Clinical and audiological follow up of a family with the 8363G>A mutation in the mitochondrial DNA.

Hearing loss is relatively common in mtDNA-related disorders. While auditory function has been assessed fully in the syndrome of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes, few studies have investigated the degree of progressive hearing deficit in individuals bearing other mtDNA mutations. We performed a 4-year clinical and audiological follow up in a family carrying the 8363G>A mutation in the mitochondrial transfer ribonucleic acid lysine (tRNA(Lys)) gene who displayed a progressive neuromuscular disease. In addition to pure tone audiometry, we considered distortion products of otoacoustic emissions, a sensitive indicator of cochlear dysfunction, as well as brainstem auditory evoked responses. A generalized increase in the auditory threshold at follow up, indicating a cochlear impairment in three cases, was noted. Distortion products of otoacoustic emissions may reveal sub-clinical cochlear dysfunction, even in oligosymptomatic patients. A complete and periodical assessment of the hearing function should be encouraged in asymptomatic relatives of patients carrying the tRNA(Lys) 8363G>A mutation.

Autosomal dominant hereditary spastic paraplegia: DHPLC-based mutation analysis of SPG4 reveals eleven novel mutations.

We set up a new denaturing high-performance liquid chromatography (DHPLC)-based protocol to screen patients with autosomal dominant hereditary spastic paraplegia (AD-HSP) for mutations in SPG4. Six patients had a complicated form and 49 a pure HSP phenotype. We also analyzed 19 unrelated patients presenting with an HSP phenotype (pure in 17 and complicated in two subjects) but no clear family history, as such patients may be cases of dominant inheritance with low penetrance. The overall frequency of SPG4 mutations in our study of HSP (in which prior linkage data were unavailable) was 32.4%, rising to 46.9% when only pure AD-HSP patients were considered. This figure falls well within the range reported in different populations. Rather as expected, the clinical data available for the patients did not support an easy genotype-phenotype correlation. Moreover, the clinical picture was not influenced by the length of the predicted residual gene product. As well as identifying novel variants in SPG4, this study constitutes the molecular characterization of the largest cohort of Italian AD-HSP patients studied to date. In addition, it provided an efficient, cost-effective, and reliable detection protocol for mutational screening of SPG4, which might facilitate medical genetic counseling.

Current insights into familial spastic paraparesis: new advances in an old disease.

Hereditary spastic paraparesis (HSP) comprises a clinically and genetically heterogeneous group of disorders characterized by progressive spasticity and hyperreflexia of the lower limbs. The past few years have witnessed an exponential increase in knowledge of this disease and we can now list 19 loci mapped on the human genome and eight genes cloned. However, this wider knowledge of the molecular basis of HSP has had limited impact on clinical practice: the use of antispastic drugs and regular physiotherapy still remain crucial in the therapeutic management of patients. Nonetheless, the identification of new genes mutated in HSP furthers comprehension of the pathomechanisms involved and helps in genetic counseling, especially of asymptomatic individuals who request molecular analyses.

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

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-func-tion 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.