D. Fortini

Intrafamilial variability in hereditary spastic paraplegia associated with an SPG4 gene mutation

Article abstract The authors studied a family with pure autosomal dominant spastic paraplegia (ADHSP) that showed a marked intrafamilial variability in both age at onset and clinical severity, ranging from severe congenital presentation to mild involvement after age 55. They found a novel mutation in the SPG4 gene, which segregates with the disease in six patients. The mutation affects the consensus donor splice site of SPG4 intron 16, resulting in a premature termination codon at amino acid 578. The data confirm the pathologic significance of SPG4 mutations in pure ADHSP and add to the list of known SPG4 allelic variants.

Mitochondrial myopathy, parkinsonism, and multiple mtDNA deletions in a Sephardic Jewish family

The authors describe a family of Sephardic Jews with progressive external ophthalmoparesis, skeletal muscle weakness, and parkinsonism. Autosomal recessive inheritance was suggested by many consanguineous marriages, although a dominant disorder could not be excluded. No linkage to known progressive external ophthalmoparesis locus was found. The presence of cytochrome c oxidase-negative ragged-red fibers, biochemically reduced respiratory chain complexes, and multiple mitochondrial DNA deletions in muscle biopsies from four patients suggested a new mitochondrial disorder of intergenomic communication.

Mitochondrial G8363A mutation presenting as cerebellar ataxia and lipomas in an Italian family

We report an Italian family harboring the mitochondrial DNA (mtDNA) G8363A mutation in the tRNALys gene in association with various combinations of encephalopathy, ophthalmoparesis, and horse collar lipomas. These findings add to the complex relationship between mtDNA pathogenetic mutations and disease phenotype. The proband (III-10), a 22-year-old man, developed normally until age 9 years, when he had progressive gait ataxia and dysarthria. Neurologic examination also showed progressive external ophthalmoparesis, dysphagia, myoclonic jerks, and bilateral hearing impairment. Venous lactic acid was elevated (5 mmol/L; normal <2.4 mmol/L). The maternal grandmother (I-1) reportedly had a late-onset gait disorder. Our proband’s mother (II-4) started to have gait and truncal ataxia at age 22. At age 60, neurologic examination revealed limited upper gaze, mild hearing impairment, and brisk tendon reflexes. Her serum lactate was 2.7 mmol/L. Similar clinical features were found in Patients II-5 and II-6, whose onset was in late adolescence. In addition, Patients II-4, II-5, and II-6 …

Assessing the relative incidence of mitochondrial DNA A3243G in migraine without aura with maternal inheritance

Objective.—To determine whether patients with migraine without aura with maternal “inheritance” are affected by a monosymptomatic form of the MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes) or carry the most common mitochondrial DNA (mtDNA) mutation associated with MELAS, namely the A3243G transition in the transfer RNA (tRNA)Leu(UUR) gene.

Missense and splice site mutations in SPG4 suggest loss-of-function in dominant spastic paraplegia.

Abstract We studied nine Italian families with a pure form of autosomal dominant spastic paraplegia (ADHSP) to assess the frequency of mutations in the SPG4 gene. We observed marked intrafamilial variability in both age-at-onset and clinical severity, ranging from severe congenital presentation to mild involvement after age 55 years to healthy carriers of the mutation after age 70. Four of nine probands harboured SPG4 mutations, We identified three new SPG4 mutations, all predicting a loss-of-function with apparently important consequences for spastin function. RT-PCR studies predict loss-of-function as a possible mechanism leading to spastin-related HSP. The current study expands the spectrum of allelic variants in SPG4, confirming their pathological significance in pure AD-HSP and suggesting implications for the presumed function of spastin.

mtDNA A3243G MELAS mutation is not associated with multigenerational female migraine

Article abstract The authors searched for mitochondrial DNA (mtDNA) A3243G mutation in peripheral blood leukocytes from female migraine patients with pure matrilinear history of migraine along two or three generations. The current study was designed to exclude any male transmission of the disease. The mutation was absent in all patients. We conclude that mtDNA A3243G mutation does not contribute to the pathogenesis of pure matrilinear multigenerational migraine with or without aura.

Migraine comorbidity: from genotype to phenotype

Abstract In this paper, we review the “current” and “ancient” concepts of comorbidity in migraine attack and disease. We emphasize the role of migraine as a complex disease and stress the appropriate consideration that genetic determinants require in modern taxonomy of migraine headaches. Novel attempts to revise migraine nosography should consider the complexity of genotype-phenotype-environment interactions in order to identify more rational approaches to treatment.