Prenatal diagnosis of a rare de novo centromeric chromosome 6 variant.

Cytogenetic heteromorphisms are described as heritable variations at specific chromosomal regions without phenotypic effect. Polymorphisms of the size of heterochromatic centromeric regions of chromosomes 1, 9 and 16 have been well documented in humans but only four previous reports described centromeric polymorphism of chromosome 6. We present a prenatal diagnosis of a rare de novo centromeric chromosome 6 variant. Cytogenetic and molecular techniques were used to characterize this variant and confirm the de novo nature of this event. This case illustrates the importance of reporting unusual variant chromosomes for genetic counseling and for determination of the frequency of variant chromosomes in the general population.

The effect of genotype on the natural history of eIF2B-related leukodystrophies.

BACKGROUND: Recessive mutations in the five eucaryotic initiation factor 2B (eIF2B) subunits have been found in leukodystrophies of variable age at onset and severity. OBJECTIVES: To evaluate the clinical spectrum of eIF2B-related disorders and search for a phenotype-genotype correlation. METHODS: Ninety-three individuals (78 families) with an undetermined leukodystrophy were selected on MRI-based criteria of childhood ataxia with central hypomyelination/vanishing white matter (CACH/VWM) for EIF2B genes analysis. RESULTS: Eighty-nine percent of individuals with MRI criteria of CACH/VWM have a mutation in one of the eIF2B beta to epsilon subunits. For 83 individuals (68 families), 46 distinct mutations (90% missense) in four of the five eIF2B subunits (beta, gamma, delta, epsilon) were identified. Sixty-four percent were in the epsilon subunit, a R113H substitution was found in 71% of eIF2B epsilon-mutated families. A large clinical spectrum was observed from rapidly fatal infantile to asymptomatic adult forms. Disease severity was correlated with age at onset (p < 0.0001) but not with the type of the mutated subunit nor with the position of the mutation within the protein. Mutations R113H in the epsilon subunit and E213G in the beta subunit were significantly associated with milder forms. CONCLUSIONS: The degree of eIF2B dysfunction, which is involved in the regulation of protein synthesis during cellular stress, may play a role in the clinical expression of eIF2B-related disorders.

Genetic heterogeneity of megalencephalic leukoencephalopathy and subcortical cysts.

Reported are the clinical, neuroradiologic, and molecular findings in 18 patients with megalencephalic leukoencephalopathy and subcortical cysts (MLC) syndrome. Marked clinical intrafamilial and interfamilial variability in mutation-proven cases was found. A broad spectrum of pathogenetic mutations (missense, splice site, insertion, and deletions) were identified in the MLC1 gene, enlarging the spectrum of allelic variants without a straightforward genotype-phenotype correlation. Five patients did not harbor mutations in MLC1, supporting the existence of at least one other MLC locus.

Infantile ascending hereditary spastic paralysis (IAHSP): clinical features in 11 families.

OBJECTIVE: To report clinical, neuroradiologic, neurophysiologic, and genetic findings on 16 patients from 11 unrelated families with a remarkable uniform phenotype characterized by infantile ascending hereditary spastic paralysis (IAHSP). METHODS: Sixteen patients from 11 families, originating from North Africa and Europe, who presented severe spastic paralysis and ascending progression were studied. RESULTS: Spastic paraplegia started in the first 2 years of life in most patients and extended to the upper limbs by the end of the first decade. The disease progressed to tetraplegia, anarthria, dysphagia, and slow eye movements in the second decade. The clinical course showed a long survival and preservation of intellectual skills. Clinical, neuroradiologic, and neurophysiologic findings were consistent with a relatively selective early involvement of the corticospinal and corticobulbar pathways. No signs of lower motor neuron involvement were observed, whereas motor evoked potentials demonstrated predominant involvement of the upper motor neurons. MRI was normal in young patients but showed brain cortical atrophy in the oldest, predominant in the motor areas, and T2-weighted bilateral hyperintense signals in the posterior arm of the internal capsule. The ALS2 gene, recently found mutated in consanguineous Arabic families with either an ALS2 phenotype or a juvenile-onset primary lateral sclerosis, was analyzed. Alsin mutations were found in only 4 of the 10 families, whereas haplotype analysis excluded the ALS2 locus in one family. CONCLUSIONS: The syndrome of IAHSP is genetically heterogeneous, and no clinical sign can help to distinguish patients with and without Alsin mutations.

Fatal infantile leukodystrophy: a severe variant of CACH/VWM syndrome, allelic to chromosome 3q27.

OBJECTIVE: To describe clinical and neuropathologic studies and linkage analysis on two sisters with a severe form of leukodystrophy. METHODS: A detailed study was performed on the second sister. Genotyping markers for chromosome 3, including eight additional markers surrounding the vanishing white matter (VWM) locus, were used. RESULTS: During the first year of life, two sisters developed a severe neurologic condition after an intercurrent infection. It was accompanied by irritability and stupor with rapid loss of their motor abilities. Results of extensive metabolic studies were negative. Brain MRI showed severe and diffuse abnormalities of the encephalic white matter. Neuropathologic examination showed a severe lack of myelin with diffuse vacuolating white matter lesions in the brain, associated with an increased density of oligodendrocytes and a reduced number of astrocytes on morphometric analysis. In sharp contrast, the spinal cord white matter was preserved. The affected sibpairs shared a common haplotype for a broad region in chromosome 3. They were homozygous between markers D3S1565 and D3S3669, including the VWM locus. CONCLUSIONS: This condition is an unusual variant of childhood ataxia with diffuse central hypomyelination (CACH)/VWM, with characteristic shrinking and perivascular clustering of astrocytes. Haplotype analysis suggests that this variant is allelic to the VWM locus located on chromosome 3q27.