present in both North African and European populations.

Sequence alterations within CYP7B1 implicate defective cholesterol homeostasis in motor-neuron degeneration

The hereditary spastic paraplegias (HSPs) are a genetically and clinically heterogeneous group of upper-motor-neuron degenerative diseases characterized by selective axonal loss in the corticospinal tracts and dorsal columns. Although numerous mechanisms involving defective subcellular transportation, mitochondrial malfunction, and increased oxidative stress have been proposed, the pathogenic basis underlying the neuronal loss is unknown. We have performed linkage analysis to refine the extent of the SPG5 disease locus and conducted sequence analysis of the genes located within this region. This identified sequence alterations in the cytochrome P450-7B1 (CYP7B1) associated with this pure form of HSP. In the liver, CYP7B1 offers an alternative pathway for cholesterol degradation and also provides the primary metabolic route for the modification of dehydroepiandrosterone neurosteroids in the brain. These findings provide the first direct evidence of a pivotal role of altered cholesterol metabolism in the pathogenesis of motor-neuron degenerative disease and identify a potential for therapeutic intervention in this form of HSP.

Molecular genetic basis of familial ALS

Familial amytrophic lateral sclerosis (FALS) is transmitted in a mendelian fashion as an autosomal dominant (DFALS) or an autosomal recessive (RFALS) trait.Both DFALS and RFALS are genetically heterogeneous. Fifteen percent of DFALS families have mutations in the gene for Cu, Zn superoxide dismutase (SOD1) which is coded on chromosome 21. The locus for one form of RFALS maps to chromosome 2q33. Forty-six mutations in the SOD1 gene have been reported in DFALS families. These mutations result in decreased SOD1 activity and shortened half-life of the protein in most instances. Transgenic mice overexpressing mutated SOD1 protein develop an ALS-like disease which suggests that the degeneration of motor neurons in DFALS is caused by the gain of a novel toxic function by mutated SOD1 rather than by the decrease of SOD1 activity. Several possible mechanisms of the novel neurotoxic function of mutated SOD1 are discussed. NEUROLOGY 1996;47(Suppl 2): S27-S35

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

Article abstract 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.

Familial amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis is sporadic in ninety percent of cases and familial (FALS) in ten percent. Both forms of FALS whether transmitted as an autosomal dominant (DFALS) or as an autosomal recessive (RFALS) trait is genetically heterogeneous. The locus for one form of RFALS maps to chromosome 2q33. Fifteen percent of DFALS families have mutations in the gene for Cu, Zn superoxide dismutase (SOD1) gene which is coded on chromosome 21. These mutations result in decreased SOD1 activity and shortened half-life of the protein in most instances. Transgenic mice overexpressing mutated SOD1 protein develop an ALS-like disease which suggests that the degeneration of motor neurons in DFALS is caused by the gain of a novel toxic function by mutated SOD1 rather than by the decrease of SOD1 activity. Possible mechanisms of the novel neurotoxic function of mutated SOD1 are discussed.

VZV encephalitis that developed in an immunized patient during fingolimod therapy

We report the case of a 66-year-old woman with progressive relapsing multiple sclerosis (MS) who developed varicella-zoster virus (VZV) encephalitis while on fingolimod despite vaccination. She presented with a stuttering course over several weeks. Five months after starting fingolimod, she was treated for a presumed MS flare with a 5-day course of high-dose IV methylprednisolone. A brain MRI showed stable chronic white matter lesions. She presented 18 days later with transient word-finding difficulty, was diagnosed with a TIA, and started on aspirin and a statin. She presented 9 days later after a generalized tonic-clonic seizure; she had no history of prior seizures. Levetiracetam was started, and dalfampridine was stopped, with control of her seizures. During this admission, MRI showed restricted diffusion and T2 hyperintensity in the left caudate head. CSF had glucose of 50, protein of 74, 13 erythrocytes, 133 leukocytes (61% lymphocytes); VZV was detected by PCR (other viral studies were negative; CSF VZV immunoglobulin M and immunoglobulin G [IgG] were not assessed). In the interval preceding this admission, uveitis was diagnosed in her right eye; while there were no skin vesicular lesions, in retrospect we consider the uveitis a likely manifestation of VZV infection. Fingolimod was stopped, and she was treated for 11 days with IV acyclovir, but her mental status worsened 5 days after stopping acyclovir. A subsequent MRI showed progression of the caudate lesion (figure, A and B) thought to be caused by direct parenchymal infection, so she was restarted on IV acyclovir and steroids with clinical improvement and eventual discharge to a rehabilitation facility.

A Novel Mutation in the Sterol 27-hydroxylase Gene of a Pakistani Family with Autosomal Recessive Cerebrotendinous Xanthomatosis

Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disorder of lipid storage with prominent neurologic features.The disease is associated with mutations in CYP27, which encodes mitochondrial sterol 27-hydroxylase, an enzyme that catalyzes the oxidation of sterol intermediates during bile acid synthesis. The loss of this enzyme results in accumulation of cholestanol in the nervous system and other tissues. Six different mutations have been previously described in CTX. We analyzed a Pakistani family, which included four affected individuals with clinical characteristics of CTX, for mutations in CYP27. The exons of CYP27 in the family DNA were amplified by polymerase chain reaction (PCR) and analyzed for mutations by band shifts (single stranded conformational polymorphism [SSCP]) and DNA sequencing. The PCR product for exon 4 showed an SSCP change in this family. The DNA of affected individuals showed an abnormal mobility pattern interpreted as homozygous for the mutation. One non-affected sibling was homozygous for the normal migrating pattern, whereas the parents and another non-affected sibling were heterozygous. The sequence of exon 4 of affected individuals showed a substitution of C to T in codon 237, thus substituting arginine to a stop codon. This mutation would terminate the translation, which may result in a protein half the size of the wild type rendering it practically inactive. NEUROLOGY 1997;48: 258-260